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Introduction to Drug Utilization Research 2003
                                                                                            Introduction to Drug
                                                                                            Utilization Research




Tittel: Introduction to Drug Utilization
Research
Opplag: 2 500
Design: Grete Søimer
Foto: Photo Alto/Laurent Hamels
Trykk: Nordberg Aksidenstrykkeri AS


ISBN 82-8082-039-6
IN 0000-2069
                                                                                            2003
Introduction to
Drug Utilization Research




World Health Organization

WHO International Working Group for Drug Statistics Methodology

WHO Collaborating Centre for Drug Statistics Methodology

WHO Collaborating Centre for Drug Utilization Research and Clinical

Pharmacological Services
WHO Library Cataloguing-in-Publication Data

    Introduction to drug utilization research / WHO International Working Group for Drug
    Statistics Methodology, WHO Collaborating Centre for Drug Statistics Methodology,
    WHO Collaborating Centre for Drug Utilization Research and Clinical Pharmacological
    Services.

    1. Drug utilization 2. Research 3. Manuals I.WHO International Working Group for
    Drug Statistics Methodology II.WHO Collaborating Centre for Drug
    Statistics Methodology III.WHO Collaborating Centre for Drug Utilization Research
    and Clinical Pharmacological Services

       ISBN 92 4 156234 X                                  (NLM classification: WB 330)




2




    © World Health Organization 2003
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    that they are endorsed or recommended by the World Health Organization in preference to
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    The World Health Organization does not warrant that the information contained in this
    publication is complete and correct and shall not be liable for any damages incurred as a
    result of its use.

    Printed in Oslo, Norway, 2003
3
Contents


Preface: Drug utilization research - the early work ...........................................................................6

Chapter 1: What is drug utilization research and why is it needed? ...............................................8
  1.1 Definition and domains............................................................................................................8
  1.2 Why drug utilization research? ................................................................................................9
        1.2.1 Description of drug use patterns ....................................................................................9
        1.2.2 Early signals of irrational use of drugs .......................................................................10
        1.2.3 Interventions to improve drug use - follow-up ............................................................10
        1.2.4 Quality control of drug use...........................................................................................10
  1.3 Drug utilization studies and drug policy decisions................................................................11
  1.4 General reading ......................................................................................................................12

Chapter 2: Types of drug use information ........................................................................................13
  2.1 Drug-based information .........................................................................................................13
        2.1.1 Level of drug use aggregation .....................................................................................13
        2.1.2 Indication .....................................................................................................................13
        2.1.3 Prescribed daily doses .................................................................................................14
  2.2 Problem or encounter-based information ..............................................................................15
  2.3 Patient information.................................................................................................................16
  2.4 Prescriber information ...........................................................................................................16
  2.5 Types of drug utilization study ..............................................................................................17
  2.6 Drug costs ..............................................................................................................................17
  2.7 General reading ......................................................................................................................18
  2.8 Exercises ................................................................................................................................19

Chapter 3: Sources of data on drug utilization ................................................................................20
  3.1 Large databases ......................................................................................................................20
  3.2 Data from drug regulatory agencies ......................................................................................20
  3.3 Supplier (distribution) data ....................................................................................................20
  3.4 Practice setting data ...............................................................................................................21
        3.4.1 Prescribing data ............................................................................................................21
        3.4.2 Dispensing data ............................................................................................................22
        3.4.3 Aggregate data .............................................................................................................22
        3.4.4 Over-the-counter and pharmacist-prescribed drugs ....................................................22
        3.4.5 Telephone and Internet prescribing .............................................................................22
  3.5 Community setting data .........................................................................................................23
  3.6 Drug use evaluation ...............................................................................................................23
  3.7 General reading ......................................................................................................................24
  3.8 Exercises ................................................................................................................................24

Chapter 4: Economic aspects of drug use (pharmacoeconomy) ....................................................26
  4.1 Introduction ............................................................................................................................26
  4.2 Cost-minimization analysis....................................................................................................26
  4.3 Cost-effectiveness analysis ....................................................................................................26
  4.4 Cost-utility analysis ...............................................................................................................27
  4.5 Cost-benefit analysis ..............................................................................................................27
  4.6 General reading ......................................................................................................................28
  4.7 Exercises ................................................................................................................................28
Chapter 5: Drug classification systems..............................................................................................33
  5.1 Different classification systems .............................................................................................33
  5.2 The ATC classification system...............................................................................................33
  5.3 Ambivalence towards an international classification system ................................................35
  5.4 Implementation of the ATC/DDD methodology ...................................................................36
  5.5 General reading ......................................................................................................................36
  5.6 Exercises ................................................................................................................................37

