复旦大学：《循证医学》课程教学资源（预习资料）药物不良反应分析评价预习.pdf_大学文库

Unit 9：药物不良反应的分析评价主讲教师：朱畴文助理教师：高虹授课时间：2010 年 4 月 20 日（1 班）；2010 年 4 月 23 日（2 班）一、教学目的：掌握和熟悉药物不良反应的研究、评价和应用的原则及方法二、教学内容： 1. 了解药物不良反应研究的历史和进展—药物流行病学 2. 掌握药物不良反应的定义、重要意义和有关监测研究的主要基本方法 3. 初步掌握药物不良反应的确定方法（宏观和微观评价） 4. 熟悉流行病学中各种相关性或因果研究方法的特点（带复习性质） 5. 了解药物不良反应监测、药物流行病学的应用及前景三、教学重点：药物不良反应的研究方法四、教学难点：药物不良反应的判断五、中文和英文关键词 Adverse Drug Reaction 药物不良反应 Pharmacoepidemiology 药物流行病学 Causal Association 因果关联六、阅读文献：中文 1. 朱畴文第三篇第 18 章不良反应。于：《循证医学与临床实践》（第 2 版），王吉耀主编，北京科学出版社 2006 英文：(all in: “Strom BL ed, Pharmacoepidemiology (2nd ed), Chichester: John Wiley & Sons, 1994”) 2. Brian L. Strom. What is Pharmacoepidemiology? 3. Brian L. Strom. Study designs available for pharmacoepidemiology studies. 4. Brian L. Strom. When should one perform pharmacoepidemiology studies? 5. Brian L. Strom. How should one perform pharmacoepidemiology studies? Choosing among the available alternatives 七、讨论思考题：（一）微观判断：使用 Naranjo 模式和我国卫生部 ADR 中心评分法，推断如下临床病例发生药物不良反应的可能性一位 29 岁的女性在过去一周已经接受nitrofurantoin（呋喃妥因）治疗 2 次。在她服下第 3 次治疗的第 1 片药的 4 小时后，她出现发热（39o C）、呼吸窘迫和呕吐。她随即停了药，一天后她的全科医师开了胸片检查，发现为“过敏性肺炎”的表现。她的白细胞稍增多（12*10^9/L）伴 9% 嗜酸性细胞。数日后，患者完全康复。第 166 页

What is Pharmacoepidemiology BRIAN L. STROM University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA a desire to take medicine is, perhaps, the great fields. The history of drug regulation will then be feature which distinguishes man from other ani. briefly and selectively reviewed, focusing on the Sir william Osler. 1891 US experience as an example, demonstrating how it has led to the development of this new field In recent decades, modern medicine has been bles- Next the current regulatory process for the sed with a pharmaceutical armamentarium which approval of new drugs will be reviewed, in order is much more powerful than what it had before. to place the use of pharmacoepidemiology and Although this has given us the ability to provide postmarketing drug surveillance into proper much better medical care for our patients, it has spective. Finally, the potential scientific and per- also resulted in the ability to do much greater ical contributions of pharmacoepidemiology harm. It has also generated an enormous number be discussed of product liability suits against pharmaceutical manufacturers, some appropriate and others inap- propriate.In fact, the history of drug regulation parallels the history of major adverse drug reac- DEFINmION OF tion"disasters. "Each change in pharmaceutical PHARMACOEPIDEMIOLOGY law was a political reaction to an epidemic of Pharmacoepidemiology is the study of the use/of adverse drug reactions. The harm that drugs can and the effects of drugs in large numbers of cause has also led to the development of the field people. The term pharmacoepidemiology con- of pharmacoepidemiology, which is the focus of tains two components: "pharmaco"and"epide this book. More recently, the field has begun to miology "In order to better appreciate and expand its focus to include issues other than understand what is and what is not included in adverse reactions, as well this new field, it is useful to compare its scope to To clarify what is, and what is not, included that of other related fields. The scope of pharma within the discipline of pharmacoepidemiology, coepidemiology will first be compared to that of this chapter will begin by defining pharmacoepi- clinical pharmacology, and then to that of epide- demology, differentiating it from other related molo Pharmacoepidemiology(Second edition). Edited by Brian L Strom 第169页

PHARMACOEPIDEMIOLOGY PHARMACOEPIDEMIOLOGY VS CLINICAL does not normally involve or require the mea PHARMACOLOGY surement of drug levels. However, pharmacoepi demology can be used to shed light on the Pharmacology is the study of the effects of drugs. pharmacokinetics of a drug, such as exploring Clinical pharmacology is the study of the effects whether aminophylline is more likely to cause e of drugs in humans (see also Chapter 4).Phar- nausea when administered to a patient simulta- macoepidemiology can be considered, therefore, neously taking cimetidine. However, this is a to fall within clinical pharmacology. In attempt- relatively unusual application of the field ing to optimize the use of drugs, one central Specifically, the field of pharmacoepidemiology principle of clinical pharmacology is that therapy has primarily concerned itself with the study of should be individualized, or tailored to the needs adverse drug effects. Adverse reactions have tra- of the specific patient at hand. This individuali- ditionally been separated into those which are zation of therapy requires