prepare-fda-inspection.ppt

Click to edit Master title style,MN Chapter,ACRP 30 Mar 06,*,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,How to Prepare for an FDA Inspection,30 March 2006,Presented by:Christine Boes,Senior Manager,Clinical Quality,Cardiac Rhythm Disease Management,Topics for Today,How does the FDA inspector prepare to inspect?,How can you be prepared?,How should you act during the inspection?,How should you respond post-inspection?,2,MN Chapter,ACRP 30 Mar 06,Site Inspections-BIMO,Data Submission Reviews IDE,PMA,510(k),IND,NDA,FDA Organization,3,MN Chapter,ACRP 30 Mar 06,FDA Inspections of Investigators,Purpose:,Determine that the rights,safety and welfare of subjects have properly been protected,Assess adherence to FDA regulations and statutory requirements,Determine quality and integrity of data submitted in support of products pending FDA approval,4,MN Chapter,ACRP 30 Mar 06,Permitting FDA Inspections:Investigators and Sponsors,Regulations require that sponsors and investigators grant access to authorized FDA employees,Any location where devices are manufactured,processed,packed,installed,used or implanted or where records of use/results are kept(IDE Regulations),Regulations allow inspection and copying of all records relating to an investigation,5,MN Chapter,ACRP 30 Mar 06,FDA Inspections of Investigators,Two types of inspections:,Routine Surveillance,Occur after PMA/NDA submitted,“For Cause”,Suspicion of wrong doing,complaints,termination of a site,etc.,6,MN Chapter,ACRP 30 Mar 06,Reasons for Inspecting an Investigator Could Include:,The investigator is doing a large volume of work,Gaps in IRB approvals and/or IRB suspension,The investigator has done work outside of his/her field of specialty,The investigator reports substantially superior efficacy for a device when compared to data generated by other investigators studying the same device,The investigator reports no severe or few adverse effects when other investigators report numerous adverse effects of a given type,7,MN Chapter,ACRP 30 Mar 06,Reasons for Inspecting an Investigator Could Include C,ont.:,The investigator seems to have too many patients with a given disease for the locale or setting in which he/she practices,The investigator reports results showing a lack of visit-to-visit variability or which are inconsistent with results submitted by other investigators,Investigator participated in clinical investigation for which data was used to support a PMA/NDA.,8,MN Chapter,ACRP 30 Mar 06,190,214,357,350,353,CDRH BIMO Inspections:Fiscal Years 2000-2004,Reference:“Building Quality into Device Clinical Trials”,Medical Alley,April 20,2005,9,MN Chapter,ACRP 30 Mar 06,Investigator Deficiencies:FY 2000-2004,Reference:“Building Quality into Device Clinical Trials”,Medical Alley,April 20,2005,10,MN Chapter,ACRP 30 Mar 06,IRB Deficiencies:FY 2000-2004,Reference:“Building Quality into Device Clinical Trials”,Medical Alley,April 20,2005,11,MN Chapter,ACRP 30 Mar 06,9,15,41,41,CDRH BIMO Complaints:“Allegations of Research Misconduct,”,Reference:“Building Quality into Device Clinical Trials”,Medical Alley,April 20,2005,12,MN Chapter,ACRP 30 Mar 06,Preparing for Inspection,Ensure all site personnel are trained,prior,to study start,Discuss potential for inspection and what to expect,Notify appropriate interested parties immediately if contacted,Assess the site,Discuss potential issues,Identify work space for inspector,13,MN Chapter,ACRP 30 Mar 06,When the FDA calls for Inspection:,Schedule the inspection as soon as possible after being called by the FDA investigator.Generally the inspection is requested/scheduled within a few business days to a week of the call,When confirming the appointment,request information on the reason for the inspection and any special areas to be emphasized during the inspection,14,MN Chapter,ACRP 30 Mar 06,Conduct of Inspection,Identify the primary contact person for inspection,Upon arrival,the FDA investigator MUST present credentials and issue a Notice of Inspection,Form FDA-482,The inspectors name and credentials numbers should be obtained and documented.,The Investigator and/or primary contact person should arrange for and attend all interviews conducted by the FDA investigator,Escort the FDA Inspector to a designated work area and escort throughout inspection,Establish a schedule for the visit,15,MN Chapter,ACRP 30 Mar 06,Conduct of Inspection cont.,Interview Guidelines:,Do not engage