Major Advances in International Pharmacoepidemiology Hugh H. Tilson,

MD, DrPH

Phawnacoepidemiology applies rhe principles of epidemiology to the problems of pharmacotherapy-particularly addressing society’s need to know more about drug safety issues &an the highly structured pre-approwal clinical trials programs can provide. Thus, the concerns are truly international, and the approaches mwt ak;o be international, tempered by the ability to generalize from one nation’s experience, and by the availability of specialized research resources. Studying the impact of medical and medicinal interventions, the field is especially well-serwed by the major advances in computer system’s support of medical settings and the multipurpose linked automated data base, linking automated pharmacy-dispensing data with same-pop&ion automated hospital discharge and other medical and demographic data. The development of such resources, the direction of their fruits to complement the hard work of hands-on traditional epidemiologic appoaches in this field, the recruitment and support of trained researchers in the jield, and the international coordination of policy and practice realistic to the capacity while responsiwe to the demand are all among the exciting ch&nges uhead Ann Epidemiol 1990; I :205-2 I2 KEYWORDS:

International

phawnucoepidemiology.

Pharmacoepidemiology is that branch of our field which applies both the epidemiologic method (i.e., nonexperimental observational techniques) and the epidemiologic perspective (i.e., emphasis on the large population, the long-term, and the public health approach and philosophy) to the problems and contributions of modem therapeutics. The objectives of this field are to maximize the benefits and minimize the harm needed medicines bring to populations. To do this job, it is critically important to know as much as we can as quickly and as accurately as we can following the marketing of a new medicine regarding its safety in general clinical use. Regarding the importance of these questions, there can be little doubt! It has been scarcely more than 25 years since society learned from the thalidomide tragedy how gravely important and far-reaching unanticipated and undetected adverse reactions to drug therapy can be (1). Since then, society has experienced over a dozen examples where an ostensibly safe medication, launched to treat an important medical condition, has had its full potential for toxicity realized only subsequent to its marketing (2, 3). On balance, medications remain “remarkably nontoxic” (4). However, occasionally these adverse experiences have been so serious as to result in withdrawal of the drug from the market (5-7). How could this happen particularly in the face of a system of regulatory standards for review of pharmaceutical safety and efficacy that is more extensive and thorough than ever before in the history of regulation?

LIMITS

OF CLINICAL

TRIALS

When a drug is first approved for marketing in one of the major world markets (e.g., United States, United Kingdom, continental Europe, and more recently, Japan), the From the Division of Epidemiology, Information and Surveillance, Burroughs Wellcome Co., Triangle Park, NC. Address reprint requests to: Hugh H. Tilson, MD, DrPH, Director, Division of Epidemiology, tion and Surveillance, Burroughs Wellcome Co., Research Triangle Park, NC 27709. 0 1990 Elsevier Science Publishing Co., Inc.

