What Is Pharmacoepidemiology?

Pande V. V.

All drugs have adverse effects. Pharmacoepidemilogy will never succeed in preventing them. It can only detect them, hopefully early, and thereby educate health care providers and public, which will lead to better medication use. The net results of increased activity in Pharmacoepidemiology will be better for industry and Academia but most importantly, for public’s health.

Pharmacoepidemilogy can minimize its adverse public health impact by detecting it early. At the same time, it can improve the use of drugs that have genuine role, protecting against the loss of useful of useful drugs. The past few decades have demonstrated the utility of this field. They also have pointed out some of its problems. With luck, the next few years will see the utility accentuated and the problems ameliorated. The harm that drugs can cause has led to the development of the field of Pharmacoepidemiology

Introduction

In recent decades, modern medicine has been blessed with a pharmaceutical armamentarium that is much more powerful than 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. Recent data indicate that 100000 Americans die each year from Adverse Drug Reactions, and 1.5 million US hospitalizations each year result from Adverse Drug Reactions; yet, 20-70% of Adverse Drug Reactions may be preventable. The harm that drugs can cause has led to the development of the field of Pharmacoepidemiology. ¹

Pharmacoepidemiology:

Pharmacoepidemiology is the study of the use of and the effects of drugs in large numbers of people.

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. Pharmacoepidemiology falls within Clinical Pharmacology. To optimize use of drugs, Clinical Pharmacology specifies that therapy should be individualized, or tailored to the needs of the specific patient at the hand. Doing so requires o prescriber to be aware of the potential beneficial and harmful effects of drugs in question and to know how elements of 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 treat the 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 ²

Pharmacoepidemiology can be useful in providing information about the beneficial and harmful effects of 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 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 these fields, exploring the effects achieved by administering a drug regimen. It does not normally involve or require measurement of drug levels. Pharmacoepidemiology can be used to shed light on the pharmacokinetics of a drug, such as exploring whether aminophylline is more likely to cause nausea when administered to a patient simultaneously taken with cimetidine. ³

Pharmacoepidemiology is primarily concerned itself with study of adverse drug effects. The usual approach to studying adverse drug reactions has been the collection of spontaneous reports of drug related morbidity or mortality. However, determining causation in case reports of adverse reactions can be problematic, as can attempts to compare effects of drugs in the same class. This has led academic investigators, industry, the FDA, and the legal community to turn to the field of epidemiology. ⁴

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 judgement 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 new field Pharmacoepidemiology. ^5,

Pharmacology versus Epidemiology

Epidemiology is study of distribution and determinants of diseases in populations. Since Pharmacoepidemilogy is study of the use of and effects of drugs in large numbers of people, it obviously falls within epidemiology as well. Epidemiology is traditionally subdivided into two basic areas. The fieldbegan as the study of infectious diseases in large populations i.e. epidemics. It has also been concerned with study of chronic diseases. The field of Pharmacoepidemilogy uses the techniques of chronic diseases epidemiology to study the use of and effects of drugs. Although application of the methods of pharmacoepidemilogy can be useful in performing the clinical trials of drugs that are performed before marketing, the major application of these principles is after drug marketing. This has primarily been the context of post-marketing drug surveillance. Thus pharmacopepidemiology is a relatively new applied field bridging between clinical pharmacology and epidemiology. ⁶

From clinical pharmacology, Pharmacoepidemilogy borrows its focus of inquiry. From epidemiology, pharmacoepidemilogy borrows its methods of inquiry. In other words, it applies methods of epidemiology to the content area of clinical pharmacology. In the process, multiple special logistical approaches have been developed and multiple special methodologic issues have arisen. ⁷

Need of Pharmacoepidemilogy

Recently, with publication of the results from the women’s Health Initiative indicating that combination hormone replacement therapy causes an increased risk of myocardial infarction rather than a decreased risk ^{8, 9} there has been increased concern about reliance solely on non experimental methods to study drug safety after marketing and we are beginning to see the use of massive randomized clinical trials as part of post marketing surveillance. ^{10, 11}

There is also increasing recognition that most of the risk from most drugs to most patients occurs from known reactions to old drugs. Yet, nearly all of the efforts by the FDA and other regulatory bodies are devoted to discovering rare unknown risks from new drugs. In response, there is growing concern, in Congress and among US public at least, that perhaps the FDA is now approving drugs too fast. ¹²

There also calls for the development of Independent Drug Safety Board, analogous to National Transportation Safety Board with a mission much wider than the FDA’s regulatory mission, to complement the latter. ^{13, 14}

For example such a board could investigate drug safety crisis such as those cited above, looking for ways to prevent them, and could deal with issues such as improper physician use of drugs, the need for training and development of new approaches to the field of Pharmacoepidemilogy.

