Cobert's Manual Of Drug Safety And Pharmacovigilance (Third Edition). William Gregory
Intervals
Most studies are based on samples, not entire populations. The confidence interval reflects the resulting uncertainty.
Based on the sample of the population, a particular result is obtained, e.g., 15% of the users of drug A had serious AEs. Because we did not study the whole population, we cannot be totally sure that the 15% figure represents the true value for the whole population rather than by chance for the smaller sample studied. The confidence interval represents the range of the correct or true value for the whole population. One can calculate various levels of “assurance”, 90%, 95%, 99%, 99.9%, and so on, for the confidence interval. Usually, the 95% level is used. It is better to have a narrower or smaller distance between the upper and lower values of the confidence interval (called the “confidence limits”). In general, the more subjects in the study, the narrower (better) the confidence interval. To put it another way, if the 95% confidence interval for a study group is (43–79 units), then we can be confident that the true value for the entire population is between 43 and 79, 95 times if we were to repeat the study in 100 different samples of the population. If the 95% confidence interval is narrower (59–66) because more subjects were studied or for various other reasons, we have a more precise sense that the true population value is closer to the value found in the sample studied.
Other possible designs incorporate a self-controlled case series or risk window, as these are often used in safety studies and have increasing utility for cancer, vaccines, and biologicals. These designs can control within cases-only, e.g., for genetic background features.
With the arrival of formal risk management as an integral part of the development and life span of all drugs, the fields of pharmacoepidemiology and drug safety are now more tightly linked than ever.
Health authorities require epidemiologic safety studies, particularly as post-marketing commitments or requirements. Large databases and practitioners who know how to conduct these studies have become more and more available and the methodology has become more refined and automated. Many pharmaceutical companies now have risk management/pharmacoepidemiology departments to handle these studies.
Indeed, the role of pharmacoepidemiology in risk assessment and signal detection has become more prominent as risk management programs become increasingly active over the entire life cycle of products.
Q: I never was particularly gifted with math and numbers. Do I really have to learn this stuff? Do I really need it in drug safety?
A: Yes, you really need it to interpret and make informed decisions. As electronic medical records become more widespread and large databases are used for epidemiology and observational safety studies, data mining, Bayesian analysis, and other statistical techniques, numerical literacy — as it is called — will be very useful and probably obligatory at some point.
1See Jon Deeks, What is an Odds Ratio? (www.bandolier.org.uk/band25/b25-6.html).
CHAPTER
7
Regulations, Directives, Guidance, Laws and Consensus Documents
Pharmacovigilance (PV) is governed by a large body of requirements. Some are written and rigid. Others are written, but are far less rigid. Others are not requirements but only guidances or guidelines, and still others are unwritten customs and (best or optimal) practices. Obviously, laws and regulations vary from country to country. The sections that follow summarize briefly the obligations in the US and the EU for drugs and over-the-counter (OTC) products, but also provide means and references to remain “up to date” on PV requirements.
United States
Legal requirements for drug safety come from multiple areas. There are laws, regulations, and guidances issued by the United States’ federal government. These are the predominant formal requirements governing drug safety. In the US, a “law” is a written statute, requirement, or ordinance that has been passed by a legislature and then signed into law (where required) by the executive. That is, a federal law is passed by Congress in Washington, D.C., and signed by the president. Laws may be created at multiple levels of government (federal, state, and local). Regulation of interstate commerce is the FDA’s main enforcement authority.
The law governing investigational drugs (“New Drugs”) is found in Section 505(i) [21 U.S.C. 355], and the law governing marketed drugs is found in Section 505(k) of the Food Drug and Cosmetic Act (https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/FederalFoodDrugandCosmeticActFDCAct/default.htm).
In addition to laws, the US Food and Drug Administration (FDA) is empowered by Congress to create regulations. Regulations are rules issued by government authorities under the power of laws. Regulations thus have the force of law. To create a regulation, the FDA publishes the proposed version of the new or amended regulation in the Federal Register (https://www.federalregister.gov/). A period is defined during which time the public may send written comments on the proposal to the FDA. After review, a final regulation is published in the Federal Register and in the Code of Federal Regulations (https://www.ecfr.gov/cgi-bin/ECFR?page=browse). A long period may elapse between publishing the draft and the final regulation (e.g., 6 months or more) and FDA is under no obligation to finalize a draft regulation or guidance. Also, a draft regulation may be withdrawn. While a proposed or final regulation may be published and put into force anytime, the Code of Federal Regulations is updated with final regulations once a year, on April 1st.
Finally, the FDA issues guidances that contain the FDA’s preferences on laws and regulations. Guidances are often an offshoot of guidelines that are developed by consensus organizations, e.g., the International Council for Harmonization (ICH) or the Council of International Organizations of Medical Sciences (CIOMS).
As the FDA states on its Center for Drug Evaluation and Research (CDER) Guidance page (https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm): “Guidance documents represent the Agency’s current thinking on a particular subject. They do not create or confer any rights for or on any person and do not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both.” However, it is generally held in practice in the industry to be a wise course of action to follow FDA guidances. Some of the applicable pharmacovigilance (PV) guidances can be found at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064993.htm. Clinical trial guidances may be found at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064981.htm.
European Union
The EU situation is different from the US situation, in particular because the EU is composed of 27 separate Member States (formerly 28 before the UK left the EU — Brexit) plus three affiliated states that are organized differently from the 50 United States. The EU member states are sovereign countries, whereas the states