Chapter 6: Drug utilization metrics and their applications ............................................................38
  6.1 The concept of the defined daily dose (DDD).......................................................................38
  6.2 Prescribed daily dose and consumed daily dose....................................................................39
  6.3 Other units for presentation of volume..................................................................................39
  6.4 Cost ......................................................................................................................................39
  6.5 General reading .....................................................................................................................40
  6.6 Exercises ...............................................................................................................................41

Chapter 7: Solutions to the exercises .................................................................................................74

Acknowledgements...............................................................................................................................84
Preface:
    Drug utilization research - the early work

    The development of drug utilization research              became clear that we need to know the answers
    was sparked by initiatives taken in Northern              to the following questions:
    Europe and the United Kingdom in the mid-                 • why drugs are prescribed;
    1960s (1, 2). The pioneering work of Arthur               • who the prescribers are;
    Engel in Sweden and Pieter Siderius in Holland            • for whom the prescribers prescribe;
    (3) alerted many investigators to the importance          • whether patients take their medicines correctly;
    of comparing drug use between different count-            • what the benefits and risks of the drugs are.
    ries and regions. Their demonstration of the
    remarkable differences in the sales of antibiotics        The ultimate goal of drug utilization research
    in six European countries between 1966 and                must be to assess whether drug therapy is rational
    1967 inspired WHO to organize its first meeting           or not. To reach this goal, methods for auditing
    on «Drug consumption» in Oslo in 1969 (4).                drug therapy towards rationality are necessary.
    This led to the constitution of the WHO                      The early work did not permit detailed compa-
    European Drug Utilization Research Group                  risons of the drug utilization data obtained from
    (DURG).                                                   different countries because the source and form
       The pioneers of this research understood that a        of the information varied between them. To
    correct interpretation of data on drug utilization        overcome this difficulty, researchers in Northern
    requires investigations at the patient level. It          Ireland (United Kingdom), Norway and Sweden
6




    Figure 1 Utilization of insulin and oral antidiabetic drugs in seven European countries from 1971-1980 expressed
    in defined daily doses (DDDs) per 1000 inhabitants per day. For comparison the prescribed daily doses (PDD)
    per 1000 inhabitants per day of oral antidiabetic drugs are given for Northern Ireland (UK) and Sweden for 1980
    (indicated with an asterisk).
developed a new unit of measurement, initially                  Scandinavica, 1984, Suppl. 683:7-9.
called the agreed daily dose (5) and later the
                                                          2.    Dukes MNG. Development from Crooks to the
defined daily dose (DDD) (6). This unit was
                                                                nineties. In: Auditing Drug Therapy.
defined as the average maintenance dose of                      Approaches towards rationality at reasonable
the drug when used on its major indication in                   costs. Stockholm, Swedish Pharmaceutical
adults. The first study used antidiabetic drugs                 Press, 1992.
as an example: it was found that the sum of the
                                                          3.    Engel A, Siderius P. The consumption of drugs.
DDDs of insulin and oral antidiabetic drugs
                                                                Report on a study 1966-1967. Copenhagen,
(about 20 DDDs per1000 inhabitants per day)                     WHO Regional Office for Europe, 1968 (EURO
roughly corresponded to the morbidity due to                    3101).
diabetes after correction for the number of pati-
ents treated with dietary regimens alone. Among           4.    Consumption of drugs. Report on a symposium
                                                                in Oslo 1969. Copenhagen, WHO Regional
the first countries to adopt the DDD methodo-
                                                                Office for Europe, 1970 (EURO 3102).
logy was the former Czechoslovakia (7) and the
first comprehensive national list of DDDs was             5.    Bergman U, et al. The measurement of drug
published in Norway in 1975 (8). Another                        consumption. Drugs for diabetes in Northern
important methodological advance was the adop-                  Ireland, Norway, and Sweden. European
                                                                Journal of Clinical Pharmacology, 1975,8:83-
tion of the uniform anatomical therapeutic che-
                                                                89.
mical (ATC) classification of drugs (see chapter                                                                    7
5.2). The use of standardized methodology allo-           6.    Bergman U et al., eds. Studies in drug utilizati-
wed meaningful comparisons of drug use in                       on. Methods and applications. Copenhagen,
different countries to be made (Fig. 1).                        WHO Regional Office for Europe, 1979 (WHO
                                                                Regional Publications, European Series No. 8).
   Drug utilization research developed quickly
during the following 30 years and soon became a           7.    Stika L et al. Organization of data collection in
respectable subject for consideration at inter-                 Czechoslovakia. In: Bergman U et al., eds.
national congresses in pharmacology, pharmacy                   Studies in drug utilization. Methods and appli-
and epidemiology. Particularly rapid develop-                   cations. WHO Regional Office for Europe,
                                                                Copenhagen, 1979 (WHO Regional Publications
ments were seen in Australia (9) and Latin
                                                                European Series No. 8) pp.125-136.
America (10). The number of English-language
papers on the subject listed in the Cumulative            8.    Baksaas Aasen I et al. Drug dose statistics, list
index medicus rose from 20 in 1973 (when the                    of defined daily doses for drugs registered in
term «drug utilization« first appeared) to 87 in                Norway. Oslo, Norsk Medicinal Depot, 1975.
1980, 167 in 1990, and 486 in 2000.
                                                          9.    Hall RC. Drug use in Australia. In: Sjöqvist F,
   History has taught us that successful research               Agenäs I, eds. Drug utilization studies:
in drug utilization requires multidisciplinary col-             Implications for medical care. Acta Medica
laboration between clinicians, clinical pharmaco-               Scandinavica, 1983, Suppl. XXX:79-80.
logists, pharmacists and epidemiologists.
                                                          10.   Drug Utilization Research Group, Latin
Without the support of the prescribers, this rese-
                                                                America. Multicenter study on self-medication
arch effort will fail to reach its goal of facilita-            and self-prescription in six Latin American
ting the rational use of drugs.                                 countries. Clinical Pharmacology and
                                                                Therapeutics, 1997, 61:488-493.
References
                                                          11.   Bergman U, Sjöqvist F. Measurement of drug
1.    Wade O. Drug utilization studies - the first              utilization in Sweden: methodological and clini-
      attempts. Plenary lecture. In: Sjöqvist F,                cal implications. Acta Medica Scandinavica,
      Agenäs I. eds. Drug utilization studies: implica-         1984, Suppl 683:15-22.
      tions for medical care. Acta Medica
Chapter 1: What is drug utilization research
    and why is it needed?