in conversation unless asked a direct question,Restrict statements to answering those questions asked by the FDA Investigator,Do not,provide excuses or shift blame(either on previous employees,staff members,IRB),Do not guess at answers If uncertain of correct answer,obtain the correct information and provide to the FDA Investigator,Do not answer questions which lie outside the authority of the Inspector(sales data,personnel information relating to salaries,performance reviews,etc),16,MN Chapter,ACRP 30 Mar 06,Conduct of Inspection:Interview Guidelines cont.,Be responsive and cooperative,but do not volunteer information,Should a question be unclearclarify!,Should a question or request seem unreasonable,state your objection,The FDA keeps notes on everything you state,make sure it is the truth,FDA will ask you and/or others similar questions multiple times to ensure similar response,17,MN Chapter,ACRP 30 Mar 06,Conduct of Inspection cont.,Generally,inspections follow the format established in FDAs Compliance Program Guidance Manual 7348.811.,Make certain that all documents are current and immediately accessible.Since the inspector(s)will want to review source documentation,notify your medical record departments of the scheduled inspection so medical records will be easily accessible.,18,MN Chapter,ACRP 30 Mar 06,Conduct of Inspection cont.,Provide requested copies of documents and stamp confidential(keep extra copy as a reference),Maintain notes of requests/questions of the Investigator during the inspection,FDA will request a list of other study/research projects that the investigator is involved,Clarify any misunderstandings or confusion as soon as possible,19,MN Chapter,ACRP 30 Mar 06,Conduct of Inspection cont.,Areas to be addressed will include:,Identify who is responsible for various tasks,examples:,Who verified eligibility criteria,Who obtained informed consent,Who collected adverse event data,Determine,degree authority is delegated to other staff members-how the investigator supervised the conduct of the trial,20,MN Chapter,ACRP 30 Mar 06,Finding from a 2003 Warning Letter to an investigator:,“Delegating work to research staff does not relieve you of the responsibility to supervise the clinical investigation.You are responsible for the accuracy and completeness of the study records and for any discrepancies found in the records.”,21,MN Chapter,ACRP 30 Mar 06,Conduct of Inspection cont.,What the IRB reporting/communication requirements are,(e.g.:specific adverse event and protocol deviation reporting)?,What is your process for informed consent?,22,MN Chapter,ACRP 30 Mar 06,Findings from a 2002 Warning Letter an Investigator:,“You failed to ensure that legally effective informed consent was obtained.For example,study subjects with randomization numbers X through Y signed a wrong version of the consent form.”,23,MN Chapter,ACRP 30 Mar 06,Conduct of Inspection cont.,How,when,and where study data/activities is collected/performed,How investigational product is accounted for,and,controlled(whether or not devices are“on the shelf”or not),Monitors communications with the clinical investigator,The monitors evaluations of the progress of the investigation,24,MN Chapter,ACRP 30 Mar 06,How FDA Trains BIMO Inspectors,Get Technical,-Read x-rays,EKGs,lab results,dont just inventory,Fill in the Blanks,-Question missing dates,times,information,offer to retrieve records yourself,Be suspicious of blame shifting-,tell CI he/she is totally responsible for the conduct of the study,Expect Fraud,-Start from the assumption the records are bogus and the study is a fraud,and work back,Cultivate Whistleblowers,-establish rapport with study staff,be approachable and available,listen to grievances,observe working conditions,Reference:Stan W.Woolen,Associate Director for Bioresearch Monitoring,FDA,“Misconduct in Research Innocent Ignorance or Malicious Malfeasance?”2003,25,MN Chapter,ACRP 30 Mar 06,Study Documents Required for the Inspection Will Include:,Reports of unanticipated adverse events/serious adverse events reported to IRB and sponsor,Your,IRBs,SOPs for AE/Protocol Deviations,All IRB approvals,including all approved versions of informed consent,Progress reports to the IRB,Clinical Investigation Plan/protocol(all versions)and Case Report Forms,Investigator Agreement/1572 and CVs,26,MN Chapter,ACRP 30 Mar 06,Study Documents Required for the Inspection Will include cont.,Training records of all site