the determination of a the result of an exaggerated but otherwise usual risk/benefit ratio specific to the patient at hand. pharmacological effect of the drug, so-called Doing so requires a prescriber to be aware of the Type A reactions, vs. those which are aberrant potential beneficial and harmful effects of the effects, so called Type B reactions. Type A reac- drug in question and to know how elements of tions tend to be common, dose-related, pre the patient' s clinical status might modify the dictable, and less serious. They can usually be probability of a good therapeutic outcome. For treated by simply reducing the dose of the drug example, consider a patient with a serious infec. They tend to occur in individuals who have one tion, serious liver impairment, and mild impair- of three characteristics. First, the individuals may ment of his or her renal function. In considering have received more of a drug than is customarily whether to use gentamicin to treat the infection, required. Second, they may have received a con it is not suficient to know that gentamicin has a ventional amount of the drug, but they may small probability of causing renal disease. A metabolize or excrete the drug unusually slowly, good clinician should realize that a patient who leading to drug levels that are too high. Third, has impaired liver function is at a greater risk of they may have normal drug levels, but for some suffering from this adverse effect than one with reason are overly sensitive to them. normal liver function. Pharmacoepidemiology In contrast, Type B reactions tend to be can be useful in providing information about the uncommon, not related to dose, unpredictable, beneficial and harmful effects of any drug, thus and potentially more serious. They usually permitting a better assessment of the risk/benefit require cessation of the drug. They may be due balance for the use of any particular drug in any to what are known as hypersensitivity reactions particular patient. or immunologic reactions. Alternatively, Type B Clinical pharmacology is traditionally divided reactions may be some other idiosyncratic reac- into two basic areas, pharmacokinetics and phar: tion to the drug, either due to some inherited macodynamics. Pharmacokinetics is the study of susceptibility(e.g glucose-6 hosphate dehy he relationship between the dose administered of drogenase deficiency) or due to some other a drug and the serum or blood level achieved. It mechanism. Regardless, Type B reactions are the deals with drug absorption, distribution, metabo- most difficult to predict or even detect, and major focus study of the relationship between drug level and- logic studies of adverse drug reactions drug effect. Together, these two fields allow one The usual approach to studying adverse drug to predict the effect one might observe in a reactions has been the collection of spontaneous patient from administering a certain drug regi- reports of drug-related morbidity or mortality men. Pharmacoepidemiology encompasses ele-(see Chapters 10 and 11). However, determining ments of both of these fields, exploring the effects causation in case reports of adverse reactions can achieved by administering a drug regimen. It be problematic(see Chapter 26), as can attempts 第170页

WHAT IS PHARMACOEPIDEMIOLOGY? to compare the effects of drugs in the same class. (focus of inquiry. From epidemiology, pharma This has led academic investigators, industry, coepidemiology borrows its methods of inquiry. FDA, and the legal community to turn to the In other words, it applies the methods of epide- field of epidemiology. Specifically, studies of miology to the content area of clinical pharma adverse effects have been supplemented with stu- cology. In the process, multiple special logistical dies of adverse events. In the former, investigators approaches have been developed and multiple examine case reports of purported adverse drug special methodological issues have arisen. These reactions and attempt to make a subjective clin- are the primary focus of this book. ical judgment on an individual basis about whe ther the adverse outcome was actually caused by the antecedent drug exposure. In the latter, con- HISTORICAL BACKGROUND trolled studies are performed examining whether the adverse outcome under study occurs more The history of drug regulation in the US is simi often in an exposed population than in an unex- lar to that in most developed countries, and osed population. This marriage of the fields of reflects the growing involvement of governments clinical pharmacology and epidemiology has in attempting to assure that