Bart’s Corner: EU Proposals on Updates for Good PV Practices

Sep 29, 2014

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert

On September 15, 2014, the EMA published proposals on changes to the Good Pharmacovigilance (PV) Practices covering revisions of Module VI on the management and reporting of adverse reactions In particular post-authorisation safety studies and on Module III on new Union procedures for pharmacovigilance inspections.

There is a request for public comment.

In a guideline accompanying the proposed revisions, the EMA summarizes the history of the modules and defines PV and how it is done. Of note, they describe the increasing PV roles of healthcare professionals (HCPs) and the public in addition to the roles played by the EMA, member states and Marketing Authorisation holders (companies). They note that in the past, the main role for HCPs was spontaneous reporting of suspected adverse reactions (SARs). The roles of the public and HCPs are now being expanded to include reporting by patients of SARs (which has been commonplace in the US and Canada for many years), participation by patient and HCP representatives on the Pharmacovigilance and Risk Assessment Committee (PRAC) and attending public hearings on PV and benefit risk issues.

Module III- PV Inspections contains revisions relating to the new Union procedures for inspections (Section III.B.5). These changes occur in the section describing the inspection process developed and implemented by the PV Inspections Working Group and covers the methodology of the EMA and the member states in developing harmonization of inspection conduct, joint inspections, training and sharing of inspection results. The issues covered include:

  • Sharing of information
  • Inspection planning
  • Pre-authorisation inspections
  • Coordination of PV inspections in the EU
  • Coordination of third country inspections 9ncluding inspections of contractors in third countries
  • Preparation of PV inspections
  • Conduct of PV inspections
  • Reporting of inspections and inspection follow-up
  • Record keeping and archiving
  • Unannounced inspections
  • Sanctions and enforcement in case of serious non-compliance
  • Recommendations on training and experience of PV inspectors

Module VI – Management and reporting ARs was revised in July and then again in September 2014. The revisions came into effect September 16, 2014 and cover several areas. The important ones are:

  • Section VI.A.2.1.1 Causality: The causality of spontaneously reported cases, even if the relationship is unstated or unknown, is considered to be an adverse reaction. That is, for cases reported by HCPs or patients, there is a suspicion of causality implied in the report. What is interesting here is the note that if “the reporters specifically state that they believe the events to be unrelated or that a causal relationship can be excluded”, the cases may be considered unrelated. In the US, this is not explicitly stated and many companies will consider all spontaneous reports to be possibly related even if the reporter says it is unrelated. There are usually very few of these cases however.
  • Section VI.A.2.4 Seriousness: The standard definition of seriousness is presented. What is of interest is the comment on the Important Medical Event List (IME) of selected MedDRA terms. This is a list of terms that can be considered serious. There are about 7600 such terms and the EMA notes in this module that the list aims to “facilitate the classification of suspected ADRs, the analysis of aggregated data and the assessment of the individual case safety reports in date to day PV activities.” It is intended as guidance and not all cases with one of these terms is automatically considered serious. Many companies use this list and declare all of these cases to be serious automatically.
  • Section VI.B.1.2 Solicited Reports: The module discusses what happens when the receiver (the company) of a solicited report disagrees with the reporter. That is, if the company feels that there is not a reasonable possibility of a causal relationship between the suspected product and the AR, the case should NOT be downgraded to a non-related event. Thus, if either the company or the reporter indicates that the case is possibly related, the case should be considered possibly related for regulatory reporting purposes. Note that this is different in some circumstances in the US where the company may override the investigator’s opinion for certain SUSARs in clinical trials. It is somewhat less clear for solicited cases.
  • Section VI.C.1 Reporting rules for clinical trials and post-authorisation studies in the EU: This section has been changed, as has been the title of the section. Post-approval studies, whether for safety or efficacy, may be clinical trials or non-interventional ones. Safety reporting thus can fall under different directives and regulations depending upon this classification. SARs should NOT be reported under both; duplicate reporting is to be avoided. The appropriate reporting scheme should be used. There is a Venn diagram, which has been slightly altered, from “non-interventional studies” in the older versions of this module to “non-interventional post-authorisation studies.” The point here is to classify a trial correctly, to decide which reporting directive/regulation applies and to avoid duplicate reporting. See the section for more detail. In theory, companies should already be doing this correctly.
  • Section VI.C.2.2.2 Solicited reports: This section is slightly changed from previous versions. Cases from within or from outside the EU in post-authorisation studies when initiated, managed or financed by the MAH must record all SARs. For non-interventional post-authorisation studies, this obligation applies to study designs based on primary data collection. For all solicited reports, the MAH must have mechanisms in place to record and document complete and comprehensive information to allow case assessment and reporting of valid ICSRs related to the study medication. The MAH must perform due diligence with follow up to seek the view of the primary source (reporter usually) regarding the causal role of the medicinal product. If the opinion is missing, the MAH should use its own judgment. This requirement does not apply to studies based on secondary use of data as ICSR reporting is not required here. Safety data from solicited sources must be presented in the appropriate parts of the PSUR.
  • Section VI. Reports of suspected ARs originating from organized data collection systems and other systems: This section makes some changes in the classification of different types of studies consistent with the other changes in this module.
    • The first section refers to non-interventional studies which are: compassionate use in the EU, patient support programs and market research programs. These are solicited reports and this section gives information on how to populate certain fields in the E2B(R2) transmission. If the AR is only suspected to be related to a product which is not subject to an organized data collection system and there is no interaction with the medicinal product, the case should be considered spontaneous.
    • The second section refers to non-interventional post-authorisation studies in which there is no SAR collection or from compassionate use or named patient studies in the EU where active AE collection is not required; any such cases that come to the MAH should be considered spontaneous.
    • The third section covers trials where the AR is only suspected to be related to a non-investigational product and there is no interaction with the investigational product; the case should be considered spontaneous.
    • Cases which are reported to EudraVigilance which originate from post-authorisation studies and which don’t fall under the clinical trials directive should be submitted to the post-authorisation module of EudraVigilance.
    • This section is rather confusing and you should refer to the document for full and further detail with references to the appropriate directives, modules and regulations.
  • B.7 Reporting of ICSRs: There is a clarification of “day zero.” The description of day zero now reads “it is the first day when a receiver gains knowledge of a valid ICSR, irrespective of whether the information is received during a weekend or public holiday. Reporting timelines are based on calendar days. There is added emphasis that for medical literature review the clock starts with awareness of a publication containing the minimum information for reporting. If out-sourced there should be detailed agreements in place to ensure that this is done.

There are some other changes regarding language of cases and a table in appendix 3.1.1. The reader should refer to these sections to be sure that current systems in place in the MAH are consistent with these new requirements.


These changes are relatively minor and consist of clarification of solicited reports primarily. Most MAHs or companies handling cases for EU reporting should have systems in place which already meet these requirements or which will require small adaptations to meet the new requirements. Nonetheless, personnel involved in case processing should carefully reread this document (which runs 90 pages) to be sure they have the appropriate procedures in place.

Note that in comparison to the US, Canada and some other countries, the rules and regulations in place in the EU and the member states are far more detailed and complex. This seems to reflect a philosophic difference on how drug safety is handled in different geographic areas. Whether we will return to more harmonized systems and procedures remains to be seen, but the trend seems to be away from harmonization.

Finally, if you have any comments, by all means send them to the EMA!


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