Pharmacoepidemiology: Current Status, Prospects, and Problems Modern medicine is now blessed with drug therapies that are much more powerful than before, enabling us to provide much better medical care but also to do much greater harm. Adverse drug reactions are a major source of morbidity (1) and are potentially preventable. Adverse drug reactions have been reported to cause 3% to 6% of all medical admissions (2) and as many as 160 000 deaths each year (3). After preclinical animal testing, drugs undergo three phases of clinical testing. Generally, between 500 and 3000 patients are exposed to a drug before marketing, in order to be able to detect less common adverse reactions, even if drug efficacy can be demonstrated in much smaller samples. Although this system provides assurances about the efficacy of a drug for selected indications and about the absence of relatively common adverse drug effects, much information is still missing (1). From premarketing data alone, for example, it cannot be known how the drug will be prescribed and whether it will be used rationally. The drug's economic and social impact also cannot be determined. Delayed drug effects and adverse effects that occur in less than 0.1% of exposed patients, even if serious, are unlikely to be detected before marketing. Drug effects that occur in between 0.1% and 1% of exposed patients will not be reliably detected. Even more common drug effects may need more precise quantitation of frequency. For example, at the time of marketing prazosin was known to cause a dose-dependent first-dose syncope, but the Food and Drug Administration (FDA) requested the manufacturer to conduct a postmarketing surveillance study to quantitate its incidence more precisely (4). The need for rigorous postmarketing evaluation of drug effects has led to the development of the field of pharmacoepidemiology (5), the study of the use and effects of drugs in large numbers of persons. Pharmacoepidemiology has already made many contributions to public health that have resulted in more rational drug use, including the discovery of the serious blood dyscrasias resulting from the use of chloramphenicol (6), and the discovery of clear-cell adenocarcinoma of the cervix and vagina and other genital malformations resulting from in-utero exposure to diethylstilbestrol 1 August 1990 • Annals of Internal Medicine • Volume 113 • Number 3
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20 years earlier (7). Pharmacoepidemiology studies have also led to the discovery of many recent serious, if uncommon, adverse effects of new drugs, resulting in withdrawal of the drug from the market, including zomepirac (Zomax, McNeil Pharmaceutical, Spring House, Pennsylvania) (8), ticrynafen (Selacryn, SmithKline Beecham Laboratories, Philadelphia Pennsylvania) (9), benoxaprofen (Oraflex, Eli Lilly and Company, Indianapolis, Indiana) (10), suprofen (Suprol, McNeil Pharmaceutical) (11) or labeling changes, for example, isotretinoin (Accutane, Roche Laboratories, Nutley, New Jersey) (12), and others (1, 4, 5). Over the next few years, however, pharmacoepidemiology is likely to have an increasing impact on clinical medicine. For example, the Joint Commission for Accreditation of Health Care Organizations (13) has recently begun enforcing new requirements for all hospitals to develop the capability to document and evaluate adverse drug reactions that occur in their patients and to conduct ongoing drug utilization review programs. Thus, every physician in the United States who practices in a hospital will soon be confronting these pharmacoepidemiology activities. As another example, until the catastrophic health insurance program was repealed, Medicare was planning to begin reimbursing persons on Medicare for their prescription medications. The law establishing these new pharmaceutical benefits included a requirement for drug utilization review; physicians would have received routine notifications if their patients had received inappropriate prescriptions (14). Most Medicaid programs and many health maintenance organizations already have such programs. Finally, the FDA has been under enormous pressure to approve drugs earlier, especially drugs for the treatment of the acquired immunodeficiency syndrome and cancer. Initiatives undertaken to achieve this with, for example, zidovudine, have resulted in an increased need for and use of pharmacoepidemiology studies (15). The usual way to discover adverse drug reactions after drug marketing is through spontaneous reporting by practitioners of such reactions to medical journals, pharmaceutic manufacturers, and the FDA (16). Spontaneous reports are a major resource for detecting previously unknown adverse drug effects. It is important for clinicians to be familiar, however, with the limitations of spontaneous reports (1, 4, 5, 16), and to keep these in mind as they read case reports of adverse drug reactions. First, spontaneous reports of adverse reactions are subject to overascertainment: Physicians may attribute an adverse outcome to a drug when in fact it is not. Second, these reports are subject to underascertainment: Physicians may not recognize that an adverse outcome is caused by a drug when it is. Third, these reports are subject to underreporting: Physicians may not report an adverse reaction even when they do recognize it. Finally, and perhaps most importantly, because spontaneous reports are not accompanied by good estimates of the population at risk, it is not possible to calculate rates of adverse reactions. There is, therefore, no way to differentiate whether a given number of spontaneous reports of adverse reactions is smaller or larger than one would expect simply by chance. For all these reasons, spontaneous reports 180
