TGA Presentation: Pharmacovigilance inspections
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An update on the Pharmacovigilance Inspection Program, practical tips for inspections and developing a Corrective And Preventive Plan
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TGA Presentation: Pharmacovigilance inspections
- 1. Pharmacovigilance inspections Update on the PVIP, learnings, helpful tips and workshop Sarah May (Lead), Saqif Shams and Kasia Hoffler Pharmacovigilance Inspectors Risk Management Plan Evaluation Pharmacovigilance and Special Access Branch TGA ARCS Pharmacovigilance workshop 27 March 2019 Canberra
- 2. Meet the inspector team • Sarah May – lead pharmacovigilance inspector • Saqif Shams – pharmacovigilance inspector • Kasia Hoffler – pharmacovigilance inspector • My Di Luu – pharmacovigilance inspector Pharmacovigilance inspections 1
- 3. Outline • Update on the PVIP • Practical tips for inspections • Inspection experiences from an inspectee • Workshop – developing a CAPA plan Pharmacovigilance inspections 2
- 4. Update on the Pharmacovigilance Inspection Program (PVIP) Pharmacovigilance inspections 3
- 5. The PVIP • Commenced 1 September 2017 • First inspection under the program undertaken January 2018 • Conducted twelve inspections under the program to date • Have inspected sponsors of innovators, generics, biosimilars, OTC and complementary medicines Pharmacovigilance inspections 4
- 6. PVIP metrics report • The first report was published on 20th March 2019 and covers 1 September 2017 to 31 December 2018. • Available at https://www.tga.gov.au/pharmacovigilance-inspection-program-metrics-report-sep-2017-dec-2018 • The report contains the following information: – Summary of inspections conducted, including type of inspections, types of sponsors and number of findings – Description of inspection findings by topic area – Details of the common areas of findings – Comparisons of inspection findings over time • Reports will be published annually covering a 12 month period hereafter • All information has been de-identified Pharmacovigilance inspections 5
- 7. PVIP metrics report Reporting period 1 September 2017 to 31 December 2018 Number of inspections 10 Types of inspections 10 Routine inspections Nil For-cause inspections Nil Re-inspections Inspection findings Nil Critical deficiencies 50 Major deficiencies 29 Minor deficiencies Pharmacovigilance inspections 6
- 9. PVIP metrics report Areas of findings Critical (0) Major (50) Minor (29) Management of significant safety issues - 9 - Collection and collation of adverse drug reactions - 12 3 Management of adverse drug reactions - 9 - Ongoing safety evaluation - 5 5 Management of reference safety information - 10 1 Risk management - 1 3 Australian pharmacovigilance contact person and the QPPVA - 1 - Record-keeping requirement - - 1 Quality management system - 1 11 Other post-approval commitments - 2 5 Pharmacovigilance inspections 8
- 10. PVIP metrics report Areas of findings Critical (0) Major (50) Minor (29) Management of significant safety issues - 9 - Collection and collation of adverse drug reactions - 12 3 Management of adverse drug reactions - 9 - Ongoing safety evaluation - 5 5 Management of reference safety information - 10 1 Risk management - 1 3 Australian pharmacovigilance contact person and the QPPVA - 1 - Record-keeping requirement - - 1 Quality management system - 1 11 Other post-approval commitments - 2 5 Pharmacovigilance inspections 9
- 11. PVIP metrics report 10 0 2 4 6 8 10 12 14 16 Management of significant safety issues Collection and collation of adverse drug reactions Management of adverse drug reactions Ongoing safety evaluation Management of reference safety information Risk management Quality management system Other post-approval commitments Australian pharmacovigilance contact person Record-keeping requirement Number of deficiencies (any grading) Topicareas Pharmacovigilance inspections
- 12. PVIP metrics report 0 2 4 6 8 10 12 14 16 Management of significant safety issues Collection and collation of adverse drug reactions Management of adverse drug reactions Ongoing safety evaluation Management of reference safety information Risk management Quality management system Other post-approval commitments Australian pharmacovigilance contact person Record-keeping requirement Number of deficiencies (any grading) Topicareas Pharmacovigilance inspections 11
- 13. Common areas of findings 1. Management of significant safety issues 2. Collection and collation of adverse drug reactions 3. Management of adverse drug reactions 4. Management of reference safety information 5. Quality management system Pharmacovigilance inspections 12
- 14. Common areas of findings • Failure to notify the TGA of significant safety issues • Late notification of significant safety issues outside the regulatory 72 hours Management of significant safety issues Pharmacovigilance inspections 13
