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Pharmacoepidemiology: a basic science for drug administration and drug safety
PIIA Kb4ACEUTICA XTA HELVETIAE ELSEVIER
Pharmaceutics
Pharmacoepidemiology:
Acta Helvetiae 71 (1996) 363-365
a basic science for drug administration and drug safety
Walter 0. Spitzer a,b, Rudolf Bruppacher a Depat-tment ofEpidemiology b Potsdam Institute for Pharmacoepidemiology Received
a,b,*
and Biostatistics, McGill University, Montreal, Canada and Technology Assessment, University of Potsdam, Potsdam, Germany
16 February
1996; accepted 8 May 1996
Abstract Pharmacoepidemiology
is defined
as the study
of medicines
Keywords:
Adverse drug reactions;
Drug research:
Drug safety; Epidemiology;
1. Benefits and risk of modern pharmacotherapy An amazing number of new pharmaceutical products and pharmaceutical principles have been developed in the past decades. They probably amount to us much progress in the healing sciences as all other therapeutic and preventive advances in the same period and perhaps as much as all the progress in medicine since the dawn of history. HZ-receptor antagonists, the physiologically targeted cardiovascular drugs or particularly antihypertensives, vaccines and antibiotics are some examples (Black et al., 1972; Ondetti et al., 1977). But effective medicines used to treat and prevent disease also have the capacity to do harm. There is no such thing as an absolutely safe drug, as a knife is either blunt or sharp. Both individuals and whole groups of patients are vulnerable to adverse consequences of pharmacological therapy, both to expected and not expected undesirable
* Corresponding author. Alleeweg 8, CH-4310 Rheinfelden, land. Tel.: +41-61-8331010; Fax: +41-61.8331012. 003 l-6865/96/$15.00 Copyright PI2 SO03 l-6865(96)00034-9
of health and disease in populations. It is a bridge science epidemiology, biostatistics, demography and social sciences. The development of more and more potent but also increasingly drug administration and drug safety, of which pharmacoepidemito meet such needs.
as determinants
bringing together pharmacology and pharmacy, clinical specialties, Epidemiology and clinical pharmacology are the two main bridgeheads. expensive medicines will accentuate the need for skilled practitioners of ology is the basic science. Strategies in education have to be developed
Switzer-
Pharmacotherapy
effects. This includes major events as serious disease, permanent disability or even death. Questions are raised: “is the benefit of a newly developed product worth the cost of the patient and group society?“, “how distinct have advantages of a new drug or a biological to be in order to justify its disadvantages in risk or in cost?“. Patients, physicians, public health authorities and the general public are challenged to pursue a balance of benefit and harm that does not neglect the need neither of the patients nor the legitimated needs of the society.
2. Pharmacoepidemiology, plines
linking
established
disci-
Pharmacoepidemiology is the study of drugs as determinants of health and disease in the general unselected population. It incorporates the science of measuring drug mediated health events in large, unselected, well defined populations (Friedman, 1980, Strom, 1994). It links exposure with terms of therapeutic gain of life, quality of life or
0 1996 Elsevier Science B.V. All rights reserved.
364
W.O. Spitzer, R. Bruppacher/
Pharmaceutics
adverse events for any appropriate subgroup in any selected medicine. In simple words it studies “what people do with drugs and what drugs do to people”. Pharmacoepidemiology is a new bridge science drawn from the disciplines of pharmacology, therapeutics, epidemiology and statistics. Not only does it have a long and cumbersome name, but it is not a clearly demarcated field. It is best characterized by its spans, its overlaps or even by its incursions rather than by its borders. Only in the past decades have epidemiology and pharmacology been joined by creative development, largely stimulated by unfortunate events following drug administration. Instrumental in these have been Slone et al. (1966), Jick et al. (1970) from Boston, the founders of the Boston Collaborative Drug Surveillance Program, which in 20 years produced more than 200 scientific publications covering a wide field of drug related issues (Cohen, 1986). Other pioneers comprise Inman (198 1) with his innovative system of “Prescription Event Monitoring in the UK”, Strom from Philadelphia, Lasagna (1974) and Wardell (1974) from Rochester, then Ray from Tennessee, Bergman et al. (1979) from Stockholm, Porta and Hartzema (1988) and Laporte from Barcelona. Seminal theoretical advances were published by Miettinen (1976) and Feinstein (1985) in the same period of time. Some investigators moulded the new field working in governmental settings and include West (1987) and Strand in Saskatchewan, and Faith et al. (1987) Rossi and Stadel in the US Food and Drug Administration. Important contributions and support came from industry (Guess et al., 1988; Tilson and Bruppacher, 1990). The foregoing does not pretend to be an exhaustive list of those who initiated and furthered the discipline, nor can the references reflect adequately their work and its chronology.
