Frequently asked questions for Good Pharmacovigilance Practice

Inspection process and findings

How does the MHRA determine when to inspect a marketing authorisation holder?
Originally the intention was to inspect every marketing authorisation holder on a three-yearly cycle but a more risk-based approach is being developed, due to the large number of MA holders.  This will help to focus resource to better protect public health where there is a potentially higher risk.

Several factors affecting the planning of inspections include:

• QPPV details not provided to MHRA
• Black Triangle Products
• Products with known safety risks
• Poor compliance history
• Non-compliance with 15-day reporting
• MAHs with risk management plans to ensure commitments are being met

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?
The size of the inspection team varies from one to four inspectors plus occasional observers e.g. from the MHRA Pharmacovigilance and Enforcement Groups, dependent on the type of products marketed by the company, the complexity of the pharmacovigilance system and type of inspection (e.g. routine systems, triggered, national or requested by the CHMP). On average, for a routine systems inspection of a small company ("size" relates to the number of products authorised in the EEA), one to two inspectors would be present at a site for two to three days. For medium-sized companies, on average, two inspectors would be present for three to four days. For large companies, two to three inspectors would routinely perform the inspection over one week. 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.

Are there any plans to publish the trends identified from pharmacovigilance inspections in the future? If so, will these be available on the net?
Anonymised findings from MHRA pharmacovigilance inspections have been presented at MHRA symposia in the past and will be presented at future symposia. Inspection Metrics for 2006 are now available on our website (see ‘News’ section) and it is the intention to publish metrics approximately every six months. In addition, common inspection findings and areas of concern may be presented in publications such as MHRA MAIL.

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. 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.

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. For CHMP requested inspections the competent authority of the member state in whose territory the Marketing Authorisation Holder’s QPPV is located will usually be the most likely to perform an inspection.

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 e.g. 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.

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)?
The MHRA intends to perform routine pharmacovigilance inspections of UK marketing authorisation holders. If a MAH has delegated important pharmacovigilance activities to a contract company, then the contract company may also be included in the inspection. 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 GCP inspection, during which systems for clinical trial drug safety (if applicable) may be examined.

How often will an MHRA pharmacovigilance inspection be performed on a marketing authorisation holder?
This will depend on 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.  Once the inspection programme becomes fully established it is likely the inspections will be performed on a three-yearly cycle.

The most common 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 and there is no out of office hour’s procedure to deal with enquiries / adverse reaction reports.  There is no reconciliation between these departments and others (e.g. 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.

Has the release of Volume 9A had any impact on the conduct of MHRA pharmacovigilance inspections?
There has been no change to the general inspection process but additional items will need to be 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 e.g. 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.

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?
Background information: The Pharmacovigilance IAG is a non-statutory, multi-disciplinary group constituted to advise the Director, I&S Division and/or the Director of the Post-Licensing 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:

1. Conditions that are likely to cause or lead to a significant risk to public health
2. 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 EMEA, where appropriate e.g. in relation to applications that may be under consideration. In one case, this led to a CHMP-requested EU inspection.
• Sending a “warning letter”.
• Meetings with MAH representatives to discuss the issues.
• One case was referred to Enforcement for criminal investigation.

Possible actions for the future may include:

• Macrory administrative fines (2008 onwards?)
• EU infringement procedure (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 e.g. suspension of CTA and of pending applications.

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

The MHRA used to make a request for feedback after an inspection. Since the last 2 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?
- Added August 2008

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). Whilst the Pharmacovigilance Inspectorate welcomes ongoing feedback on the conduct of inspections a questionnaire is currently not being sent to each inspected MAH. The Pharmacovigilance Inspectorate will be initiating another project to gain similar feedback in the future. At present questionnaires are being sent out post GCP inspections. The programme is such that individual GxPs in rotation send out questionnaires which are returned to the Quality Manager.

Qualified Person responsible for pharmacovigilance (QPPV)

When you say the QPPV should be permanently available, what exactly do you mean? Can you explain e.g. 24/7; dedicated mobile?
The Qualified Person should be the main point of contact for pharmacovigilance issues, for EEA competent authorities. The qualified person responsible for pharmacovigilance (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. The procedure should enable the qualified person to contact other personnel who may be required to assist with obtaining information to respond to urgent safety queries e.g. product medical experts and personnel who can search the company's pharmacovigilance database. A suitably experienced deputy qualified person should be nominated to cover for the qualified person when they are absent. The name and contact details of the qualified person and any changes to these details must be notified to the EEA competent authorities and, for centrally authorised products, to the EMEA.