- 15. Common areas of findings • A significant safety issue is considered to be any new important safety issue or validated signal that may impact on the risk-benefit profile of a medicine. • Our definition of a “validated signal” is in line with that stated in the Guideline on good pharmacovigilance practices (GVP) Module IX – Signal management (Rev 1): – “Validated signal: A signal for which the signal validation process has verified that the available documentation contains sufficient evidence demonstrating the existence of a new potentially causal association, or a new aspect of a known association, and therefore justifies further analysis of the signal.” • Use your clinical and profession judgement • Not necessarily a confirmed signal • Depending on the potential seriousness, can include requests for information by comparable international regulator regarding a potential signal, or early safety information prior to evaluation completion. • Be conservative, contact us for advice Management of significant safety issues Pharmacovigilance inspections 14
- 16. Common areas of findings • Case collection, including monitoring, identification and reconciliation • Spontaneous sources of safety data e.g. medical information, product quality complaints • Literature searching • Solicited sources of safety data, including patient support or market research programs • Safety data exchange agreements Collection and collation of adverse drug reactions Pharmacovigilance inspections 15
- 17. Common areas of findings • Case processing, including data entry, coding, causality and seriousness assessment, follow-up and reporting • Data management, including migration of safety data Management of adverse drug reactions Pharmacovigilance inspections 16
- 18. Common areas of findings • Maintenance of reference safety information, including the Company Core Data Sheets, Product Information (PI) and Consumer Medicine Information (CMI), minimum PI and package leaflets • Maintenance of safety information on sponsor websites and social media • Dissemination and communication of Australian Reference Safety Information (internally and externally) Management of reference safety information Pharmacovigilance inspections 17
- 19. Common areas of findings • Procedures, record management, pharmacovigilance training • Audit and deviation management, including Corrective and Preventive Action management • Information technology systems and applications Quality management system Pharmacovigilance inspections 18
- 20. What next? • Understand your Australian PV requirements and responsibilities • Review your PV system – start with the common areas of findings discussed • Continually review and improve your PV system • Be inspection ready at all times Pharmacovigilance inspections 19
- 21. Practical tips for inspections Pharmacovigilance inspections 20
- 22. Pharmacovigilance Inspection Lifecycle Notification Inspection preparation INSPECTION Issue of inspection report Assessment of sponsor CAPA Close out of Inspection Presentation title 21
- 23. Practical tips for inspections • Following TGA notification of inspection (6-8 weeks): – nominate a main contact person for the inspection – confirm the inspection dates with the TGA as soon as possible – complete the Australian Pharmacovigilance Systems Summary (APSS) – due 4 weeks from notification – decide on the preferred inspection site ensure safety database and QMS are readily accessible so staff are able to run reports and extract data upon request tele/video conferencing, inspection room, printing facilities – ensure all staff are aware of and prepared for the inspection Pre-inspection Pharmacovigilance inspections 22
- 24. Practical tips for inspections • Submission of pre-inspection documents (Sheet A): – single zip file on a USB, courier to TGA office (preferred) – e-mail to pharmacovigilance.inspections@health.gov.au – Health Data Portal – register using AUSkey (testing phase) Pre-inspection Presentation title 23
- 25. Practical tips for inspections • Inspection plan: – Organise which staff will be attending what interview session – Inform the TGA of any tele/video conferencing necessary with global staff – Book the meeting room Pre-inspection Presentation title 24
- 26. Practical tips for inspections • Interview Sessions – Ensure that staff who are directly performing the role for the process being audited are present in the inspection room (not just business unit managers) – Ensure all company staff are aware of the inspection in progress – anyone may be requested to speak to an inspector at any time – If staff cannot attend in-person (e.g. global), interview via tele/video conference is acceptable During Inspection Pharmacovigilance inspections 25