of adverse reactions are only useful for raising hypotheses of possible adverse drug effects. Many of these hypotheses are not confirmed when subjected to more rigorous testing (4). How is such testing done? The study designs used are the usual ones of clinical epidemiology, especially randomized clinical trials, cohort studies, and case-control studies (17). There are, however, three major differences. First, before drug marketing, randomized clinical trials must be done to document drug efficacy. Thus, this design has less to add after the drug is marketed, unless such studies are investigating different questions. Second, before marketing between 500 and 3000 patients are exposed to a drug in order to be reasonably sure that adverse effects are detected if they occur with an incidence of 1 to 6 per 1000 (4, 5, 18). To detect an adverse effect one tenth as common (that is, to be 95% certain of detecting any adverse effect that occurs with an incidence of 3/10 000 or greater), postmarketing studies of drug effects must include at least 10 000 exposed subjects in a cohort study or tap a population of equivalent size for a case-control study. Third, postmarketing questions about adverse drug effects often represent clinical, public health, regulatory, and commercial crises. As such, studies often must be done very quickly. These requirements raise major logistic obstacles to conducting financially feasible studies, and have led to the development of a set of special research approaches (4, 5). These include the use of hospital-based nurse monitors to perform cohort studies of the short-term effects of drugs (19). Nurse monitors may also take histories of lifetime drug exposure for case-control studies to explore whether one or more of these antecedent exposures may have caused the disease that resulted in hospitalization (20). A number of efforts recently have been underway to try to take advantage of the large data bases of medical claims information that are being developed by insurers and organized medical care systems for management purposes (21). For example, considerable work has been done using data from the Group Health Cooperative of Puget Sound (22) and the Kaiser Permanente Medical Care Program (23). Attempts have also been made to use data from Medicaid claims (24) and from Saskatchewan Health (25). Although each has advantages and disadvantages (4, 5), all of these approaches can be used to conduct rigorous nonexperimental studies, in many cases designed to test the hypotheses generated by spontaneous reports. Interest in pharmacoepidemiology is increasing rapidly. Pharmacoepidemiology research in the United States is receiving increasing support from the FDA, the National Institutes of Health (NIH), and the pharmaceutic industry. Canada's Arthritis Society held a 2-day workshop on the use of pharmacoepidemiology to study anti-rheumatic drugs, and McGill and McMaster Universities are developing pharmacoepidemiology programs. Several journals are now actively soliciting pharmacoepidemiology papers; an annual international meeting attracts over 250 participants; and a new International Society for Pharmacoepidemiology has been formed. Good pharmacoepidemiology research requires collaboration among many different disciplines. Experts in
1 August 1990 • Annals of Internal Medicine • Volume 113 • Number 3
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this field should understand clinical medicine and clinical pharmacology as well as the research methods of clinical epidemiology. However, although there is a clearly perceived need for more scholars in this field, funding for training still needs to be addressed. In large part funding is scarce because governmental sources for research training, for example the NIH, tend to be organized by organ system, so that interdisciplinary training depends on non-federal funding. Many institutions are now capable of carrying out such training; for example, those with clinical epidemiology training programs. Scientists interested in receiving training in pharmacoepidemiology, however, usually can only do so if they qualify for otherfinancialsupport; the funding available for training in pharmacoepidemiology per se is extremely limited. Pharmacoepidemiology is a new field that, despite its problems, has already shown its ability to contribute to increasing the rational use of drugs. It has developed a number of possible approaches to detecting and evaluating possible adverse and beneficial drug effects. Spontaneous reports of such reactions are the most common that clinicians will see, and they serve an important role in raising hypotheses. However, only rigorous controlled studies, experimental or nonexperimental, can be used to test these hypotheses. Brian L. Strom, MD, MPH University of Pennsylvania School of Medicine Philadelphia, PA 19104-6095 Peter Tugwell, MD, MSc McMaster University Hamilton, Ontario L8N 3Z5 Annals of Internal Medicine. 1990;113:179-181. Grant Support: Cooperative agreement FD-U-000079 from the U.S. Food and Drug Administration, NIH grants R01-HD24316 and R01HD20531, and funds from The Andrew W. Mellon Foundation and The Rockefeller Foundation. Requests for Reprints: Brian L. Strom, MD, MPH, 315R NEB, Clinical Epidemiology Unit, Section of General Internal Medicine, Departments of Medicine and Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6095. References 1. Strom BL. Post-marketing surveillance: an idea whose time has come. In: Melmon KL, ed. Drug Therapeutics. New York: Elsevier-North Holland; 1982:155-63.
