Textbook of Pharmacoepidemiology

Brian L. Strom, Stephen E. Kimmel, Sean Hennessy, Brian L. Strom, Stephen E. Kimmel, Sean Hennessy

• Publisher: Wiley-Blackwell
• Year: 2013
• ISBN:
  9781118344842
• Edition: 2
• Topic: Medicine
• Subtopic: Pharmacology

Textbook of Pharmacoepidemiology, Second Edition, provides an introduction to pharmacoepidemiology and the data sources, methods and applications used in clinical research, the pharmaceutical industry
and regulatory agencies.

Drawing upon the fifth edition of the authoritative reference, Pharmacoepidemiology, this new edition covers the key learning requirements of the discipline. The textbook provides an introduction to
pharmacoepidemiology, pharmacoepidemiological data sources, special issues in methodology, special applications and future developments in the field. Updated learning features such as case studies, key points and Suggested Further Reading are included throughout the text.

Textbook of Pharmacoepidemiology is a practical educational resource for upper-level undergraduates, graduate students, post-doctoral fellows in schools of public health, pharmacy and medicine, and for everyone learning and working in pharmacoepidemiology.

Part I

Introduction to Pharmacoepidemiology

Chapter 1

What is Pharmacoepidemiology?

Brian L. Strom

Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

“A desire to take medicine is, perhaps, the great feature which distinguishes man from other animals.”

Sir William Osler, 1891

Introduction

In recent decades, modern medicine has been blessed with a pharmaceutical armamentarium that is much more powerful than what it had before. Although this has given health care providers the ability to provide better medical care for their patients, it has also resulted in the ability to do much greater harm. It has also generated an enormous number of product liability suits against pharmaceutical manufacturers, some appropriate and others inappropriate. In fact, the history of drug regulation parallels the history of major adverse drug reaction “disasters.” Each change in pharmaceutical law was a political reaction to an epidemic of adverse drug reactions. A 1998 study estimated that 100 000 Americans die each year from adverse drug reactions (ADRs), and 1.5 million US hospitalizations each year result from ADRs; yet, 20–70% of ADRs may be preventable. The harm that drugs can cause has also led to the development of the field of pharmacoepidemiology, which is the focus of this book. More recently, the field has expanded its focus to include many issues other than adverse reactions, as well.

To clarify what is, and what is not, included within the discipline of pharmacoepidemiology, this chapter will begin by defining pharmacoepidemiology, differentiating it from other related fields. The history of drug regulation will then be briefly and selectively reviewed, focusing on the US experience as an example, demonstrating how it has led to the development of this new field. Next, the current regulatory process for the approval of new drugs will be reviewed, in order to place the use of pharmacoepidemiology and postmarketing drug surveillance into proper perspective. Finally, the potential scientific and clinical contributions of pharmacoepidemiology will be discussed.

Definition of Pharmacoepidemiology

Pharmacoepidemiology is the study of the use, and effects, of drugs and other medical devices in large numbers of people. The term pharmacoepidemiology obviously contains two components: “pharmaco” and “epidemiology.” In order to better appreciate and understand what is and what is not included in this new field, it is useful to compare its scope to that of other related fields. The scope of pharmacoepidemiology will first be compared to that of clinical pharmacology, and then to that of epidemiology.

Pharmacoepidemiology versus Clinical Pharmacology

Pharmacology is the study of the effects of drugs. Clinical pharmacology is the study of the effects of drugs in humans (see also Chapter 4). Pharmacoepidemiology obviously can be considered, therefore, to fall within clinical pharmacology. In attempting to optimize the use of drugs, one central principle of clinical pharmacology is that therapy should be individualized, or tailored, to the needs of the specific patient at hand. This individualization of therapy requires the determination of a risk/benefit ratio specific to the patient at hand. Doing so requires a prescriber to be aware of the potential beneficial and harmful effects of the drug in question and to know how elements of the patient's clinical status might modify the probability of a good therapeutic outcome. For example, consider a patient with a serious infection, serious liver impairment, and mild impairment of his or her renal function. In considering whether to use gentamicin to treat his infection, it is not sufficient to know that gentamicin has a small probability of causing renal disease. A good clinician should realize that a patient who has impaired liver function is at a greater risk of suffering from this adverse effect than one with normal liver function. Pharmacoepidemiology can be useful in providing information about the beneficial and harmful effects of any drug, thus permitting a better assessment of the risk/benefit balance for the use of any particular drug in any particular patient.

