Further guidance
1. What are the regulators' expectation of industry with regards to Good Pharmcovigilance Practice (GPvP ) comments/guidance/ advisory notes posted in Q&A sections on the website of eg Human Medicines - European Medicines Agency Post-Authorisation Procedural Advice (external link) or Frequently asked questions for Good Pharmacovigilance Practice?

Are marketing authorisation holders (MAHs) expected the monitor these Q&A sites on a regular/ongoing basis?
Will the MHRA be inspecting MAHs against GPvP comments/guidance/advisory notes posted on these web sites?

With regards to the frequently asked questions section on the MHRA GPvP web pages, these contain previous questions discussed at symposia, Pharmacovigilance Consultative Committee meetings and others received by the Pharmacovigilance Inspectorate. These FAQs have been compiled to provide all MAHs the opportunity to review previous questions the Pharmacovigilance Inspectorate has received.

They aim to provide information on the expectation of the MHRA and additional clarification on existing legislative requirements and associated guidelines (eg Volume 9A) and do not include additional requirements that the MAH must comply with. They aim to educate the MAH on the current thinking on a specific topic and expectations on how existing requirements can be fulfilled.

The FAQs are reviewed and updated regularly and we encourage MAHs to regularly review them. We have now implemented an email alert service to notify subscribers when the GPvP webpages are updated. Users can subscribe to the email alerting service via the stay connected section of the website

The MHRA is not the author of the European Medicines Agency post-authorisation guidance included on their website and therefore cannot specifically comment on this. However, on review of these Q&As (in relation to pharmacovigilance) the objective seems similar to the MHRA web pages in which these provide clarification on existing legislative requirements and associated guidelines and do not introduce any new requirements that would be subject to inspection. With respect to centrally authorised products, the expectation is that the advice contained in the European Medicines Agency Q&As should be followed, unless the MAH can provide good justification for deviating from this advice.

2. Where can I find more guidance about pharmacovigilance? Inspection process and findings How does the MHRA determine when to inspect an MAH?
In November 2008, the MHRA published the “Good Pharmacovigilance Practice Guide” which provides practical guidance to individuals and organisations involved in pharmacovigilance. The guide is intended to complement currently available EU legislation and guidance.

It is available from Pharmaceutical Press (external link)

3. How does the MHRA determine when to inspect a marketing authorisation holder? - Updated April 2010
From April 2009, the GPvP Inspectorate has implemented a formal risk-based inspection process. Full details regarding the process are provided in the Good Pharmacovigilance Practice risk-based inspections section of our website.

4. How often will an MHRA pharmacovigilance inspection be performed on an MAH? - Updated April 2010
This is determined by the information provided on the risk-based inspection compliance report and the findings from the previous inspection. If the inspection results in a critical finding it is likely the MAH will be re-inspected within 12 months, with a particular focus on corrective actions agreed following the last inspection. The frequency of routine re-inspections where no critical issues have been identified will vary but is expected to be approximately three yearly.

5. What are the size of inspection teams and duration of inspections to small/medium sized companies? How does the MHRA decide the number of inspectors that are sent out to a site and is this number of any significance? - Updated April 2010
The size of the inspection team varies depending on the type of products marketed by the company, the complexity of the pharmacovigilance system and type of inspection (eg routine systems, triggered, national or requested by the Committee for Medicinal Products for Human Use (CHMP)). Information from the risk-based inspections compliance report is used to determine an approximate amount of time required to perform the inspection.

However, if the organisation of the pharmacovigilance system is complex or if serious issues are identified, more time may be spent on site and additional site visits may be performed. A routine systems inspection may involve between one and four inspectors for between one and five days. Occasionally observers eg from the MHRA Pharmacovigilance and Enforcement Groups or other Competent Authority Inspectorates may also participate in an inspection.

6. Are there any plans to publish the trends identified from pharmacovigilance inspections in the future? If so, will these be available on the net? - Updated April 2010
Anonymised findings from MHRA pharmacovigilance inspections are presented at MHRA symposia and conferences at which inspectors present. Inspection metrics summarising data from 2006 onwards are available in the pharmacovigilance inspections metrics section of our website.

7. Where a company has several MAHs with separate company numbers, but no pharmacovigilance activities are conducted in the UK, but in the EU, would they be subject to a pharmacovigilance inspection by the MHRA?
Any MAH with an UK marketing authorisation is subject to pharmacovigilance inspection by the MHRA. If pharmacovigilance activities are performed within the EU but outside the UK, the MHRA may ask company personnel from other EU sites to participate in an inspection at a UK site and/or may request inspectorates in other Member States to perform an inspection at site(s) in their country or to share results from recent inspections.

If a group of associated MAHs shares the same pharmacovigilance system, the inspectors would examine the agreements between the companies to determine whether the agreements clearly describe the responsibilities for pharmacovigilance activities.

8. If the MHRA has performed a pharmacovigilance inspection, is it likely that another EEA competent authority will wish to also perform an inspection?
In relation to inspections performed at UK sites by the MHRA, mutual recognition exists with other EEA Member States. EEA Competent Authorities can request copies of inspection reports for inspections performed by the MHRA. Other EEA Competent Authorities would contact the MHRA, if they wish a site to be inspected in the UK by the MHRA.

However, the performance of a pharmacovigilance systems inspection by the MHRA at a site in the UK does not preclude other EEA member states from performing pharmacovigilance inspections at sites in their own country or in third countries (in order to fulfil national statutory obligations). For CHMP requested inspections the competent authority of the Member State in whose territory the MAH’s QPPV is located will usually be the most likely to perform an inspection.