2. Davies DM. Textbook of Adverse Drug Reactions. 3d ed. New York: Oxford University Press; 1985:4. 3. Shapiro S, Slone D, Lewis GP, Jick H. Fatal drug reactions among medical inpatients. JAMA. 1971;216:467-72. 4. Joint Commission on Prescription Drug Use. The Final Report of the Joint Commission on Prescription Drug Use, Inc. Washington, DC: Joint Commission on Prescription Drug Use; 1980. 5. Strom BL. The promise of pharmacoepidemiology. Annu Rev Pharmacol Toxicol. 1987;27:71-86. 6. Erslav AJ, Wintrobe MM. Detection and prevention of drug induced blood dyscrasias. JAMA. 1962;181:114-9. 7. Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med. 1971;284:878-81. 8. Strom BL, Carson JL, Morse ML, West SL, Soper KA. The effect of indication on hypersensitivity reactions associated with zomepirac sodium and other nonsteroidal antiinflammatory drugs. Arthritis Rheum. 1987;30:1142-8. 9. Ticrynafen recalled. FDA Drug Bull. 1980;10:3-4. 10. Suspension of benoxaprofen (Opren). Br Med J. 1982;285:519. 11. Strom BL, West SL, Sim E, Carson JL. The epidemiology of the acute flank pain syndrome from suprofen. Clin Pharmacol Ther. 1989;46:693-9. 12. Marwick C. FDA ponders approaches to curbing adverse effects of drug used against cystic acne. JAMA. 1988;259:3225. 13. Koska MT. JCAHO accreditation: top trouble spots for hospitals. Hospitals. 1989;63:34. 14. Sturek JK. Point-of-service computer system and drug-use evaluation: implications for pharmacy practice in ambulatory care. Am J Hosp Pharm. 1989;46:S 17-20. 15. Ezzell C. AZT given the green light for clinical treatment of AIDS. Nature. 1987,326:430. 16. Faich GA. Adverse-drug-reaction reporting. N Engl J Med. 1986; 314:1589-92. 17. Sackett DL, Haynes RB, Tugwell P. Clinical Epidemiology: A Basic Science for Clinical Medicine. Boston: Little, Brown; 1985. 18. Strom BL. Sample size considerations for pharmacoepidemiologic studies. In: Strom BL, ed. Pharmacoepidemiology. New York: Churchill Livingstone; 1989;27-38. 19. Miller RR, Greenblatt DJ. Drug Effects in Hospitalized Patients. New York: Wiley; 1976. 20. Slone D, Shapiro S, Miettinen OS. Case-control surveillance of serious illnesses attributable to ambulatory drug use. In: Colombo F, Shapiro S, Slone D, Tognoni G, eds. Epidemiological Evaluation of Drugs. Littleton, Massachusetts: PSG Publishing Company; 1977: 59-70. 21. Strom BL. Medical databases in post-marketing drug surveillance. Trends in Pharmacological Sciences. 1986;7:377-80. 22. Stergachis A. Group health cooperative of Puget Sound. In: Strom BL, ed. Pharmacoepidemiology. New York: Churchill Livingstone; 1989:149-60. 23. Friedman GD. Kaiser Permanente Medical Care Program: northern California and other regions. In: Strom BL, ed. Pharmacoepidemiology. New York: Churchill Livingstone; 1989:161-72. 24. Strom BL, Carson JL, Morse ML, LeRoy AA. The computerized on-line Medicaid pharmaceutical analysis and surveillance system: a new resource for postmarketing drug surveillance. Clin Pharmacol Ther. 1985;38:359-64. 25. Strand LM, West R. Health databases in Saskatchewan. In: Strom BL, ed. Pharmacoepidemiology. New York: Churchill Livingstone; 1989:189-200. © 1990 American College of Physicians
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Policy on Repetitive Publication and Copyright: Annals of Internal Medicine Scholarly publication is expensive, and competition among authors for space in journals is intense. Readers can be confused when they find through literature searching apparently unrelated papers that in fact represent repetitive publication. For these reasons, this journal is committed in policy to discouraging repetitive publication. Authors submitting papers to this journal must confirm that the paper, as submitted or its essence in another version, has not been published elsewhere, is not under consideration for publication elsewhere, and will not be submitted for publication elsewhere while under consideration by Annals. Prior publication of some content of the paper may not preclude the paper's publication in Annals. Authors must, however, provide full information in the cover letter sent with the submitted manuscript on any possibly repetitive publication of content. Possibly repetitive publication is illustrated by these examples: 1) reworked data already reported; 2) cases or subjects in a study cohort already described in a published report; 3) previously reported single or multiple cases; 4) content already published or to be published in another format such as the proceedings of a meeting or a symposium, a chapter in a book, or a letter to the Editors; 5) content published in a language other than English. Papers with content that has been presented at a meeting or in a poster session are usually not considered to have been published previously unless the paper has been published in full in a proceedings or most of the data has been reported as a result of press coverage of the oral presentation with scientific detail sufficient to support the main conclusion. Authors are free to discuss their research with representatives of the
