women to prevent morning sickness and was widely available for this use in Europe and was even sold OTC in Germany. Though never marketed in the US, thalidomide was used in the investigational setting in the US. By 1962, the terrible teratogenic (birth defect) aspect of the drug became known as babies were born, mostly in Europe, with severely deformed arms and legs (phocomelia).
In 1962, the Kefauver-Harris Amendment became law and introduced the modern era of drug regulation. Drug manufacturers now had to demonstrate to the FDA both safety and efficacy before marketing a new drug. In 1971, the National Drug Experience Reporting System was begun as was the publication of “The FDA Drug Bulletin” to alert physicians and pharmacists to drug issues. In 1985, the regulations on AE reporting for marketed drugs were strengthened, and new requirements for Investigational New Drug Applications (INDs) were introduced. Over the years, the FDA has had multiple reorganizations and alterations in its structure and function as the overseer of drug safety and efficacy in the US. The result is the complex system of AE collection, analysis, and reporting that we know today.
The regulations, laws, guidances, guidelines, and other relevant documents covering drug safety are detailed, arcane, and scattered throughout multiple places in the Code of Federal Regulations (CFR) for the US and in various venues for European Union (EU) and member state documents. The EU PV requirements are designed at the EMA level (Regulations, Directives, and Guidances) and then implemented in each EU country; nevertheless, some countries can be more (but never less) demanding. Most of the EU documents are updated fairly frequently. Most other countries in the world have their own set of local laws, regulations, and guidances (often available only in the local language).
Requirements in most countries are fairly similar in their intent of protecting patient safety (including subjects in clinical trials). Most local regulations require nearly all SAEs and some non-serious AEs to be reported quickly if there appears to be a potential impact on public health. The definitions of “serious” and “non-serious” AEs are more or less standardized, although there are nuances that apply in various jurisdictions.
More “routine” individual AEs are analyzed and reported at periodic intervals. Most countries also require some form of aggregate reporting of serious and non-serious AEs at periodic intervals (e.g., every 3 months, 6 months, yearly, every 3 years), depending upon whether the drug is in clinical trials or on the market and whether it is new or old. Although the rules are similar throughout the world, they are sufficiently different in detail (“the devil is in the details”) to be infuriating and well nigh impossible to track, categorize, and keep up to date without personnel in each country tracking such matters. The major documents for the US and the EU are listed below. Those with an asterisk should be read and digested by anyone doing drug safety for a living. The contents of these documents are topics of this book. In the US, FDA’s regulation-making authority derives from legislation passed by the US Congress and signed into law by the US President. Most of the FDA-directed legislation gives FDA broad ability to introduce regulations and to enforce the related requirements. The FDA regulations do not explicitly state that a department or group must exist to deal with drug safety. Rather, sponsor/applicant obligations are spelled out. A “sponsor” is responsible for clinical trials and an “applicant” is responsible for meeting requirements associated with a marketing application and in the post-marketing phase. To do this adequately, an organized system or department is necessary.
The EU regulations are more specific and require that a formal pharmacovigilance system be put in place and that it is fit-for-purpose: Good Pharmacovigilance Practices (GVPs) Module I — Pharmacovigilance systems and their quality systems. In addition, the EU regulations require an EU Qualified Person for Pharmacovigilance” (EU QPPV) be nominated by the pharmaceutical company: this EU QPPV ensures that the company meets its legal obligations for the safety monitoring of all registered products.
Drug safety in the US is covered under several sections of the Code of Federal Regulations (CFR). FDA regulations are consolidated in Title 21 of the CFR or 21 CFR (a searchable version of 21 CFR is available at www.regulations.gov).
21CFR312 covers INDs: 21CFR312.32 covers IND safety reports, including expedited 7- and 15-day reports. 21CFR33 covers IND annual reports. The NDA regulations for drugs are found in 21CFR314.80.
Updates to regulations are published in the Federal Register on a daily basis and are viewable (www.regulations.gov). Note that the consolidated CFR is only updated with the final FDA regulations from the daily Federal Register only once a year, on April 1st. The Food, Drug and Cosmetic Act is available at https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/FederalFoodDrugandCosmeticActFDCAct/default.htm.
A summary of safety documents for the EU can be found at the EudraVigilance website (www.eudravigilance.eu), the European Commission website (www.ec.europa.eu), and the EMA website (www.ema.europa.eu).
There are several major documents covering drug safety: EudraLex Volume 10 is for clinical trials (amended in 2019 with the implementation of Regulation (EU) No 536/2014). For post-marketing, the regulations have been completely reviewed in 2010–2012; the main documents are as follows:
There are several subsections devoted to drug safety also available at this website. “Volume 10 — Clinical Trials Guidelines” includes the following:
Pharmaceutical companies are obliged to capture AEs, analyze them, and report them to their health agency locally and to other health authorities, or to companies abroad for submission to their HAs if there are formal corporate arrangements for sales and trials outside the home country. Thus, a company needs to create or have full-time