    1.1. Definition and domains                                                    not. Sophisticated utilization-oriented pharma-
                                                                                   coepidemiology may focus on the drug (e.g.
        Drug utilization; pharmacoepidemiology;                                    dose-effect and concentration-effect relationships),
    [   pharmacosurveillance; pharmacovigilance                           ]        the prescriber (e.g. quality indices of the prescrip-
                                                                                   tion), or the patient (e.g. selection of drug and
    • Drug utilization research was defined by                                     dose, and comparisons of kidney function, drug
    WHO in 1977 as «the marketing, distribution,                                   metabolic phenotype/genotype, age, etc.).
    prescription, and use of drugs in a society, with                                 Drug utilization research is thus an essential
    special emphasis on the resulting medical, social                              part of pharmacoepidemiology as it describes the
    and economic consequences». Since then, a                                      extent, nature and determinants of drug exposure.
    number of other terms have come into use and it                                Over time, the distinction between these two
    is important to understand the interrelationships                              terms has become less sharp, and they are some-
    of the different domains.                                                      times used interchangeably. However, while
    • Epidemiology has been defined as «the study                                  drug utilization studies often employ various
    of the distribution and determinants of health-                                sources of information that focus on drugs (e.g.
    related states and events in the population, and                               aggregate data from wholesale and prescription
    the application of this study to control of health                             registers) the term epidemiology implies defined
    problems».                                                                     populations in which drug use can be expressed
8   • Pharmacoepidemiology applies epidemiologi-                                   in terms of incidence and prevalence (see
    cal methods to studies of the clinical use of                                  chapter 1.2.1).
    drugs in populations. A modern definition of                                      Together, drug utilization research and pharma-
    pharmacoepidemiology is: «the study of the use                                 coepidemiology may provide insights into the fol-
    and effects/side-effects of drugs in large numbers                             lowing aspects of drug use and drug prescribing.
    of people with the purpose of supporting the
    rational and cost-effective use of drugs in the                                • Pattern of use: This covers the extent and pro-
    population thereby improving health outcomes».                                 files of drug use and the trends in drug use and
    • Pharmacosurveillance and pharmacovigi-                                       costs over time.
    lance are terms used to refer to the monitoring                                • Quality of use: This is determined using audits
    of drug safety, for example, by means of spon-                                 to compare actual use to national prescription
    taneous adverse-effect reporting systems, case-                                guidelines or local drug formularies.1 Indices of
    control and cohort studies.                                                    quality of drug use may include the choice of
                                                                                   drug (compliance with recommended assort-
    Pharmacoepidemiology may be drug-oriented,                                     ment), drug cost (compliance with budgetary
    emphasizing the safety and effectiveness of indi-                              recommendations), drug dosage (awareness of
    vidual drugs or groups of drugs, or utilization-                               inter-individual variations in dose requirements
    oriented aiming to improve the quality of drug                                 and age-dependence), awareness of drug inter-
    therapy through pedagogic (educational) inter-                                 actions and adverse drug reactions, and the pro-
    vention. Drug utilization research may also be                                 portion of patients who are aware of or unaware
    divided into descriptive and analytical studies.                               of the costs and benefits of the treatment.
    The emphasis of the former has been to describe                                • Determinants of use: These include user cha-
    patterns of drug utilization and to identify pro-                              racteristics (e.g. sociodemographic parameters
    blems deserving more detailed studies.                                         and attitudes towards drugs), prescriber characte-
    Analytical studies try to link data on drug utili-                             ristics (e.g. speciality, education and factors
    zation to figures on morbidity, outcome of treat-                              influencing therapeutic decisions) and drug cha-
    ment and quality of care with the ultimate goal                                racteristics (e.g. therapeutic properties and affor-
    of assessing whether drug therapy is rational or                               dability).
    1 An audit in drug use was defined by Crooks (1979) as an examination of the way in which drugs are used in clinical practice carried out at intervals
    frequent enough to maintain a generally accepted standard of prescribing.
• Outcomes of use: These are the health out             price. Without a knowledge of how drugs are
comes (i.e. the benefits and adverse effects) and       being prescribed and used, it is difficult to initiate
the economic consequences.                              a discussion on rational drug use or to suggest
                                                        measures to improve prescribing habits.
The initial focus of pharmacoepidemiology was           Information on the past performance of prescri-
on the safety of individual drug products (phar-        bers is the linchpin of any auditing system.
macosurveillance), but it now also includes stu-           Drug utilization research in itself does not
dies of their beneficial effects. The driving force     necessarily provide answers, but it contributes to
behind this development was a growing awa-              rational drug use in important ways as described
reness that the health outcomes of drug use in          below.
the rigorous setting of randomized clinical trials
are not necessarily the same as the health outco-       1.2.1 Description of drug
mes of drug use in everyday practice. The clini-        use patterns
cal trials needed to obtain marketing authori-          Drug utilization research can increase our under-
zation for new drugs involve limited numbers of         standing of how drugs are being used as follows.
carefully selected patients, who are treated and
followed-up for a relatively short time in strictly     • It can be used to estimate the numbers of pati-
controlled conditions. As a result, such trials do      ents exposed to specified drugs within a given
