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Safety Reports: The importance of high quality content from regulatory perspective

The action plan developed by the AEMPS and published April 2016 focuses on the set up of specific activities, such as the publication of Risk Management Plans Summaries by the agency or the need to increase the number of inspections included in the Good Pharmacovigilance Practice programmes for human and veterinary use. Essentially, this infers that periodic safety update reports (PSURs) and risk management plans (RMPs) are expected to be more thoroughly revised, as well as to undergo a continuous monitoring of the relevant risk minimisation measures.

In the above setting and in order to comply with the requirements set out by the authorities, it is of outmost importance to benefit from experts´ knowledge on particularities of each of these reports, as well as on the strong interconnection that lies between them. Experts should make sure that report preparation follows the highest quality standards in terms of data and analysis, since the dedicated timeframes for provision of responses are noticeably limited and the difficulty of responses may be elevated. An incomplete analysis of safety data included within these reports may erroneously lead to the conclusion that the day-by-day management of drug safety issues is not rigorously conducted.

In their PSUSA assessments of PBRERs, the PRAC, CMDh and CHMP have lately become more strict, requesting that the MAHs develop each section of the report according to the indications available in GVP Module VII. Moreover, additional specific information is being requested, such as cumulative reviews of cases regarding certain safety concerns and how these relate to epidemiologic data available, as well as the need to provide toxicology data on excipients, which might contribute to the knowledge on a definite safety concern. Furthermore, the MAHs should be aware of the fact that PSUSA outcomes apply both to products included in the scope of the PSUSA procedure and those products containing the same active substance not considered under the scope of the procedure. Considering the above, wherever a variation of the conditions of the marketing authorization is deemed necessary as a result of a PSUSA procedure, all MAHs of the same active substance are to implement the applicable amendments. These variations include changes to the SmPC and PIL, among others.

Another relevant fact may be represented by RMP assessments, which may lead to further actions to be implemented by MAHs, e.g. the provision of additional information in order to justify the inclusion/exclusion of a safety concern or the adoption of precise routine /additional risk minimisation measures. Further to this, in future versions of the RMP prepared after the initial version, the MAH should explain how the effectiveness of the previously proposed risk minimization measures is to be measured and assessed. The risk minimization measures should have been implemented after approval of the RMP, the failure of which could result in a critical finding during an inspection. Measures detailed in the RMP should be monitored by the MAH.

On the other hand, legislation regarding safety reports is becoming more and more stringent. The GVP Module V, which includes RMP- related responsibilities is currently being revised. As a consequence, the safety concerns initially chosen should be revised during renewal of the marketing authorization and at the time of submission of the first PBRER after renewal. There is an emphasis on the fact that each identified safety concern should be clearly supported by scientific data and that each change in the classification of a safety concern (e.g. changing from a potential risk to an identified risk) should be properly justified. The pharmaceutical form is also to be taken into account, as excipients may play an important role in risk analysis, being specifically related to a certain safety concern.

Therefore, safety report preparation cannot constitute a mere administrative issue, based on inclusion of safety data with tidious line listings and poor analysis. Regulatory requirements regarding these types of reports should be correctly understood and assimilated, as well as the standards for the assessment of different European regulatory agencies/PRAC etc. Although a certain need for procedural harmonisation is perceived at the level of European authorities in this respect, there is a tendency for a common approach leading towards a high level of analysis of all available safety information.

In this sense, in order to provide for an adequate preparation of PBRERs, RMPs and ACOs there is a need for a preliminary analysis of the current/up-to-date safety information on the active substance/product arising from different sources:

  • Number of cases detected during the period of the report and cumulatively. The case review should not be limited to internal cases only, but it should also rely on other international databases, such as Vigibase, FAERS, or Eudravigilance
  • Safety signals published by different regulatory agencies including those published by the FDA (although AEMPS advises to first take into account those cases detected at European level). Internal signals should also be considered and discussed in the report.
  • Safety concerns (identified/potential risks and missing information) displayed within RMP Summaries or published by the EMA/HMA or different European agencies. It is important to note that all medicines have safety concerns, even though they might appear safe
  • Safety variations to the SmPC
  • Scientific publications, clinical studies or post-authorisation studies
  • Potential medication errors, cases of abuse, misuse etc occurring with the product or different products with the same active substance
  • Other aspects: assessment of the environmental risk of the product, new preclinical and toxicological studies, possible toxicological risk of the excipients, occupational exposure, in silico prediction models for the molecule or the excipients e.g. in cases of hypersensitivity, off-label use, risk factors, counterfeit etc

Once the preliminary data analysis is done, the following steps would apply:

  • Applicable safety concerns should be determined and classified into identified, potential risks or missing information. In order to classify the safety concerns, one should be aware of their source, meaning if they arise from preclinical/clinical studies or due to post-authorisation safety signals
  • Based on the above, the safety concerns should be characterized, including information about incidence, prevalence, mechanism of action, impact on the individual or public health impact etc
  • Decision should be made regarding the need for applicable measures of risk prevention; it should be considered whether routine pharmacovigilance activities are sufficient or there is a need to call upon additional activities. It may be necessary to update the Company´s CCSI/CCDS, as well as the product information, or distribute a DHPC/educational programme for patients and healthcare professionals.

The above mentioned steps are to be taken into account during preparation of both PBRERs and RMPs, since safety concerns need to be included in both types of reports. The same approach applies to ACOs and DSURs, although these reports have not been mentioned in the present article, as the DSUR cross-refers to the RMP in those cases where the product subjected to study is already on the market.

Ultimately, in the context of an increasing authority demand of harmonization of data coming from different sources, the complexity of safety reports has markedly evolved. This calls for a permanent update and a higher knowledge/expertise. In order to comply with regulatory exigency, there is a need for a multidisciplinary group of pharmacovigilance experts, including physicians, epidemiologists and toxicologists, among others, to be involved in the analysis of safety data and be able to comply with health authority requirements in a timely and effective manner.


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