3. Pharmacoepidemiology a basic surveillance and drug administration
science
for
drug
Even though epidemiology has a lot to contribute to the development of drugs, its major activity so far has focussed on the period after registration of a drug by a regulatory agency usually referred to as ‘Phase IV research’ or ‘post-marketing surveillance studies’ (Porta and Hartzema, 1988). The practice of post-marketing surveillance by companies and authorities includes activities such as spontaneous report collections. Specimen examples are the yellow card system of the Medicines Control Agency in the United Kingdom or the adverse event reporting system of the Food and Drug Administration in the United States. Spontaneous report systems, however, are rather designed to
Acta Helretiae
71 (19961363-365
detect signals and raise questions, not to answer them. Pharmacoepidemiology is the basic science for the practice of drug safety or drug mediated public health, in so far as it adapts and refines the methods of studies, validates the tactic use in the applications, tests hypotheses generated by the ongoing surveillance system and develops ad hoc active surveillance approaches. Strategies employed are the same as in other field of epidemiology: case control studies, cohort studies and surveys. The clinical trials as employed during the development of a drug and also in Phase IV can be considered as a special form of such cohort studies. Too little employed so far are still the interventional studies, where part of the populations are exposed to a different kind of drug supply or of information about a drug, and that could be well used to validate also the impact of change in product information. Adverse drug reactions are rather rare, and this is why study populations need to be quite big to get enough statistical power in order to test the hypotheses. In the past decades, methods have therefore been developed to use large databases, usually collected for other purposes (billing data, computerized practices). This type of so-called ‘record linkage studies’ requires special experience and expertise to avoid falling victim to the many of the possible biases and distortions inherent in these exercises.
4. Need for educational
strategies
The need for education in pharmacoepidemiology going in public concern over drug safety and closer regulation of drug development and drug surveillance lead to an increased need for expertise in the field of pharmacoepidemiology. Senior governmental public servants and executives from the private sector must be able to evaluate issues or risk and benefit in the context of public and political concern when taking decisions, which affect economically important market drugs. But, most important, the practitioner and the pharmacist prescribing or handing out the drugs should be knowledgeable in this field and also should be in a position to know how experience with the public health impact is elaborated and help to contribute also to new knowledge. There could be a process of ad hoc training by experience on the job or self-planned continuing education, there seems to be, however, an increasing need to also build in the type of training in the usual curricula of students, both in medicine and in pharmacy. Particularly pharmacists are very close to actual administration and handling of drugs. They are frequently advisors of patients and physicians and need a profound knowl-
W.O. Spitzer, R. Bruppacher/
Pharmaceutics
edge in the practical aspects of drug administration in order to put them to best possible use. Only a drug that is used adequately can exert all its benefits and avoid unnecessary negative effects. It is in this sense that a good training in pharmacoepidemiology is also an essential part of the pharmaceutical curriculum. But also the pharmacists involved in hospital care, and in the industrial development and manufacturing of medicines have to be aware of conditions and impact of the everyday use of the products which usually differ from the results obtained in the artificial situation of clinical studies. The health care system of today and tomorrow will need pharmacists who by their knowledge and determination can help to put pharmaceutical products to optimal use in the population they serve.
