Post Marketing PV AUDIT AND INSPECTION HOSTING. Michael Ramcharan Reumat Consulting Ejaz Butt ZigZag Associates

Transcription

1 Post Marketing PV AUDIT AND INSPECTION HOSTING Michael Ramcharan Reumat Consulting Ejaz Butt ZigZag Associates

2 Agenda Background Preparation Conduct Post Audit & Inspection CAPA Management Audit & Inspection Findings/Scenarios MHRA Symposium update MHRA Inspection Metrics

3 Disclaimer The content and opinions expressed in this presentation are those of the presenters and should not be attributed to those of any specific Company

4 Background - Aims To ensure the processes allows the MAH to comply with the regulatory requirements and identify non-compliance that may cause risk to public health To ensure that process follows company policies and procedures Provide confidence that deliverables (e.g. Aggregate, Signal detection) are using data that is accurate

5 Background Key Drivers Over the years there has been an increase in Regulators performing pharmacovigilance Inspections and different approaches being adopted (eg; desk-top assessments by MHRA). References outlined below: USFDA POSTMARKETING ADVERSE DRUG EXPERIENCE (PADE) REPORTING INSPECTIONS M pdf Statutory MHRA Pharmacovigilance Inspection statutory since /WC pdf Legal requirement in the EU to perform Pharmacovigilance Inspection GVP Module III Pharmacovigilance Inspections Pharmacovigilance Inspection Metrics: /Pharmacovigilance_Inspection_Metrics_Report_ _FINAL.pdf

6 Background- Types of Audits & Inspections System/Process Review procedures, systems, personnel and facilities in place to determine compliance with regulatory obligations. Product specific examples may be used to demonstrate the operation of the PV system Product Primary focused on product-related pharmacovigilance issues including product specific activities and documentation. Some aspect of the general system may still be examined

7 Background- Types of Audits Systems & Processes Affiliates Vendors Partners Distributors Routine For-cause

8 Background- Types of Inspections Routine Inspections Pre-Authorisation Inspections For Cause Inspection

9 Background- Identifying Audit & Inspection Candidates Risk based Audit programmes Assessing each audit entity against agreed criteria (eg; Audit history, outsourcing, product safety profile) Likelihood versus Impact versus Detection = total risk score High, Medium and Low risk candidates Conduct audits (Remote and/or on-site) based on risk

10 Background- Criteria for Risk Based Assessments Products with a known safety issue/class effect Critical finding from another GXP inspection Major finding related to clinical safety/phv from a GCP Inspection or related to quality complaints from a GMP Inspection A previous critical finding related to PhV Unsatisfactory responses received from previous PhV Inspection Poor compliance for submission of expedited reports

11 Background- Criteria for Risk Based Assessments Poor quality ADR reports or PSURs Vaccines/biologicals/NCE products Previously withdrawn products due to safety concerns A major increase in the number of products authorised Mergers Divestment of products Grant of first MA for a company Number, status and types of products Reports of non-compliance from other Competent Authorities

12 Preparation Confirm the Scope & Logistics Audit/Inspection Plan Timings Locations Personnel Involved ( SME, Host, back-room, management room)

13 Preparation Key Documentation to consider Maintenance of PSMF Review Audit history and CAPA s Provide all Pre-Audit/Inspection document requests Internally review documentation and locations Gather Authority inspection intelligence (metrics) Mock Interviews QA support

14 Preparation Audit Tools: Document Request Forms (see next slide) QC forms Tracker for Document Requests Standard s Communications (Roles & Responsibilities) Written Process required to outline this

15 Conduct Opening Meeting Clarify and confirmation of the inspection agenda Provide a short presentation, relevant introduction focusing on key aspects e.g. high level overview of systems Areas that may be covered: Inbound Reporting case receipt and case processing Outbound Reporting case submission and aggregate reporting Review of Regulatory Affairs activities & local regulatory requirements Safety Reporting in Clinical Trials Literature Search Activities Product Quality Complaints (PQCs) Medical Information Activities/Call Centre Marketing and Sales Activities Quality Management including training and QA/QC Activities Quality Assurance: internal/external audits and inspections, including CAPA management and follow-ups 3rd Party Contracts Process for PV & Clinical Activities Market Research Activities Data Storage, On-Site and Off-Site Archiving, Business Continuity Plan & Disaster Recovery Plans

16 Conduct Document request process: Plan on managing document requests: Tracking of documents Robust QC with speed and accuracy Always anticipate questions and requests Keep Auditors & Inspectors informed of any delays + Ad hoc sessions

17 Conduct Closing Meeting to cover: Summary of the inspection findings to ensure that the results of the inspection are clearly understood An opportunity to correct misconceptions and misunderstandings in response to the findings Reporting process CAPA process

18 Post Audit & Inspection Lesson Learned meeting Commence preparations of Observation responses

19 Post Audit & Inspection SMART Specific (Does the action address the finding?) The Company must consider not only how to address the specific examples cited, but also the root cause of the problem. The period under review for retrospective activity should be justifiable Measurable (How can completion be checked?) The Company should clearly state what actions it intends to take to address the finding, to an appropriate level of detail. Achievable / Realistic (Will it be happening?) The Company should not make promises it cannot deliver on, as corrective actions will be followed-up by an inspector at re-inspection. Companies must comply with the appropriate legislation and so should consider the best way to do so in the context of their business model. Time Driven The Company should clearly state the timeline for the corrective / preventative action (s) for each finding.