not accurately reflect how drug use will affect         time period. Such estimates may either refer to          9
health outcomes in everyday practice under every-       all drug users, regardless of when they started to
day circumstances. Pharmacoepidemiological              use the drug (prevalence), or focus on patients
studies often make useful contributions to our          who started to use the drug within the selected
knowledge about effectiveness and safety, because,      period (incidence).
unlike clinical trials, they assess drug effects in     • It can describe the extent of use at a certain
large, heterogeneous populations of patients over       moment and/or in a certain area (e.g. in a coun-
longer periods.                                         try, region, community or hospital). Such des-
   Drug utilization research also provides insight      criptions are most meaningful when they form
into the efficiency of drug use, i.e. whether a         part of a continuous evaluation system, i.e. when
certain drug therapy provides value for money           the patterns are followed over time and trends in
and the results of such research can be used to         drug use can be discerned.
help to set priorities for the rational allocation of   • Researchers can estimate (e.g. on the basis of
health care budgets.                                    epidemiological data on a disease) to what extent
                                                        drugs are properly used, overused or underused.
1.2 Why drug utilization                                • It can determine the pattern or profile of drug
research?                                               use and the extent to which alternative drugs are
  Description of drug use pattern; early signals        being used to treat particular conditions.
  of irrational use of drugs; interventions to          • It can be used to compare the observed patterns
  improve drug use; quality control cycle;              of drug use for the treatment of a certain disease
  continuous quality improvement                        with current recommendations or guidelines.
                                                        • It can be used in the application of quality indi-
The principal aim of drug utilization research is       cators to patterns of drug utilization. An exam-
to facilitate the rational use of drugs in popu-        ple is the so-called DU90% (drug utilization
lations. For the individual patient, the rational       90%), a further development of the «top-ten»
use of a drug implies the prescription of a well-       list.
documented drug at an optimal dose, together               The DU90% segment reflects the number of
with the correct information, at an affordable          drugs that account for 90% of drug prescriptions
and the adherence to local or national prescrip-     mal practice, whether pedagogic interventions
     tion guidelines in this segment. This general        (education) are required or whether the guide-
     indicator can be applied at different levels (e.g.   lines should be reviewed in the light of actual
     individual prescriber, group of prescribers, hos-    practice. These hypotheses should apply to both
     pitals, region or county) to obtain a rough esti-    under use and over use of drugs.
     mate of the quality of prescribing.
     • Drug utilization data can be fed back to pre-      1.2.3 Interventions to improve
     scribers. This is particularly useful when the       drug use - follow-up
     drug prescribing by a particular individual can      Drug utilization research undertaken in the follo-
     be compared with some form of «gold standard»        wing ways may enable us to assess whether
     or best practice, and with the average prescrip-     interventions intended to improve drug use have
     tions in the relevant country, region or area.       had the desired impact.
     • The number of case reports about a drug pro-       • The effects of measures taken to ameliorate
     blem or adverse effects can be related to the        undesirable patterns of drug use (e.g. provision
     number of patients exposed to the drug to assess     of regional or local formularies, information
     the potential magnitude of the problem. If it is     campaigns and regulatory policies) should be
     possible to detect that the reaction is more com-    monitored and evaluated. The researchers
     mon in a certain age group, in certain conditions    should bear in mind that prescribers may have
10   or at a given dose level, improving the informa-     switched to other drugs that are equally undesi-
     tion on indications, contraindications and           rable. These potential alternative drugs should
     appropriate dosages may be sufficient to ensure      be included in the survey to assess the full
     safer use and avoid withdrawal of the drug from      impact of the measure.
     the market.                                          • The impact of regulatory changes or changes
                                                          in insurance or reimbursement systems should
     1.2.2 Early signals of irrational use                be assessed using a broad survey. This is neces-
     of drugs                                             sary because the total cost to society may remain
     Drug utilization research may generate hypothe-      the same or may even increase if more expen-
     ses that set the agenda for further investigations   sive drugs are used as alternatives.
     as outlined below, and thus avoid prolonged irra-    • The extent to which the promotional activities
     tional use of drugs.                                 of the pharmaceutical industry and the educatio-
     • Drug utilization patterns and costs between        nal activities of the society affect the patterns of
     different regions or at different times may be       drug use should be assessed.
     compared. Hypotheses can be generated to form
     the basis for investigations of the reasons for,     1.2.4 Quality control of drug use
     and health implications of, the differences          Drug use should be controlled according to a
     found. Geographical differences and changes in       quality control cycle that offers a systematic
     drug use over time may have medical, social and      framework for continuous quality improve-
     economic implications both for the individual        ment. The components of such a cycle are illu-
     patient and for society, and should therefore be     strated on the next page.
     identified, explained and, when necessary cor-
     rected.                                              After step 4, the cycle begins again with new
     • The observed patterns of drug use can be com-      analyses, the setting of new targets, and so on.
     pared with the current recommendations and             The quality control cycle can be applied at
     guidelines for the treatment of a certain disease.   many levels, ranging from local or regional dis-
     Hypotheses can then be generated to determine        cussion groups consisting of physicians, clinical
     whether discrepancies represent less than opti-      pharmacologists or pharmacists to national and
Step 1. Plan. Analyse current situation to               Step 2. Do. Implement the plan on a small
 establish a plan for improvment (e.g. analyse            scale (e.g. provide feedback on possible
 current prescription patterns of individual              overuse, underuse or drug misuse of
 prescribers, groups of prescribers, or health            individual drugs or therapeutic groups).
 facilities).