Potential Contributions of Pharmacoepidemilogy

Since early 1970’s FDA has required post-marketing research at the time of approval for about one third of drugs. In this section we will first review the potential for Pharmacoepidemilogy studies to supplement the information available prior to marketing, and then review the new types of information obtainable from post-marketing Pharmacoepidemilogy studies but not obtainable prior to drug marketing. Finally we will review the general, and probably most important, potential contributions such studies can make. In each case relevant information available from premarketing studies will be briefly examined first, to clarify how post marketing studies can supplement this information. ¹⁵

Supplementary Information:

Pre-marketing studies of drug effects are necessarily limited in size. After marketing, nonexperimental epidemiologic studies can be performed, evaluating the effects of drugs administered as part of ongoing medical care. These allow cost effective accumulation of much larger numbers of patients than those studied prior to marketing, resulting in a more precise measurement of the incidence of adverse and beneficial drug effects. ¹⁶

For example, at the time of drug marketing, prazosin was known to cause dose-dependent first dose syncope but the FDA requested the manufacturer to conduct a post marketing surveillance study in the US to quantitate its incidence more precisely. ¹⁷

In recent years there has been attempt, in selected special cases, to release selected critically important drugs more quickly by taking advantage of the work that can be performed after marketing. Probably the best known example is Zidovudine ¹⁸ .Also noted above; the increased sample size available after marketing also permits a more precise determination of the correct dose to be used. ¹⁹

Premarketing studies also tend to be very artificial. Important subgroups of patients are not typically included in studies conducted before drug marketing, usually for ethical reasons. Examples include the elderly, children, and pregnant women. Studies of effects of drugs in these populations generally must await studies conducted after drug marketing. ²⁰

Additionally, for reasons of statistical efficiency, premarketing clinical trials generally seek subjects who are as homogeneous as possible, in order to reduce unexplained variability in the outcome variables measured and increased the probability of detecting a difference between the study groups, if one truly exists .For these reasons, certain patients are often excluded, including with other illness or those who are receiving other drugs. Post-marketing studies can explore how factors such as other illnesses and other drugs might modify the effects of drugs, as well as looking at the effects of differences in drug regimen, compliance, etc ²¹ For example after marketing the ophthalmic preparation of timolol was noted to cause many serious episodes of heart block and asthma, resulting in over 10 deaths. These effects were not detected prior to marketing, as patients with underlying cardiovascular or respiratory disease were excluded from premarketing studies. ²²

Finally, to obtain approval to market a drug, a manufacturer needs to evaluate its overall safety and efficacy, but does not need to evaluate its safety and efficacy relative to any other drugs available for the same indication. To the contrary, with exception of illnesses that could not ethically be treated with placebos, such as serious infections and malignancies, it is generally considered preferable, or even mandatory, to have studies with placebo controls.

There no reasons for this preference:-

1. It is easier to show that a new drug is more effective than a placebo than to show it is more effective than another effective drug.
2. One cannot actually prove that a new drug is as effective as a standard drug. A study showing a new drug is no worse than another effective drug does not provide assurance that it is better than a placebo; one simply could have failed to detect that it was infact worse than the standard drug.

One could require a demonstration that a new drug is more effective than another effective drug, but this is a standard that does not and should not have to be met.Yet, optimal medical case requires information on the effects of a drug relative to the alternatives available for the same medication. This information must often await studies conducted after drug marketing. ^{23, 24 25}

Potential Contributions Of Pharmacoepidemiology

A) Information which supplements the information available from premarketing Studies- better quantitation of the incidence of known adverse and beneficial effects.

a. Higher precision.

b. In patients not studied prior to marketing e.g. the elderly, children, in pregnant women.

c. As modified by other drugs and other illnesses.

d. Relative to other drugs used for the same medication.