only safe and effec- resulted in the development of a new field: phar- tive drug products were available and that appropriate manufacturing and marketing prac- the P Food and Drug Act,. was passed in1%6似造 PHARMACOEPIDEMIOLOGY VS. response to excessiv ve adult eration and misbrand EPIDEMIOLOGY ing of the food and drugs available at that time. Epidemiology is the study of the distribution and There were no restrictions on sales or require determinants of diseases in populations (see also ments for proof of the efficacy or safety of mar Chapter 2). Since pharmacoepidemiology is the keted drugs. Rather, the law simply gave the study of the use of and effects of drugs in large federal government the power to remove from the market any product that was adulterated or numbers of people, it falls within epidemio\oy misbranded. The burden of proof was on the as well. Epidemiology is also traditionally sul divided into two basic areas. The field began as federal government. the study of infectious diseases in large popula- In 1937, over 100 people died from renal fail- concerned with the study of chronic diseases, as gill Company of elixir of sulfanilimide dissolved_2* techniques of chronic disease epidemiology to Drug, and Cosmetic Act was passed. Preclinical study the use of and the effects of drugs. toxicity testing was required for the first time. In Although application of the methods of pharma- addition, manufacturers were required to gather coepidemiology can be useful in performing the clinical data about drug safety and to submit clinical trials of drugs which are performed prior these data to the FDA prior to drug marketing to marketing(see Chapter 25),the major app The FDA had 60 days to object to marketing or cation of these principles is after drug marketing. else it would proceed. No proof of efficacy was This has primarily been in the context of post- required marketing drug surveillance, although in recent Little attention was paid to adverse drug reac- years the interests of pharmacoepidemiologists tions until the early 1950s, when it was dis- have broadened covered that chloramphenicol could cause Thus, pharmacoepidemiology is a relatively aplastic anemia. In 1952 the first textbook new applied field, bridging between clinical phar- adverse drug reactions was published. 6 In the macology and epidemiology. From clinical phar- same year, the AMA Council on Pharmacy and macology, pharmacoepidemiology borrows its Chemistry established the first official registry of 第171页

PHARMACOEPIDEMIOLOGY adverse drug effects, to collect cases of drug controlled investigations, including clinical inves- induced blood dyscrasias. In 1960 the FDA tigations. Functionally, this has generally been began to collect reports of adverse drug reactions interpreted as requiring randomized clinical trials and sponsored new hospital-based drug monitor- to document drug efficacy prior to marketing. ing programs. The Johns Hopkins Hospital and This new procedure also delayed drug marketing gram developed the use of in-hospital monitors some modifications, these are the requirements to perform cohort studies to explore the short. still in place in the US today. In addition, the term effects of drugs used in hospitals&9(see also amendments required the review of all drugs Chapter 12). This approach was later to be approved between 1938 and 1962, to determine if transported to the University of Florida-Shands they too were efficacious. The resulting DESI Teaching Hospital, as well. 1( (Drug Efficacy Study Implementation) process, In the winter of 1961 the world experienced the conducted by the National Academy of Sciences' infamous "thalidomide disaster"Thalidomide National Research Council with support fror was marketed as a mild hypnotic, and had no contract from the FDA, has recently been com- obvious advantage over other drugs in its class. pleted, and has resulted in the removal from the Shortly after its marketing, a dramatic increase US market of many ineffective drugs and drug was seen in the frequency of a previously rare combinations. The result of all these changes has birth defect, phocomelia-the absence of limbs or been a great prolongation of the approval pro- parts of limbs, sometimes with the presence cess, with attendant increases in the cost of drug instead of flippers. Epidemiologic studies estab- development, the so-called drug lag. However, lished its cause to be in utero exposure to thalido. the drugs which are marketed are presumably mide. In the United Kingdom, this resulted in the much safer and more effective establishment in 1968 of the Committee on Safety The mid-1960s also saw the publication of a of Medicines. Later the World Health Organiza- series of drug utilization studies. 