MHRA Pharmacovigilance System Master File (PSMF) Inspection Findings

MHRA Pharmacovigilance System Master File (PSMF) Inspection Findings Gretel Sakyi Medical Information and Patient Safety Manager AstraZeneca UK 07 June 2018

Agenda MHRA inspections How inspectors use the PSMF Overview MHRA 2017-2018 GVP Inspection Metrics Overview of MHRA 2016-2017 GVP Inspection Metrics Common PSMF inspection findings PSMF inspection readiness Summary Group discussion Questions

MHRA Inspections MHRA inspections are conducted to examine compliance with existing EU and national pharmacovigilance regulations and guidelines. Good pharmacovigilance practice (GPvP) is the minimum standard for monitoring the safety of medicines on sale to the public in the EU. MHRA inspects marketing authorisation holders (MAH) and their contractors, to ensure they: ü Have an adequate and effective quality system for monitoring the medicines they have licences for ü Maintain a pharmacovigilance system master file ü Document all actions they take ü Have enough competent, appropriately qualified and trained staff to work the system

How the PSMF is used in inspections PSMF is usually requested when the MAH is notified of inspection by the MHRA. MHRA can request the MAH to provide the PSMF within 7 days or immediately. PSMF is an important document for gaining a better understanding of the organization and for inspection planning. It helps the inspectors to map out the scope and length of the inspection.

Inspection readiness PSMF To inform risk assessment, scope and for preparation Complete and accurate, whenever requested / submitted Advance document requests To address gaps in the PSMF, to allow inspectors to refine the scope of specific areas and prepare Expect to provide documents from inspection announcement, and before on-site dates Planning /Agenda discussions To clarify scope and ensure that facilities/ people will be available Be prepared to discuss the contribution of third parties, relevant staff and logistics Document provision Records and information to navigate the system and evidence of compliant activity Discuss, rather than infer, be prepared to provide records, increasing can be remotely inspected MHRA Symposium (2018), Changing the face of inspections

Inspection Metrics Year No. Inspections conducted April 2017-March 2018 22 April 2016- March 2017 37 April 2015-March 2016 35 There is been a significant decrease in the number of inspections between April 2016- March 2017 to April 2017-March 2018 (15 less inspections conducted)

Inspection Metrics: Critical findings April 2017-March 2018 2 2 1 1 1 *4 critical findings reported vs 6 in 2016-2017 0 Signal Management Risk Management Supervision and Oversight Provisional data not all 2017/18 inspections have been closed. 1 critical finding reported in every 7 inspections vs 1 on 6 in 2016-2017 Graph to show number critical findings April 2017-March 2018 MHRA symposium (2018), Inspection finding trends

Inspection Metrics: Critical findings April 2016-March 2017 6 critical findings reported vs 11 in 2015-2016 Reduction in critical findings could indicate that significant issues identified at previous inspections were found to have been largely resolved during re-inspection or that there has been a positive trend toward compliance more generally. Graph to show number critical findings April 2016-March 2017 MHRA GPvP Inspection Metrics: April 2016 March 2017 It could also be indicative of the fact that the inspection programme in April 2016 to March 2017 mainly included routine, rather than targeted, inspections. 1 critical finding reported in every 6 inspections vs 1 in 3 in 2015-2016.

Inspection Metrics: Critical findings April 2012-March 2018 Graph to show number critical findings April 2012-March 2018 MHRA symposium (2018), Inspection finding trends

Critical findings reported over time The graph below displays the average number of critical findings reported per inspection over time: MHRA GPvP Inspection Metrics: April 2016 March 2017 See next slide for summary of the graph

Summary of critical findings reported over time Average number of critical findings has decreased in the past two years. Average number of critical findings identified per inspection in this reporting period is 0.16 (rounded up to 0.2 in the graph), compared to 0.3 in the previous reporting period. This translates to a critical finding being reported approximately every six inspections on average, compared to every three inspections on average in the previous reporting period.

Inspection Metrics: Major findings April 2016-March 2017 150 major findings reported from 37 inspections Graph to show number major findings April 2016-March 2017 per inspected organisation MHRA symposium (2018), Inspection finding trends 1

Inspection Metrics: Major findings April 2016-March 2017 Graph displays the distribution of major findings by topic area 12 major findings in relation to PSMF MHRA GPvP Inspection Metrics: April 2016 March 2017

Inspection Metrics: Minor findings April 2016-March 2017 The chart below displays the distribution of minor findings by topic area o 84 minor findings were identified during the reporting period o Largest proportion of minor findings was in relation to the PSMF MHRA GPvP Inspection Metrics: April 2016 March 2017