182
popular media if they wish to do so, but we ask that authors not distribute copies of papers being considered for publication in Annals or accepted for publication. In general, brief reports in the popular media of work described in a submitted paper are not considered prior or repetitive publication by the Editors of Annals. Authors should be aware, however, that problems with copyright ownership could arise from publication of substantial portions of their papers in the popular press. Authors should fully inform the Editors of any circumstance that might be construed as repetitive publication and include copies of such reports of their findings for review by the Editors. The American College of Physicians holds copyright on Annals and asks that authors transfer to the College all rights for print publication; electronic publication; production of reprints, facsimiles, microfilm or microfiche; and publication in languages other than English. All authors, except U.S. Government employees whose work was done as part of their official duties, must sign a transfer-of-copyright form (published in the advertising pages of each issue of Annals). Xerographic copies of Annals articles may be made for not-for-profit educational purposes and for use by libraries. Anyone wishing to reproduce articles or portions of articles for any other use must request permission from the Managing Editor. Other details involving permissions are given on the transfer-of-copyright form. Because there are many other ethical and legal as well as technical issues to be considered when submitting articles, we urge authors to read the long form of our "Information for Readers and Authors," which appears in the 1 January and 1 July issues. -The Editors
1 August 1990 • Annals of Internal Medicine • Volume 113 • Number 3
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20 years earlier (7). Pharmacoepidemiology studies have also led to the discovery of many recent serious, if uncommon, adverse effects of new drugs, resulting in withdrawal of the drug from the market, including zomepirac (Zomax, McNeil Pharmaceutical, Spring House, Pennsylvania) (8), ticrynafen (Selacryn, SmithKline Beecham Laboratories, Philadelphia Pennsylvania) (9), benoxaprofen (Oraflex, Eli Lilly and Company, Indianapolis, Indiana) (10), suprofen (Suprol, McNeil Pharmaceutical) (11) or labeling changes, for example, isotretinoin (Accutane, Roche Laboratories, Nutley, New Jersey) (12), and others (1, 4, 5). Over the next few years, however, pharmacoepidemiology is likely to have an increasing impact on clinical medicine. For example, the Joint Commission for Accreditation of Health Care Organizations (13) has recently begun enforcing new requirements for all hospitals to develop the capability to document and evaluate adverse drug reactions that occur in their patients and to conduct ongoing drug utilization review programs. Thus, every physician in the United States who practices in a hospital will soon be confronting these pharmacoepidemiology activities. As another example, until the catastrophic health insurance program was repealed, Medicare was planning to begin reimbursing persons on Medicare for their prescription medications. The law establishing these new pharmaceutical benefits included a requirement for drug utilization review; physicians would have received routine notifications if their patients had received inappropriate prescriptions (14). Most Medicaid programs and many health maintenance organizations already have such programs. Finally, the FDA has been under enormous pressure to approve drugs earlier, especially drugs for the treatment of the acquired immunodeficiency syndrome and cancer. Initiatives undertaken to achieve this with, for example, zidovudine, have resulted in an increased need for and use of pharmacoepidemiology studies (15). The usual way to discover adverse drug reactions after drug marketing is through spontaneous reporting by practitioners of such reactions to medical journals, pharmaceutic manufacturers, and the FDA (16). Spontaneous reports are a major resource for detecting previously unknown adverse drug effects. It is important for clinicians to be familiar, however, with the limitations of spontaneous reports (1, 4, 5, 16), and to keep these in mind as they read case reports of adverse drug reactions. First, spontaneous reports of adverse reactions are subject to overascertainment: Physicians may attribute an adverse outcome to a drug when in fact it is not. Second, these reports are subject to underascertainment: Physicians may not recognize that an adverse outcome is caused by a drug when it is. Third, these reports are subject to underreporting: Physicians may not report an adverse reaction even when they do recognize it. Finally, and perhaps most importantly, because spontaneous reports are not accompanied by good estimates of the population at risk, it is not possible to calculate rates of adverse reactions. There is, therefore, no way to differentiate whether a given number of spontaneous reports of adverse reactions is smaller or larger than one would expect simply by chance. For all these reasons, spontaneous reports 180
of adverse reactions are only useful for raising hypotheses of possible adverse drug effects. Many of these hypotheses are not confirmed when subjected to more rigorous testing (4). How is such testing done? The study designs used are the usual ones of clinical epidemiology, especially randomized clinical trials, cohort studies, and case-control studies (17). There are, however, three major differences. First, before drug marketing, randomized clinical trials must be done to document drug efficacy. Thus, this design has less to add after the drug is marketed, unless such studies are investigating different questions. Second, before marketing between 500 and 3000 patients are exposed to a drug in order to be reasonably sure that adverse effects are detected if they occur with an incidence of 1 to 6 per 1000 (4, 5, 18). To detect an adverse effect one tenth as common (that is, to be 95% certain of detecting any adverse effect that occurs with an incidence of 3/10 000 or greater), postmarketing studies of drug effects must include at least 10 000 exposed subjects in a cohort study or tap a population of equivalent size for a case-control study. Third, postmarketing questions about adverse drug effects often represent clinical, public health, regulatory, and commercial crises. As such, studies often must be done very quickly. These requirements raise major logistic obstacles to conducting financially feasible studies, and have led to the development of a set of special research approaches (4, 5). These include the use of hospital-based nurse monitors to perform cohort studies of the short-term effects of drugs (19). Nurse monitors may also take histories of lifetime drug exposure for case-control studies to explore whether one or more of these antecedent exposures may have caused the disease that resulted in hospitalization (20). A number of efforts recently have been underway to try to take advantage of the large data bases of medical claims information that are being developed by insurers and organized medical care systems for management purposes (21). For example, considerable work has been done using data from the Group Health Cooperative of Puget Sound (22) and the Kaiser Permanente Medical Care Program (23). Attempts have also been made to use data from Medicaid claims (24) and from Saskatchewan Health (25). Although each has advantages and disadvantages (4, 5), all of these approaches can be used to conduct rigorous nonexperimental studies, in many cases designed to test the hypotheses generated by spontaneous reports. Interest in pharmacoepidemiology is increasing rapidly. Pharmacoepidemiology research in the United States is receiving increasing support from the FDA, the National Institutes of Health (NIH), and the pharmaceutic industry. Canada's Arthritis Society held a 2-day workshop on the use of pharmacoepidemiology to study anti-rheumatic drugs, and McGill and McMaster Universities are developing pharmacoepidemiology programs. Several journals are now actively soliciting pharmacoepidemiology papers; an annual international meeting attracts over 250 participants; and a new International Society for Pharmacoepidemiology has been formed. Good pharmacoepidemiology research requires collaboration among many different disciplines. Experts in
1 August 1990 • Annals of Internal Medicine • Volume 113 • Number 3