Research Informa-

1047-2797190/$03.50

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standards for regulatory approval require that the drug be shown to be effective in at least one clinical “indication’‘-i.e., show a statistically significant and medically significant difference in a clearly scientifically documentable endpoint against an appropriate scientific standard comparison, preferably placebo, Requirements for the approval of a New Drug Application in the United States include two such wellcontrolled clinical trials. As the complexity of clinical trial requirements increase, so do costs, and thus it becomes necessary to reduce the size and ambition of the clinical trials program prior to regulatory approval. The very survival of the drug industry, with current costs per drug successfully brought to market exceeding $100 million (8), depends on a costefficient approach. Thus, the numbers of patients included in a comprehensive clinical trials program are likely to be fewer than 2000-and, particularly for drugs for lifethreatening conditions such as acquired immunodeficiency syndrome (AIDS), likely to be limited to several hundred. Therefore, existence of a serious or even lifethreatening side effect occurring once in every thousand treatments is not likely to be known at the time of initial approval-no matter how good a detection system exists. Rare effects will only be detected when utilization is more extensive. And of course, special concerns, e.g., drug-drug or drug-disease interactions or problems in special subpopulations (small children, pregnant women), cannot be known if these groups are excluded from “tight” clinical trials. Thus, progressively, regulatory expectations, industry focus, and academic interest have been directed to using epidemiologic techniques to continue to evaluate drugs after marketing begins. In typical systems for the spontaneous reporting of adverse drug effects, physicians are asked, voluntarily, to register unusual medical experiences in their clinical practices that they attribute as side effects of medications. Voluntary reporting may focus on industry (to which 85% of such reports in the United States are submitted) (9) or regulatory authorities (to which over 85% are registered in the United Kingdom’s renowned Yellow Card system). Through such spontaneous reporting, the experiences of all treating physicians can be tapped, and signals of very rare, but nevertheless potentially important, toxicity can be received-assuming that the patient becomes aware of the problem, the physician recognizes rhe problem and its possible drugrelatedness, and either reports the event in a way that can be effectively registered. While numerous major international efforts are being made to improve reporting in all countries and improve the international coordination of such spontaneous reports, there is also an emerging consensus that spontaneous reporting alone cannot do the necessary job. This is true not only because of problems of very substantial under-reporting and biases even when events are reported, but also because of the inherent difficulty in attribution. Attribution of a cause to a prior drug may, for example, require linking adverse experiences that may be caused by a drug to a prior drug exposure, which may have anteceded the experience by over a decade (e.g., in the case of drug-associated cancers), have been prescribed by another physician (e.g., in the case of ocular side effects from systemic medicines), or have been procured under differing circumstances (e.g., in the case of patient self-medication). Increasing emphasis is being given to the study of actual rates of such events in structured epidemiologic study of adverse drug effects in many medication-exposed populations and appropriate nonexposed cohorts. These matters are international in scope and interest. Pharmacologic development, marketing, education, application, and regulation are achieving worldwide emphasis as international scientific communications and standards become more closely unified, international regulatory expectations and practices are more rigorously

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analyzed and aggressively reconciled, and the international marketplace expands. With these trends, also emerging are an increasing awareness of, and an intolerance for, the risks associated with medication. At times it seems that society has an unrealistic expectation to reduce the therapeutic endeavor to a risk-free activity. This is naive, considering it will never be reasonable to expect a zero side-effects profile. However, a more reasonable expectation is that society will require, and research will provide, a more aggressive and extensive approach to reduction of the uncertainty concerning risks through broader, earlier, and more expert epidemiologic approaches.

AUTOMATED

LINKED

DATABASES

Initially driven by this evolving expectation, and now supporting it, has been unprecedented development of an enormously useful and powerful epidemiologic resource in North America-the large, automated, multipurpose database. Developed first for administrative purposes (to support claims payment and institutional or plan management), automated databases emerged for hospital administration in the early 1970s and by the mid-1970s were applied to pharmacy management as well (10). In the former, patient-base accounting and billing include patient identifying information, demographic data, and as a minimum, coded diagnoses (generally using the Intermittent Classification of Diseases (ICD) 9 codes) of all discharge diagnoses. To the epidemiologist, this administrative development has the “side effect” of providing a wealth of already assembled, diagnostic information awaiting epidemiologic data management. Automation has proved a boon to community and, more recently, hospital pharmacies-permitting, with a single data entry, cost accounting, inventory control, individual patient profiling, and direct label printing. Into such a database the patient’s identifying information, and information about drug, dose, and duration need to be entered only once; the “computer can do the rest.” To the student of drug utilization, these data have the happy “side effect” of permitting instant studies. But, for pharmacoepidemiology, the key ingredient is the “link.” In many organizations-health maintenance organizations or hospitals-a single patient identifying number is used universally for such accounting purposes. Thus, these administrative data systems provide a wonderful opportunity for data linkage across time (e.g., the creation of longitudinal patient experience or drug utilization profiles, which can permit detection of possible drug-drug interactions) and datasets (e.g., the linkage of drug exposures with all indications, for drug utilization purposes) and with subsequent important medical events (e.g., hospitalizations by diagnosis), to detect excess frequencies of important and perhaps unexpected events occurring in differing drugexposed populations. Thus, the linked automated outpatient pharmacy and inpatient diagnosis database for a population (e.g., all enrollees in a health maintenance organization) permits population-based drug disease association studies without the enormous costs and long delays of earlier “hands-on” pharmacoepidemiologic methods. The concept of record linkage was coined in Oxford when the Oxford Record Linkage Study “linked,” through manual capture, all prescriptions and all subsequent important medical events into a single population-based data system (11). However, the United States was thrust to the forefront of the field in the mid-1970s by the administrative coincidences that required automation of such data. With the use of automated, multipurpose databases, international pharmacoepi-