9. Would senior executives be interviewed during an inspection?
Inspectors normally interview operational personnel that are involved in pharmacovigilance activities or activities associated with safety reporting. All MAH staff should be aware of their obligations with respect to safety reporting and should receive appropriate training.
If considered necessary eg if serious issues are identified relating to a business area that a senior executive is responsible for, it might be necessary to interview a senior executive and senior executive(s) might be requested to attend the closing meeting.

10. Will a contract research organisation (CRO) be inspected on its own or only as part of an inspection of a marketing authorisation holder (MAH)? Does a CRO have to have a qualified person responsible for pharmacovigilance (QPPV) and have to produce a Summary of Pharmacovigilance Systems (SPS)? - Updated April 2010
The remit of the MHRA is to perform statutory pharmacovigilance inspections of UK MAHs. At present, there is no statutory power for the MHRA to undertake pharmacovigilance inspections of a CRO in isolation. If an MAH has delegated important pharmacovigilance activities to a contract company, then the pharmacovigilance systems, process and procedures of the contracted organisation may be reviewed during an inspection of the MAH.

MAHs in the EEA must appoint a QPPV and are requested to complete a SPS document in preparation for an MHRA pharmacovigilance inspection. Pharmacovigilance contractors would not be required to do this, unless these activities have been formally delegated by a MAH to a contractor.

CROs will also be subject to statutory GCP inspections, during which systems for clinical trial drug safety (if applicable) may be examined.

11. A critical finding from a pharmacovigilance inspection relates to ‘overall system failure’. What does this mean and can you provide specific examples?
An overall system failure can sometimes mean that there is no pharmacovigilance system in place, but more commonly it relates to multiple serious deficiencies leading to an inadequate pharmacovigilance system. Two examples of what would constitute overall system failure are provided below.

Example 1:
Company X has no global pharmacovigilance system due to inadequate safety data exchange with affiliates/subsidiaries for products with different invented names but containing the same active substance. There are no timescales or formal arrangements for transfer of individual case safety reports (ICSRs) or other safety information. This results in either lack of or late expedited reporting of ICSRs and periodic safety update reports (PSURs) containing incomplete safety data. There is also no quality assurance auditing of the affiliate companies.

Example 2:
Company Y does not have a back-up for processing ADRs if the safety officer is absent and there is a lack of follow-up on ADRs and pregnancy cases. There is no formal process for the transfer of adverse drug reactions from medical information to the pharmacovigilance department. There is no reconciliation between these departments and others (eg product complaints department). Key personnel have not been adequately trained in pharmacovigilance. The company does not perform any signal generation/trend analysis of cumulative safety data. In addition, Summary of Product Characteristics are not being updated in a timely manner. There is no policy for retention of source documents.

12. Has the release of Volume 9A, and subsequent versions, had any impact on the conduct of MHRA pharmacovigilance inspections?
There has been no change to the general inspection process. Additional items are reviewed, including but not limited to:

review of consistency between the Detailed Description of Pharmacovigilance Systems (DDPS) and the current pharmacovigilance system
review of amendments to ICSR and PSUR requirements eg reporting in special situations
review of QPPV input/review of risk management plans (RMPs) and post-authorisation safety studies (PASS) protocols
review of the commitments made in RMPs.

13. What kind of recommendations has the Inspection Action Group (IAG) made to date? Do they intend to take actions for non-compliance? If so, what? Have they taken any enforcement action since they started conducting GPvP inspections?
The Pharmacovigilance IAG is a non-statutory, multi-disciplinary group constituted to advise the Director, IES Division and/or the Director, VRMM Division and/or the Director, Licensing Division on any recommendations or Enforcement action appropriate to the Division(s). The group meets regularly, usually monthly, to deal with ongoing business and to consider new referrals. Criteria to be met for making referrals to the IAG in relation to pharmacovigilance inspections include, but are not limited to:

conditions that are likely to cause or lead to a significant risk to public health
an inspection identifies one or more unresolved critical deficiencies.

IAG recommendations to date have consisted of:

early re-inspection: this has been the most common recommendation to date - in most cases on re-inspection, adequate progress has been observed; in some cases, a further re-inspection has been required and a minority of cases have been referred back to IAG for consideration of other actions
sharing of information with other competent authorities and the European Medicines Agency, where appropriate eg in relation to applications that may be under consideration; this has previously led to a CHMP-requested EU inspection
sending a warning letter
meetings with MAH senior representatives to discuss the issues and consequences of continued non-compliance
delays in the processing of marketing authorisation applications, where the applicant is known to have a seriously non-compliant pharmacovigilance system
referral to the MHRA Enforcement group for criminal investigation.

Possible actions for the future may include:

macrory administrative fines
referrals under the EU Infringement Regulation (fines) in relation to centrally authorised products
rejection of future applications on the basis of an inadequate Detailed Description of Pharmacovigilance Systems (DDPS), where the system is known from inspection to be non-compliant.

For GCP and clinical trials some additional actions have been taken for non-compliance eg suspension of CTA and of pending applications.

There have been no criminal prosecutions to date as a result of MHRA pharmacovigilance inspections.

14. What communication occurs between European Medicines Agency and National Competent Authorities regarding the timing of GPvP inspections? Do Competent Authorities communicate information regarding planned/completed inspections? - Added February 2008
Communications on national programmes has become more formal, particularly from 2008 onwards. On a quarterly basis, Member States provide to the European Medicines Agency (EMA) updated details of planned and conducted national inspections. This information is circulated to all Member States.

EMA also maintains a spreadsheet containing details of routine and triggered pharmacovigilance inspections (requested by CHMP) of MAHs with centrally authorised products.

EMA is seeking to improve information sharing by producing a database in which details (including reports) of planned and completed CHMP requested inspections will be recorded. Inspection reports or summaries are exchanged between Competent Authorities, on request.

