the world must be identified and the data extracted in a valid and consistent way. This is a very difficult task since data collection is not yet standardized and there is little true interoperability across IT systems. It is also important to remember that safety generally represents a secondary use of these datasets. Multiple efforts (both nationally and globally) are under way to standardize and normalize data so that they are easily collected, databased, retrieved, and analyzed in a useful, valid, and rapid manner. If every encounter a patient has with the healthcare system is digitalized, we should be able to retrieve excellent safety data rapidly. This, however, will take years to achieve on a national level, let alone a global level. When this does occur, the spontaneous reporting system may then decrease in importance. The fundamental system now in place to discover AEs with marketed products remains the spontaneous reporting system. This system is used, in one form or another, in many countries around the world; examples include the US, Canada, China, the EU, Japan, South Korea, Australia, New Zealand, South Africa, and many other countries around the world. The WHO and the Uppsala Monitoring Centre actively work with more than 150 countries to set up pharmacovigilance (PV) systems and increase capacity.
Another potential issue slowing down new mechanisms of data analysis is the increased data protection requirements being put in place around the world (particularly in the EU). We may need patient consent in one form or another to obtain their data.
The principles of the system are simple. All healthcare professionals (and consumers in most countries, including the US, the EU, and Canada) are encouraged to spontaneously report AEs to either the manufacturer or the governmental healthcare agency or a third party. Standardized forms have been developed (the MedWatch form in the United States, the CIOMS I form elsewhere) specifically for this purpose and are available online, in publications (e.g., the Physicians’ Desk Reference in the United States), as apps on the iPhone and other smartphones, and elsewhere. The form can be folded up and mailed (postage-free), faxed, or filled in online and uploaded to the healthcare agencies. Phone, on-line reports and faxes to the manufacturer and most health agencies are also possible.
The forms are one or two pages in length and include the expected information requests: patient demographics; the AEs that occurred; medical history; drugs taken, including the one or more drugs suspected of causing the AE in question (and the indication for which prescribed); comedications; comorbidities; dose, timing, and route of administration; a narrative summary of the case; and reporter information. In most cases, confidentiality is guaranteed by law, regulation, or policy regarding the patient’s identity and the reporter’s identity. In online systems, the “forms” may be intelligent in the sense that the context determines which questions are asked. For example, if the patient is a male, the pregnancy questions will be eliminated from the online form.
In the US, the United Kingdom, and other countries, information submitted spontaneously to the health authority is available for free or for a small fee to anyone in the public under Freedom of Information Acts. The cases are redacted before being released by the health agency to avoid identifying the patient or reporter. In the US, in 2017 over 60,500 individual reports were sent directly to FDA (3% of the total 1,815,000 reports received) with the remaining approximately 1,754,500 (97%) to the manufacturers, who then forward them to the FDA. Most reporters tend to be pharmacists. Redacted case report data held by FDA in the FAERS database are publically available over the Internet by using an FDA-supplied public dashboard.
In 2017, the FDA’s Office of Surveillance and Epidemiology noted the breakdown of the sources of reports was as follows:
The requirements for AE reporting have largely been standardized through the International Council for Harmonization (ICH). Reporting for healthcare professionals (and consumers in most places) is usually voluntary and is highly encouraged by agencies, although there is some skepticism about the utility and value of consumer reports, particularly those for OTC products and those not validated by a healthcare professional.
There is no time frame for reporting by a consumer or healthcare professional after the occurrence of the AE, but obviously rapid reporting is preferred for public health reasons; in some cases, it may save lives. For manufacturers, reporting is obligatory in almost all jurisdictions. Any AE that comes into a company, whether through sales representatives, phone calls, Internet and e-mail, literature reports (which must be actively searched for by the company), patient support programs, or other media must be rapidly forwarded to the Drug Safety Unit and reviewed by qualified medical personnel.
For marketed drugs in most countries, all serious AEs that are unexpected (i.e., that do not appear in the regulator-approved product labeling) must be reported to the health authority by the company within 15 calendar days. In the US, most of the remaining serious and non-serious cases must be reported to the FDA in NDA periodic reports (PADERs) or PSURs/PBRERs (quarterly for newer drugs and yearly for older drugs). In some countries aggregate periodic reporting is done as PSURs/ PBRERs, which are prepared according to a schedule, depending on the age of the drug and the country receiving the report. In the EU, PSURs (in PBRER format) no longer have a standard time interval for submission. Periodicity is established by regulators. A regulator may also request a periodic report at any time.
These reports contain line listings of various cuts of the data as well as medical analyses prepared by the company’s medical team, usually headed by a physician. They look at AEs that are expected and unexpected and indicate which need to be added to the drug labeling as new ADRs, warnings, precautions, and so forth, and which AEs/ADRs need to be watched with heightened vigilance. These reports are then scrutinized by the regulatory agencies who may agree or disagree with the company analysis and who decide on changes to the drug labeling, conditions of marketing of the drug, and so forth. There is usually dialogue between the health agency and the company before an action is taken, though health authorities are empowered to act immediately and unilaterally if the public health is at risk. At the health agency, the data are then entered into a database and reviewed. Analysis of individual AE cases and of aggregates of AE cases is done.
Many countries send extracts from their spontaneous databases of local AE reports to the Uppsala Monitoring Centre (UMC) in Sweden. At the end of 2017, there were 127 full and 29 associate member countries most of whom supply AE reports to the Center, which had more than 20,000,000 cases in December 2017. About half are from the United States, 10% from Canada, and 5% each from Germany, France, and Australia. Further information is available from the UMC describing the details of the database and the international monitoring system on its website (www.who-umc.org).
Extracts of the database are available for a fee from the UMC or from private vendors who have access to the database. Specifically regarding spontaneous reports, a company must set up a failure-proof system to receive, process, report, and analyze AEs. Time is of the essence, because some of the reports must be sent to the health authorities within 15 days. The clock for reporting starts counting down from the moment the first person anywhere in the company (or a partner, co-marketer, etc.) learns about a “valid” AE.
For phone reports, this means that any phone number in the company is a potential source of AE reports, and anyone who answers the phone in the company must be instructed what to do if an AE report comes into a place where it is not normally expected. A rapid and painless (to the caller) transfer system must be set up if the information is not immediately written down by the company employee first answering the call. No one wants to be kept on hold or to repeat the same story for the third or fourth time. No AE may be lost, so all efforts must be directed to the proper handling of the call. Because some AEs may need to be reported to one or more healthcare agencies within 15 days, time cannot be lost. The company must be ready to accept calls 24 hours a day, 7 days a week and in multiple languages if that is the normal custom in the country. Many companies do not maintain 24-hour coverage in their company, preferring to outsource this function to private companies (sometimes abroad, often in India). Many companies, even those maintaining