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demiology has been advanced. North America is the major resource for such studies because of the practice of fee-for-service reimbursement and the evolution of the health maintenance organization. One real advantage of health maintenance organization-based linked database schemes is the closed-practice, population-based approach of the health maintenance organization. Most people receive most of their important medical services via the plan, so the data are rather complete. Further the data are used for strategically important purposes for the plans; thus, they are of relatively good quality. And, because the data reside with the plans themselves, the medical records are available for validation and the pursuit of further information (e.g., potentially important confounders) which might not be in a computerized system. There are, of course, also limitations of the usefulness of such resources. Only drugs that are used can be studied; only data that are entered can be directly captured; medical records have their limits (12). However, on balance, these limitations are more than offset by the availability of data from a large population that are readily and affordably retrievable, especially from medical records, or if need be, from the prescribers themselves, for more traditional epidemiologic follow-up (13). While the advantages of health maintenance organization linked data may not be as available in other sources of automated linked records, such as billing and claimsprocessing systems, these too are available in North America, as they are in other national and regional settings in which third party payment characterizes the medical system (e.g., France, Italy, Germany, and Sweden). The largest such system in the United States is the pharmacy and hospital discharge linked billing systems of Medicaid, the payment system for the medically indigent in America. Several individual state programs have been used to advantage (14) and a major multistate system, the COMPASS database, is being used by the Food and Drug Administration and several independent researchers (15). Recent arrangements have been made to retrieve hospital records under special agreement for Medicaid-based studies, thereby increasing the ability to validate and, in the process, enhance the value of the resource. A similar linked system captures all prescription and major diagnostic data for the millionperson Saskatchewan health benefits program (16). Thus, when postmarketing epidemiologic studies are needed, it is often to North America that the world market turns. This “one nation fits all” approach has the pragmatic advantage of harnessing the cost-effective multipurpose database availability in North America. It is also perhaps pharmacologically reasonable for etiologic with notable rare exception-the pharmacologic research, i.e., in general-albeit effects and side effects of new medicines in one population tend to replicate in all other population and ethnic groups. And if there are to be population differences, they tend to derive more from universals such as the effects of differing ages, nutritional status, and income than from differing nationalities. Such a situation, for example, occurred when Burroughs Wellcome initiated its monitoring of a new antiherpes compound, acyclovir. Because of the desire to monitor large populations over long periods of time to ensure that there were no unexpected and untoward side effects from this novel nucleoside analog, an extensive program of postmarketing epidemiology was developed. This research program was based on the large automated multipurpose databases supporting the health maintenance organizations of the Group Health Cooperative of Puget Sound and the Kaiser Permanente Health Plan in Portland, Oregon (both with approximately 400,000 people) and a similar database of the Kaiser Permanente Health Plan of Los Angeles (with an