References Bergman, U., Norlin, A. and Wiholm, B.E. (1979) Inadequacies in hospital drug handling. Acta Med. Stand. 205, 79-85. Black, J.W., Duncan, A.M. and Durant, C.J. (1972) Definition and antagonism of histamine Hz-receptors. Nature 236, 385-390. Cohen, M.R. (1986) A compilation of abstracts and index published by the Boston Collaborative Drug Surveillance Program 1966-1985. Hosp. Pharm. 21,497-559. Jick, H., Miettinen, OS., Shapiro, S. et al. (1970) Comprehensive drug surveillance. JAMA 213, 1455-60. Faith, G.A., Lawson, D.H., Tilson, H.H. and Walker, A. (1987) Clinical
Acta Helvetiae
71 (1996) 363-365
365
trials are not enough: Drug development and pharmacoepidemiology. J. Clin. Res. Drug Dev. 1, 75. Feinstein, A.R. (19851 The Architecture of Clinical Research. W.B. Saunders, Philadelphia. Friedman, G.D. (1980) Primer of Epidemiology, 2nd Ed. McGraw-Hill, Toronto, p. 1. Guess, H.A., Stephenson, W.P., Sacks, S.T. and Gardner, J.S. (1988) Beyond pharmacoepidemiology: The larger role of epidemiology in drug development. J. Clin. Epidemiol. 41, 995-996. Inman, W.H.W. (1981) Postmarketing surveillance of adverse drug reactions in general practice II. Prescription event monitoring at the University of Southampton. Br. Med. J. 282, 1216-1217. Lasagna, L.L. (1974) A plea for ‘naturalistic’ study of medicines. Eur. J. Clin. Pharmacol. 7, 153-154. Miettinen, O.S. (1976) Estimability and estimation in case referent studies. Am. J. Epidemiol. 103, 226-235. Ondetti, M.A., Rubin, B. and Cushman, D.W. (1977) Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. Science 196, 44-444. Porta, M.S. and Hartzema, A.G. (1988) The contribution of epidemiology to the study of drugs. In: A.G. Hartzema, M.S. Porta and H.H. Tilson (Eds.), Pharmacoepidemiology, an Introduction. Harvey Whitney Books, Cincinnati, pp. 2-17. Slone, D., Jick, H., Borda, I. et al (1966) Drug Surveillance using nurse monitors. Lancet ii, 901-903. Strom, B.L. (Ed.) (1994) Pharmacoepidemiology (2nd Ed.). John Wiley and Sons, Chichester, New York, Brisbane, Toronto, Singapore. Tilson, H.H. and Bruppacher, R. (19901 A working group on epidemiology in the pharmaceutical industry (EPI): A new force in the field. J. Clin. Res. Pharmacoepidemiol. 4, 91-97. Wardell, W.M. (1974) Therapeutic implications of the drug lag. Clin. Pharmacol. Ther. 15, 73-96. West, R. (1987) Saskatchewan Health: A developing resource. Am. J. Prev. Med. (Suppl.), 25-27.
Pharmaceutics
Pharmacoepidemiology:
Acta Helvetiae 71 (1996) 363-365
a basic science for drug administration and drug safety
Walter 0. Spitzer a,b, Rudolf Bruppacher a Depat-tment ofEpidemiology b Potsdam Institute for Pharmacoepidemiology Received
a,b,*
and Biostatistics, McGill University, Montreal, Canada and Technology Assessment, University of Potsdam, Potsdam, Germany
16 February
1996; accepted 8 May 1996
Abstract Pharmacoepidemiology
is defined
as the study
of medicines
Keywords:
Adverse drug reactions;
Drug research:
Drug safety; Epidemiology;
1. Benefits and risk of modern pharmacotherapy An amazing number of new pharmaceutical products and pharmaceutical principles have been developed in the past decades. They probably amount to us much progress in the healing sciences as all other therapeutic and preventive advances in the same period and perhaps as much as all the progress in medicine since the dawn of history. HZ-receptor antagonists, the physiologically targeted cardiovascular drugs or particularly antihypertensives, vaccines and antibiotics are some examples (Black et al., 1972; Ondetti et al., 1977). But effective medicines used to treat and prevent disease also have the capacity to do harm. There is no such thing as an absolutely safe drug, as a knife is either blunt or sharp. Both individuals and whole groups of patients are vulnerable to adverse consequences of pharmacological therapy, both to expected and not expected undesirable
* Corresponding author. Alleeweg 8, CH-4310 Rheinfelden, land. Tel.: +41-61-8331010; Fax: +41-61.8331012. 003 l-6865/96/$15.00 Copyright PI2 SO03 l-6865(96)00034-9
of health and disease in populations. It is a bridge science epidemiology, biostatistics, demography and social sciences. The development of more and more potent but also increasingly drug administration and drug safety, of which pharmacoepidemito meet such needs.
as determinants
bringing together pharmacology and pharmacy, clinical specialties, Epidemiology and clinical pharmacology are the two main bridgeheads. expensive medicines will accentuate the need for skilled practitioners of ology is the basic science. Strategies in education have to be developed
Switzer-
Pharmacotherapy
effects. This includes major events as serious disease, permanent disability or even death. Questions are raised: “is the benefit of a newly developed product worth the cost of the patient and group society?“, “how distinct have advantages of a new drug or a biological to be in order to justify its disadvantages in risk or in cost?“. Patients, physicians, public health authorities and the general public are challenged to pursue a balance of benefit and harm that does not neglect the need neither of the patients nor the legitimated needs of the society.
