PSMF in Practice Your Questions Answered! GPvP Symposium, 14 March 2014 Jonathan Rowell, Senior GPvP Inspector
Content Answer industry questions related to the PSMF MHRA inspector s preparation: How we use the PSMF Questions and areas for further discussion 2
Disclaimer This material represents the view of the MHRA. I m not going to answer detailed questions about individual MAH scenarios during Q&A. EMA have published Q&As Update November 2012: http://www.ema.europa.eu/docs/en_gb/document_library/r egulatory_and_procedural_guideline/2012/05/wc5001276 58.pdf 3
Your Questions Answered! 8
Location and Registration (1) Where should the PSMF be located if the QPPV is a one person contractor in the UK and all PV activities are conducted outside EEA? Should the PSMF reside with the QPPV in his/her home? GVP Module II, the PSMF shall be located within the EU, either at the site where the main pharmacovigilance activities are performed or at the site where the qualified person responsible for pharmacovigilance operates. If no other site qualifies, this may include a private residence. 9
Location and Registration (2) Does a new PSMF location require a new MFL number in XEVMPD? EMA guidance document on XEVPRM: the extended EudraVigilance medicinal product report message (version 3.2): Published 31 Jan 2014 and effective 16 June 2014. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/docume nt_listing/document_listing_000336.jsp&mid=wc0b01ac058079126c Variations to the information on PSMF location may trigger the generation of new EV Codes. 10
Location and Registration (3) If the PSMF is located in another EU country (outside the UK) does that mean that we are less likely to be inspected by the MHRA? According to GVP Module III, scheduling routine inspections should be according to a risk-based methodology. MHRA does not account for PSMF location when scheduling national inspections. They can be scheduled at anytime. The scope of MHRA inspections may be tailored to account for inspections conducted by other NCAs including by the Supervisory Authority (if applicable). 11
Inspection Planning (1) How do MHRA Inspectors use the PSMF? The section on organisational structure and annex B (contracts) can help to determine the scope and length of the inspection. The section on pharmacovigilance processes describes how pharmacovigilance activities are performed, and aids preparation of the inspection plan. The PSMF can be used to establish what studies, registries or other programmes are on-going. A list may be provided in annex C or may have to be requested. 12
Inspection Planning (2) How do MHRA Inspectors use the PSMF? The section on Pharmacovigilance System Performance is key. Are regulatory reporting obligations being met? The section on Quality System may contain notes associated with audits where significant findings are raised. MHRA inspectors routinely check whether corrective and preventative actions are within proposed resolution dates. 13
EEA QPPV Do changes in QPPV contact details require a variation? Once it becomes fully functional, changes in QPPV contact details (telephone, address and email) may be updated through the Article 57 database (without a variation). Currently, changes require a type IA IN variation. What should be included in the summary CV in the body text? Abbreviated details (name, contact information and qualification) The full CV should be included in Annex A. 14
Organisational Structure and Annex B: Contracts Which sub-contracted/ delegated activities should be included in the list? Can it be limited to agreements at corporate level? GVP guidance includes: distributors, licensing partners, co-marketing partners medical information, auditors, PSP and data management other technical providers (e.g. hosting of computer systems). Not just limited to corporate level agreements. Worldwide agreements which are applicable to EU authorised product, including agreements entered by affiliates must also be described. 15
Sources of Safety Data (1) What is the expectation for the description of main units collecting safety data? The body text description may be brief. It should highlight the main units (or types of unit) where safety data may originate on a global basis. This may include affiliates, medical information centres, studies, registries or surveillance programmes. The Annex C lists should be comprehensive and describe the country, nature of the activity, products and site contact details. 16
Sources of Safety Data (2) Does the MHRA expect to see lists of studies, registries, surveillance or support programmes in Annex C? GVP Module II: Lists of studies and support programmes may be located in an Annex or provided separately. Findings would not be raised if these lists were not included. The guidance indicates that the MAH must be able to provide such lists for inspection purposes. They will routinely be requested by MHRA Inspectors. It is preferable (not mandatory) that they are included in the PSMF. 17
Computerised Systems (1) Besides the safety database, which other systems or databases need to be described? Any MAH system used to receive, collate, record and report safety information. This might include: medical information systems product quality databases clinical trial systems any system important for the collection of safety data. An element of judgment is involved. 18
Computerised Systems (2) What should be included in Annex D of the PSMF Computerised Systems? There is limited guidance in GVP. The body text should provide descriptive information about the location, functionality (including validation status) and operational responsibility for computerised systems. Annex D can be used to provide tabular information about those systems. 19
Pharmacovigilance Processes Is it acceptable to simply list the documented procedures of the MAH or is something further required? A description of the following processes should be included: Continuous monitoring of risk-benefit profile(s) Risk management system(s) ICSR collection, collation, follow-up and reporting PSUR scheduling, production and submission Communication of safety concerns Implementation of safety variations 20
Pharmacovigilance System Performance (1) Case processing is delegated to a vendor. The vendor maintains KPIs to monitor the quality of ICSRs. Should this be provided to the MAH for inclusion in the PSMF? The MAH and QPPV should monitor the quality of ICSRs. A description of quality monitoring must be included in the PSMF. If the MAH monitors quality using metrics then these should be supplied in the PSMF. The MAH may delegate aspects of quality to the vendor (but retains responsibility). If the MAH uses the vendor quality metrics for its own purpose then these should be in the PSMF. 21