 Step 4. Act Revise plan or implement plan                Step 3. Check Check to see if expected
 on large scale (e.g. guide national imple-               results are obtained (e.g. evaluate whether
 mentation of plan).                                      prescription patterns really improve).

international initiatives. An important technique     and validated from 1992-1994. Since then,
that can be used in conjunction with this cycle       annual reviews of drug utilization have been
is benchmarking. By comparing drug utiliza-           used to provide background information for
tion data from different localities, it is often      decisions on regulatory and reimbursement poli-
possible to detect substantial differences that       cies in Estonia; two examples are described
require further evaluation, which may then lead       below.
to the identification and promotion of best prac-        If physicians have high rates of inappropriate
tice. Such comparisons will be accurate and           prescribing, drug regulatory authorities can          11
truthful provided that the data are collected and     require educational intervention or impose
aggregated in a standardized, uniform way (see        restrictions on specific drugs or on practitioners.
chapter 5).                                           In Estonia, it was decided to stop the import and
                                                      use of some hazardous products, such as phena-
1.3 Drug utilization studies and                      cetine, older sulphonamides and pyrazolones,
drug policy decisions                                 after clarifying and explaining the reasons for
Many of the questions asked in drug utilization       this in the national Drug information bulletin,
research and the answers obtained are important       which is distributed free by the drug regulatory
for initiating and modifying a rational drug poli-    authority to all prescribers in Estonia.
cy at both national and local levels. Two suc-           In planning the reimbursement policies, the
cessful examples of the use of such research are      total volume of drug use in DDDs was monito-
given below.                                          red carefully. During the 1990s, the use of pre-
                                                      scription-only medicines measured as number of
Drug use in Estonia                                   DDDs per capita was less than one third of that
An important reason for undertaking studies of        reported from the Nordic countries. This proved
drug use in Estonia after its independence was        to be the result of under-treatment of certain
the need to make decisions on drug policy. At         chronic diseases (i.e. hypertension and schizo-
the time, no information was available in the         phrenia), and therefore the decision was to incre-
country on which drugs were used (sold), or on        ase the availability and use of cardiovascular and
the quantities and there was therefore no rationale   neuroleptic drugs. Thus, the national drug use
for regulating the drug market. Moreover, in the      surveys in Estonia have been used to monitor the
absence of any feedback system it was impos-          impact of drug regulatory activities as well as to
sible to gauge the impact of possible future          follow the increase in drug expenditure.
interventions. A national drug classification         Because data on drug use are only part of the
system was therefore developed for Estonia, and       background material relevant to the discussions
a reporting system from wholesalers, based on         and decisions on therapeutic strategies - at both
this classification, was implemented, checked         the local and national levels - it is difficult to
evaluate the specific influence of drug utilization                     rent social-class districts in the catchment areas
     research on developments in drug policies. It is,                       of 11 health centres.1
     however, reasonable to assume that such studies
     have contributed to a more rational use of drugs                        1.4 General reading
     in Estonia.1                                                            Bergman U et al. Drug utilization 90% - a sim-
                                                                             ple method for assessing the quality of drug pre-
     Drug use in Latin America                                               scribing. European Journal of Clinical
     The second example is the successful work within                        Pharmacology, 1998, 54:113-118.
     the Latin American DURG, in association with                               Crooks J. Methods of audit in drug use. In:
     the WHO Collaborating Centre of Pharmaco-                               Duchene-Marulla ZP, ed. Advances in pharma-
     epidemiology in Barcelona, Spain.                                       cology and therapeutics. Proceedings of 7th
       In September 1991, health professionals from                          International Congress of Pharmacology, Paris,
     Spain and eight Latin American countries met in                         1978. Oxford, Pergamon Press, 1979:189-195.
     Barcelona for the «First Meeting of Latin                                  Diogène E et al. The Cuban experience in
     American Groups for Drug Epidemiology». It                              focusing pharmaceuticals policy to health popu-
     was made clear that in most of the countries                            lation needs: initial results of the National
     taking part, data on drug utilization were scarce                       Pharmacoepidemiology Network (1996-2001).
     and fragmentary. Some national drug regulatory                          European Journal of Clinical Pharmacology,
12   authorities had no access to either quantitative or                     2002, in press.
     qualitative data on drug consumption and reali-                            Drug Utilization Research Group, Latin
     zed that information on patterns of drug utili-                         America. Multicenter study on self-medication
     zation would be useful for designing drug policy                        and self-prescription in six Latin American
     and educational programmes about drugs.                                 countries. Clinical Pharmacology and
       It was agreed at this meeting to set up a Latin                       Therapeutics, 1997, 61:488-493.
     American network (later called DURG-LA),                                   Dukes MNG, ed. Drug Utilization Studies:
     with the following aims:                                                Methods and Uses. Copenhagen, WHO Regional
     – to promote drug utilization research in Latin                         Office for Europe, 1993 (WHO Regional
       American countries;                                                   Publications European Series No. 45)
     – to exchange experiences and information                                  Einarson TR, Bergman U, Wiholm BE.
       between the participating groups;                                     Principles and practice of pharmacoepidemiolo-
     – to use the knowledge generated to give techni-                        gy. In: Avery’s Drug Treatment, 4th ed. Adis
       cal advice to drug regulatory authorities and to                      International:371-392.
       guide teaching of pharmacology;                                          Figueras A et al. Health need, drug registration
     – to write and disseminate information aimed at                         and control in less developed countries - the
       improving drug use, and                                               Peruvian case. Pharmacoepidemiology and Drug
     – to participate in the training of health pro-                         Safety, 2001, 10:1-2.
       fessionals in pharmacoepidemiology and thera-                            Laporte JR, Porta M, Capella D. Drug utiliza-
       peutics.                                                              tion studies: a tool for determining the effecti-
                                                                             veness of drug use. British Journal of Clinical
     Seven further DURG-LA meetings have been                                Pharmacology, 1983, 16:301-304.
     held over the subsequent ten years to promote                              McGavock H. Handbook of drug use research
     drug utilization research. Part of the initial core                     methodology 1st ed. Newcastle upon Tyne,
     group participated in a first multicentre study in                      United Kingdom Drug Utilization Research
     six Latin American countries to examine self-                           Group, 2000.
     medication and self-prescription. The study was                            Strom BL. Pharmacoepidemiology, 3rd ed.
     carried out in a sample of pharmacies from diffe-                       New York, J Wiley, 2000.
     1 The information about DURG-LA was provided in a personal communication by Dr Albert Figueras and Professor Joan-Ramon Laporte,
       Barcelona, Spain.
Chapter 2: Types of drug use information