- 27. Practical tips for inspections • Document requests – Assign a person to manage all the document requests – Ensure your computer system allows data extraction onto a USB and printing – If unsure of a request, please clarify – Provide documents as they are ready – Aim to provide all documents to inspectors by the morning of the final inspection day During inspection Pharmacovigilance inspections 26
- 28. Practical tips for inspections • Inspection report and CAPA plan – Provide any outstanding document requests to the inspectors as soon as possible – inspection report will be issued 4 weeks from receipt of final document – Send the inspection report once received to the relevant persons/parties for response within 4 weeks – You should have a method of recording and tracking your CAPA commitments – Inform us of any errors in the report with evidence – we will correct this in the final report – Contact us if you have an queries Post inspection Presentation title 27
- 29. Summary • Be organised and prepared • Make sure staff are clear on their roles and responsibilities prior to, during and post inspection • Maintain regular communication with the TGA • Ask questions and provide feedback Presentation title 28
- 31. Workshop: CAPA plan development Pharmacovigilance inspections 30
- 32. CAPA plan Root Cause Analysis investigating the cause of deficiency Corrective Action addressing the deficiency Preventive Action preventing recurrence of the deficiency Pharmacovigilance inspections 31
- 33. Developing a CAPA plan • Consider: – What is the deficiency? – Why did it happen? – Who is responsible for the CAPA? Who is affected and who will implement it? – How should we address this deficiency and how do we prevent it from recurring? • Be clear, specific and sufficiently descriptive in your response • Be broad in your thinking and problem solving – reflect on the root cause and system as a whole • Be reasonable with timelines for CAPA completion dates Pharmacovigilance inspections 32
- 34. CAPA workshop • What would be the recommended follow up/CAPA? Pharmacovigilance inspections 33
- 35. CAPA workshop • Scenario 1: Collection and collation of adverse drug reactions • Scenario 2: Management of significant safety issues • Scenario 3: Management of adverse drug reactions • Scenario 4: Management of reference safety information Pharmacovigilance inspections 34
- 36. Example of an acceptable CAPA plan • Deficiency: Case collection from partners and third party service providers – There were delays in the receipt of adverse event reports from partners and service providers, resulting in late reporting of serious adverse reactions (>15 days) to the TGA – There were also adverse reaction cases identified that had not been appropriately forwarded to the sponsor and not reported to the TGA accordingly – The sponsor was not performing routine reconciliation of adverse event data with vendors to ensure the integrity of data transfer – To date, the sponsor has not audited any of their vendors or partners who perform pharmacovigilance activities for the company – The sponsor could not provide records of pharmacovigilance training of market research and patient support program staff undertaken before the date of program initiation and did not have adequate oversight of this Pharmacovigilance inspections 35
- 37. Example of an acceptable CAPA plan • Response date: 27 March 2019 • Identified Root Cause of the deficiency: – The safety agreements in place (and current template) does not clearly state the responsibilities and timelines for reporting to sponsor and TGA if necessary (company process is to report any adverse reactions within 24 hours of receipt to the sponsor safety department, however this is not formalised in any documents) – The safety agreement does not include provisions for reconciliation – The sponsor has not audited any of their partners and third party service providers, however, they are able to at any time as stipulated in the safety agreement. – The safety agreement specifies that pharmacovigilance training is to be provided by the partner or vendor, however the sponsor does not request evidence of this. Pharmacovigilance inspections 36
- 38. Example of an acceptable CAPA plan • Proposed Corrective and Preventative action/s to the Root Cause: – Serious adverse reaction case #12345AB and #98765CD, which had not been received by the sponsor, were reported to the TGA – Other non-serious adverse reaction cases were recorded into the GSD – The safety agreement template will be amended to clearly stipulate reporting responsibilities and timeframes (within 24 hours of receipt to sponsor), monthly reconciliation – The safety agreements will also be amended to require up to date pharmacovigilance training (upon employment and annually) and records to be held for inspection – New SOP will be developed describing the sponsor audit process of partners and vendors. The sponsor will undertake 6 monthly meetings to discuss the annual audit schedule. This will be risk-based and the scope of the audits will include reviewing pharmacovigilance training of staff. – A communication will be sent to all partners and vendors to notify them of the above process changes and obligations in the interim Pharmacovigilance inspections 37
