CIOMS I - Expedited Reporting of Individual ADRs

CIOMS I - EXPEDITED REPORTING OF INDIVIDUAL ADRS

RATIONALE

It is well established that continuous ADR surveil-lance is critical to assuring the safety of approved drugs in clinical practice. Prior to 1984, regulatory authorities restricted their requirements for the receipt of individual ADRs to domestic reports only. However, between 1984 and 1987 the United King-dom, France, the United States, Italy and Germany introduced regulatory requirements for the submis-sion of foreign reports. That is, manufacturers were required to report ADRs occurring in one coun-try to the regulatory authorities in other countries where the drug was also marketed. As each regulatory authority had different requirements regarding time frames, formats and definitions, and were concerned about different types of ADRs, manufacturers were confronted with many problems.

The purpose of the CIOMS I working group was, therefore, to develop an internationally acceptable reporting method so that manufacturers could report post-marketing ADRs rapidly, efficiently and effec-tively to regulators.

PROCESS

On the understanding that the CIOMS members would modify their own international reporting procedures accordingly, the working group set out to define what constituted a reportable individual reaction, the elements of a report and the procedure and format for submitting individual reports. As most reporting depends on legal requirements, it became clear that the regulators needed to reach consensus. When this had been achieved a pilot test was undertaken to demon-strate the feasibility and utility of standardised report-ing. The effort was geared towards the international exchange of post-approval reports of suspected, unex-pected (unlabelled) serious ADRs. The manufacturers in the working group reported local cases according to the domestic requirements in that country and then entered the cases on to single common forms and submitted them to the other regulatory authorities represented on the CIOMS working group. Reports received from a country outside the participating six were entered on a single report and submitted to all six regulators.

The advantages of standardisation to the manufac-turers were that it avoided a multitude of different requirements from different regulators, eased commu-nication of reports between international corpo-rate affiliates, and lessened regulatory ambiguities. From the regulatory perspective, standardisation could improve standards and reporting compliance by manu-facturers and facilitate the exchange of information between regulators.

RECOMMENDATIONS

The CIOMS recommendations for the case criteria for expedited reporting of a foreign ADR were defined as follows:

·    serious;

·    medically substantiated;

·    unlabelled (unexpected);

·    suspected to be product-related;

·    occurring with a marketed product; and

·    in an identifiable patient.

Such reports were to be submitted in English on the prescribed CIOMS form within 15 working days of receipt. The subsequent amendments to these recom-mendations are mentioned later in this chapter.

CIOMS reports were, and still are, restricted to ADRs and not ‘events’. This implies that a physician or other professional healthcare worker has judged it a reasonable possibility that the observed clinical occurrence was caused by the drug. In addition, it was emphasised that manufacturers should not select cases for reporting based on their own causality assess-ment. All spontaneous reports of serious unlabelled reactions made by a medical professional should be considered as CIOMS reports. Submission of such a report does not necessarily constitute acceptance of causality by the manufacturer.

As product labelling differs from country to coun-try it was suggested that manufacturers should review all serious reports and then decide on a country-by-country basis, either centrally or at affiliate level, whether the reported ADR is labelled or not. It was also agreed that there should be a minimum of four pieces of information before a report is considered to have reached the standard threshold for reporting. These are an identifiable report source; a patient (even if not precisely identified by name and date of birth); a suspect drug; and a suspect reaction.

CIOMS reports should be submitted to regulatory authorities as soon as they are received and in no case later than 15 working days after receipt. The 15-day period begins as soon as a company, or any employee in any part or affiliate of a company, receives the report. The CIOMS I report was published in 1990 (CIOMS, 1990).

INCORPORATION IN REGULATION

Many of the CIOMS I criteria for expedited reporting were incorporated into ICH E2A, Clinical Safety Data Management: Definitions and Standards for Expe-dited Reporting, which reached final agreement in October 1994 (ICH, 1994). This document expanded on the CIOMS I definitions and terminology. In particular, it introduced the concept of the ‘medi-cal’ seriousness category that recognised that events may not be immediately life-threatening, or result in death or hospitalisation, but may jeopardise the patient or require intervention to prevent such outcomes. Although ICH E2A focused on pre-approval clini-cal trials, its definitions and other criteria have been applied by regulators to expedited reporting of both pre- and post-marketed products. The reporting time frame was reduced from 15 working days to 15 calen-dar days, with 7 days for the initial report on fatal or life-threatening suspected adverse reaction cases from clinical trials. More recently, ICH E2D, Post-approval Safety Data Management: Definitions and Standards for Expedited Reporting, which reached step 4 agreement in November 2003 (ICH, 2003a), formally applied the ICH E2A concepts to the post-approval phase of the product life cycle as well as incorporating many of the good case management practices proposed by CIOMS Working Group V.