personnel involved in trial,Source documents for CRF entries,prior medical history,condition of the subject at the time of entry into study,meds,if required by study,laboratory reports,and any special testing per protocol.,Documentation for any correction to,CRFs,All correspondence,records,&reports,Investigational device/drug accountability,27,MN Chapter,ACRP 30 Mar 06,Finding from a 2003 Warning Letter to an investigator:,“In addition to the failure to use the device control documents required by the investigational plan,you failed to prepare and maintain accurate,complete,and current device accountability records,as required by 21 CFR 812.140(a)(2).Specifically,records of investigational devices returned to the sponsor contained inaccurate information regarding lot numbers and quantities.”,28,MN Chapter,ACRP 30 Mar 06,Finding from a 2003 Warning Letter to an investigator:,“,You failed to fulfill you device control responsibilities under the investigational plan.,You did not ensure that the investigational devices were maintained under controlled access storage.,The devices were received by hospital staff not part of the clinical investigationpersonnel who were not clinical study staff had keys to the storage area where devices were kept”,29,MN Chapter,ACRP 30 Mar 06,What Happens After an Inspection?,FDA Investigator will conduct exit interview,Will discuss findings=issue a written Form FDA 483(Inspectional Observations),Clarify any questions/confusion,Investigator may respond verbally during exit interview and/or respond in writing(strongly recommended to respond in writing),Be accountable to issues;have a corrective action plan!,Direct responses to FDA District Office in upper left corner of 483,30,MN Chapter,ACRP 30 Mar 06,What Happens After an Inspection cont:,Inspector prepares detailed report called Established Inspection Report(EIR),EIR,483(if applicable),copies of all materials collected during inspection,any responses from Investigator are forwarded to the FDA Center,FDA Center evaluates information,31,MN Chapter,ACRP 30 Mar 06,Evaluation to Classify and May Prompt Letter to Investigator,NAI No Action Indicated,A,letter that generally states that the FDA observed no significant deviations from regulations.Letter may not actually be sent all the time,VAI Voluntary Action Indicated(483),An,informational or untitled letter,identifies deviations from statutes and regulations for which voluntary corrective action is sufficient(unless otherwise specified),32,MN Chapter,ACRP 30 Mar 06,Evaluation to Classify and May Prompt Letter to Investigator cont.,OAI Official Action Indicated(Warning letter),A,Warning Letter,identifies serious deviations from statutes and regulations.A Warning Letter generally requests prompt corrective action by the clinical investigator and formal written response to the agency(FDA).,33,MN Chapter,ACRP 30 Mar 06,Investigator Non-Compliance,FDA may disclose to Sponsors and,IRBs,records indicating violation or potential violation by investigator that is conducting or has conducted studies,Besides issuing letters,FDA may take other administrative action against investigator,May initiate process of disqualifying an investigator from receiving investigational product or research if he/she has:,Repeatedly or deliberately violated FDA regulations,Submitted false information to the Sponsor or FDA,34,MN Chapter,ACRP 30 Mar 06,In Conclusion.,The,best preparation,for an FDA inspection is close adherence to the Clinical Investigational Plan/protocol and FDA regulations,Particular attention should be paid to documentation of:,medical histories,adverse events/deviations,receipt and disposition of investigational product,documentation of informed consent process,training,The importance of orderly,accurate records can not be underestimated!,35,MN Chapter,ACRP 30 Mar 06,483 Finding from a 1999 Investigator Inspection:,“Consent form contained unapproved whiteout where subjects signature appears.”,483 Finding from a 1995 Investigator Inspection:,“Several instances of data being scratched out(obliterated)rather than lined out were noted.One instance of liquid paper being used to correct data was noted”,36,MN Chapter,ACRP 30 Mar 06,FDA Information,FDA Home Web Page,www.fda.gov,FDA Compliance Web Page,www.fda.gov/ora/compliance_ref/default.htm,Compliance Program Guidance Manuals,Disqualified List,Debarment List,Warning Letters,Recalls,37,MN Chapter,ACRP 30 Mar 06,Questions?,Thank You!,