Pharmacovigilance and Drug Safety

Pharmacovigilance and Drug Safety for the UK and Europe.

ICSRs: Definition, Features and Pharmacovigilance Services’ Roles (Part Two)

Individual Case Safety Reports (ICSRs) are vital drug safety documents required by EU pharmacovigilance law for each and every medicine or medicinal product a Marketing Authorisation would apply to.  In the first part of our overview of we discussed their definition and key formatting required by regulators. There was also a brief mention of the roles external pharmacovigilance services often undertake for small to medium pharmaceutical companies in relation to ICSRs. In the second and final part, we will examine the type of key content the regulators require, and again touch upon services often used by small to medium sized Marketing Authorisation Holders.

In particular, Volume 9a of The Rules Governing Medicinal Products in the European Union [1] makes reference to compliance with ICH E2A by ensuring the ICSR contains a “case narrative”, meaning a comprehensive and complete medical description of the case. This should include [2]:

  • Patient characteristics
  • Diagnosis
  • Therapy Details
  • Medical History
  • Narrative of Clinical events
  • Known adverse reactions alongside the relevant outcome
  • Results of laboratory tests along with the normal ranges
  • “any other information that refutes or confirms an adverse reaction” [2]

As well as inclusion of component items, the report must follow the formatting guidelines as a matter of obligation rather than the regulators preference. Volume 9a is quite clear that this may require some of the information stipulated to be repeated [2]. The format must also apply when new information is added for follow-up reporting, which should be clearly delineated from the original case narrative.  Except to describe results of standard tests, abbreviations are to be avoided [2].

Pharmaceutical companies clearly have complex legal obligations in this area of drug safety monitoring. Many choose to outsource the compilation of ICSRs to external pharmacovigilance services providers for this very reason. Whilst there is a provision for times when information is not available in some circumstances, incorrectly submitted ICSRs are to be avoided at all costs. Many external providers offer a ‘complete’ service, processing the necessary data into the final format for compliant electronic submission. This can be of particular value to small to medium sized companies where it may sometimes be the case that not all available staff have current training and experience in the exacting requirements for both ICSR format and content.

References:

  1. Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use. 2011. Part III, p.159-171 [ONLINE] Available at: http://ec.europa.eu/health/files/eudralex/vol-9/pdf/vol9a_09-2008_en.pdf. [Accessed 22 January 2011].
  2. Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use. 2011. Part III, Article 5.1, p. 164. [ONLINE] Available at: http://ec.europa.eu/health/files/eudralex/vol-9/pdf/vol9a_09-2008_en.pdf. [Accessed 22 January 2011].

Pharmacovigilance spontaneous reporting

Spontaneous reporting

This is the reporting by healthcare professionals (and in some countries, patients, relatives and others) “spontaneously” of their suspicion of an adverse reaction having occurred. The reporting might be directly to the company marketing the product, or it could be made to the regulatory authority. If there has been spontaneous reporting of a suspected ADR to a pharmaceutical company (including reporting to any employee, such as sales representatives or to contractors) there are legal obligations on the company to report serious reactions within a specified time frame to the regulatory authority (“expedited reporting). This takes place to the authorities in that country where the report was received and possibly to other regulatory authorities also. For non-serious reactions, reports usually have to be included in periodic safety update reports (see below).

In addition, the pharmaceutical company has to identify reports of adverse reactions published in the medical and scientific literature (by a process of weekly “literature screening”) and cases must be reported by the company in a similar way to the regulatory authorities.

The authorities in turn are required to report to each company anonymised information on the serious adverse reactions that they have received in relation to that company’s marketed products. There are also requirements for companies to report spontaneous cases of serious adverse reactions that they have received from certain regulatory authorities to their own authorities. There are mechanisms in place to identify and remove duplicate reports.

All these cases – ‘Individual Case Safety Reports’ (ICSRs) – are entered on the company’s safety database and on the regulatory authority’s safety database. They are examined individually and in the aggregate for a product in order to identify clusters of reports that could represent a signal of a previously unknown adverse reaction or drug interaction or some change in the character of a known adverse reaction. It may also be possible to recognise a new risk factor for a reaction to a product, such as a sub-group of patients at particular risk.

The main limitation of spontaneous reporting schemes is that there is under-reporting of adverse reactions, as in most countries the process for the initial reporter (i.e. the healthcare professional) is voluntary and unpaid. However, their main purpose is not the quantification of the frequency of adverse reactions, but the identification of signals.

In addition to the national regulatory agency databases of spontaneous reports and the company databases, there are two over-arching international databases. The EMEA maintains the EUDRAVIGILANCE safety database, including ICSRs received from all companies with products marketed in the European Economic Area, reports received by the national regulatory agencies in the EEA, and serious cases from clinical trials. This database is linked electronically to the national regulatory agency databases and exchanges data with them and with the company databases electronically.

In addition, the World Health Organization operates a global scheme involving national collaborating centres (most of the national regulatory agencies worldwide) and a coordinating centre in Sweden – the Uppsala Monitoring Centre (UMC). The regulatory authorities send the UMC all serious adverse reaction reports that they have received. The UMC database (“Vigibase”) is the only database in the world that includes all the regulatory authority and company ADR reports. The UMC has a panel of independent experts who review the data for signals of new adverse reactions. Aggregate data from Vigibase are made available to pharmaceutical companies for purchase.

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