Bart’s Corner: EU Pharmacovigilance Inspection Update

Jul 24, 2014

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert

Several documents were published by the EMA and went into effect in June 2014 regarding EU Pharmacovigilance (PV) inspections.

Some of the more important points are summarized here:

Inspection Findings Impacting the Benefit-Risk Profile

The Pharmacovigilance Risk Assessment Committee (PRAC) adopted a new procedure entitled: “Union procedure on the management of pharmacovigilance inspection findings which may impact the robustness of the benefit-risk profile of the concerned medicinal products” dated 21March 2014. It came into effect 1June2014.

This document describes the bureaucratic procedures in place for actions that result from inspections by EMA/Member States that find significant issues that may impact on the benefit-risk (BR) profile of a product. It does not cover the routine and less severe findings.

The players involved are the PV inspectors, the PRAC representative for centrally approved products, the EU member state assessor for nationally approved products, the supervisory authority, the PRAC itself, the Agency Compliance and Inspections Department, the Agency Product Leader/Procedure Manager and, of course, the MA Holder (company).

This is a complex procedure involving multiple parties in multiple countries. The reader should review the document in detail if this is in your domain. In a nutshell, here are the salient points:

After the inspection, the inspectors should obtain and review the MAH’s CAPA (corrective action, preventive action) plan. The review should include not just whether the findings may alter the BR profile but also whether the entire PV system in the company has issues that may impact the safety of other products also. This could include failure to update risk minimization measures, failure to communicate safety information to healthcare professionals and patients etc. The document outlines three scenarios:

  1. The inspection findings do not impact the BR profile and have not led to significant delays in risk minimization measures. In this case the inspector should see if the CAPA is adequate and should consider early re-inspection.
  2. The inspection findings may impact the BR profile or led to significant delays in risk minimization measures. In this case, after the inspector reviews the CAPA, the situation should be escalated to the assessor(s) in the member state(s) to comment on whether routine PV activities and the PSUR/signal detection activities are sufficient or whether additional follow-up actions are needed including elevation to the PRAC.
  3. The findings, after discussion with assessors, are considered highly likely to impact the BR profile or led to delays in risk minimization measures. In this case the CAPA should be tracked by the inspectors and the Agency Compliance and Inspections Department must be informed of issues that require discussion at the PRAC so that they can coordinate actions and assist the PRAC. Referral procedures may be initiated if the safety and welfare of the public may be or is at risk. In egregious situations of non-compliance, recommendations for enforcement action against the MAH may be done.

Thus, mechanisms for follow-up, tracking, re-inspection and, if required, punishment are described.

Non-critical findings which generally do not have to be escalated to the PRAC include:

  • Routine CAPA follow up
  • Expedited submission of missed cases to EudraVigilance with subsequent routine signal detection activities
  • Inclusion in PSURs. The inspector may request an ad hoc PSUR even the next one is too far in the future

Critical findings which should be elevated to the PRAC representative for advice and a decision on whether to escalate the issue to the entire PRAC include (though not limited to):

  • Failure to provide pharmacovigilance data to competent authorities or the Agency, which may impact ongoing safety assessments.
  • Failure to evaluate safety signals which may affect the benefit-risk profile of the concerned product(s).
  • Failure to take action when a signal assessment demonstrates a new risk.
  • Failure or significant delays in the implementation of risk minimization measures.
  • If the findings impact multiple products (central, national or both)

If multiple member states are involved the information should be conveyed to those concerned agencies.

For the inspectors and assessors to determine whether the PRAC should be involved, the findings will be reviewed in the context of the impact on public health. These include:

  • The missed ICSRs compared to the total ICSRs submitted (late/on-time expedited reports)
  • The nature, source and seriousness of the missed cases
  • The next PSUR date
  • Total number of patients exposed to the product(s) in the EU and the rest of the world
  • Whether the missed ICSRs include unlabeled ARs.

There is a long discussion on how the PRAC will operationally handle issues escalated to them. Following the PRAC (and possibly the CHMP) discussion, the “advice” will be sent to the MAH. The lead inspector will then assess the MAH’s compliance with the CAPA and comments and may do follow-up inspections. Persistent non-compliance can lead to more severe actions.

Comment: There are no major surprises in this document which describes the operational processes for handling findings after an inspection. Unlike the US, there are multiple agencies, member states, the PRAC and different modes of approval (national vs central) which produce different bureaucratic pathways for action. A key take-away point is that the major player in this situation is the lead inspector. It is he/she who determines and initiates the course of many of the actions that ensue.

