9. Literature reports

“Scientific & medical literature is a significant source of information for the monitoring of the safety profile and of the risk benefit balance of medicinal products, particularly in relation to the detection of new safety signals or emerging safety issues.”

Literature report is any adverse drug reactions reported in

1. Published abstracts or

2. Articles in medical/scientific journals

3. Unpublished manuscripts involving case reports

4. Important safety findings or clinical studies including posters, letters to the editors, and associated communication from scientific meetings.

Current regulatory guidance:

• Per the European Medicines Agency (EMA), MAHs are required to monitor local scientific and medical publications in countries where they have a marketing authorisation, irrespective of commercial status of products. 
• The US Food and Drug Administration (FDA) requires submission of reports of serious, unexpected adverse drug reactions (ADRs) described in the scientific literature for products with the same active moiety as products marketed in the US, even though excipient, dosage forms, strengths, routes of administration and indications may vary.
• The “literature” section of the periodic benefit– risk evaluation report (PBRER) requires a summary of new and significant safety findings for approved products, obtained from published peer-reviewed scientific literature or unpublished manuscripts during the reporting interval.
• EMA guidelines also require inclusion of relevant applicable safety information for other active substances of the same class as the marketed drug. Consequently, any potentially relevant event identified in the literature may be considered an emerging safety issue requiring prompt immediate analysis and, if needed, corrective and preventive action.
• Marketing authorisation holders are therefore expected to maintain awareness of possible publications through a systematic literature review of widely used reference databases (e.g. Medline, Excerpta Medica or Embase, Eudravigilance) no less frequently than once a week.

Summary of MLM guidelines:

• MAHs should perform a systematic literature review of widely used reference databases no less frequently than once a week, unless the active substances of their products are present in the list of publications monitored by the European Medicines Agency (EMA) pursuant to Article 27 of Regulation (EC) No 726/2004. 
• However, the MAHs need to continue to monitor all other medical literature not covered by the literature reference databases applied for the service by the EMA.
• The MLM services of EMA started on September 1st, 2015. The full monitoring list contains more than 400 active substance groups. The EMA is responsible for monitoring selected medical literature and for entering identified reports of suspected adverse reactions in EudraVigilance.
• The clock for reporting starts (Day 0) with awareness of a publication containing the minimum information for reporting. 
• All the suspect adverse reactions found by the EMA in the listed medical literature, both serious (EU and non-EU) and non-serious (EU only), are not transmitted to MAHs, indeed they are transmitted to EudraVigilance and National Competent Authorities (NCAs) and made available to MAHs via EudraVigilance. 
• The MAHs, however, should download and include these ICSRs in their safety database. They can provide an assessment of the case, describe a disagreement with, and/or alternatives to the diagnoses given by the primary source and/or indicate the degree of suspected relatedness of each medicinal product to the adverse reactions.
• Where the MAH identifies a literature case entered by EMA to be a duplicate of the company’s individual case, which was previously submitted to EudraVigilance, there is a need to send a follow-up with the world-wide unique case identifier to EudraVigilance. 
• In addition to the activities above, MAHs should also monitor the scientific and medical publications in local journals in countries where medicinal products have a MA.
• Reports of suspected adverse reactions from the scientific and medical literature, including relevant published abstracts from meetings and draft manuscripts, should be reviewed and assessed by MAHs to identify and record possible ICSRs.

How the companies search relevant cases in database:

• Search criteria for adverse event/adverse reactions terms:
  • It is important that, in addition to searching for adverse events/reactions, the search is constructed to retrieve any special situation reports (e.g. pregnancy and breastfeeding, overdose, abuse, misuse, medication errors, occupational exposure) and, if relevant, use in specific patient populations (e.g. paediatrics). 
  • The search strategy should also be able to retrieve reports of off-label and compassionate use. 
• Search criteria for medicinal products:
  • As a general rule, searches should be performed using the active substance. 
  • For combination products, all active substances need to be included in the search strategy. 
  • Searches should not be routinely conducted that exclude unbranded products. 
  • It is common for authors of literature articles to refer to a generic medicinal product and the MAH should assume ownership of the product if it can not, with absolute certainty, confirm that the product is not its own. 
  • In addition, where the formulation is not specified, ownership of the product should be assumed.
  • For some regulators, reports should not be excluded based on the formulation. 
  • Articles referring to a class of drugs that describe a class effect, whilst not appropriate for ICSRs may be relevant for inclusion in periodic reports. 

Safety information: Below safety information is collected from literature reports.

• New, unexpected serious and non-serious ICSR reports with a reasonable causal association with the product.
• Pregnancy outcomes (including termination) with no adverse outcomes
• Use in paediatric populations
• Compassionate supply, named patient use
• Lack of efficacy
• Asymptomatic overdose, abuse or misuse
• Medication error where no adverse events occurred
• Important non-clinical safety results

Processing of Confirmed ICSRs

1. For literature reports of confirmed cases which can generate ICSRs, a full text of the citation is obtained and, if not in English, translated into English though it is not specified how/who does this or how long this takes).

2. The article is reviewed and the number of valid ICSRs is determined and seriousness/non-seriousness is noted.

3. An ICSR is then created along with a case narrative for serious cases. No narrative is prepared for non-serious ICSRs.

4. Causality assessment and relatedness also performed.

A regulatory reporting form with relevant medical information should be provided for each identifiable patient. The regulatory reporting time clock starts as soon as the MAH has knowledge that the case meets minimum criteria for reportability.

Examples of new events identified through literature review:

Nifedipine and Fatal Aplastic Anemia (1998): Article described a case- control study linking six cases of fatal aplastic anemia with nifedipine Report identified a Type B ADR (bizarre or idiosyncratic, dose independent and unpredictable reaction) Reference: Laporte JR, Ibanez L, Ballarin E, Perez E, Vidal X. Fatal Aplastic anemia associated with nifedipine. Lancet. 1998;352: 619-20

Tamsulosin and ‘Floppy Iris Syndrome” (2005): 15 cases were described in the literature in April, 2005 At the time of publication, none had been reported to the Regulatory Authorities! Reference: Chang DF, Campbell JR,. Intraoperative floppy iris syndrome associated with tamsulosin. J Cataract Refract Surg. 2005;3: 664-73