Could the Agency comment on the scenario where a company had 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?
Volume 9A EudraLex, EU Pharmacovigilance Rules for Human & Veterinary Medicinal Products, Notice to Marketing Authorisation Holders, April 2007, part I, section 1.2, states that the marketing authorisation holder should have permanently and continuously at its disposal, in the European Economic Area (EEA), a qualified person responsible for pharmacovigilance (QPPV). The name and 24-hour contact details of the QPPV should be provided to the competent authorities of the member states in which marketing authorisations are held and in addition for centrally authorised products to the EMEA.

Therefore, in order to comply with the legislation every marketing authorisation holder (or group of marketing authorisation holders) in the EEA must appoint one qualified person responsible for pharmacovigilance.

Volume 9A clearly states that each company (i.e. Applicant/Marketing Authorisation Holder or group of Marketing Authorisation Holders 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 e.g. 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.

Is it expected that compliance metrics for expedited reporting are maintained in countries that are not part of the EEA (e.g. 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 e.g. to ascertain if the processes for ensuring compliance in the EEA are different from those employed in the US.

Pharmacovigilance database

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.

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 i.e. 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.

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 e.g. 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.

For a company with a low volume of ADR reports - is it acceptable to have a paper-based system for logging and reporting ADRs?
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.

Record retention

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 whilst 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.

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.

Spontaneous case processing and literature cases

It is known that some competent authorities (e.g. Health Canada) publish ADR reports via website postings and potentially there were numerous reports that the MAH may not have received directly, but are accessible on websites. What are the expectations of the MHRA in relation to collation of such reports and should MAHs be routinely searching such websites and where necessary report cases to the MHRA? - Updated February 2008
Volume 9A, Section I.4.3.3 Information on Adverse Reactions from the Internet states, “The MAH should regularly screen websites under their management or responsibility, for potential reports on adverse reactions." 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 (e.g. 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.

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.

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.

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 e.g. 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.

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.

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’ e.g. 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, e.g. 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, i.e. 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.yellowcard.gov.uk

Some of the Anonymised Single Patient Reports (ASPRs) received from the MHRA seem to be assessed as non-serious (i.e. the narrative stated that the reporter considered the reaction to be non-serious and all seriousness criteria have been set to ‘N’).  Why are Marketing Authorisation Holders receiving non-serious ADRs from the MHRA?
All ASPRs sent to Marketing Authorisation Holders are considered serious, even if all of the seriousness criteria have been set to ‘N’.  Only reactions assessed as serious are communicated to Marketing Authorisation Holders (in accordance with Volume 9A, Part II, Section 1.3.4) and so all ASPRs are serious adverse reactions.

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 e.g. 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.

Do the LOCAL literature search requirements specified in EudraLex Volume 9A apply outside of Europe, i.e. 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.

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.

When will the MHRA be able to 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.

Miscellaneous
 
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 procedures and inspectors would expect to see these procedures described in writing. However, the type and extent of the trend analysis procedures will vary depending on a variety of factors. For some companies and products, the use of complex signal generation tools may be inappropriate and relatively simple mechanisms may be employed.

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), which 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.

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” i.e. 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).

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 6-12 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 inspector.

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. Where possible, some combined sessions have been run to save on resource e.g. quality management (auditing, SOPs, archiving). Feedback from MAHs has been that they did not mind the joint inspection; they were very busy while the inspectors were there but it was over and done with in one hit rather than two.

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 the 1st May 2004, the international birth date should be applied.' Is this statement only applicable for the marketing authorisation holder (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 date of the ASR for sponsors who are not the MAH holder, run from the first 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' i.e. within a couple of months of the due date for an ASR, then 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.

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?
There is a Memorandum of Understanding (MOU) between the COREC (now NRES) / MHRA / GTAC, accessible here: Memorandum of Understanding (MOU)

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

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).

Can you provide examples of the finding, "failure to adhere to EU data protection legislation when transferring data outside the EU"?
EU data protection legislation states that personal data should only be transferred to a third country if the third country in question "ensures an adequate level of protection" (information can be transferred for reasons of public safety). Marketing Authorisation Holders need to consider this when transmitting patient data outside of the EEA.

For Investigator Initiated Studies what would be expected in relation to the transfer of safety information between the Marketing Authorisation Holder / 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 e.g. 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).