3-17 These stu- tion established a bureau to collect and collate dies provided the first descriptive information on information from this and other similar national how physicians use drugs, and began a series of drug monitoring organizations(see Chapter 11) investigations of the frequency of poor prescrib- The US had never permitted the marketing of ing and determinants of poor prescribing(see thalidomide and, so, was fortunately spared this also Chapters 27 and 28) epidemic. However, the "thalidomide disaster" With all of these developments, the 1960s can was so dramatic that it resulted in regulatory be thought to have marked the beginning of the change in the US as well. Specifically, in 1962 the field of pharmacoepidemiology Kefauver-Harris Amendments were passed Despite the more stringent process for dru These amendments strengthened the requirements regulation, the late 1960s, 1970s, and especially for proof of drug safety, requiring extensive pre- the 1980s and 1990s have seen a series of major clinical pharmacologic and toxicologic testing adverse drug reactions. Subacute myelo-optic fore a drug could be tested in humans. The neuropathy (SMON was found to be caused by data from these studies were required to be sub- clioquinol, a drug marketed in the early 1930s mitted to the FDA in an Investigational New but not discovered to cause this severe neurologic Drug Application (IND) before clinical studies reaction until 1970. 8 In the 1970s, clear cell could begin. Three explicit phases of clinical test- adenocarcinoma of the cervix and vagina and Ing were defined hich are described in more other genital malformations were found to be detairbelow. In addition, a new requirement was due to in utero exposure to diethylstilbestrol two added to the clinical testing, for"substantial evi- decades earlier. 9 The mid-1970s saw the dis- dence that the drug will have the effect it pur- covery of the oculomucocutaneous syndrome ports or is represented to have. Substantial caused by practolol, five years after drug market- evidence"was defined as "adequate and well- ing. In 1980 the drug ticrynafen was noted to 第172页

WHAT IS PHARMACOEPIDEMIOLOGY? cause deaths from liver disease 21 In 1982 behox- histamines terfenadine and astemizole 50,sI aprofen was noted to do the same." Subse- Hypertension, seizures, and strokes were noted quently the use of zomepirac, another from postpartum use of bromocriptine 52.53 nonsteroidal anti-inflammatory drug, was noted Multiple different adverse reactions were linked tto phyl itopid reactions. Serious blood dyscrasias drug was never convincingly linked to, th i X perforations were noted to be caused by a parti- coveries led to the removal of the drug involved cular slow release formulation of indomethacin. from the market. Interestingly, however, this Bendectin, a combination product indicated to withdrawal was not necessarily performed in all treat nausea and vomiting in pregnancy, was of the different countries in which each drug was removed from the market because of litigation marketed. Most of these discoveries have led to claiming it was a teratogen, despite the absence litigation, as well, and a few have even led to of valid scientific evidence to justify this claim 26 criminal charges against the pharmaceutical man- (see also Chapter 9). Acute flank pain and rever- ufacturer and/or some of its employees sible acute renal failure were noted to be caused Each of these was a serious but uncommon by suprofen. Isotretinoin was almost removed drug effect, and these and other serious but from the US market because of the birth defects uncommon drug effects have led to an acceler- it causes. "4 The eosinophilia-myalgia syn- ated search for new methods to study drug drome was linked to a particular brand of L- effects in large numbers of patients. This has led tryptophan. Triazolam, thought by the Nether- to a shift from adverse effect studies to adverse lands in 1979 to be subject to a disproportionat number of central nervous system side effects, event studies In part in response to concerns about adverse was discovered by the rest of the world to be drug effects, the early 1970s saw the development problematic in the early 1990s. Silicone of the Drug Epidemiology Unit, now the Slone breast implants, inserted by the millions in the Epidemiology Unit, which extended the hospital- US for cosmetic purposes, were accused of caus- based approach of the Boston Collaborative ing cancer, rheumatologic disease, and