Critical and substantial major findings from inspections conducted as part of the EMA’s four-year plan of routine pharmacovigilance inspections of MAHs with centrally authorised products are routinely shared with the EMA and other competent authorities. This is described in the following publication:

Procedure for the Preparation of a Risk-Based Programme for Routine Pharmacovigilance Inspections of MAHs Connected with Human Centrally Authorised Products (CAPs) (external link)

15. Are there similar communications with the FDA regarding planned/completed inspections, as with the European Medicines Agency and individual Member States? - Added February 2008
An agreement is in place between the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) which provides high-level details on regular exchange of listings of Pharmacovigilance inspection information (including performed and planned inspections). The FDA normally provides at least two weeks notice of pharmacovigilance inspections which they intend to conduct at sites in the UK.

At the current time, there is no formal coordination of inspections between the MHRA and the FDA. Mechanisms are in place for discussion of topics of mutual interest. It should be noted that there tends to be a difference in focus between US and EU pharmacovigilance inspections (partly as a result of the differences in legislative frameworks). Further information on this agreement can be accessed from the Inspections section of the European Medicines Agency website.

16. The MHRA used to make a request for feedback after an inspection. Since the last two inspections, we’ve never had a feedback form to complete, and they don’t seem to refer to it any more. Would the MHRA please confirm if they still operate the system, and if so, what is the return rate of completed forms? - Updated April 2010
The analysis of the feedback from industry on pharmacovigilance inspections can be found in the News section on the GPvP webpage. This feedback was a specific project covering the period up to March 2007 (the results of which were analysed by MHRA’s Quality and Standards Manager, therefore, independently of the team).

While the Pharmacovigilance Inspectorate welcomes ongoing feedback on the conduct of inspections, a questionnaire is currently not being sent to each inspected MAH. The programme is such that individual GxPs in rotation send out questionnaires which are returned to the Quality and Standards Manager. The GPvP team will be sending out questionnaires later in 2010.

Qualified Person responsible for pharmacovigilance (QPPV)
17. When you say the QPPV should be permanently available, what exactly do you mean? Can you explain - eg 24/7, dedicated mobile?
The QPPV should be the main point of contact for pharmacovigilance issues, for EEA competent authorities. The QPPV (or their backup) must be permanently and continuously available. To meet this requirement, there must be an adequate procedure for out-of-working hours contact (provision of a mobile phone number and testing of the contact system may be sufficient for this purpose).

The procedure should enable the QPPV to contact other personnel who may be required to assist with obtaining information to respond to urgent safety queries eg product medical experts and personnel who can search the company's pharmacovigilance database.

A suitably experienced back-up should be designated to cover for the QPPV when they are absent. The name and contact details of the QPPV and any changes to these details must be notified to the EEA competent authorities and, for centrally authorised products, to the European Medicines Agency.

18. Could the Agency comment on the scenario where a company has multiple MAH units operating in the EEA/UK. Can there be a QPPV for each MAH or should there be one QPPV for all the MAH units? Are there specific requirements if the former is acceptable? - Amended April 2010
Volume 9A states that the MAH should have permanently and continuously at its disposal, in the European Economic Area (EEA), a Qualified Person responsible for pharmacovigilance (QPPV).

Therefore, in order to comply with the legislation every MAH (or group of MAHs) in the EEA must appoint one Qualified Person responsible for pharmacovigilance.

Volume 9A clearly states that each company (ie applicant/MAH or group of MAHs using a common pharmacovigilance system) should appoint one QPPV responsible for overall pharmacovigilance for all medicinal products for which the company holds marketing authorisations within the EU. It may be appropriate for a group of associated MAHs to appoint a different qualified person if more than one system is in operation eg one system for ‘over-the-counter’ products and one for Prescription Only Medicines.

Alternatively, the same individual can act as the Qualified Person for both systems across a group of MAHs with different systems. However, there must be clear agreements between the companies and with the Qualified Person clearly describing the pharmacovigilance roles and responsibilities of each party.

In addition to which, the Qualified Person would need to be suitably experienced, would need to have access to a medically qualified person (if not medically qualified), and would need to be permanently and continuously at the disposal of each MAH / group of MAHs.

The Qualified Person would need to have sufficient authority to take responsibility for the establishment and maintenance of the pharmacovigilance system on behalf of each MAH / group of MAHs. The Qualified Person would also need to have an overview of compliance with pharmacovigilance requirements for each MAH/group of MAHs.

19. Is it expected that compliance metrics for expedited reporting are maintained in countries that are not part of the EEA (eg USA)? - Added February 2008
The MHRA is interested in expedited reporting to EU/EEA Competent Authorities. It is expected that the QPPV will receive compliance metrics from non-EEA offices, in relation to the compliance of affiliates/partners when sending cases to the case processing centres, in order to ensure that cases will be reported on time within the EEA.

While the MHRA has no remit to ensure that reporting to the FDA is performed in compliance with US requirements, there may be circumstances where this activity is reviewed on inspection, eg to ascertain if the processes for ensuring compliance in the EEA are different from those employed in the US.

20. Is it acceptable for a QPPV to reside in the Isle of Man or the Channel Islands? - Added April 2010
As noted in Volume 9A, the QPPV should reside in the EU or EFTA states. Residents of the Isle of Man and the Channel Islands are not considered to be resident within the Community and therefore, it is not acceptable for a QPPV to reside in these locations.
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Pharmacovigilance database
21. Should reconciliation between the pharmacovigilance database and clinical database extend to non-serious events in clinical trials?
In general, there is no requirement for non-serious adverse events that are not expeditable, which are reported from clinical trials, to be entered in the global pharmacovigilance database. Therefore, in most cases it would not be possible to perform the database reconciliation referred to in the question.

22. Does the MHRA expect the same level of validation for medical information databases?
The level of validation expected for medical information databases will depend on whether source information relating to suspected adverse drug reaction reports is captured directly in the medical information database.