Different types of drug use information are           2.1.2 Indication
required depending on the problem being exami-        For drugs with multiple indications, it will usually
ned. These include information about the overall      be important to divide data on use according to
use of drugs, drug groups, individual generic         indication to allow a correct interpretation of the
compounds or specific products. Often, infor-         overall trends. An example is the relative use of
mation about the condition being treated, the         drug groups in treating hypertension. The over-
patient and the prescriber is also required. In       all data might suggest that the relative use of
addition, data on drug costs will be important in     diuretics is comparable to that of ACE inhibitors
ensuring that drugs are used efficiently and eco-     and higher than the use of calcium channel bloc-
nomically. These types of drug information are        kers (column A in Table 1). However, analysis
described in detail below, together with exam-        of the data according to indication may reveal
ples to illustrate the ways in which the informa-     that 75% of ACE inhibitors are used to treat
tion can be used to promote the rational use of       hypertension whereas only 43% of diuretics are
drugs.                                                used for this indication (most of the high-ceiling
                                                      diuretics used are for treating heart failure). The
2.1 Drug-based information                            picture that emerges of the use of the two drug
Knowledge of the trends in total drug use may         groups in the treatment of heart failure is mar-
be useful, but more detailed information invol-       kedly altered when use according to indication is
ving aggregation of data on drug use at various       taken into account (column B of Table 1).                          13
levels, and information on indications, doses and
dosage regimens is usually necessary to answer
                                                      Table 1 Relative use of drug groups in the treatment
clinically important questions.                       of hypertension in Australia in 1998a