Pharmacovigilance System Performance (2) What are the expectations regarding the performance indicator targets for ICSR and PSUR submission compliance? There is no defined acceptable level of non-compliance. Targets can only reasonably be defined depending upon the volume of submissions within your organisation. As a general rule, ICSR expedited reporting compliance which drops below 95% may raise questions during inspection. PSUR submission targets are harder to define. In a small organisation, one missed PSUR may represent 100% failure. 22
Quality System: Audits (1) Questions about the inclusion of audit findings and deviations in the PSMF was the most popular topic from delegates. Article 104(2) of the Directive: The marketing authorisation holder shall perform a regular audit of his pharmacovigilance system. He shall place a note concerning the main findings of the audit on his pharmacovigilance system master file. The legal requirement only relates to audits conducted or commissioned by the MAH on its own system. 23
Quality System: Audits (2) If the MAH conducts an external audit of a partner or contractor, do the major and critical findings need to be recorded in the MAH PSMF? Yes. This audit is conducted or commissioned by the MAH. This is an example of an audit of the MAH s PV system, as the partner/ contractor is performing activities on behalf of the MAH (this may only include case collection in a single territory). The MAH is not the CAPA owner but CAPA implementation should still be confirmed or verified by the MAH. 24
Quality System: Audits (3) Do major and critical findings identified during an audit of the MAH by a partner company need to be recorded in the MAH PSMF? No. The audit is not conducted or commissioned by the MAH. It is not mandatory to include the findings identified by partners in the MAH PSMF. However, the MAH is encouraged to include significant findings (to the extent that they are relevant to the MAH s PV system). The result of partner audits could be an input to the MAH s own risk-based audit planning. As a result the MAH may trigger its own internal audit. 25
Quality System: Audits (4) A vendor identifies critical or major findings through its own internal audit. Do these findings need to be recorded in the MAH PSMF? No. The legal requirement for PSMF inclusion relates to audits conducted or commissioned by the MAH. The MAH should be notified of relevant non-compliance identified by the vendor and this should be stipulated in the contract with the vendor. The findings should be inputs into the MAH s own risk-based audit planning. As a result the MAH may trigger its own vendor audit. 26
Quality System: Audits (5) Do open CAPA from Competent Authority Inspections need to be included in the PSMF? GVP guidance is only applicable to audit findings and deviations. NCAs routinely have access to inspection findings from other Member States through information sharing processes. It can be helpful [but is not mandatory] to include open CAPA from NCA inspection in the PSMF. 27
Quality System: Audits (6) Can audit findings be included in the PSMF annex rather than the body text? It is easier the manage the addition and removal of annex information. The EU legal interpretation is that the note should be in the PSMF body text. The addition, amendment or removal of audit notes must be recorded in the logbook. Only body-text sections are subject to logbook control. Recording removal in the logbook verifies that sufficient improvement has been demonstrated or independently verified. 28
Quality System: Deviations Do all deviations or only those equivalent to major and critical need to be described in the PSMF? The PSMF shall document deviations from pharmacovigilance procedures (including impact) until they are resolved. There is no additional guidance in GVP. MHRA would not expect to see every single SOP deviation recorded in the PSMF (although repeat deviations to the same process may indicate an underlying issue). Both planned and unplanned deviations should be considered. An element of judgment is involved. 29
Annex G: Audit Schedule Should the Annex G audit schedule also include the internal audit plans of partner companies? No. The intention is to give an overview of audits planned and conducted by the MAH (including those conducted by an external auditor on behalf of the MAH). 30
Annex H: Product List (1) Annex H requires information about products and their presence on the market. What exactly is required? A product which was last shipped to a country may still be on the market with a long shelf-life. Annex H should include a list of products covered by the pharmacovigilance system master file. A product is considered to be on the market whilst it remains available to patients i.e. during its shelf-life. Pharmacovigilance requirements continue as long as a product is on the market. GVP Module VI includes requirements and recommendations for products which have been suspended (or withdrawn). 31
Annex H: Product List (2) MAH 1 places its products on the market but uses the system of MAH 2 to fulfil its pharmacovigilance obligations. Which PSMF should cover the relevant products? The product should be included in the PSMF of MAH 2 (i.e. the pharmacovigilance system in which it resides). MAH 1 should make reference to the additional PSMF in the annex of its own PSMF. Thus the entire MAH product portfolio can be related to the set of pharmacovigilance system master files. 32
Logbook To what extent should changes be recorded in the logbook? The Commission Implementing Regulation states that the MAH shall record any alteration of the content of the [PSMF] made within the last five years, with the exception of the information referred to in point 1(b) to (e) of Article 2 and in Article 3. It is not considered necessary log-book minor formatting changes such as typos and grammatical errors. 33
Version Control (1) Does a change to the annex require an immediate change in PSMF version number? Annex information may change rapidly and can be managed outside of the PSMF. Change history for the annex information should be available on demand. PSMF content and annex information may be independently versioned. 34
Version Control (2) Can changes to annex information be introduced periodically rather than immediately after each change? The PSMF is a living document and may constantly change. If requested by a NCA, the PSMF must be submitted within 7 days and it should be up-to-date at the time of submission. It is understood that some companies have implemented a quarterly revision cycle. This may be acceptable as long as an up-to-date version can be provided on request (i.e. in 7 days). 35
Your Questions Answered (hopefully).. 36
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