many Drug Surveillance Program by collecting lifetime other problems, and were restricted from use drug g exposure histories from hospitalized except for breast reconstruction after mas- patients and using these to perform hospital tectomy. Human insulin was marketed as one based case-control studies(see also Chapter of the first of the new biotechnology drugs, but 22). The year 1976 saw the formation of the soon thereafter was accused of causing a dis- Joint Commission on Prescription Drug Use, an proportionate amount of hypoglycemia, 36-40 interdisciplinary committee of experts charged Fluoxetine was marketed as a major new impor- with reviewing the state of the art of pharmaco- tant and commercially successful psychiatric pro- epidemiology at that time, as well as providing duct, but then lost a large part of its market due recommendations for the future. The Compl to accusations about its association with suicidal terized Online Medicaid Analysis and Surveil- ideation. 41 4 An epidemic of deaths from asthma lance System was first developed in 1977, using in New Zealand was traced to fenoterol, and Medicaid billing data to perform pharmacoepide- later data suggested that similar, although smal- miologic studies(see also Chapter 15).The ler, risks may be present with other beta-agonist Drug Surveillance Research Unit, now called the inhalers. The possibility was raised of cancer Drug Safety Research Trust, was developed in from depot-medroxyprogesterone, resulting in the United Kingdom in 1980, with its innovative initial refusal to allow its marketing for this system of Prescription Event Monitoring5Each purpose in the US. 7 the conduct of multiple of these represented major contributions to the studies, 8.49 and ultimately drug approval. field of pharmacoepidemiology. A number of Arrhythmias were linked to the use of the anti- other even newer resources have been developed 第173页

PHARMACOEPIDEMIOLOGY as well, and are discussed in Part III of this order to evaluate rigorously a drug's efficacy a book, along with the older resources. to provide more information on its toxicity Finally, the 1980s and especially the 1990s least one of the phase 3 studies needs to be have seen another shift in the field, away from randomized clinical trial(see Chapter 2) its exclusive emphasis on drug utilization and meet FDA standards, at least one of the ranc adverse reactions, to the inclusion of other mized clinical trials usually needs to be co interests as well, such as the use of pharmacoepi- ducted in the US. Generally between 500 a demology to study beneficial drug effects, the 3000 patients are exposed to a drug during pha application of health economics to the study of 3, even if drug efficacy can be demonstrated w drug effects, quality-of-life studies, meta-analysis, much smaller numbers, in order to be able etc. These are discussed in more detail in Part iv detect less common adverse reactions, For exar of this book ple, a study including 3000 patients would allo one to be 95% certain of detecting any adver reactions which occur in at least one expos THE CURRENT DRUG APPROVAL patient out of 1000. At the other extreme 4o PROCESS of 500 patients would allow one to be 95%ca tain of detecting any adverse reactions whi process in the Us occur in six or more patients out of every 10 and in most ed countries includes exposed. Adverse reactions which occur le preclinical followed by three commonly than these are less likely to be dete phases of clinical testing. Phase 1 testing is ted in these premarketing studies. The samp usually conducted in just a few normal volun- sizes needed to detect drug effects are discuss teers,and represents the initial trials of the drug in more detail in Chapter 3 in humans. Phase 1 trials are generally con- ducted by clinical pharmacologists, to determine the metabolism of the drug in humans, a safe POTENTIAL CONTRIBUTIONS OF dosage range in humans, and to exclude any PHARMACOEPIDEMIOLOGY extrem ely common toxic reactions which are unique to humans. The potential contributions of pharmacoepid Phase 2 testing is also generally conducted by miology are only beginning to be realized, as it clinical pharmacologists, on a small number of so new a field. However, some of them a patients who have the target disease. Phase 2 already apparent(see Table 1.1). In fact, sin testing is usually the first time patients are the early 1970s the FDa has required pos exposed to the drug. The exceptions to this are marketing research at the time of appre f drugs which are so toxic that it would not nor- about one-third of drugs. 