2.1.1 Level of drug use aggregation
                                                        Drug group                       Ab         Bc       Cd
The level at which data on drug use are aggrega-
ted will depend on the question being asked.            ACE inhibitors (C09A)            31.80      36.6     34.8
For example, the question might concern the             Calcium channel blockers
relative use of drug groups in the treatment of         (C08C)                           24.50      28       26.7
hypertension. It would then be appropriate to           Diuretics (C03)                  29.60      19.4     15.9
aggregate data on diuretics, beta-blockers and          Beta-blockers
angiotensin-converting enzyme (ACE) inhibitors,
                                                        (C07AA, C07AB)                   11.20      11.5     15.7
etc. If, however, the question concerns the rela-
tive use of beta-blockers in hypertension, data at      ATII antagonists
the substance (generic drug) level would be nee-        (C09CA)                          3.00       4.6      6.9
ded. Information on the relative scale of use of
individual products will sometimes be required,
for example to find the market leader or to           Source: Australian Drug Utilization
assess the relative use of generic versus branded     Subcommittee and BEACH Survey April-
or innovator products. Information down to the        December 1998, Sydney University, GPSCU
level of dose strength will be necessary, for         1999.
example, to determine whether there is a trend
                                                      a Values are the use of the drug group expressed as a percenta
towards use of higher strengths of antibiotics, or
                                                        ge of the total use for these drug groups.
to determine the relative use of strengths of anti-   b Based on total use.
depressants to assess whether they are being          c Adjusted for the percentage of total use of each group for the
used at effective doses.                                treatment of hypertension.
                                                      d Relative prescribing of these drug groups in hypertension
                                                       community practice patient encounters.
Another example of a situation in which the             when making such comparisons. The PDDs dif-
     indication is important is antibiotic utilization.      fer between countries and ethnic groups, and
     In determining whether the use of a particular          even between areas or health facilities within the
     antibiotic, for example, amoxicillin, is rational, it   same country. The PDD will also often differ
     will usually be necessary to know what infecti-         for different indications of the same drug, so it
     ons or problems it is being used to treat. It           will sometimes be necessary to reach this level
     would therefore be necessary to break down data         of detail to interpret overall use data.
     on amoxicillin use into indications and compare            Data on the use of tricyclic antidepressants
     these uses with the appropriate guidelines. If it       and selective serotonin reuptake inhibitors
     were found that there was substantial use of            (SSRIs) in Australia are shown in Table 2 as
     amoxicillin to treat acute sore throat, for exam-       both DDDs and prescription volumes.
     ple, this finding would indicate a problem that            The two metrics give different results for the
     needed to be addressed. This is because a nar-          relative use of the two groups of antidepressant
     row-spectrum agent (or no drug) would be a              drugs because of the different relationship bet-
     more appropriate treatment for a sore throat, and       ween the PDDs and the DDDs for the two drug
     if amoxicillin is used to treat mononucleosis,          groups. On average, the PDD is lower than the
     which can present as a sore throat, there is a          DDD for the tricyclics and higher for the SSRIs.
     high incidence of rash.                                 In this case, knowledge of the PDDs is necessary
14                                                           for clinical interpretation of the data.
     2.1.3 Prescribed daily doses                               The DDD per 1000 inhabitants per day is
     The prescribed daily dose (PDD) is the average          often used to derive a rough estimate of the pre-
     daily dose prescribed, as obtained from a repre-        valence of use in the population being studied,
     sentative sample of prescriptions. The use of           and for chronic diseases it may even be used to
     DDD per 1000 inhabitants per day allows aggre-          assess the prevalence of a disease when the drug
     gation of data across drug groups and compari-          is prescribed for a single indication. Such esti-
     sons between countries, regions and health faci-        mates are valid only if the DDDs and the PDDs
     lities. However, the DDD metric may not reflect         are similar.
     the actual PDDs, and this needs to be considered