If yes, the source documentation is the electronic record and, as such, this information must be retained ie according to Directive 2001/83/EC (as amended by 2004/27/EC), article 104 and Regulation 726/2004, article 24: "The marketing authorisation holder shall be required to maintain detailed records of all suspected adverse reactions occurring either in the community or in a third country.”

Validation provides a high degree of assurance that the database is fit for purpose.

23. When a validated ADR reporting database is on the company server in the USA, what additional validation (if any) is required to be done in the UK, when used by the UK company for the reporting of ADRs in the EU?
The level and type of user-testing/validation to be done in the UK depends on the type of application, how it is used and whether the application is installed locally or solely resides on a company server in the USA. Therefore, it is not possible to provide a general response to this question.

Standard guidance documents for validation of computerised systems, eg PIC/S, GAMP, ACDM/PSI, should be referred to when assessing the level of validation/user-testing to perform. Inspectors will examine the appropriateness of the testing that has been performed to ensure that the system works as intended and in a consistent way.

The inspectors may ask to examine validation documentation from validation activities performed outside the UK.

24. For a company with a low volume of ADR reports - is it acceptable to have a paper-based system for logging and reporting ADRs? - Updated April 2010
The MAH is required to establish and maintain a system for pharmacovigilance which ensures that information about all suspected adverse reactions which are reported to the MAH is collected and collated in order to be accessible at least at one point within the Community. Whatever system for pharmacovigilance is implemented by the MAH, it must be sufficient to allow compliance with applicable regulations and guidelines.

Although the regulations do not state that a database is required, in practice, use of a database is one of the best mechanisms to ensure that information is collected and collated in order to be accessible at one point. A database may also facilitate trend analysis and electronic reporting. However, the computer application used does not have to be complex and, in some circumstances, an electronic spreadsheet (with appropriate security and quality controls) may be sufficient.

Additional guidance on this topic is provided in Chapter 2 of the Good Pharmacovigilance Practice Guide.

Record retention
25. Is there a time limit for keeping records ('over a long period' was mentioned at the symposium)? How long do we have to archive for?
Statutory Instrument 1994:3144 states that "the holder of a marketing authorisation shall maintain a record of reports of which he is aware of suspected adverse reactions". The legislation does not indicate that these records can be destroyed.

The current position of the MHRA is that, as a minimum standard, pharmacovigilance records should be kept while a product is marketed and for several years thereafter.

However, the term ‘several years’ is difficult to quantify, as it is dependent on the type of the product, expiry date, therapeutic use, reason for withdrawal from the market and several other factors.

Due to these constraints, the MHRA would not encourage the disposal of any pharmacovigilance records. If a company considers there is a strong case that records can be destroyed several years after marketing has ceased, this should be discussed on a case-by-case basis with the Inspectorate.

The preferred position of the MHRA is that pharmacovigilance records should be kept indefinitely.

26. For archiving purposes does hard copy source documentation need to be kept or will scanned versions of source documents be acceptable? - Updated April 2008
Competent Authorities may request pharmacovigilance data at any time and, therefore, data must be stored for an indefinite period of time. If the MAH wishes to destroy pharmacovigilance documentation or to destroy paper records after transferring the information into an electronic format, the MAH should first perform an appropriate risk assessment and should document this assessment.

If paper copy records are being transferred to electronic media sufficient evidence should exist that the process retains all the information present in the original in a legible manner and that the media used for storage will remain readable over time.

Where questions relating to the evaluation of benefits and risks may arise, in relation to a product for which a MAH holds a marketing authorisation (or held a marketing authorisation in the past), it is inadvisable for the MAH to destroy pharmacovigilance documentation relating to the product.

The MAH is not expected to screen external websites for information on adverse reactions. However, if a MAH becomes aware of an adverse reaction on any other website the MAH should review the case and determine whether it should be reported in an expedited manner.

The method of receiving adverse reaction reports from Competent Authorities within the EEA (eg receiving ASPRs via the MHRA Portal) does not fall within this guidance, since these are reports MAHs are sent directly by the Competent Authority (as required by Article 105 2001/83/EC as amended) and the MAH should therefore have full awareness of such reports.

28. What is the MHRA’s expectation regarding due diligence for follow-up of spontaneously reported cases?
For consumer cases, the MHRA would expect an MAH to ask the consumer for permission to contact his/her healthcare professional (HCP), and if permission was granted to attempt to follow-up with the HCP. The number of attempts to get follow-up information may depend on the type of case, for example a serious unexpected reaction may require more attempts than a non-serious expected case. Further guidance is provided in the report of CIOMS working group V.

29. If an MAH holds a national licence for a generic product in the UK only and a literature case is identified originating outside the UK, is the MAH expected to report the case? - Updated August 2008
The following guidance is in accordance with the Eudravigilance Expert Working Group Volume 9a Implementation Questions & Answers Version 1.2 and is reproduced below for completeness:

In Volume 9A, Chapter I.4 Section 3.2 ‘Reports published in the worldwide literature’ it is stated: "if the medicinal product source and /or the invented name is not specified and ownership of the product cannot be excluded on the basis of the active substance, formulation or route of administration, the MAH should assume that it is one of their products the publication refers to, although the report should indicate that the specific product source and the invented name was not identified."

As regards the interpretation of the ‘medicinal product source’ the MAH may also take the occurrence or the primary source country of the adverse reaction(s) into account to assume that it is one of their products. In practice this means that if in reports published in the world literature the occurrence or the primary source country is provided and the MAH does not have a marketing authorisation in this country, the company does not need to submit these cases.

The likelihood to miss reports published in the worldwide literature is negligible compared to the number of potential duplicates submitted for the same case by various companies.

