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Epidemiology and Pharmacoepidemiology: What Are They? What Are Their Limitations and Advantages?

This chapter is not meant to be an introduction to epidemiology or pharmacoepidemiology. There are many excellent textbooks and references in those fields. Rather, this chapter attempts, briefly, to place epidemiology and pharmacoepidemiology in the context of their use in the practical world of drug safety. An excellent website to visit is that of the International Society of Pharmacoepidemiology (Web Resource 18-1).

What is epidemiology? There are several similar definitions:

• The study of the distribution and determinants of diseases in populations. Epidemiological studies can be divided into two main types:
  
  
  
  • Descriptive epidemiology describes disease and/or exposure and may consist of calculating rates, for example, incidence and prevalence. Such descriptive studies do not use control groups and can only generate hypotheses, not test them. Studies of drug utilization would generally fall under descriptive studies.
    
  • Analytic epidemiology includes two types of studies: (1) observational studies, such as case-control and cohort studies, and (2) experimental studies, which would include clinical trials, such as randomized clinical trials. The analytic studies compare an exposed group with a control group and are usually designed as hypothesis-testing studies. (From the International Society of Pharmacoepidemiology, Web Resource 18-2.)
  
  
• The study of the distribution and determinants of health-related states or events in specified populations, and the application of this study to the control of health problems. (From the Centers for Disease Control and Prevention, Web Resource 18-2.)
  
• The study of the frequency, distribution, and behavior of a disease within a population (Web Resource 18-3).
  
• The study of the incidence, distribution, and control of disease in a population (Web Resource 18-4).
  
• The study of a disease that deals with how many people have it, where they are, how many new develop, and how to control the disease (Web Resource 18-5).
  
• Study of disease incidence, distribution, and behavior in populations, as well as the relationship between environment and disease.
  
• The branch of medicine that deals with the study of the causes, distribution, and control of disease in populations (Web Resource 18-3, the American Heritage Dictionary).
  
• The study of the incidence, distribution, and determinants of an infection, disease, or other healthrelated events in a population. Epidemiology can be thought of in terms of who, where, when, what, and why. That is, who has the infection/disease, where are they located geographically and in relation to each other, when is the infection/disease occurring, what is the cause, and why did it occur (Web Resource 18-4).

What is pharmacoepidemiology?

• The study of the utilization and effects of drugs in large numbers of people. To accomplish this study, pharmacoepidemiology borrows from both pharmacology and epidemiology. Thus, pharmacoepidemiology can be called a bridge science spanning both pharmacology and epidemiology. (From the International Society of Pharmacoepidemiology, Web Resource 18-2.)
  
• The study of the utilization of drugs, good and bad, by populations, and the effect of these drugs on those populations, for better or for worse.

For the purposes of this chapter, the terms epidemiology and pharmacoepidemiology will be used interchangeably even though purists will object to this since the two are not entirely the same.

Of necessity, pharmacoepidemiology uses numbers and statistical analyses. It is the study of populations as opposed to the study of individuals. Thus, it is used to answer questions about groups of people rather than about individual patients. It is also used to extrapolate and generalize from individuals to groups and populations. Thus, it would answer questions like “Are the women who live on Long Island, New York, at greater risk for breast cancer than those who live elsewhere?” or “Is the use of drug X associated with a higher incidence of atrial fibrillation in elderly men?” as opposed to questions like “Does Ms. Jones have breast cancer because she lives on Long Island?” or “Did drug X produce atrial fibrillation in 79-year-old Mr. Jones?”

In the world of drug safety, epidemiology is used to answer questions about adverse events (AEs), and in particular serious adverse events (SAEs), in populations after (usually) a signal has been generated based on one or more individual case reports. The purpose is to confirm and quantify the signal or to rule it out. Such studies can rarely answer questions about causality but rather give information on risks and associations.

In this chapter, we give a very high-level view of the handful of concepts that continually appear in the drug safety and pharmacovigilance literature and for which a passing knowledge (at least) is useful. Pharmacoepidemiology is now an area of much research and interest and it will play a greater role in drug safety as risk-based pharmacovigilance becomes the mainstay of drug safety and better and bigger databases and data warehouses are developed and populated.

