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In our last posting we discussed problems in quality management systems found during audits and inspections.  In this posting we want to discuss problems seen during inspections regarding the processing of individual case safety reports (ICSRs).

Health agencies, in particular the FDA and the EMA/member states, have detailed requirements on how to process individual case safety reports.  This includes SUSARs and serious adverse events (SAEs).  In EU, this is detailed in module VI of the Guidelines on Good Pharmacovigilance Practices: Management and Reporting of Adverse Reactions to Medicinal Products. See: https://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129135.pdf

In a nutshell the requirements from this Module are:

“Competent authorities and marketing authorisation holders should take appropriate measures in order to collect and collate all reports of suspected adverse reactions associated with medicinal products for human use originating from unsolicited or solicited sources.

For this purpose, a pharmacovigilance system should be developed to allow the acquisition of sufficient information for the scientific evaluation of those reports.

The system should be designed so that it helps to ensure that the collected reports are authentic, legible, accurate, consistent, verifiable and as complete as possible for their clinical assessment.

All notifications that contain pharmacovigilance data should be recorded and archived in compliance with the applicable data protection requirements. The system should also be structured in a way that allows for reports of suspected adverse reactions to be validated in a timely manner and exchanged between competent authorities and marketing authorization holders within the legal reporting time frame.”

In the United States, the Code of Federal Regulations (21CFR314.80 and elsewhere) specifies in less detail the requirements for clinical trial and post marketing serious adverse experiences.

“Each applicant…shall promptly review all adverse drug experience information obtained or otherwise received by the applicant from any source, foreign or domestic, including information derived from commercial marketing experience, postmarketing clinical investigations, postmarketing epidemiological/surveillance studies, reports in the scientific literature, and unpublished scientific papers… shall also develop written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences to FDA.

The applicant shall report each adverse drug experience that is both serious and unexpected, whether foreign or domestic, as soon as possible but in no case later than 15 calendar days of initial receipt of the information by the applicant.

The applicant shall promptly investigate all adverse drug experiences that are the subject of these postmarketing 15-day Alert reports and shall submit follow-up reports within 15 calendar days of receipt of new information or as requested by FDA. If additional information is not obtainable, records should be maintained of the unsuccessful steps taken to seek additional information.”

During a governmental or third party inspection the timeliness of reporting of expedited reports is one of the most common areas that inspectors examine.  That is, the inspectors will request a listing of on-time and late expedited reports submitted to them.  Usually the inspector will walk in with a list of such late reports and will ask to see the list maintained by the company in order to compare them – they had better agree.  Thus, it is critically important for the company to track expedited reporting to the FDA, EMA and all other health authorities that must receive such reports.  This listing will be one of the first things that the inspector will request during an audit.  If the company does not routinely track such listings they will then have to create a listing ad hoc.  If the company is not rapidly able to produce such a list this will likely be cited by the inspectors in their report.

Another routine part of the inspection involves the review of the company’s procedural documents, including work instructions, SOP’s, manuals, guidelines and even  unofficial “cheat sheets”.  Of course, the company must have procedural documents in place which cover, both at a high level and detailed level, the processing of serious adverse events.  These SOPs will be reviewed by the inspectors and two comparisons will be made.  The first will be an examination of the procedural documents against the laws and regulations that are in effect to ensure that the company’s procedures comply with these requirements.  The second will be an examination of the procedural documents against the actual workflow and case handling done by the drug safety/pharmacovigilance group.   The inspectors may actually visit the drug safety department, interview the staff, and follow a case or cases through the process from start to finish. If there are significant deviations or errors in the case processing there will also be a citation by the inspectors.  This visit can be quite stressful to the staff processing the cases.

In theory the processing of a serious adverse event should be relatively straightforward.  In practice however there are many different kinds of SAEs in both the clinical trial and post marketing areas.  In the clinical trial setting, cases may come from individual sites either electronically or by paper, from CROs, from other companies or business partners and elsewhere.

In the post marketing area, cases may come from many sources: medical information, telephone call centers, subsidiaries and business partners, the FDA and other health authorities, healthcare professionals, patients, lawyers, social media, poison control centers and other Internet sources and even lawyers.  This means that in practice there will be many variations on the actual procedure(s) covering the handling of serious adverse events.  Many one-offs will occur to accommodate the receipt and transmission of cases to governments, CROs, business partners and others both internal and external to the company.  Unless there is a mechanism built into the procedural documents allowing for such one-offs and waivers and exceptions, there is a possibility that the inspector will cite deviations from the SOP in the final report.  This may be the case even if the cases are properly handled and are reported on time.

Since SAE reporting is such a critical part of drug safety and pharmacovigilance, this will be a major focus of almost all inspections and audits.  As a consequence, the company must ensure that this processing is impeccably done.  Alas, frequently it is not impeccably done and frequently is, in fact, poorly done.

Although the FDA does not publish data on the findings in their inspections, the UK MHRA does publish such information on their website.  See https://www.mhra.gov.uk/home/groups/is-insp/documents/websiteresources/con175416.pdf for the findings during period of April 2011 to March 2012.

The findings can be summarized as follows:

Critical findings: 37% involved reference safety information (labeling, investigator brochures, CCSI etc.) which are used for determination of expectedness amongst other things; 11% spontaneous case processing issues, 5% clinical trial.  Thus case processing and related issues covered more than half the critical findings.

Major findings: 19% spontaneous case processing, 12% reference safety information, clinical trial PV 4%. Here over one third of the major citations were for case processing issues.

Minor/Other findings: 13% spontaneous case processing, 7% reference safety information, 3% clinical trial PV, 1% literature searches. Here nearly a quarter of the findings were related to case processing.

In addition, MHRA has a slide presentation that includes examples of findings (https://www.mhra.gov.uk/home/groups/is-insp/documents/websiteresources/con015700.ppt):

From the many audits I have performed, some noteworthy findings include:


Bottom line: This is a high risk area of drug safety and PV that must be done correctly all the time.  It is “low hanging fruit” for inspectors and errors and problems are usually easily picked up.  The company must ensure that it is done correctly.


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