30. For ADRs received from partner companies what should be defined as day 0 for regulatory reporting purposes?
Volume 9A Part I Section 4.2 Reporting Time Frames states:

“The clock for expedited reporting starts (day 0) as soon as the minimum information (see Chapter I.4, Section 1), has been brought to the attention of any personnel of the marketing authorisation holder or an organisation having a contractual arrangement with the marketing authorisation holder, including medical representatives. ………..In general, where the marketing authorisation holder has set up contractual arrangements with a person or organisation for eg the marketing of, or research on a medicinal product authorised to this marketing authorisation holder, the clock starts as soon as any personnel of the marketing authorisation holder or the other person/organisation receives the minimum information that constitutes a reportable case.”

Day 0 is therefore defined as when the partner company receives the ADR and not the MAH.

31. Death as an adverse event: if a case in which the patient died is submitted to a MAH with no specific AE, is it reportable to the Competent Authority if all other criteria for reporting are present? In the absence of an AE, do we consider death an outcome only or an important event worthy of reporting to the Competent Authority?
It is expected that fatal cases without a specific AE would be reported to the MHRA. These cases should be followed up to determine the cause of death.

32. Regarding section 4.3.5 of Volume 9a: “When a consumer submits medical documentation that supports the occurrence of the adverse reaction, this should be considered sufficient to report the individual case if it provides the minimum information.” What is and what is not acceptable as ‘medical documentation’ eg what about ECGs, x-rays, CAT scan results, photos of rashes taken by a patient etc?
In general terms, the confirmatory document(s) provided should appear to come from a medical source and should include clear confirmation that an adverse reaction has occurred (rather than providing information that requires a separate assessment, eg an ECG tracing without an associated written confirmation of the abnormality). The document should provide confirmation that the adverse reaction occurred in relation to the concerned patient.

The MAH has to judge whether sufficient information is available to make the case valid for reporting at that time (a conservative approach should be adopted, ie if the documents appear to provide health care professional confirmation, this should be accepted, but appropriate follow up should be performed).

If the patient has taken the trouble to provide confirmatory documentation, it is probable that the patient will provide permission for the case to be followed up with the relevant health care professional. Therefore, we would expect to see that the company has made appropriate attempts to follow up the case.

Patients can also submit adverse reaction reports directly to the MHRA, even without confirmation from a health care professional via our web site www.mhra.gov.uk/yellowcard

33. Some of the Anonymised Single Patient Reports (ASPRs) received from the MHRA seem to be assessed as non-serious (ie the narrative stated that the reporter considered the reaction to be non-serious and all seriousness criteria have been set to ‘N’). Why are MAHs receiving non-serious ADRs from the MHRA? - Updated April 2010
All ASPRs sent to MAHs are considered serious according to CIOMS criteria only (in accordance with Volume 9A, Part II, Section 1.3.4). (Previously, the MHRA used to send out additional ASPRs based on internal flags of seriousness assigned to dictionary terms, but this is no longer the case.)

34. Is medical review of a recognised ADR for an old, established product with a well-established safety profile really necessary in non-serious cases?
The MAH should decide, based on risk assessment, when medical review of non-serious ADR reports is appropriate. A number of factors will be involved in the decision-making process, eg the type of product, the safety profile of the product, the expectedness of the reaction etc.

Inspectors will examine the management of these cases during inspection. Even if pharmacovigilance physicians do not review expected non-serious cases on an individual basis, physicians should be involved in the company's trend analysis processes, which should include review of non-serious data.

35. Do the LOCAL literature search requirements specified in EudraLex Volume 9A apply outside of Europe, ie would it be expected that the MAH local office reviews relevant scientific journals in Russia? - Added February 2008
Yes, if products authorised in the EEA are marketed in those territories by the same MAH (it should be noted that this is guidance and cannot be legally enforced in non-EEA countries). The aim of literature searching is to gain knowledge about those products authorised in the EEA.
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36. If the MAH receives a serious adverse drug reaction report from a Competent Authority within the EEA, should this be expedited to any other Competent Authority within the EEA? - Added February 2008
There may be scenarios where this case should be expedited to another Competent Authority within the EEA. Volume 9A, Part I, Section 4.3.1 states:
“For medicinal products authorised through the mutual recognition or decentralised procedures and for medicinal products which have been the subject of a referral procedure, the marketing authorisation holder is responsible for ensuring that all serious adverse reactions received from healthcare professionals or Competent Authorities within the EU are reported to the Reference Member State.”

In addition, if the product is under intensive surveillance in the UK (denoted by a black triangle), it should be expedited to the MHRA (regardless of the procedure under which the product is authorised), if it meets the definition of a spontaneous report or a report from a non-interventional study.

37. When will the MHRA be able to 37. When will the MHRA be able to access non-UK reports from the EudraVigilance Data Warehouse and Analysis System?access non-UK reports from the EudraVigilance Data Warehouse and Analysis System? - Added August 2008
The MHRA has had access to the EudraVigilance Data Analysis System since late 2007.

Clinical trials and post-authorisation studies
38. The 'Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use (April 2006)', with regards to the production of Annual Safety Reports (ASRs) for Investigational Medicinal Products (IMPs) in clinical trials states that 'If marketing authorisation was granted for the IMP before 1 May 2004, the international birth date should be applied.' Is this statement only applicable for the MAH and should a sponsor (not the MAH) still follow the anniversary date of the granting of the first CTA or do we (the sponsor) need to find out from the MAH when the international birth date was and use that date? Should ASRs be sent to the competent authority and ethics committee if all trials on that IMP have ended in that member state?
Clarification from the Clinical Trials Unit: The due dates of the ASR for sponsors who are not the MAH holder run from the date that the study was first authorised in any member state. Sponsors who are not the MAH are not required to find out the birth date for marketed products. If a study has finished in a member state and the study report is 'imminent', ie within a couple of months of the due date for an ASR, then the CTU do not need to receive the ASR as well. However, if an ASR is being prepared for submission to another member state and is being prepared anyway, then CTU would like to receive it.

