Preparing a Site for FDA Audits-09012009.ppt

1 1A Product Development ServicesCompanyFrom Lab to Market ApprovalFDA MeetingsThis Seminar is Brought to you byAmarex Clinical ResearchWashington DC metro Amarex, LLCG lobal Regulatory SubmissionsGlobal Clinical TrialsStatistics & Data managementStrategy Implementation Pre-Clinical AssaysContact: Patrick Burkeat 301-528-7000 RAPS Annual Conference, Philadelphia, Sep 13-16, Amarex, LLC2 India Essentials, Sep 14, 2009 1:30-3:00 PMAmarex s India Business WorkshopGermantown (Washington DC area)Sep 11, 2009 Various kinds of grants available Eligibility requirements Application Amarex, LLC3 Application Process Time-lines and milestones Application review process Terms of the grants Logistics of US-India Development projects And much Samantha for an FDA Audit for GCP ComplianceM kh KPhD Sep 2009 Mukesh Kumar, PhD, RACS enior Director, Regulatory AffairsAmarex Clinical ResearchGermantown, MDFDA Inspection: An Intimidating Thought Are we in trouble?

2 What did we do?O! Amarex, LLC5 Don t Panic Oops! Are we ready? How to prepare?Why Does FDA Audit Sites? To use the money paid for NDA review They like giving us a hard time To show that they canThlik t tl t t Amarex, LLC6 They like to travel at tax-payers expense We have done something seriously wrong Process ValidationIt s the Law: FDA is responsible for assuring that the products it approves are safe for people: developed, manufactured, reported and distributed appropriately2 Who Gets Audited? Everyone Amarex, LLC7 Selected Few: high priority targets When there is an accidentWho Gets Audited by FDA? File for an approval application NDA/PMA High Risk ProductzUsed in vulnerable populationzUsed in large Amarex, LLC8 Used in large populationszNew technology, unknown mechanism, etc.

3 High Risk ProcesszSafety concerns at clinical siteszInadequate process controls (SOPs, Monitoring, etc)An FDA Audit: Are you next?The FDA may conduct announced or unannouncedinspections of clinical investigator sites for various reasons such as:zRoutinely to verify data that has been submitted to the AgencyzAs a result of a complaint to the Agency about the Amarex, LLC9pgyconduct of the study at the site [ , for cause ]zIn response to sponsor concerns or termination of the clinical sitezAt the request of an FDA review divisionzAnd related to certain classes of investigational products that the FDA has identified as products of special interest in its current work plan ( targeted inspections based on current public health issues).

4 Is Subject to FDA Audit?Everything Laboratory processes (GLP) Clinical process (GCP) Amarex, LLC10zSites, investigators, etc Manufacturing processes (GMP) Safety Reporting processes (GRP)Sponsor Audits (QA) Vs FDA Audit Sponsor Audits: z Silent Topic at FDA: No explicit regulatory requirement for auditing by sponsor audit reports would not be req ested b Amarex, LLC11requested by requiredbut essential. Without audit there is no way to know if the system is working. FDA Audits zare becoming more GCP guideline and Frequent are FDA Audits? It s a daunting task More studies; more sites; greater volume at each site About 50,000 clinical studies under IND Expansion and fluidity of clinical investigator pool New players in new roles (CRO s, SMO s) More participation by vulnerable Amarex, LLC12 Global process GLP, GCP, GMP, distribution, safety reporting issues Lack of surprise inspections New technologies Electronic record-keeping Higher communication Information age Higher level of awareness Accidents are amplifiedNot frequent enough3 Who are the FDA auditors?

5 Enforcement arm of the FDA: zOffice of Compliance, Division of Scientific InvestigationszThe Bioresearch Monitoring (BIMO) Amarex, LLCzSince 1976, about 600 auditorszEither work for FDA head-quarters (Washington DC area) or regional offices Trained in FDA auditing manual Experienced in fraud detection13 Audit Audit = Process validation: Process to establish documented evidence which provides a high degree of assurance that a specific process will consistently produce a dtti itdti Amarex, LLC14product meeting its pre-determined specifications and quality must exhibitWell-Organized, Well-Documented Common SenseFDA Amarex, LLCO bjective: To detect MisconductKey Regulations Good Laboratory Practices: 21 CFR 58 Good Clinical Practices: 21 CFR 312 and ICH E6 GdM fti P ti Amarex, LLC16 Good Manufacturing Practices.