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enrolled population in excess of 1.5 million). With this assurance of large-scale, longterm monitoring, similar considerations regarding postmarketing surveillance in other nations became moot (17). However, there are reasons why multination studies of drug safety are appropriate. Differing medical ecologies and cultures may dictate differing prescription patterns, adoption rates, and utilization. In different countries, despite the emerging consensus regarding regulatory practices, the same new drugs may be approved for different uses. In addition, the drugs commonly used and coprescribed in one country may not be those used in the country where monitoring is standardly done. An example of this is atracurium, a nondepolarizing neuromuscular blocking agent recently developed by Burroughs Wellcome Co. (United States) and the Wellcome Foundation (United Kingdom) (18, 19). In the United States, anesthesiology practice tends to involve multiple concomitant medications, extensive premeditation, and fairly conservative dosing. The product was initially approved with a recommended dosing of 0.5 mg/kg. In the United Kingdom, conversely, fewer premeditations tend to be given, different medications for preoperative and intraoperative relaxation tend to be used, and the use of neuromuscular blockade tends to be more aggressive. The initially approved dose was 0.6 mg/kg. Because of the residual possibility of an infrequent, though potentially important problem with histamine release with this product, a binational congruent approach was thought to be appropriate and a single postmarketing surveillance protocol was jointly launched at the Group Health Cooperative Hospital in Seattle (13) and the Royal Infirmary in Glasgow (20). (It might be of interest to note that despite the differences in practice patterns, no substantial differences in adverse experience rates were found.) Databases in North America can provide populations that are large enough and monitored long enough to answer many of the worlds important epidemiologic questions-at least for widely used medications. However, many nations approve drugs faster than is the current practices in the United States. Thus, it is likely that a medication developed in Europe will be available on the market in Europe for several years prior to US approval. In that event, epidemiologic monitoring overseas is important and desirable. Unfortunately, the lack of the large automated multipurpose databases may make “hands-on” epidemiologic monitoring the only alternative, and the expense and tedium may not be cost-effective. Thus, a product might eventually later be marketed in the United States before a potentially serious, but infrequent, adverse experience could be detected using database monitoring, while several years of prior experience in Europe had failed to reveal the problem because of the lack of such systems. The need for better databases in Europe has led to recent active advocacy for the development of postmarketing epidemiologic monitoring capacity in the United Kingdom and Europe. Particularly promising in the United Kingdom, for example, are several approaches to harness the prescription data currently available through the universal Prescription Pricing Authority (PPA). In the United Kingdom, all prescriptions for medications covered under the PPA are paid through a central bureau. Professor W.H.W. Inman at the University of Southampton has pioneered a systematic approach to “capture” these prescriptions-by hand!-and monitor subsequent adverse events through a mailed questionnaire system, the so-called PrescriptionEvent Monitoring (PEM) (21). Thus, to learn about the safety of a novel antihistamine marketed first in the United Kingdom (acrivastine), we turned to this system. Recent computerization of the system has failed to include the National Health