Clinical pharmacology is traditionally divided into two basic areas: pharmacokinetics and pharmacodynamics. Pharmacokinetics is the study of the relationship between the dose administered of a drug and the serum or blood level achieved. It deals with drug absorption, distribution, metabolism, and excretion. Pharmacodynamics is the study of the relationship between drug level and drug effect. Together, these two fields allow one to predict the effect one might observe in a patient from administering a certain drug regimen. Pharmacoepidemiology encompasses elements of both of these fields, exploring the effects achieved by administering a drug regimen. It does not normally involve or require the measurement of drug levels. However, pharmacoepidemiology can be used to shed light on the pharmacokinetics of a drug when used in clinical practice, such as exploring whether aminophylline is more likely to cause nausea when administered to a patient simultaneously taking cimetidine. However, to date this is a relatively novel application of the field.

Specifically, the field of pharmacoepidemiology has primarily concerned itself with the study of adverse drug effects. Adverse reactions have traditionally been separated into those which are the result of an exaggerated but otherwise usual pharmacologic effect of the drug, sometimes called Type A reactions, versus those which are aberrant effects, so called Type B reactions. Type A reactions tend to be common, dose-related, predictable, and less serious. They can usually be treated by simply reducing the dose of the drug. They tend to occur in individuals who have one of three characteristics. First, the individuals may have received more of a drug than is customarily required. Second, they may have received a conventional amount of the drug, but they may metabolize or excrete the drug unusually slowly, leading to drug levels that are too high (see also Chapter 4). Third, they may have normal drug levels, but for some reason are overly sensitive to them (see Chapter 14).

In contrast, Type B reactions tend to be uncommon, not related to dose, unpredictable, and potentially more serious. They usually require cessation of the drug. They may be due to what are known as hypersensitivity reactions or immunologic reactions. Alternatively, Type B reactions may be some other idiosyncratic reaction to the drug, either due to some inherited susceptibility (e.g., glucose-6-phosphate dehydrogenase deficiency; see Chapter 14) or due to some other mechanism. Regardless, Type B reactions are the most difficult to predict or even detect, and represent the major focus of many pharmacoepidemiologic studies of adverse drug reactions.

One typical approach to studying adverse drug reactions has been the collection of spontaneous reports of drug-related morbidity or mortality (see Chapter 7), sometimes called pharmacovigilance (although other times that term is used to refer to all of pharmacoepidemiology). However, determining causation in case reports of adverse reactions can be problematic (see Chapter 13), as can attempts to compare the effects of drugs in the same class. This has led academic investigators, industry, FDA, and the legal community to turn to the field of epidemiology. Specifically, studies of adverse effects have been supplemented with studies of adverse events. In the former, investigators examine case reports of purported adverse drug reactions and attempt to make a subjective clinical judgment on an individual basis about whether the adverse outcome was actually caused by the antecedent drug exposure. In the latter, controlled studies are performed examining whether the adverse outcome under study occurs more often in an exposed population than in an unexposed population. This marriage of the fields of clinical pharmacology and epidemiology has resulted in the development of a new field: pharmacoepidemiology.