A case report, also called an “individual case safety report” (ICSR), is a clinical observation of a patient who received a drug and experienced one or more AEs. The most common paper formats for presentation of a case report are the MedWatch form and the CIOMS I form. The electronic equivalent is the E2B report, which is an electronic file transmitted to a health authority or company or elsewhere with all the elements of the ICSR. Sometimes cases are published as short reports in medical journals, some of which have been previously reported to health authorities and some not. These cases are picked up in the periodic review of the medical literature done by companies.

Aggregate reports are descriptions, or compilations and analyses, of a group of patients exposed to a drug (or sometimes more than one drug, e.g., combination products) and the AEs and other safety issues such as medication errors or quality problems. There are multiple standard formats, of which the Periodic Safety Update Reports (PSUR) is the main one. The U.S. aggregate reports are called, sometimes confusingly, NDA Periodic Reports, Periodic Reports, and PADERs (Periodic Adverse Drug Experience Reports). To worsen the situation, PADERs is also occasionally used to refer to PSURs. And the FDA also accepts PSURs. Whatever they are called, companies are obliged to prepare them in a serious and careful manner and to submit them on time to concerned health authorities.

This is the type of study that most people are familiar with. It is an experimental study, not an observational study, because a protocol, used by the investigators, determines who receives what drug treatment; the protocol may differ from the normal practice of medicine. In an observational trial, one merely observes and records what happens in the normal course of medical practice and treatment. An observational trial may have a protocol, but it does not dictate treatment, which is left up to the treating physician/investigator.

A randomized clinical trial is prospective. It involves two or more groups of patients with a disease receiving different treatments. For example, one group may get drug A and the other group may get drug B or placebo. It may be single blinded (the patient does not know what the treatment is) or double blinded (neither the patient nor the investigator knows what the treatment is). The study may also be randomized to minimize known and unknown biases (factors other than the drugs tested that may alter or explain the results). These studies are often long and costly. They represent the gold standard of research: the double-blind, randomized, controlled trial. These studies are usually done during phases I, II, and III of drug development, and for many reasons (ethical, availability of patients, etc.), may not be feasible after the drug is marketed. The results are usually clear and easily understandable with the calculation of a risk difference between groups. For example, the group receiving drug A had a 4.1% incidence of AEs and the placebo group a 2% incidence of AEs, a difference of 2.1%. These trials, especially before approval for marketing, are usually prepared primarily to examine efficacy. The patient numbers and design are done to maximize the likelihood of finding a meaningful clinical and statistical result with the primary efficacy endpoints. The studies are usually “powered” to show this one way or the other. (Statistical power refers to the likelihood that the trial and statistical test will reject a false null hypothesis, or, to put it another way, power is the probability that one will observe a treatment effect in the trial when such effect really occurs.) The safety data from the trials are rarely sufficient to draw conclusions because rare adverse drug reaction (ADRs) will not be picked up with only a few to several thousand patients studied. The studies are not powered to pick up safety information and one might falsely conclude that a drug is “safe” or, more precisely, that doses do not differ from the comparator drug in terms of safety. Thus, the safety information is just presented as tables or listings without statistical tests. This is sometimes known as “descriptive statistics.”

A newish methodology in clinical trials is being used more frequently and is called “adaptive clinical trials.” They have been used for some years in phase I in sequential dose tolerance studies in which three or four patients are treated with a fixed dose. If well tolerated, another three patients are then treated with a higher dose, and so on until a toxicity occurs that precludes further dose elevations. Many different methodologies have been developed, all of which have in common the use of the early data to determine what changes to make (to adapt) in the next patients being treated in that trial. Bayesian techniques are used to determine how the trial will be adapted. The goals of these trials are to obtain efficacy information and minimize toxicity by eliminating cohorts or treatments that do not work or are toxic. When successful, efficacy information can be obtained more rapidly and with fewer patients or cohorts. In terms of safety, however, fewer patients will be exposed to different treatments (as the unsuccessful ones are rapidly abandoned). If this means that efficacy is determined with fewer patients treated, a clear upside, the number of patients examined for adverse events will drop and the infrequent AEs will be less likely to be found, a clear downside. How this methodology, which the health agencies support in general, plays out in terms of safety remains to be seen.

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