39. Can you share what type of PV information the MHRA might share with Ethics Committees? Are you aware of any other similar arrangements for other EU states?
In the UK, there is a Memorandum of Understanding (MOU) between the Centre of Research Ethical Centre (COREC) (now the National Research Ethics Service (NRES) and the MHRA and the Gene Therapy Advisory Committee (GTAC).

Memorandum of Understanding (MOU)

In relation to clinical trials, the MOU provides examples of when information would be shared.

40. For Investigator Initiated Studies, what would be expected in relation to the transfer of safety information between the MAH/company and the investigator? - added September 2008
This would depend on any arrangement between the MAH/company and the investigator. If the MAH/company is providing product or any other assistance to the investigator, it would be expected that there would be written provisions in place outlining clearly defined requirements for the exchange of safety-related information to the MAH/company.

It should cover the immediate exchange of significant new safety concerns as a minimum. Additional detail contained within a formal agreement will depend on the specific arrangements relating to the study and the type of product. It is not possible to provide a response that covers all situations, as each case should be assessed individually.

The MAH/company should perform a risk assessment based on the type of trial and type of product, to determine what type of information should be exchanged and within what timeframes. This risk assessment should be documented. Where appropriate, exchange should be a two-way process eg if the MAH/company becomes aware of significant new safety concerns relating to their product, which may be relevant to the trial being conducted by the investigator, the MAH/company should promptly communicate this to the investigator.

For clarity, the agreement should identify the responsibility for expedited reporting of SUSARs (which is the ultimate responsibility of the sponsor of the study).

41. Whose responsibility is it for the reporting of ADRs from post authorisation safety studies if a number of organisations are involved?
If the MAH is the sponsor (which includes studies requested as part of a Risk Management Programme or other post-marketing commitment), then the responsibility for reporting lies with the MAH. If the MAH is not the sponsor but is aware of the study or is providing funding or any other additional assistance, clear contractual arrangements should outline the responsibilities of the respective parties involved.

42. A SUSAR of an myocardial infarction (MI) is reported from a clinical trial by the sponsor within the 15-day timeline (the case was not immediately life threatening); follow-up information comes into the sponsor's safety group that the subject has now died as a result of the MI. What are the new timelines for this case to be reported? - Updated April 2010
Guidance on this topic is provided in Eudralex Volume 10 (external link).
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Risk management plans
43. Is it necessary to submit a risk management plan (RMP) when submitting a piggy-back application?
In general, if the originator has a RMP the piggy-back application would be expected to duplicate this. However, if the originator does not have a RMP, an RMP is probably not required for the piggy-back application. If the company is in any doubt the MHRA Licensing Division should always be contacted.
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44. In situations where the MAH does not consider an RMP is required, based on requirements in Volume 9A, should the MAH discuss with the National Competent Authority (NCA) prior to submitting the application, or should the application be submitted and then wait to receive a request to submit an RMP if required by the NCA? - Added February 2008
An MAH should ensure that they do not need an RMP. If one is required, an application would be invalid until the RMP is available. It is suggested that MAHs check the need for an RMP to avoid any delays with the application. In relation to the Decentralised Procedure, where a product is well established in one Member State, but not in another, there is ongoing work to establish some guidelines as to when an RMP would be required.

Miscellaneous
45. Should companies be running signal generation?
The MAH is responsible for on-going pharmacovigilance evaluation during the post-authorisation period. Therefore, MAHs should implement trend analysis/signal generation processes. See also following question and answer. For some companies and products, the use of complex signal generation tools may be inappropriate and relatively simple mechanisms may be employed.

46. Signal detection seems to pose lots of problems for companies (especially smaller companies and generics). While there is useful information available on the MHRA website under Good Pharmacovigilance Practice FAQs, members have requested more detailed and practical guidance. The industry is aware that there are always lots of findings during inspections relating to signal detection. Is there any information on the minimum requirements for signal detection? Are there any plans for the MHRA to run a technical meeting in this area? Will signal detection be covered in detail within the Good PV Practice Guide? - Updated April 2010
Volume 9A, Part I, Section 8 “Overall Pharmacovigilance Evaluation and Safety-Related Regulatory Action” describes the principles of signal detection and highlights the sources of information where a signal may be detected.
Further guidance on signal detection is provided in Chapter 6 of the Good Pharmacovigilance Practice Guide.

The proposed revisions to EU pharmacovigilance legislation may reinforce the requirement for MAHs to monitor their products for safety signals. The Commission also intends to produce Good Vigilance Practice documents that may provide more guidance on this topic.

47. Are there plans to include herbal and homeopathic manufacturers to pharmacovigilance reporting in the future?
Pharmacovigilance requirements are contained within the Herbal Medicinal Products Directive (2004/24/EC). These were required to be implemented by the EU Member States by October 2005. Manufacturers of products that are covered by the Directive are therefore subject to inspection. Such organisations have been inspected to date.

48. Can you clarify what kind of training/experience you expect for pharmacovigilance auditors?
Neither the legislation nor the MHRA dictates standards in this area. However, MHRA would expect pharmacovigilance auditors to be ‘appropriately qualified’, ie to have knowledge of applicable pharmacovigilance legislation and guidance, adequate auditor training and, ideally, to have spent some time working in the area of pharmacovigilance (but this is not essential).

49. Is there a set number of inspections or a set period of time required for a new MHRA pharmacovigilance inspector to be considered competent?
Each inspector must become accredited. The aim is for new inspectors to gain accreditation within six to 12 months, but it is very much dependent on the individual’s background. Training plans are tailored to each inspector, and there is no set number of inspections required.