2. Pharmacoepidemiology, plines
linking
established
disci-
Pharmacoepidemiology is the study of drugs as determinants of health and disease in the general unselected population. It incorporates the science of measuring drug mediated health events in large, unselected, well defined populations (Friedman, 1980, Strom, 1994). It links exposure with terms of therapeutic gain of life, quality of life or
0 1996 Elsevier Science B.V. All rights reserved.
364
W.O. Spitzer, R. Bruppacher/
Pharmaceutics
adverse events for any appropriate subgroup in any selected medicine. In simple words it studies “what people do with drugs and what drugs do to people”. Pharmacoepidemiology is a new bridge science drawn from the disciplines of pharmacology, therapeutics, epidemiology and statistics. Not only does it have a long and cumbersome name, but it is not a clearly demarcated field. It is best characterized by its spans, its overlaps or even by its incursions rather than by its borders. Only in the past decades have epidemiology and pharmacology been joined by creative development, largely stimulated by unfortunate events following drug administration. Instrumental in these have been Slone et al. (1966), Jick et al. (1970) from Boston, the founders of the Boston Collaborative Drug Surveillance Program, which in 20 years produced more than 200 scientific publications covering a wide field of drug related issues (Cohen, 1986). Other pioneers comprise Inman (198 1) with his innovative system of “Prescription Event Monitoring in the UK”, Strom from Philadelphia, Lasagna (1974) and Wardell (1974) from Rochester, then Ray from Tennessee, Bergman et al. (1979) from Stockholm, Porta and Hartzema (1988) and Laporte from Barcelona. Seminal theoretical advances were published by Miettinen (1976) and Feinstein (1985) in the same period of time. Some investigators moulded the new field working in governmental settings and include West (1987) and Strand in Saskatchewan, and Faith et al. (1987) Rossi and Stadel in the US Food and Drug Administration. Important contributions and support came from industry (Guess et al., 1988; Tilson and Bruppacher, 1990). The foregoing does not pretend to be an exhaustive list of those who initiated and furthered the discipline, nor can the references reflect adequately their work and its chronology.
3. Pharmacoepidemiology a basic surveillance and drug administration
science
for
drug
Even though epidemiology has a lot to contribute to the development of drugs, its major activity so far has focussed on the period after registration of a drug by a regulatory agency usually referred to as ‘Phase IV research’ or ‘post-marketing surveillance studies’ (Porta and Hartzema, 1988). The practice of post-marketing surveillance by companies and authorities includes activities such as spontaneous report collections. Specimen examples are the yellow card system of the Medicines Control Agency in the United Kingdom or the adverse event reporting system of the Food and Drug Administration in the United States. Spontaneous report systems, however, are rather designed to
Acta Helretiae
71 (19961363-365
detect signals and raise questions, not to answer them. Pharmacoepidemiology is the basic science for the practice of drug safety or drug mediated public health, in so far as it adapts and refines the methods of studies, validates the tactic use in the applications, tests hypotheses generated by the ongoing surveillance system and develops ad hoc active surveillance approaches. Strategies employed are the same as in other field of epidemiology: case control studies, cohort studies and surveys. The clinical trials as employed during the development of a drug and also in Phase IV can be considered as a special form of such cohort studies. Too little employed so far are still the interventional studies, where part of the populations are exposed to a different kind of drug supply or of information about a drug, and that could be well used to validate also the impact of change in product information. Adverse drug reactions are rather rare, and this is why study populations need to be quite big to get enough statistical power in order to test the hypotheses. In the past decades, methods have therefore been developed to use large databases, usually collected for other purposes (billing data, computerized practices). This type of so-called ‘record linkage studies’ requires special experience and expertise to avoid falling victim to the many of the possible biases and distortions inherent in these exercises.