6 21 CFR 211, 21 CFR 820 Compliance Program Guidance Enforcement Policy Compliance with regulations is expected Industry is constantly monitored and given opportunity to correct/prevent violations Enforcement response metered to the severity of Amarex, LLC17 No tolerance for fraud, intentional violation or gross negligence Enforcement based on science, logic Works with local, state, federal and international health officials Maximize enforcement resourcesProhibited Acts Adulteration or misbranding of productszAll unapproved products Shipping or receiving above products Facilitating creation of above Amarex, LLC18 Facilitating creation of above products Refusal to allow FDA inspectionNote: FDA oversight is over products it approves, process oversight is in-direct.

7 Processes leading to no viable application for approval might never get audited., , R&D is not directly audited, only when used to support an constitutes Misconduct? Recognizing Research MisconductzResearch misconduct means Falsification ofdata in proposing, designing, performing, recording, supervising or reviewing research, or in reporting research Amarex, LLC19 Falsification of data includes creating, altering, recording, or omitting data in such a way that the data do not represent what actually occurred. Safety risk, reliability of dataIf it is not written it wasn t done, if it s written and not done it is fraudMisconduct in Clinical Research The Misconduct Scale zInnocent Ignorance Lack of knowledge of regulations Incomplete or incorrect CRF Non-preserving source documentszSurprising Amarex, LLC20pgpp In-attention to detail Lack of supervision Protocol shortcuts zMalicious Malfeasance Deliberate falsification of data (Fraud) Sponsor s obligation: Detecting, Correcting and Preventing Misconduct FDA Sanctions for MisconductGCP.

8 Good Clinical Practices Apply to all human studies to support an application for research (IND, IDE) or marketing approval (NDA/PMA)zDirect or contracted studieszIRB approval also Amarex, LLC21zIRB approval also required FDA does notprovide a GCP certificationzLots of guidance ( )zPrivate vendors do GCP training and validation All studies need to be GCP compliant, without exceptionGCP Basics Site Organization and PersonnelzQualified physicians and safety personnelzTraining, safety, managementzQuality AssurancezDistribution of Amarex, LLC22 FacilitieszVisiting area, consenting areazPharmacy procedureszStudy procedures (SOPs, manuals, etc)zProtocol management Sample handling Record keeping and documentation21 CFR 312 ICH E6So, FDA contacted Most FDA audits are scheduled about 1-2 weeks in advancezSurprise audits do occurz1-2 weeks notice could be a surprise for you if you are not Amarex, LLC23pp Almost all audits are study/application specific Almost all audits are safety related Being selected for audit by FDA does not necessarily imply fault on your part Be courteous and professionalzFDA auditor is a person doing his/her jobBefore FDA visits Contact the sponsorzInform of the dates, ask advisezSponsor might be able to provide a Amarex.

9 LLC24 Make a Plan Do a thorough check of documentationzOrganize and clean-upzStudy document and process review zAll internal audit findings (QC and QA issues)5 Before FDA visits Prepare staffzMock interviews Two questions and a request: zWhat do you do?zHow do you do the work? Amarex, LLC25zHow do you do the work?zShow mezAssign responsibilities for interacting Trouble-shootzIdentified issues and their potential resolutionThe FDA Investigator is here! Amarex, LLC26 FDA Inspection: Dos and Don ts Access should to announces in reception personnel escort to designated area4 Check credentials never try to copy (its illegal) Amarex, credentials, never try to copy (its illegal) 482 presented, documents and orientation, escort to all the areas of the company that he/she wants to access to be controlled and recorded FDA Inspection: Dos and Don ts Make readily accessible: Source documentszSOPs, manualszStudy documentationzRaw data access (Labs)zTraining Amarex, LLC28zTraining files Make readily accessible.

10 FacilitieszLabszClinicszPatient areas Be available, make senior management aware of progressFDA Inspection: Dos and Don ts Make good notes, everything is being recorded Keep everyone calmzPeople get nervous and Amarex, LLC29zTrain people to only say what they know not what they believezNever make unsubstantiated commentszIf you don t know, say so, don t make up! Good hospitality and personable people make the process flow (Plenty of chocolate helps)FDA Inspection: Final Minutes Exit interviewzSummarize findingszClear any misimpressionszDocument discussionsFDA Inspector has two Amarex, LLC30 FDA Inspector has two optionszNo findings (you are very good!!)zFindings (FDA 483) Nobody s perfect, don t get shocked Don t argue or get defensive Respond in writing at a later date FDA 483 and your response becomes public information6 Common Audit Findings (from 483s) GCP.