Cobert's Manual Of Drug Safety And Pharmacovigilance (Third Edition). William Gregory
a safety team or department equipped to handle spontaneous and clinical trial AEs (as required) or to outsource this function. If the company is based solely in one country, the department may be relatively small and uncomplicated. In the simple setting, AEs are reported only to the HA in that country. If, however, AEs can come from (or need to go to) subsidiaries or affiliates in other countries or from business partners with which the company has contractual relationships, the complexity of the needs and requirements grows enormously. If a single-country company is doing clinical trials outside its borders, it must be able to report AEs and handle all other safety and regulatory matters with other countries’ health agencies.
Different languages, time zones, ever-changing government requirements, reporting due dates, documents and formats, electronic transmission, and so forth must be taken into account. Standard operating procedures, Medical Dictionary for Regulatory Activities (Med-DRA®), and training systems must be in place. An electronic safety database must be built (an enormous task) or purchased or leased (still a complex and costly endeavor). Risk evaluation and management/mitigation systems must be in place.
Healthcare personnel, including physicians, nurses, pharmacists, and support staff, must be hired. The business relationships with other concerned departments within the company, such as regulatory affairs, sales and marketing, legal, clinical research, and others, must be established. In other words, creating a safety department is a complex and expensive endeavor that must be done absolutely correctly.
After an AE report is received by the safety department, it must be entered or uploaded into the safety database, which is used for storage, retrieval, analysis, and reporting data. Although such transactional databases may start out in small companies as spreadsheets with the data typed onto paper forms, most companies respond to this need by purchasing an expensive (up to hundreds of thousands or millions of dollars, depending on the number and location of users and information technology, IT, maintenance staff) dedicated safety database. In addition to a transactional database, some large organizations have developed data warehouses to organize and store large amounts of safety data. Much of this is now out-sourced and stored in the cloud. They create complex departments with tight standard operating procedures to ensure that the company remains in full compliance with all laws, regulations, and guidelines and will withstand inspections and audits from the FDA, EMA, and other HAs, business partners, outside auditing companies and others.
There is usually a senior executive (typically a vice president for drug safety), who is also an experienced physician, to oversee the entire group. Within the drug safety group, there are multiple functions to handle. Depending on the size of the company, separate people or groups may handle each of the categories below. In small companies, all functions may fall on one or two people or are outsourced.
To support the drug safety group, there is often a dedicated informatics (IT/computer) group, a signaling/pharmacovigilance group, a training group, a standard operating procedure (quality) group, an epidemiology group, a risk management group, and more. These groups may be within or separate from the drug safety department. Sometimes a medical report writing group also falls under drug safety to prepare aggregate reports, such as Periodic Safety Update Reports (PSURs, PBRERs), annual reports, NDA periodic reports, IND annual reports, and so on.
Similar groups often exist within HAs. Some authorities (FDA, MHRA, Health Canada, ANSM, TGA, EMA, and others) receive reports directly from healthcare professionals and consumers. The agencies may form departments similar to those in companies to receive, enter, and evaluate data and make medical judgments on the cases. The volumes in companies may run to tens or even hundreds of thousands of cases per year. The FDA received 1,779,428 post-marketing ICSRs in 2017, of which 926,304 (52%) were expedited. There were 59,044 (3%) received directly from the healthcare community or consumers (refer to the FDA website, www.fda.gov). These reports (redacted) are available over the Internet using a public dashboard.
This is a large task and is performed by most health agencies throughout the world. Because serious cases tend to be reported to all health agencies, there is enormous duplication of effort in creating databases in each agency and company. In practice, only HAs in large countries with advanced pharmacovigilance practices are able to maintain relatively complete databases and conduct meaningful signal analyses.
There are four major databases with large but not total overlap for post-marketing AEs: the FDA in the United States, the EudraVigilance database in the EMA (London/Amsterdam), the MHRA database (UK), and the Vigibase at the Uppsala Monitoring Centre in Sweden. There are others as well.
Clinical trial AEs tend to be more scattered and far less transparent than AEs for marketed products because most of the information on drugs not yet on the market is proprietary and guarded as secret information by both companies and HAs. In many countries, clinical trials by pharmaceutical companies, universities, consortia, health agencies, and others must be entered into web-based registries. The largest is the clinical trial website maintained by the US National Library of Medicine at the National Institutes of Health (www.clinicaltrials.gov), with more than 276,000 trials from more than 204 countries registered as of the middle of 2018. The data, however, are variable, and often there is little or no safety data and the data are not up to date. Various countries, including the US, have mandated regular posting and updating of “Basic Results” for safety (and efficacy) data. When the database first went into production in 2000, trial listings and data were incomplete, but this has gradually improved over the ensuing years.
The mission of the drug safety group must be clearly defined and made known to all employees of the company, in particular to senior management, marketing and sales. It is also good policy to let the general public know of the company’s or health agency’s commitment to patient safety. For example, see FDA’s Sentinel Initiative Mission Statement. Companies also explain their safety functions to the public, see for example, Pfizer (www.pfizer.com), Merck (www.merck.com), and Novartis (www.novartis.com).
The mission of the drug safety group, whether in a company or a health agency, is first and foremost to protect the public health by maintaining accurate, up-to-date, and complete safety information. Medical analyses must be done with patient safety in mind, not “product and sales protection”. It is argued that the best product and sales protection comes from ensuring that full, unbiased, scientific, and complete safety information is available to all stakeholders: patients, medical professionals, health agencies, and the company in a form that can be understood by the particular target audience. Secondary goals within a company’s safety department relate to such corporate functions as consultation within the company on safety issues, legal matters including litigation, response to patient and healthcare professional queries, training, and supporting the sales force.
There is often enormous pressure on the