- 39. Example of an acceptable CAPA plan Proposed Corrective and Preventative action/s to the Root Cause (continued..): – The sponsor will perform a reconciliation with their partners and vendors of the last 12 months (or from program start date) to ensure no adverse reports have been missed – All partners and vendors have agreed to provide (re-)training to applicable staff to ensure staff training is up to date – A tracker will be used by the partners and vendors to track adverse reaction reports and track receipt to sponsor by recording the GSD number Objective evidence provided: – Amended safety agreement template (pending) – due to be completed June 2019 – Annual Audit Schedule for 2019 (provided) – completed April 2019 – Records of staff training of partner and vendor staff (pending) – due to be completed June 2019 Pharmacovigilance inspections 38
- 41. Contact us • For PVIP-related questions: – pharmacovigilance.questions@health.gov.au • For general pharmacovigilance questions: – pharmacovigilance.enquiries@health.gov.au Presentation title 40
Editor's Notes
- This is the outline of the session on PV inspections today… Update on the PVIP, including metrics, learnings and common mistakes We will provide practical information on how to prepare for a PV inspection from the time of receipt of the notification to successful close out We will hear feedback and comments from an inspectee, Kristina from Alexion, about her experiences of her inspection At the end, we will be running a workshop which will give you an opportunity to discuss and develop a CAPA plan for a number of case scenarios
- So firstly, we are going to give you an update on how the PVIP is going and what we have found from the inspections.
- As you all would be aware, the PVIP officially launched 1 September 2017 after a successful pilot inspection program of 10 volunteer sponsors in 2015-16. We had our inaugural inspection under the PVIP in January 2018, and have undertaken a total of 12 since then. These included a wide variety of sponsors, from innovators, biotech and generic companies to OTC and complementary medicine companies, selected based on our assessment of their risk profile.
- The report is mainly a summary of inspection statistics. We have included details of the common areas of findings to help sponsors in reviewing their PV systems.
- In terms of the key information from the PVIP metrics report – over the period from 1 September 2017 (i.e. from program inception although it is actually from 1 January 2018 when the first inspection was performed) to 31 December 2018, we have conducted a total of 10 PV inspections. All of these were routine inspections, none for-cause (or targeted) inspections and none re-inspections. During the 10 inspections we identified no critical deficiencies, 50 major deficiencies and 29 minor deficiencies
- You should be familiar with the definitions to the deficiency classifications in the PVIP guidelines…
- This table summarises the number of each type of deficiency identified in the different areas of the PV system.
- Highlighted in red are the most common topic areas of findings of any deficiency.
- This is the representation of the same data as a bar chart…
- And again, the key areas of findings are highlighted in red.
- We will be further discussing these common areas of findings, of any grading, in the next few slides.
- This finding is associated with failure to notify and/or late notification of significant safety issues outside the regulatory 72 hours
- We get a lot of questions on what is considered to be a SSI. A significant safety issue is considered to be any new important safety issue or validated signal that may impact on the risk-benefit profile of a medicine. We expect the sponsors to use their clinical and professional judgement when assessing whether a safety issue should be urgently reported to the TGA. Please note that a ‘validated signal’, in line with the definition in the GVP Module IX, is not necessarily a ‘confirmed signal’. Depending on the potential seriousness of the safety matter, this can include: requests for information by international regulator regarding a potential signal, or Early/interim information before an evaluation is complete. Be conservative in your decision-making and do not hesitate to contact us for advice! Your timely notification of such issues allow the TGA to further investigate to determine if any prompt regulatory action is warranted to protect public health in Australia.