PSMF examples affecting inspection days Information required Details Complete clinical trial listings PASS including investigator initiated studies Countries of sites PV activities undertaken by third parties Complete list of SOP, audits, CAPA and deviations Coverage of local (national) obligations Inclusion of content from non Drug Safety departments relevant to PV activities (e.g. medical affairs, clinical operations, regulatory affairs) Computerised systems List of computerized systems in use in relation to PV (not just the global safety database ) Table adapted from MHRA Symposium (2018), Changing the face of inspections

Common PSMF Inspection Findings PSMF Annex Inspection finding details Annex B - Organisational Structure Not all contracts and agreements included (e.g. missing service providers or commercial agreements) Roles under taken and the concerned product(s)and territories not clearly described Annex C - Sources of Safety Information Non-EU affiliates and med info services not included If a list of studies is included it is not complete PSPs not considered

Common PSMF Inspection Findings cont. PSMF Annex Inspection finding details Annex F - PV System Performance Metrics presented not accurate (e.g. delays in PSUR submission not taken into account) Metrics provided were not up-to-date Metrics not prepared using all relevant information (e.g. variation submission timeliness for updates to the SmPC did not include all variations submitted) Annex G - Quality System Not all audits included in the list of audits completed Annex H- Products List not up-to-date Non-EU territories where the product is authorised/marketed not included Marketing status of products authorised in the EU not indicated

Common PSMF Inspection Findings cont. Sources of Safety Data PSMF Main body Inspection finding details This section of the PSMF did not include all third party arrangements including outlicensing partners, distributors and pharmacovigilance vendors PV Processes A description of the process, data handling and records for the performance of pharmacovigilance was not included in the main body PV System Performance No performance indictors described in the PSMF No associated targets relevant to the performance indicator

Common PSMF Inspection Findings cont. PSMF Main body Inspection finding details Quality System Notes and CAPAs associated with significant audit findings and quality system deviations were contained within the annexes and not within the main body. Not all significant audit findings and quality system deviations included in the PSMF. In some instances no deviations are included. CAPAs associated with significant findings not included and no due date for CAPA closure specified. List of scheduled audits not included.

Summary April 2017-March 2018, the MHRA conducted 22 inspections. April 2016 to March 2017, the MHRA conducted a total of 37 pharmacovigilance inspections; this is an increase of two inspections compared to the previous year. The 37 inspections conducted approximately 35% of these inspections were of MAHs/ organisations that had not previously undergone a MHRA pharmacovigilance inspection. The largest number of inspections were routine re-inspections (15 in total, 41%). Six critical findings were reported during April 2016 to March 2017. 150 major findings were reported during this period, with 36 out of the 37 inspections conducted resulting in at least one major finding being reported. The largest proportion of major findings for a specific topic area was in relation to the quality system and quality assurance activities.

Summary cont. 84 minor findings were identified during the reporting period. Largest proportion of minor findings was in relation to the PSMF. The topic areas representing the largest proportion of inspection findings in this period are associated with the quality system and quality assurance activities, signal management, maintenance of the PSMF and maintenance of reference safety information. The PSMF is an essential tool used in inspection planning. It can also be used to help MAHs maintain oversight of the performance of their system and aid in audit planning. The PSMF is also a source of recurring inspection findings as detailed in this presentation and may be a reflection of wider system failings.

GROUP DISCUSSION What have been your experiences from audits or MHRA inspection findings in relation to the PSMF? What systems or processes have you implemented in your department to improve PSMF maintenance? What challenges have you experienced in the maintenance of the PSMF?

Glossary Inspection finding definitions Critical: a deficiency in pharmacovigilance systems, practices or processes that adversely affects the rights, safety or well-being of patients or that poses a potential risk to public health or that represents a serious violation of applicable legislation and guidelines. Major: a deficiency in pharmacovigilance systems, practices or processes that could potentially adversely affect the rights, safety or well-being of patients or that could potentially pose a risk to public health or that represents a violation of applicable legislation and guidelines. Minor: a deficiency in pharmacovigilance systems, practices or processes that would not be expected to adversely affect the rights, safety or well-being of patients. MHRA GPvP Inspection Metrics: April 2016 March 2017

Glossary cont. Inspection type definitions UK routine inspection (initial) this comprises inspections performed according to the national inspection programme and where it is the first MHRA pharmacovigilance inspection of the MAH. UK routine inspection (re-inspection) this comprises routine reinspections of MAHs under the national inspection programme. UK triggered - these inspections are performed under the national inspection programme and are triggered by either previous critical findings, requests from other MHRA divisions or as a result of other intelligence. CHMP triggered inspections requested by the CHMP in response to a specific trigger. MHRA GPvP Inspection Metrics: April 2016 March 2017

References MHRA GPvP Inspection Metrics Report: April 2016 March 2017 MHRA symposium (2018), Inspection finding trends

Questions