4. Need for educational
strategies
The need for education in pharmacoepidemiology going in public concern over drug safety and closer regulation of drug development and drug surveillance lead to an increased need for expertise in the field of pharmacoepidemiology. Senior governmental public servants and executives from the private sector must be able to evaluate issues or risk and benefit in the context of public and political concern when taking decisions, which affect economically important market drugs. But, most important, the practitioner and the pharmacist prescribing or handing out the drugs should be knowledgeable in this field and also should be in a position to know how experience with the public health impact is elaborated and help to contribute also to new knowledge. There could be a process of ad hoc training by experience on the job or self-planned continuing education, there seems to be, however, an increasing need to also build in the type of training in the usual curricula of students, both in medicine and in pharmacy. Particularly pharmacists are very close to actual administration and handling of drugs. They are frequently advisors of patients and physicians and need a profound knowl-
W.O. Spitzer, R. Bruppacher/
Pharmaceutics
edge in the practical aspects of drug administration in order to put them to best possible use. Only a drug that is used adequately can exert all its benefits and avoid unnecessary negative effects. It is in this sense that a good training in pharmacoepidemiology is also an essential part of the pharmaceutical curriculum. But also the pharmacists involved in hospital care, and in the industrial development and manufacturing of medicines have to be aware of conditions and impact of the everyday use of the products which usually differ from the results obtained in the artificial situation of clinical studies. The health care system of today and tomorrow will need pharmacists who by their knowledge and determination can help to put pharmaceutical products to optimal use in the population they serve.
References Bergman, U., Norlin, A. and Wiholm, B.E. (1979) Inadequacies in hospital drug handling. Acta Med. Stand. 205, 79-85. Black, J.W., Duncan, A.M. and Durant, C.J. (1972) Definition and antagonism of histamine Hz-receptors. Nature 236, 385-390. Cohen, M.R. (1986) A compilation of abstracts and index published by the Boston Collaborative Drug Surveillance Program 1966-1985. Hosp. Pharm. 21,497-559. Jick, H., Miettinen, OS., Shapiro, S. et al. (1970) Comprehensive drug surveillance. JAMA 213, 1455-60. Faith, G.A., Lawson, D.H., Tilson, H.H. and Walker, A. (1987) Clinical
Acta Helvetiae
71 (1996) 363-365
365
trials are not enough: Drug development and pharmacoepidemiology. J. Clin. Res. Drug Dev. 1, 75. Feinstein, A.R. (19851 The Architecture of Clinical Research. W.B. Saunders, Philadelphia. Friedman, G.D. (1980) Primer of Epidemiology, 2nd Ed. McGraw-Hill, Toronto, p. 1. Guess, H.A., Stephenson, W.P., Sacks, S.T. and Gardner, J.S. (1988) Beyond pharmacoepidemiology: The larger role of epidemiology in drug development. J. Clin. Epidemiol. 41, 995-996. Inman, W.H.W. (1981) Postmarketing surveillance of adverse drug reactions in general practice II. Prescription event monitoring at the University of Southampton. Br. Med. J. 282, 1216-1217. Lasagna, L.L. (1974) A plea for ‘naturalistic’ study of medicines. Eur. J. Clin. Pharmacol. 7, 153-154. Miettinen, O.S. (1976) Estimability and estimation in case referent studies. Am. J. Epidemiol. 103, 226-235. Ondetti, M.A., Rubin, B. and Cushman, D.W. (1977) Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. Science 196, 44-444. Porta, M.S. and Hartzema, A.G. (1988) The contribution of epidemiology to the study of drugs. In: A.G. Hartzema, M.S. Porta and H.H. Tilson (Eds.), Pharmacoepidemiology, an Introduction. Harvey Whitney Books, Cincinnati, pp. 2-17. Slone, D., Jick, H., Borda, I. et al (1966) Drug Surveillance using nurse monitors. Lancet ii, 901-903. Strom, B.L. (Ed.) (1994) Pharmacoepidemiology (2nd Ed.). John Wiley and Sons, Chichester, New York, Brisbane, Toronto, Singapore. Tilson, H.H. and Bruppacher, R. (19901 A working group on epidemiology in the pharmaceutical industry (EPI): A new force in the field. J. Clin. Res. Pharmacoepidemiol. 4, 91-97. Wardell, W.M. (1974) Therapeutic implications of the drug lag. Clin. Pharmacol. Ther. 15, 73-96. West, R. (1987) Saskatchewan Health: A developing resource. Am. J. Prev. Med. (Suppl.), 25-27.