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this field should understand clinical medicine and clinical pharmacology as well as the research methods of clinical epidemiology. However, although there is a clearly perceived need for more scholars in this field, funding for training still needs to be addressed. In large part funding is scarce because governmental sources for research training, for example the NIH, tend to be organized by organ system, so that interdisciplinary training depends on non-federal funding. Many institutions are now capable of carrying out such training; for example, those with clinical epidemiology training programs. Scientists interested in receiving training in pharmacoepidemiology, however, usually can only do so if they qualify for otherfinancialsupport; the funding available for training in pharmacoepidemiology per se is extremely limited. Pharmacoepidemiology is a new field that, despite its problems, has already shown its ability to contribute to increasing the rational use of drugs. It has developed a number of possible approaches to detecting and evaluating possible adverse and beneficial drug effects. Spontaneous reports of such reactions are the most common that clinicians will see, and they serve an important role in raising hypotheses. However, only rigorous controlled studies, experimental or nonexperimental, can be used to test these hypotheses. Brian L. Strom, MD, MPH University of Pennsylvania School of Medicine Philadelphia, PA 19104-6095 Peter Tugwell, MD, MSc McMaster University Hamilton, Ontario L8N 3Z5 Annals of Internal Medicine. 1990;113:179-181. Grant Support: Cooperative agreement FD-U-000079 from the U.S. Food and Drug Administration, NIH grants R01-HD24316 and R01HD20531, and funds from The Andrew W. Mellon Foundation and The Rockefeller Foundation. Requests for Reprints: Brian L. Strom, MD, MPH, 315R NEB, Clinical Epidemiology Unit, Section of General Internal Medicine, Departments of Medicine and Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6095. References 1. Strom BL. Post-marketing surveillance: an idea whose time has come. In: Melmon KL, ed. Drug Therapeutics. New York: Elsevier-North Holland; 1982:155-63.
2. Davies DM. Textbook of Adverse Drug Reactions. 3d ed. New York: Oxford University Press; 1985:4. 3. Shapiro S, Slone D, Lewis GP, Jick H. Fatal drug reactions among medical inpatients. JAMA. 1971;216:467-72. 4. Joint Commission on Prescription Drug Use. The Final Report of the Joint Commission on Prescription Drug Use, Inc. Washington, DC: Joint Commission on Prescription Drug Use; 1980. 5. Strom BL. The promise of pharmacoepidemiology. Annu Rev Pharmacol Toxicol. 1987;27:71-86. 6. Erslav AJ, Wintrobe MM. Detection and prevention of drug induced blood dyscrasias. JAMA. 1962;181:114-9. 7. Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med. 1971;284:878-81. 8. Strom BL, Carson JL, Morse ML, West SL, Soper KA. The effect of indication on hypersensitivity reactions associated with zomepirac sodium and other nonsteroidal antiinflammatory drugs. Arthritis Rheum. 1987;30:1142-8. 9. Ticrynafen recalled. FDA Drug Bull. 1980;10:3-4. 10. Suspension of benoxaprofen (Opren). Br Med J. 1982;285:519. 11. Strom BL, West SL, Sim E, Carson JL. The epidemiology of the acute flank pain syndrome from suprofen. Clin Pharmacol Ther. 1989;46:693-9. 12. Marwick C. FDA ponders approaches to curbing adverse effects of drug used against cystic acne. JAMA. 1988;259:3225. 13. Koska MT. JCAHO accreditation: top trouble spots for hospitals. Hospitals. 1989;63:34. 14. Sturek JK. Point-of-service computer system and drug-use evaluation: implications for pharmacy practice in ambulatory care. Am J Hosp Pharm. 1989;46:S 17-20. 15. Ezzell C. AZT given the green light for clinical treatment of AIDS. Nature. 1987,326:430. 16. Faich GA. Adverse-drug-reaction reporting. N Engl J Med. 1986; 314:1589-92. 17. Sackett DL, Haynes RB, Tugwell P. Clinical Epidemiology: A Basic Science for Clinical Medicine. Boston: Little, Brown; 1985. 18. Strom BL. Sample size considerations for pharmacoepidemiologic studies. In: Strom BL, ed. Pharmacoepidemiology. New York: Churchill Livingstone; 1989;27-38. 19. Miller RR, Greenblatt DJ. Drug Effects in Hospitalized Patients. New York: Wiley; 1976. 20. Slone D, Shapiro S, Miettinen OS. Case-control surveillance of serious illnesses attributable to ambulatory drug use. In: Colombo F, Shapiro S, Slone D, Tognoni G, eds. Epidemiological Evaluation of Drugs. Littleton, Massachusetts: PSG Publishing Company; 1977: 59-70. 21. Strom BL. Medical databases in post-marketing drug surveillance. Trends in Pharmacological Sciences. 