Feedback is provided to the trainee and mentor at the end of each inspection by the most senior inspector present. Accreditation involves a recommendation by the mentor and operations manager, compilation of a detailed package of information and assessment of the trainee by an expert or designated senior pharmacovigilance inspector.

50. Can you share your experience to date of conducting combined GCP/PV inspections and what feedback you have received?
Combined GCP/PV inspections have been conducted when it was known that both inspectorates planned to visit the same MAH at about the same time. The MAH has then been given the option of a combined inspection. Essentially the inspections have run in parallel rather than a truly combined inspection, involving separate inspection plans and reports for the PV and GCP elements.

Combined GCP/PV inspections have been conducted when it was known that both inspectorates planned to visit the same MAH at about the same time. The MAH has then been given the option of a combined inspection. Essentially the inspections have run in parallel rather than a truly combined inspection, involving separate inspection plans and reports for the PV and GCP elements.

51. Translation of documents: are certified translations required?
Translation of documents into English must be performed/overseen by an individual with an appropriate background and with adequate knowledge of both languages. The appropriateness of the individuals/procedures used for translation may be assessed during inspection. EU legislation does not require ‘certified’ translations (although companies may choose to obtain certificates to provide evidence of the process that was used).

52. Will the MHRA require a type II variation for changes to the Detailed Description of Pharmacovigilance System (DDPS) eg change of QPPV? What is the MHRA position on type II variations for the DDPS? For example, if the QPPV changes, is a type II variation required or is it sufficient to inform the European Medicines Agency? - Updated April 2010
Guidance regarding this topic can be found in the classification guideline on variations from the European Commission website (this applies to CAP, DCP and MRP products).

The MHRA has also produced guidance on variations.

The new categories will also be used for all nationally approved products.

C.I.9 Changes to an existing pharmacovigilance system as described in the DDPS		Conditions to be fulfilled	Documentation to be supplied	Procedure type
a)	Change in the QPPV	1	1	IAIN
b)	Change in the contact details of the QPPV European Commission website (external link)	1	2	IAIN
c)	Change of the back-up procedure of the QPPV	1	2	IAIN
d)	Change in the safety database (e.g. Introduction of a new safety database including transfer of safety data collection and/or analysis and reporting to the new system)	1, 2, 3	2	IAIN
e)	Changes in the major contractual arrangements with other persons or organisations involved in the fulfilment of pharmacovigilance obligations and described in the DDPS, in particular where the electronic reporting of ICSRs, the main databases, signal detection, or the compilation of PSURs is subcontracted	1	2	IAIN
f)	Deletion of topics covered by written procedure(s) describing pharmacovigilance activities	1	2	IAIN
g)	Change of the site undertaking pharmacovigilance activities	1	2	IAIN
h)	Other change(s) to the DDPS that does not impact on the operation of the pharmacovigilance system (eg change of the major storage/archiving location, administrative changes, update of acronyms, naming changes of functions/procedures)	1	2	IA
i)	Change(s) to a DDPS following the assessment of the same DDPS in relation to another medicinal product of the same MAH	4	2, 3	IAIN
Conditions
1.	The pharmacovigilance system itself remains unchanged
2.	The database system has been validated
3.	Transfer of data from other database systems has been validated
4.	The same changes to the DDPS are introduced for all medicinal products of the same MAH (same final DDPS version)
Documentation
1.	Latest version of the DDPS, including a) summary CV of the new QPPV, b) proof of QPPV EudraVigilance registration, and c) a new statement of the MAH and the QPPV regarding their availability and the means for notification of adverse reactions signed by the new QPPV and the MAH, and reflecting any other consequential changes, eg to the organisation chart.
2.	Latest version of the DDPS and/or latest version of product(s) specific addendum(s), as applicable. For b) if the contact details of the QPPV were not initially included in the DDPS, submission of a revised DDPS version is not required / only application form/notification to be provided.
3.	Reference of the application/procedure and product in which the change(s) were accepted.
Note for i): The assessment of a DDPS submitted as part of a new MAA/extension/variation may give rise to changes at the request of the national competent authority/EMEA in this DDPS. Where this occurs, the same change(s) can be introduced to the DDPS in other marketing authorisations of the same MAH by submitting a (grouped) Type IAIN variation.

Of note, ‘IN’ indicates immediate notification after implementation rather than on a 12 month basis for standard 1A.

53. What is the MHRA’s expectation of companies in relation to auditing business partners? In light of consultation MLX 345, can the MHRA provide any guidance on the assessment of risk associated with business partners? If issues are identified what do they expect companies to do to ensure issues are addressed when contracts are not typically signed by QA departments? If serious issues are raised do they expect feedback from the company auditing the business partner? - Added February 2008
The types and frequency of audits will depend on the activities being conducted by business partners (and the risks associated with those activities). In general, there is an expectation that some review of how a business partner is able to meet or is meeting its commitments will be made, and audit may be an appropriate way to address this. It is the responsibility of the MAHs to ensure that appropriate corrective actions are taken (not specifically the responsibility of the QA department).

The contract should be worded in such a way so as to facilitate audits and implement necessary corrective actions. All parties to the contract should be committed to take action to address non-compliances, and audit reports should be shared with the parties, as appropriate. MLX 345 mentions business partners in relation to risk because the MHRA has observed that serious non-compliance is often found where there are complex and numerous business partner relationships.

It was also noted that it is the responsibility of the QPPV to ensure that contracts with business partners are appropriate with respect to pharmacovigilance activities.

54. Would the MHRA accept an organisation relying on their Licensing Partner’s assurances that their PV system is working (for example certificates, top line results from audits) instead of actually auditing themselves. Would it be acceptable to provide these assurances to inspectors during a PV inspection? Or would they expect the organisation to have conducted their own audit of the Licensing Partners PV system? - added March 2009
Firstly, please refer to the FAQs above ‘What is the MHRA’s expectation of companies in relation to auditing business partners?’

