outsource after-hours calls to poison control centers or private companies. Many companies also use this number (e.g., a toll-free number) for other functions, including product information, queries, and marketing.
Similarly, any e-mail or website or social media site in which an outsider can send a message or key in free text is a potential source of AEs. Many companies, much to their chagrin, receive complaints and AEs on job-posting websites, free sample websites, survey websites, smartphone apps, customer engagement programs, and so forth.
Sales representatives must also be aware that a physician, pharmacist, or other healthcare worker they call on may be the source of an AE. Even innocuous off-the-cuff remarks about a possible AE (“Oh, by the way one of my patients took your other drug XXXX and had a heart attack the next day”) made to a company representative constitute a report to the company that must be acted on. Even offhand remarks over the barbecue on a Sunday afternoon in which a neighbor casually relates an AE to a company employee must be reported to the drug safety department! Some pharma companies include a specific sentence in the employees contract which specifies that, should he/she be informed of an ADR with a company’s drug, he/she must report this information to the drug safety department. Most companies also have this noted in their SOPs and training materials.
Many companies have media services that review transcripts of newspapers, television shows, websites, blogs, and so forth, looking for anything about their products. Should AEs be noted, they must be sent to the safety department. There is no obligation to scan the web trawling for AEs, but anything found on a company-sponsored website or merely discovered in the course of surfing is a reportable AE.
Lawsuits often represent the point of entry of AEs. The legal department must be aware that they must also report the AE noted in the suit to the safety department usually within 48 hours.
Some people still write “snail mail” letters, and the company mail room or mail screeners must be aware that AEs received in the mail are to be sent to the drug safety group immediately (usually by PDF/e-mail or fax and not interoffice mail).
One of the more complex problems companies face is the phone call or letter that notes a product complaint (“the pill was the wrong color”), an AE (“and then I took it and had violent stomach pains”), and then requests restitution (“I want my money back now!”). These cases must be handled by three or more departments in the company: (1) the drug safety group to get details and report the AE, (2) the manufacturing or quality group to see why the pill was the wrong color, and (3) the marketing/sales group to refund (or not refund) the money. Companies must set up systems to handle this.
The United States reporting requirements for spontaneous reporting are found in 21CFR314.80. Serious, unlabeled (US Package Insert), spontaneous, and literature events, whether felt to be causally related or not, must be reported within 15 calendar days (plus day 0) when the four minimum validity criteria are met. Reports from FDA, either from the MedWatch to Manufacturer Program or FOI, do not have to be sent to FDA but may need to be sent to other HAs.
The EU regulations are far more complex in terms of sponsor and applicant reporting. Some go to the health authority at the national or provincial level and some go to a non-health-authority-designated agency. All cases should go to EudraVigilance. Reporting depends on whether the case comes from an EU member state or from outside the European Union. See the extensive descriptions in Good Pharmacovigilance Practice (GVP) module VI (Collection, management and submission of reports of suspected adverse reactions to medicinal products) at the EMA website (www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000345.jsp).
The GVP modules are updated from time to time; local updates from member states should also be tracked in case of changes in the requirements.
Many countries follow the ICH/CIOMS criteria for reporting valid cases (four criteria: suspect drug, AE, patient, reporter) from spontaneous sources. It is important to triage every case immediately. If it is a serious AE and unlabeled, most jurisdictions require reporting to the health authority within 15 calendar days of first awareness. Some countries have different requirements which often revolve around receiving all domestic SAEs (whether labeled or not) but only some (SAEs that are unlabeled) non-domestic cases. Some countries do not want any non-domestic cases. Some non-English speaking countries require cases to be in the local language, particularly domestic cases.
Australia: Interestingly, Australia only requires Australian SAEs to be reported within 15 calendar days, whether expected or not, using their “blue card” system (the official Australian system to capture AEs is akin to the US MedWatch program and the United Kingdom Yellow Card system) as of this writing. In addition to the “blue card” reporting form (electronic web-form and on paper), the Therapeutic Goods Administration (TGA) accepts E2B ICSRs. Non-serious Australian AEs should be reported as line listings in the PSUR. For post-marketing studies done in Australia, similarly, all SAEs are to be reported in 15 calendar days and the non-serious AEs at the end of the study. Non-Australian cases do not have to be reported. Rather “any significant safety issue or action which has arisen from any analysis of foreign reports, or which has been taken by a foreign regulatory agency, including the basis for such action” should be reported to the health authority (TGA) within 72 hours (www.tga.gov.au).
Canada: Health Canada requires all domestic reports of serious ARs and “unusual failure in efficacy for new drugs” be reported within 15 calendar days. Foreign unexpected serious adverse reactions must be reported in 15 calendar days.
There is now a transition by companies reporting serious AEs to health agencies from paper or fax reporting of paper forms (CIOMS I) to electronic reporting using a standardized electronic format and transmission known generically as “E2B transmissions” after the ICH document of that name. This reporting is either through the Internet (using an electronic gateway or direct entry online into the database). In theory, electronic case transmission of a case is the same to all agencies around the world and simplifies the multiple reporting obligations now in force from country to country. This has not turned out to be entirely the case, however, as various countries (notably the US, Japan, and China) want special or additional information and data in the electronic transmission. Further, the EMA has created a new paper form for output of E2B(R3) ICSRs. Note that most of the local customization relates to administrative detail and not the medical case.
There is also a trend toward reporting from standardized lists of drug names, medical and surgical history, AE codes, laboratory data, and demographic codes. This allows people to document AE cases in a standardized language and format that is easily translated by the computer into any other language. The only area proving resistant to this computerization is the medical narrative, where a case is summarized in prose in a few paragraphs such that the reader can get an understanding of what happened to the patient. Whether a computer-derived narrative (or no narrative at all) will prove to be as useful as a narrative prepared by a safety-trained healthcare professional remains to be seen. Harnessing artificial intelligence and machine learning may facilitate this.
Interestingly, English has become the international language of AE reporting. PSURs and E2B transmissions are written in English. Some countries require translation of some or