1986;7:377-80. 22. Stergachis A. Group health cooperative of Puget Sound. In: Strom BL, ed. Pharmacoepidemiology. New York: Churchill Livingstone; 1989:149-60. 23. Friedman GD. Kaiser Permanente Medical Care Program: northern California and other regions. In: Strom BL, ed. Pharmacoepidemiology. New York: Churchill Livingstone; 1989:161-72. 24. Strom BL, Carson JL, Morse ML, LeRoy AA. The computerized on-line Medicaid pharmaceutical analysis and surveillance system: a new resource for postmarketing drug surveillance. Clin Pharmacol Ther. 1985;38:359-64. 25. Strand LM, West R. Health databases in Saskatchewan. In: Strom BL, ed. Pharmacoepidemiology. New York: Churchill Livingstone; 1989:189-200. © 1990 American College of Physicians
1 August 1990 • Annals of Internal Medicine
• Volume 113 • Number 3
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Policy on Repetitive Publication and Copyright: Annals of Internal Medicine Scholarly publication is expensive, and competition among authors for space in journals is intense. Readers can be confused when they find through literature searching apparently unrelated papers that in fact represent repetitive publication. For these reasons, this journal is committed in policy to discouraging repetitive publication. Authors submitting papers to this journal must confirm that the paper, as submitted or its essence in another version, has not been published elsewhere, is not under consideration for publication elsewhere, and will not be submitted for publication elsewhere while under consideration by Annals. Prior publication of some content of the paper may not preclude the paper's publication in Annals. Authors must, however, provide full information in the cover letter sent with the submitted manuscript on any possibly repetitive publication of content. Possibly repetitive publication is illustrated by these examples: 1) reworked data already reported; 2) cases or subjects in a study cohort already described in a published report; 3) previously reported single or multiple cases; 4) content already published or to be published in another format such as the proceedings of a meeting or a symposium, a chapter in a book, or a letter to the Editors; 5) content published in a language other than English. Papers with content that has been presented at a meeting or in a poster session are usually not considered to have been published previously unless the paper has been published in full in a proceedings or most of the data has been reported as a result of press coverage of the oral presentation with scientific detail sufficient to support the main conclusion. Authors are free to discuss their research with representatives of the
182
popular media if they wish to do so, but we ask that authors not distribute copies of papers being considered for publication in Annals or accepted for publication. In general, brief reports in the popular media of work described in a submitted paper are not considered prior or repetitive publication by the Editors of Annals. Authors should be aware, however, that problems with copyright ownership could arise from publication of substantial portions of their papers in the popular press. Authors should fully inform the Editors of any circumstance that might be construed as repetitive publication and include copies of such reports of their findings for review by the Editors. The American College of Physicians holds copyright on Annals and asks that authors transfer to the College all rights for print publication; electronic publication; production of reprints, facsimiles, microfilm or microfiche; and publication in languages other than English. All authors, except U.S. Government employees whose work was done as part of their official duties, must sign a transfer-of-copyright form (published in the advertising pages of each issue of Annals). Xerographic copies of Annals articles may be made for not-for-profit educational purposes and for use by libraries. Anyone wishing to reproduce articles or portions of articles for any other use must request permission from the Managing Editor. Other details involving permissions are given on the transfer-of-copyright form. Because there are many other ethical and legal as well as technical issues to be considered when submitting articles, we urge authors to read the long form of our "Information for Readers and Authors," which appears in the 1 January and 1 July issues. -The Editors
1 August 1990 • Annals of Internal Medicine • Volume 113 • Number 3
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