59 In this section of th mally be considered ethical to expose norma hapter, we will first review the potential f individuals to them, like cytotoxic drugs. For pharmacoepidemiologic studies to suppleme these, patients are used for phase I testing, as the information available prior to marketing, ar well.The goals of phase 2 testing are to obtain then review the new types of information whic more information on the pharmacokinetics of can be obtained from pharmacoepidemiology the drug and on any relatively common adverse studies and which could not be obtained prior reactions, and to obtain initial information on drug marketing. Finally, we will review the ge the possible efficacy of the drug. Specifically, eral, and probably most important, potenti phase 2 is used to determine the daily dosage contributions such studies can make. In eac and regimen to be tested more rigorously in case, the relevant information available from pr phase 3 marketing studies will be briefly examined firs Phase 3 testing is performed by clinician-inves- to clarify how postmarketing studies can ac gators in a much larger number of patients, inthis 第174页

WHAT IS PHARMACOEPIDEMIOLOGY? Table 1.1. Potential contributions of pharmacoepidemiology A. Information which supplements that available from premarketing studies- better quantitation of the incidence of b. In patients not studied prior to marketing e. g, the elderly, children, and pregnant women c As modified by other drugs and other illnesses d. Relative to other drugs used for the same indication B. New types of information not available from premarketing studies 1. Discovery of previously undetected adverse and beneficial effects a. Uncommon effects b. Delayed effects 2. Pattems of drug utilization 3. The effects of drug overdoses 4. The economic implications of drug use C General contributions of pharmacoepidemiology 1. Reassurances about drug safety 2. Fulfillment of ethical and legal obligations must await studies conducted after drug market SUPPLEMENTARY INFORMATION Premarketing studies of drug effects are necessa- Additionally, for reasons of statistical eff rily limited in size. After marketing, nonexpert- ciency, premarketing clinical trials generally seek mental epidemiologic studies can be performed, subjects who are as homogeneous as possible, in valuating the effects of drugs administered as order to reduce unexplained variability in the part of ongoing medical care. These allow the outcome variables measured and increase the cost-effective accumulation of much larger num- probability of detecting a difference between the bers of patients than those studied prior to mar- study groups, if one truly exists. For these rea- keting, resulting in a more precise measurement sons, certain patients are often excluded, includ- of the incidence of adverse and beneficial drug ing those with other illnesses or those who are effects(see Chapter 3). For example, at the time receiving other drugs. Postmarketing studies can of drug marketing prazosin was known to cause explore how factors such as other illnesses and a dose-dependent first dose syncope,, o but the other drugs might modify the effects of the FDA requested the manufacturer to luct a drugs, as well as looking at the effects of differ postmarketing surveillance study in US to ences in drug regimen, compliance, etc. For quantitate its incidence more precisely. 6 In example, after marketing, the ophthalmic pre recent years, there has even been an attempt, in paration of timolol was noted to cause many ser elected special cases, to take advantage of the ious episodes of heart block and asthma, work that can be performed after marketing to resulting in over 10 deaths. These effects were approve for marketing more quickly selected cri- not detected prior to marketing, as patients with tically important drugs. Probably the best known underlying cardiovascular or respiratory disease example of this was zidovudine. 62,63 were excluded from the premarketing studies dies also tend to be very arti. Finally, to obtain approval to market a drug a ficial. There are important subgroups of patients manufacturer needs to evaluate its safety and who are not usually included in studies con- efficacy, in general, but does not need to evaluate ducted prior to drug marketing, usually for ethi- its safety and efficacy relative to any other drugs cal reasons. Examples include the elderly, available for the same indication. To the con- children, and pregnant women. Studies of the trary, with the exception of illnesses which could ffects of drugs in these populations generally not ethically be treated with placebos, such as 第175页