Although this applies to EU inspections the wisdom is true for all inspections including FDA inspections. Treat the inspector(s) well even if they don’t treat you well.

Thus companies should insure that their interactions with the inspectors are transparent, honest, frank, forthright and scientifically correct. Again, there is nothing new here but it does highlight the need for companies to be sure that they are “inspection ready” and that a “well-oiled” team is able to be assembled to handle an inspection rapidly. There should be an SOP in place for inspection handling and they should “practice” during mock inspections and internal or third party (e.g. vendor, partner) PV audits.

Conduct of PV Inspections

Another document going into effect in June is the “Union procedure on the preparation, conduct and reporting of EU pharmacovigilance inspections.” This procedure describes the mechanics of the preparation of the inspection. Key points:

Inspections can be done at any time without prior notice but usually advance notice is given to the MAH or third party to be inspected to allow the company to prepare. Usually 6-8 weeks notice is given – usually to the QPPV.

A timeline for the inspection is also given as well as an agreement on where the inspection is to be done, particularly if the inspection is being done outside the EU. Information is requested from the company – usually the PV System Master File (PSMF) but additional information may be requested.

The inspectors will prepare in advance:

  • The objectives and scope of the inspection
  • Identification of the inspection team members and their respective roles, if more than one inspector is going to conduct the inspection
  • The date and place, where the inspection is to be conducted
  • Identification of the functional units to be inspected
  • Identification of documents/electronic tools which will be reviewed, and to which access is required, in so far as is possible
  • The expected time and duration for each major inspection activity (premises, processes etc.)
  • The schedule for the final meeting
  • Relevant aspects of the inspection plan, for example the agenda and document access requirements, may be shared with the inspected entity in advance, to ensure the availability of relevant personnel and documentation
  • If it is to be a remote (e.g. telephone, web) inspection, the appropriate logistics should be set up

The inspectors will prepare an inspection plan which can be amended during the inspection. They will review relevant documents, examine the computer systems, conduct interviews, review internal and external communications such as log books, registries etc.

The opening meeting will include the introduction of the inspectors and MAH personnel, the scope and objectives, clarification of logistics and time-frames, and a presentation by the company of the PV system in place (if desired). The inspectors will review documents, processes and systems with documentation of all observations.

A closeout meeting with the company will be held. The QPPV should ensure the appropriate personnel attend. The meeting will explain the grading definitions of the findings, the procedures in place for distribution of the inspection report, response and follow up expected, a summary of the findings and “the opportunity [for the inspected party] to correct misconceptions and misunderstandings in response to the findings.”

The inspectors will prepare an inspection report for each site inspected and will provide them to the company within 30 working days (exceptions are possible) along with a request for comments including comments on factual errors, points of disagreement and a CAPA. This should be sent back to the inspectors within 30 working days. If the CAPA is acceptable to the inspectors then the inspection will be closed.

The procedure has a link in this document for a template with the format of the inspection report but that link did not work as of this writing.

The classification used for the findings is:

  • Critical: Deficiency in PV systems, practices or processes that adversely affects the rights, safety or well-being of patients of that poses a potential risk to public health or that represents a serious violation of applicable legislation and guidelines
  • Major: Deficiency in PV systems, practices or processes that could potentially adversely affect the rights, safety or well-being of patients or that could pose a risk to public health or that represents a serious violation of applicable legislation and guidelines
  • Minor : Deficiency in PV systems, practices or processes that would not be expected to adversely affect the rights, safety or well-being of patients
  • Comment: The observations might lead to suggestions on how to improve quality or reduce the potential for a deviation to occur in the future

Comment: Again, no major surprises here but a good review of how the inspection will be handled. There are differences from the way FDA does inspections but the bottom line is largely the same. The emphasis again is that the MAH should be ready to host the inspection. All documentation should be up to date and provided to the inspectors. If there is a 6 or 8 week time frame for the inspection, that means the documents requested may need to be sent within a few days of the notification of the inspection. Companies may not easily be able to update complex documents (e.g. PSMF) in such a short time. So the company should be sure the PSMF, SOPs, expedited report files, training records, CVs, job descriptions etc. are in place. Staff should be available to immediately prepare database reports (e.g. line listings of SAEs) and then to upload all of the appropriate material onto the desired media (e.g.DVDs) for the inspectors.


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