B) New types of information not available from pre-marketing studies.

1. Discovery of previously undetected adverse and beneficial effects.

a. Uncommon effects.

b. Delayed effects.

2. Patterns of drug utilization.

3. The effects of drug overdoses.

4. The economic implications of drug use.

C) General Contributions of Pharmacoepidemilogy

1. Reassurances about drug safety.

2. Fulfillment of ethical and legal obligations.

New Types of Information Not Available From Pre-marketing Studies

Pre- marketing studies are necessarily limited in size. The additional sample size available in post-marketing studies permits the study of drug effects that may be uncommon, but important; such as drug-induced agranulocytosis ²⁶ Pre-marketing studies are also necessarily limited in time; they must come to an end, or the drug could never be marketed.

In contrast, post-marketing studies permit the study of delayed drug effects, such as unusual clear cell adenocarcinoma of vagina and cervix, which occurred two decades later in women exposed in uterus to diethyl stilbestrol ²⁷ .

The patterns of physician prescribing and patient drug utilization often cannot be predicted prior to marketing, despite pharmaceutical manufacturer’s best attempts to predict in planning for drug marketing. Studies of how a drug is actually being used, and determinants of changes in these usage patterns, can only be performed after drug marketing.

In most cases, pre-marketing studies are performed using selected patients who are closely observed. Rarely are there any significant overdoses in this population. Thus, the study of the effects of a drug when ingested in extremely high doses is rarely possible before drug marketing. Again, this must await post-marketing Pharmacoepidemilogy studies. ²⁸

Finally, it is only in past decade or two that our society has become more sensitive to the costs of medical care, and the techniques of health economics have been applied to evaluate the cost implications of drug use. ²⁹

It is clear that the exploration of the costs of drug use requires consideration of more than just the costs of drugs themselves. The costs of drugs adverse effects may be substantially higher than the cost of the drug itself, if these adverse effects result in additional medical care and possibly even hospitalizations. Conversely, a drug’s beneficial effects could reduce the need for medical care, resulting in savings that can be much larger than the cost of the drug itself. As with studies of drug utilization, economic implications of drug use can be predicted prior to marketing, but can only be rigorously studied after marketing. ^{30, 31}

General Contributions Of Pharmacoepidemilogy

As an academic or a clinician, one is more interested in new information about drug effects and drug costs that can be gained from pharmacoepidemilogy.Certainly; these are findings that receive greatest public and political attention. However often no new information is obtained, particularly about new adverse drug effects. This not a disappointing outcome, but infact, a very reassuring one, and this reassurance about drug safety is one of the most important contributions that can be made by pharmacoepidemilogy studies.

Related to this is the reassurance that the sponsor of the study, whether manufacturer or regulator, is fulfilling its organizational duty ethically and responsibly by looking for any undiscovered problems which may be there. In an era of product liability litigation, this is an important assurance. One cannot change whether a drug causes an adverse reaction, and the fact that it does will hopefully eventually become evident. What can be changed is through prescription about whether a manufacturer did everything possible to detect it and, so, whether it was negligent in its behavior. ^{32, 33}

Conclusion:

All drugs have adverse effects. Pharmacoepidemilogy will never succeed in preventing them. It can only detect them, hopefully early, and thereby educate health care providers and public, which will lead to better medication use. The net results of increased activity in pharmacoepidemilogy will be better for industry and Academia but most importantly, for public’s health. The next “thalomide disaster” cannot be prevented by Pharmacoepidemilogy. However, Pharmacoepidemilogy can minimize its adverse public health impact by detecting it early. At the same time, it can improve the use of drugs that have genuine role, protecting against the loss of useful of useful drugs. The past few decades have demonstrated the utility of this field. They also have pointed out some of its problems. With luck, the next few years will see the utility accentuated and the problems ameliorated.

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About Authors:

Pande V. V.

Parakh S. R.

Tekade A. R.

Polshettiwar S.A.

Shastri K. V

Chandorkar J.G.