- Findings under collection and collation of ADRs include deficiencies in case collection from internal employees (e.g. sales reps) and contracted third party persons/organisations (e.g. partners and vendors) of the company, literature and other solicited sources such as post market initiatives. This also includes issues with the safety agreements and contracts in place in relation to data exchange. It is important that sponsors identify all possible sources of safety data collection and ensure that the information collected is as accurate and complete as possible to be able to monitor and assess benefit risk. For e.g.: You should have safety agreements that clearly stipulate responsibilities and timeframes for reporting to the sponsor and TGA if applicable Your literature strategy should include terms that are broad enough to capture all potential relevant safety information about your medicine and you should routinely review your local journals list (due to product acquisitions, new journals or journals revealed to not be encompassed in PubMed or Medline etc.) Do you have any company sponsored social media or websites that have means for reporting ADRs? If so, are these being monitored? Who is monitoring this information? Are they appropriately trained? Do you have any information collection databases that may be used for marketing purposes, or any registries, where free-text fields may contain safety information? If so, are these being routinely reviewed? Do MI and PQC staff exercise due diligence (as reasonable) to determine if enquiries or complaints relate to an ADR or special situation? Does your GSD collect and record ethnicity details esp. Aboiginal/TSI status?
- The topic of management of ADRs embraces case processing activities from data entry and coding into the GSD, case assessment and follow up as needed and reporting to the TGA. It also includes the integrity of case data transfer for e.g. into a new database, or from a local to global database. You should consider: What QA procedures are in place to ensure data entry and assessment is correct? How does your company track follow ups and reporting to the TGA where applicable? How do you identify and handle duplicate reports?
- The management of RSI relates to the control and maintenance of the breadth of RSI documents such as CCDS, PI and CMI, minimum PI and package leaflets, standard response material used by MI staff and websites and any other promotional material/mediums that may contain safety information. You should ensure all safety information available to your staff, HCPs and consumers are up to date to ensure safe and quality use of your medicine. You should be aware of your regulatory obligations i.e. updating the PI and CMI within 2 weeks of TGA approval and have documented procedures in place to meet these requirements. We also expect safety variations to the Aus PI in response to safety-related updates to the CCDS be submitted to the TGA within 6 months of the company decision date of the need for a change. You should document justification if there is a delay and this will be considered by the TGA inspectors.
- Deficiencies (mostly minor deficiencies) in the final common area of findings – the quality management of the PV system - pertained to company procedures and procedural documents, record management, PV training, internal and external audits and databases and IT systems. You should ensure: Your company has quality management processes in place Up to date PV training of all company staff, including staff of partners and vendors undertaking pharmacovigilance activities for the sponsor You have adequate oversight of partners and vendors undertaking pharmacovigilance activities for the sponsor by conducting audits Your databases and IT systems are validated and have access controls as appropriate
- In the next part, we will be providing some practical tips on how to prepare for a PV inspection once you receive the notification from the TGA through to successful inspection close out.
- This is the pharmacovigilance Inspection lifecycle. The whole process takes at least 3 months, but can be substantially lengthier depending on the post-inspection CAPA assessment. Obviously, it is in both our interests that we close out an inspection as soon as possible.
- We will generally notify you at least 6-8 weeks prior to an inspection. Following receipt of a notification, you should: Nominate a main contact person to coordinate with the inspectors – usually the QPPVA Confirm your staff availability or any specific non-availabilities for the period given (including any global staff that may be involved) as soon as possible – respond with a date range rather than proposing a particular date as we are organising multiple inspections within the period. Complete the APSS and return to the TGA inspectors within 4 weeks of notification – this contains PV information about your company to assist us with planning the inspection Decide on the preferred site to be inspected – consider where PV documents are most easily accessible, availability of TC/VC and meeting rooms and printing facilities Communicate inspection date to all parties involved in your PV system (PVA partners, licensors, vendors) that may be asked to provide input for the inspection
- There will be quite a number of initial document requests which will need to be provided prior to the inspection. We would prefer it if this was sent by courier to the TGA office as a single zip file on a USB. You may also send the documents to our PV inspection inbox, but depending on the size, you may need to split this into multiple emails. Eventually, we hope to receive all inspection documents through the secure Health Data Portal which is currently in user acceptance testing stage.