An audit is not the definitive activity that can be used to assess a partner company’s compliance with a safety data exchange agreement. For example, the MAH can:

review procedures for and timeliness of exchange of ICSRs (how many are transmitted within specified timeframes?) as well as quality of service/information provided
check whether all cases have been transmitted as required (ie these may be identified during data reconciliation)
hold regular meetings with partner companies to discuss general processes and SDEA commitments
perform individual risk assessments of each partner company using information gathered from 1) to 3) as well as perhaps using a regular compliance questionnaire, with questions on a range of topics including the partner company’s own internal audit process and perhaps top-line results relevant to the SDEA in place. It would then be for the MAH to determine whether a formal audit is required.

55. What is the expectation from the Inspectorate for safety agreements between partner companies that were implemented prior to Volume 9a implementation (Jan 07): Usually companies have a periodic scheduled re-visit of partner agreements - should companies be re-visiting them all in advance of the scheduled review for the primary purpose of updating them for Volume 9a? And if so, what is the expectation of the MHRA on a reasonable timeline for this? - Added August 2008
The MHRA Pharmacovigilance Inspectorate had taken a pragmatic approach with regards to companies fulfilling the requirements of Volume 9A after the guidance was published, since it was not realistic to expect that processes and procedures would be amended immediately. The MHRA Pharmacovigilance Inspectorate began assessing compliance with Volume 9A from July 2007. Therefore, it is expected that all safety data exchange agreements have now been reviewed and updated where necessary to fulfil the requirements outlined in Volume 9A.

56. What is the expectation from the inspectorate regarding the expanded SAE definition in Volume 9A* to that in the EU clinical trial directive (and ICH E2D)? Which definition should be referred to in interventional/non-interventional study protocols? - Added September 2008
* This relates to the additional statement “Any suspected transmission via a medicinal product of an infectious agent is also considered a serious adverse reaction.”)
The definition of a serious adverse reaction contained within the glossary of Volume 9A provides additional guidance to that of the EU Clinical Trial Directive (and ICH E2D) highlighting that cases of suspected transmission via a medicinal product of an infectious agent, should be assessed as serious, which is in accordance with the requirement in Directive 2001/83 EC (as amended) which states: “The marketing authorisation holder shall ensure that all suspected serious unexpected adverse reactions and any suspected transmission via a medicinal product of any infectious agent occurring in the territory of a third country are reported promptly in accordance with the guidelines referred to in Article 106(1), so that the Agency and the competent authorities of the Member States in which the medicinal product is authorised are informed of them, and no later than 15 days following the receipt of the information.”
This requirement and associated guidance applies to MAHs (including non-interventional studies) and, therefore, this should be incorporated into MAH procedures. However, it would be expected that sponsors of interventional clinical studies would also incorporate this guidance into study protocols, particularly since there has not been a change in criterion on what is considered a serious adverse reaction/event.

There would not be a clear rationale to consider cases of suspected transmission via a medicinal product of an infectious agent as non-serious in the clinical trial setting (when less is typically known about the product) and to consider the same cases as serious (as required by legislation) in the marketed setting.

57. What is the Inspectorate's expectation of timeframes for publication and distribution of updated SPCs and PILs?
One of the major risk communication tools used by companies to inform patients and prescribers about risks and benefits is product information, in particular, the patient information leaflet (PIL) and Summary of Product Characteristics (SPC). Timely risk communication is essential in order to protect patients and companies should adopt appropriate standards for the timely publication and distribution of new SPCs and PILs once they have been approved by a Competent Authority.
The MHRA GPvP Inspectorate has identified numerous examples of approved safety updates which have not been communicated to patients, prescribers and relevant marketing authorisation holder (MAH) personnel in appropriate timeframes. Therefore, in order to ensure consistency across MAHs, recommended timeframes for completing specific activities are described below. This list should not be taken as exhaustive.

Note: These timeframes are considered as maximum recommendations for “routine” safety updates. Immediate communication to concerned parties may be necessary in the event of Urgent Safety Restrictions (USRs) and MAHs should always follow the timeframes for risk communication set out by the Competent Authority.

1. Communication to MAH personnel
A number of different departments within the company will need to be notified of updated product information for use within their area of responsibility. This may include staff within the medical information and pharmacovigilance departments, sales representatives, marketing staff and website coordinators. It is expected that each MAH will define relevant distribution channels within the company and that appropriate staff will be notified no later than 10 working days following approval of updated product information.

2. Company-sponsored websites
Any company sponsored websites which contain published copies of SPCs and PILs should be updated within 10 working days of approval of new product information. Companies should maintain a record of websites where product information has been published to ensure that all relevant websites can be updated in a timely manner.

3. External publication
MAH’s may choose to publish product information with a number of external sites (eg the electronic medicine’s compendium (eMC)) or to notify external organisations (eg the BNF, MIMS etc). Where applicable, the MAH should submit the update request to these organisations no later than 10 working days after approval of new SPCs and PILs. It is acknowledged that external providers will have their own timeframes for checking and publishing new product information, but it is expected that updated documents will have been submitted for the publication process within the specified timeframe.

4. Implementation of patient information leaflets in product packs
Once new packaging components have been approved by the MHRA these must be introduced into packed stock being certified for release to the market by the Qualified Person in accordance with Directive 2001/83/EC (as amended) within three to six months, unless MAHs have been advised of the need for earlier introduction of the new components for safety reasons. The Qualified Person should not certify a medicinal product for release to the market if the packaging components, at the time of certification, have not been updated within three to six months following approval.

Page last modified: 01 March 2012