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Service or other patient identifying number. However, all prescriptions are available and potentially linkable to that number. A recent effort in Scotland under the Medication Events Monitoring Program (MEMO) is automating the linked patient-identifying number. In Scotland, hospital diagnoses linked to the same patient number are already available in computer. Thus, the same sorts of automated record linkage available in a health maintenance organization or medical finance plan in North America promise to be available in Scotland. Similarly promising are automated outpatient medical record activities, in which, by entering data relating to prescriptions into the computer-supported outpatient medical record, the physician can automate the writing of a prescription, recording in the medical record, and the development of a drug profile. Other medical diagnostic information similarly entered into the computer record would also be linked. In the United States, such a system is currently available at the Harvard Community Health Plan and its applicability for drug epidemiology is being explored by the Channig Laboratories (by Dr. Richard Platt). A similar set of experiments is currently underway in the United Kingdom with two noteworthy examples of large computer support systems-AAH Meditel and Value Added Medical Products (VAMP). The latter (with epidemiologic support by Hershel Jick, the Director of the Boston Collaborative Surveillance Program and pioneer of data linkage in the Group Health Cooperative database) has already produced substantial epidemiologic evidence regarding medication safety, though its true potential is only now being tested. The potential to conduct similar linked database research exists in Europe under conditions in which medical payment plan (the National Finance Systems in Sweden, France, and Italy, e.g.) and smaller regionalized payment systems (e.g., the Krankenkasse Systems in Germany) currently are paying claims for prescription medications and for important medical events (e.g., those serious enough to require hospitalization) by diagnosis. Such circumstances provide the potential for similar linked database pharmacoepidemiology. An important variant on internationalization is the truly multinational collaborative effort. Building on and capturing the spirit of multinational monitoring of spontaneously reported adverse reactions, a series of multinational disease-specific or exposure-specific case or population registries have been undertaken. For example, registries have been started to register all persons with several cutaneous problems that might be classified as Stevens-Johnson syndrome or toxic epidermal necrolysis-irrespective of drug cause-which might permit signal generation if one drug were more frequently mentioned in association with the syndrome than others (22). A recent major international collaborative case-control study of drug-associated agranulocytosis (23) proved that, logistics and costs aside, a true multinational pharmacoepidemiologic study could be accomplished, though not without substantial methodologic problems. A Burroughs Wellcome experience in this regard has been the international registration of women with a first-trimester exposure to acyclovir. This antiherpes agent, used widely in young persons, many of them sexually active, will doubtless, however aggressive the counseling, be associated with occasional accidental continuation into pregnancy, with resulting first-trimester exposure of the fetus. The registry of such pregnancies would permit prospective follow-up relatively without bias to assess for a possible increase in adverse outcomes of pregnancy or teratogenicity. Collaborating with the US Centers for Disease Control, and the American Social Health Association, and with input from regulatory authorities and collaborating Wellcome companies throughout the world, Burroughs Wellcome US has been able to maintain such a registry (24, 25).

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MECHANISMS FOR PHARMACOEPIDEMIOLOGY

To assist the international coordination of the spontaneous voluntary adverse reactions-reporting systems of various nations, a collaborative group has been assembled under the aegis of the Council of International Organizations for the Medical Sciences (CIOMS). Regulators from seven nations and representatives from major multinational pharmaceutical manufacturers have collabsrated in the working group, which has developed recommendations regarding the standardization of reporting procedures. The CIOMS form has been adopted in a voluntary demonstration in five of the collaborator nations and has actually been required by regulation in the United Kingdom. Under these principles, common definitions, common approaches, and a reduction in duplicative activities have been possible. The CIOMS activity continues into the 199Os, currently exploring the international coordination of periodic regulatory drug safety reports from manufacturers. An international collaborative to help develop important epidemiologic resources, methods, and approaches has also been developed under the aegis of the Risk Assessment of Drugs-Analysis and Response @AD-AR) working group. With initial impetus from the Ciba-Geigy Corporation, this collaboration has spawned drug safety pharmacoepidemiology working groups in five countries (with several others currently working on developing national RAD-AR councils). Recently a multinational congress of representatives from national RAD-AR working groups convened and named itself the Epidemiologists in the Pharmaceutical Industry (EPI) Working Group. The EPI Working Group has suggested a series of multinational agendas for pharmacoepidemiology, which will make this a yet more exciting field for the decade ahead. These include the development of new and large automated multipurpose databases to support necessary research in the various countries in which such research might be feasible, the ongoing support of existing resources, and the development of trained researchers to work in this complex field; the establishment of national disease-specific registries; the development of national councils to review and reconcile international and multinational policies; and the establishment of a multidisciplinary, multisectoral, international forum. The last of these recommendations was brought to the Fifth International Conference on Pharmacoepidemiology in Minneapolis in 1989 and was favorably received by a small working group, which formed ‘the nucleus for an emerging International Society for Pharmacoepidemiology. This fledgling group in the intervening months has already assembled hundreds of members, thousands of dollars of contributed support, and its own identity with an elected international board made up of regulators, academics, practitioners, and industry specialists from around the world-all committed to advancing this important field. Thus, pharmacoepidemiology has become truly international and will be able on the international level to make significant contributions to the reduction of the harm done by medications on their way to achieving the good that they are capable of producing.

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