- We will provide you with an inspection plan approx 1 month prior to the inspection. This will help you to organise which staff need to be available when for each interview session. Ensure staff members who actually perform the role for the process being reviewed are present for interview session, not just the managers. For global processes being examined, global staff do not have to be at the inspection in person, teleconference/videoconference is acceptable. Please let us know which sessions require TC/VC with global staff – we will try to organise these for the first day with consideration to time differences. We can even work just using document requests where necessary! You will need to book a meeting room for the inspectors to use for the whole duration of the inspection.
- Make sure all company members are aware of the inspection in progress and that anyone may be requested to speak to an inspector at any stage.
- Throughout the inspection we will be requesting documents, usually after each interview session to provide evidence for what has been discussed. Make sure you have a support person who’s sole job is to manage document requests i.e. send to the responsible people, track and send to the inspectors. We prefer that this person will not be involved in most interview sessions. Most documents will be requested electronically, so ensure you have to ability to extract company documents onto USB if required. Hard copies may also be requested so also make sure you have a printing capabilities. If you are unsure what document is being requested- clarify, do not guess! Provide documents as they are ready, do not wait to finish a sheet. Also, we ask that you aim to provide all documents to inspectors by the morning of the final inspection day to allow review prior to delivery of findings at the closing meeting.
- You should provide any outstanding document requests to the inspectors as soon as possible – we will issue the inspection plan 4 weeks from the date of receipt of the last document. Once you receive the inspection report, you should circulate this to the relevant persons or parties who will be responsible for providing a response – i.e a root cause analysis and CAPA plan – to any deficiencies. We will be going through how to write CAPA plans in our workshop later this morning. You should have a method of recording and tracking your CAPA commitments – we may ask for evidence of completion of CAPAs at any time. Let us know of any errors in the report, and provide evidence if possible – we will correct this in the final report. And please contact us if you have an questions, concerns or need clarification on anything. It will save us both time and minimise a lot of back and forth of the CAPA and allow us to be able to close out the inspection as soon as possible!
- So in summary, first and foremost, be organised and prepared – with your staff, your computer systems and PV documents etc. Ensure all staff are clear on their role and responsibilities with respect to the inspection. Maintain regular communication with the TGA – let us know if their will be any issues with the inspection plan or retrieving documents And please don’t be afraid to ask us questions at any point during the inspection process. At the end of the day, we want this to be a useful exercise for both sides, after all, the common goal is to improve PV systems and protect public health and safety. We welcome any feedback you may have on the conduct of the inspection.
- We would like to now invite Kristina from Alexion who has kindly agreed to share her company’s experience of the TGA pharmacovigilance inspection.
- We will now move onto the workshop component for today which is on the topic of CAPA plan development. We are just going to give a brief overview of what a CAPA plan is and involves and then have you break off into your table groups to discuss and develop one of your own.
- We will send out the inspection report with a CAPA plan record template. This needs to be completed within 4 weeks of the date the report was received. The CAPA plan will document the identified root cause of the deficiency and the set of actions proposed by the sponsor (and ultimately approved by the TGA) to address the non-compliance identified by inspectors during PV inspection as well as to prevent recurrence of the deficiency (or potential deficiencies). We may request evidence to corroborate the completion of the CAPA.
- Things to consider when you are developing a CAPA plan:… Also, please be clear, specific and sufficiently descriptive in your response. Do not simply state that the “SOP will be updated to address the deficiency”. Rather, detail what the changes to the SOP will be e.g. “SOP will be updated to include…” Include timeframes or frequencies where relevant. Be broad in your thinking and problem solving – reflect on the root cause and PV system as a whole Be reasonable with timelines for CAPA completion dates – consider the potential impacts should there be delays.
- You will now have the opportunity to develop your own CAPA plan. On your table you will find an example inspection finding in the CAPA record template that will be attached to the inspection report for you to complete. We have provided a root cause to the deficiency and we want you to propose CAPAs and any corrections and objective evidence if applicable. There are four different case scenarios in total. Please appoint a leader for each group who will be responsible for recording the outcomes of the discussions, we have allocated some time at the end to report to the room.
- Questions? Comments? Feedback?