20 Audit & Inspection Findings/Scenarios Safety Information Common Issues Out of hours PV training No Reconciliation

21 Audit & Inspection Findings/Scenarios Case Processing Common findings from Audit and Inspection experiences over last few years: Incorrect day 0 assigned Inadequate quality control procedures Lack of appropriate follow-up of ICSR reports Inadequate procedures for identification of duplicate reports No control of deletion of ICSR reports from safety database Lack of reconciliation Significant back-log in ICSR report processing Cases are not medically reviewed or incorrectly assessed

22 Audit & Inspection Findings/Scenarios Expedited Reporting Common Findings Non-compliance with expedited reporting timelines Lack of understanding of expedited reporting requirements Incorrect decisions made regarding expedited reporting

23 Audit & Inspection Findings/Scenarios Literature Review Common findings Inadequacies in the construction of, or process used for, literature searching sources used adequacy of scope of search with respect to search objective (how will information on non-clinical data be identified?) lack of QC

24 Audit & Inspection Findings/Scenarios Medical Information Common findings Adverse events not forwarded to drug safety Ineffective QC processes Staff not trained to identified and report adverse events No access to up-to date local label and therefore safety information Agreements with vendors does not contain safety reporting language

25 Audit & Inspection Findings/Scenarios Product Quality Common findings Not all Combined AE/PQCs Identified as AEs Reconciliation not performed to catch missed events LOE not treated as safety data Especially important in products such as contraceptives and life threatening treatments Investigations of PQC not completed in a timely manner Results of investigations not forward to drug safety for assessment and entry into the safety database

26 Audit & Inspection Findings/Scenarios Regulatory Affairs Common findings Following identification of a new safety signal & MAH decision to update the CCDS, delays in submitting variation(s) to update the SPC(s). Delays of over a year have been observed. Delays in implementing SPC and PIL changes following approval of safety variations. Poor processes for ensuring that the minimum core safety information contained in the CCDS is consistently represented, as appropriate, in local product information. Unwarranted inconsistencies in safety information between reference documents e.g. CCDS, SPC(s) and IB. Use of inappropriate reference safety document for the determination of expectedness.

27 Audit & Inspection Findings/Scenarios Marketing/License Partners Common findings Reconciliation not performed with partners resulting in missed cases Case exchange not occurring Contract not updated when PV contact details change Staff not aware of requirements Insufficiently detail in contracts Do not contain safety reporting requirements Responsibilities of each party Exchange of ADRs (and other special situation cases) and product complaints Exchange of changes to Reference Safety Information Timelines Reconciliation Review period (changing regulations will likely change the agreement)

28 Audit & Inspection Findings/Scenarios Organised Data Collection Activities/Marketing/Medical Affairs Common findings Safety data not collected from all solicited sources No process for Safety Departments to be aware of market research studies MAH could not provide list of on-going research related activities Staff performing activities not trained in pharmacovigilance requirements

29 Audit & Inspection Findings/Scenarios Sales and Marketing Common findings Sales force not reporting adverse events Source documents not forwarded to Local drug safety Not carrying most up to date reference safety information Websites contain out of date reference safety information

30 Audit & Inspection Findings/Scenarios Audits & Inspections Common findings No procedures for handling audits/inspection Not all corrective actions completed as stated Not all actions completed on time Issues not fixed even though identified in previous audits or inspections Audit universe is incomplete Auditors not trained in pharmacovigilance Lack of PV audits (conducted and future plans) Extent of audits (affiliates, contractors) Scope of audits - key functions (signal detection process, label updates)

31 Audit & Inspection Findings/Scenarios Vendor Oversight Common findings Incorrect day zero used No assessment performed of suitability by Affiliate. Not appropriately trained No contract No Safety data exchange within contract No oversight of delegated activity Safety Departments not aware of local contracts

32 Audit & Inspection Findings/Scenarios Signal Detection Common findings No formal procedures for signal detection/trend analysis activities No formal and periodic review of information to identify new safety issues Documentation relating to performance of signal detection/trend analysis not retained Failure to communicate new safety issues in a prompt manner to competent authorities Not including all relevant data as part of signal detection process No signal detection other than at time of PSUR production Documentation regarding signal evaluation not produced / retained Completion of investigation not completed and tracked in appropriate timeframe

33 Audit & Inspection Findings/Scenarios Aggregate Reports Common findings Production No procedure, not in desired format, not a consistent standard Standard searches not validated (no impact assessment of database changes on queries generated) Lack of Quality control Incomplete missing cases, no summary tabulation, does not address Competent Authority requests Submissions No mechanism to track, late submissions, no submission Delays in reporting significant new safety findings from post authorisation clinical trials and studies

34 Audit & Inspection Findings/Scenarios Quality Management System common findings Archiving BCP Training Procedural Documents

35 Q&A