Whose responsibility is it for the reporting of ADRs from post authorisation safety studies if a number of organisations are involved?
If the Marketing Authorisation Holder 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.

What communication occurs between EMEA and National Competent Authorities regarding the timing of PV inspections? Do Competent Authorities communicate information regarding planned/completed inspections?
- Added February 2008
Communications on national programmes are becoming more formal, particularly from 2008 onwards. The EMEA is seeking to formalise communications by producing a database in which CAs have been requested to record details of planned and completed national inspections. This would then be updated on a periodic basis. Inspection reports are also exchanged between Competent Authorities, on request.

Are there similar communications with the FDA regarding planned/completed inspections, as with the EMEA and individual Member States?
- Added February 2008
An agreement is in place between the EMEA and the 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. There is no formal coordination of inspections between the MHRA and FDA. Also, 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 EMEA website.

Will the MHRA require a type II variation for changes to the Detailed Description of Pharmacovigilance System (DDPS) e.g. 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 EMEA? Where is it detailed what a type II variation is?
- Added February 2008
The Commission is looking at amending legislation to enable an umbrella variation to be made when changes to the DDPS are required. From the MHRA perspective, when notifying a change of QPPV, MAHs will now be requested to submit to Geraldine Richter (Geraldine.richter@mhra.gsi.gov.uk) amended parts of the DDPS (information required in Volume 9A, Part 1, Section 2.2.2, 2.2.3 a) and 2.2.3.d) third paragraph) i.e. signed statement from the MAH and the QP, CV, a copy of their registration for EudraVigilance etc. There is currently no variation charge for this submission. MHRA requirements may differ from the requirements of the EMEA and other member states. MAHs should contact the EMEA for a response concerning DDPS variation submissions for centrally authorised products. It is anticipated that the requirements will be amended following the implementation of new EU variations legislation.

A Type II variation is anything that does not qualify as a Type IA or IB. See EudraLex Volume 2A, Chapter 5, Variations and Volume 2C, Guideline on Dossier requirements for Type IA and Type IB Notifications for further information.

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.

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. It is therefore expected that all safety data exchange agreements have now been reviewed and updated where necessary to fulfil the requirements outlined in Volume 9A.

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?
- Added August 2008
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. Signal detection procedures can range from individual case review, trend analysis of case reports to the use of complex statistical methodologies (e.g. Bayesian methods). The methods used (including periodicity of review) should be determined, for example, by the product portfolio and the number of reports of suspected adverse reactions received. The MAH should, based on risk assessment, decide what signal detection methods are to be used for which products or types of products, and should document this risk assessment. All MAHs are expected to have in place systems and procedures for systematic signal detection that are adequately documented in formalised procedures (e.g. SOPs). Within this documentation it is useful to provide a definition of what constitutes a potential signal, in order to educate all personnel involved in the process and to identify what requires further evaluation. These documents should also provide detail about the roles and responsibilities of all personnel involved, the sources of information included in the analysis and the methods used for signal detection. In addition, formal written procedural documents should describe what actions MAHs intend to take based on the outcomes generated from signal detection activities. This could include escalation procedures following identification of a potential signal, such as further analysis that will be undertaken or referral to a company committee.

Whilst there are no defined minimum requirements for signal detection, whichever method is employed by MAHs for signal detection, certain criteria should apply, namely:

• The method used is appropriate for the MAH’s data set. For example, the use of complex statistical tools may not be appropriate for MAH’s with a small data set.
• That data from all appropriate sources are considered.
• MAHs have systems in place to assure the quality of their signal detection processes.
• That any outputs from cumulative data review are assessed by an appropriately qualified person in a timely manner (and that the QPPV is informed of new information relevant to the evaluation of risk/benefit).
• That the MAH takes timely and appropriate actions and decisions based on the outputs from cumulative data review.
• That the MAH adequately documents signal detection and evaluation.

Signal detection performed only at the time of PSUR production is unlikely to be adequate in most situations. However, for a generic substance with low numbers of ADRs (and other safety information) generated which is currently on a six-monthly PSUR cycle, this may be appropriate.

There is opportunity to cover topics such as signal detection at future MHRA symposia.

Signal detection and ongoing safety monitoring will be covered in more detail within the MHRA 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.

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?
* this relates to the additional statement “Any suspected transmission via a medicinal product of an infectious agent is also considered a serious adverse reaction.”
- added September 2008
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 Marketing Authorisation Holders (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.

Risk management plans - Added February 2008

Is it necessary to submit a risk management plan 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.

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 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?
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.