Pharmacoepidemiology versus Epidemiology

Epidemiology is the study of the distribution and determinants of diseases in populations. Since pharmacoepidemiology is the study of the use of and effects of drugs and other medical devices in large numbers of people, it obviously falls within epidemiology, as well. Epidemiology is also traditionally subdivided into two basic areas. The field began as the study of infectious diseases in large populations, i.e., epidemics. It has since been expanded to encompass the study of chronic diseases. The field of pharmacoepidemiology uses the techniques of chronic disease epidemiology to study the use of and the effects of drugs. Although application of the methods of pharmacoepidemiology can be useful in performing the clinical trials of drugs that are conducted before marketing, the major application of these methods is after drug marketing. This has primarily been in the context of postmarketing drug surveillance, although in recent years the interests of pharmacoepidemiologists have broadened considerably. Now, as will be made clearer in subsequent chapters, pharmacoepidemiology is considered of importance in the whole life cycle of a drug, from the time when it is first discovered or synthesized through when it is no longer sold as a drug.

Thus, pharmacoepidemiology is a relatively new applied field, bridging between clinical pharmacology and epidemiology. From clinical pharmacology, pharmacoepidemiology borrows its focus of inquiry. From epidemiology, pharmacoepidemiology borrows its methods of inquiry. In other words, it applies the methods of epidemiology to the content area of clinical pharmacology. In the process, multiple special logistical approaches have been developed and multiple special methodological issues have arisen. These are the primary foci of this book.

Historical Background

Early Legislation

The history of drug regulation in the US is similar to that in most developed countries, and reflects the growing involvement of governments in attempting to assure that only safe and effective drug products were available and that appropriate manufacturing and marketing practices were used. The initial US law, the Pure Food and Drug Act, was passed in 1906, in response to excessive adulteration and misbranding of the food and drugs available at that time. There were no restrictions on sales or requirements for proof of the efficacy or safety of marketed drugs. Rather, the law simply gave the federal government the power to remove from the market any product that was adulterated or misbranded. The burden of proof was on the federal government.

In 1937, over 100 people died from renal failure as a result of the marketing by the Massengill Company of elixir of sulfanilimide dissolved in diethylene glycol. In response, Congress passed the 1938 Food, Drug, and Cosmetic Act. Preclinical toxicity testing was required for the first time. In addition, manufacturers were required to gather clinical data about drug safety and to submit these data to FDA before drug marketing. The FDA had 60 days to object to marketing or else it would proceed. No proof of efficacy was required.

Little attention was paid to adverse drug reactions until the early 1950s, when it was discovered that chloramphenicol could cause aplastic anemia. In 1952, the first textbook of adverse drug reactions was published. In the same year, the AMA Council on Pharmacy and Chemistry established the first official registry of adverse drug effects, to collect cases of drug-induced blood dyscrasias. In 1960, the FDA began to collect reports of adverse drug reactions and sponsored new hospital-based drug monitoring programs. The Johns Hopkins Hospital and the Boston Collaborative Drug Surveillance Program developed the use of in-hospital monitors to perform cohort studies to explore the short-term effects of drugs used in hospitals. This approach was later transported to the University of Florida-Shands Teaching Hospital, as well.

In the winter of 1961, the world experienced the infamous “thalidomide disaster.” Thalidomide was marketed as a mild hypnotic, and had no obvious advantage over other drugs in its class. Shortly after its marketing, a dramatic increase was seen in the frequency of a previously rare birth defect, phocomelia–the absence of limbs or parts of limbs, sometimes with the presence instead of flippers. Epidemiologic studies established its cause to be in utero exposure to thalidomide. In the United Kingdom, this resulted in the establishment in 1968 of the Committee on Safety of Medicines. Later, the World Health Organization established a bureau to collect and collate information from this and other similar national drug monitoring organizations (see Chapter 7).

The US had never permitted the marketing of thalidomide and, so, was fortunately spared this epidemic. However, the “thalidomide disaster” was so dramatic that it resulted in regulatory change in the US as well. Specifically, in 1962 the Kefauver-Harris Amendments were passed. These amendments strengthened the requirements for proof of drug safety, requiring extensive preclinical pharmacologic and toxicologic testing before a drug could be tested in man. The data from these studies were required to be submitted to FDA in an Investigational New Drug (IND) Application before clinical studies could begin. Three expli...