     Table 2 Relative use of antidepressants in Australia in 1998

                           Prescription           % of total        DDD/1000           % of total DDD/1000
                           volume                 prescription      population/day      population/day
                           (millions)a            volume

      Tricyclics
      (N06AA)              3.53                   48.82             8.40               28.09
      SSRI
      (N06AB)              3.09                   42.74             17.20              57.53
      Moclobemide
      (N06AG02)            0.61                   8.44              4.30               14.38

      Total                7.23                   100.00            29.90              100.00


     Source: Australian Drug Utilization Subcommittee, Department of Health & Aged Care, Commonwealth of
     Australia, http://www.health.gov.au:80/haf/docs/asm.htm
2.2 Problem or encounter-based                             sistent. This consistency between data using two
information                                                different approaches (i.e. drug and problem-
                                                           based) gives confidence in the result.
  Reason for the encounter (the problem);                     Other questions that might be addressed using
  drug treatment versus non-drug treatment;                a problem-based approach include the following:
  other problems managed; severity of the pro-
  blem managed; new or continuing presenta-                • Does the severity of hypertension influence the
  tion; duration of consultation; medications              choice of single or combination therapy?
  prescribed for the problem; how the medica-              • Is the management of newly-presenting pati-
  tions were supplied; other medications pre-              ents different to that of patients already receiving
  scribed                                                  treatment?
                                                           • Are there likely to be any drug interactions
                                                           with co-prescribed treatments?
Rather than asking how a particular group of
                                                           • Is the choice of drug influenced by evidence-
drugs is used, it may be useful to address the
                                                           based outcome data?
question of how a particular problem (e.g. sore
throat, hypertension or gastric ulcer) is managed.
                                                           For some diseases it may be important to study
The different types of information that may be
                                                           the relative use of drug treatment and other the-
required are listed in the box above.
   As an example, consider how problem-based
                                                           rapeutic approaches to map out and understand          15
                                                           pharmacotherapeutic traditions and other thera-
information about the management of hyperten-
                                                           peutic approaches. As an example, drug utiliza-
sion might be used. Initially, concordance with
                                                           tion research in Estonia has shown that there was
guidelines for drug treatment or non-drug mana-
                                                           a reciprocal relationship between the use of hor-
gement of blood pressure and other risk factors
                                                           monal contraceptives and the abortion rate
might be assessed. Where drug treatment is
                                                           from1989-1997 (Fig. 2).
used, the proportion of patients treated with each
of the drug groups gives an overall picture of
                                                           Another example was the excessive use of ulcer
management (column C of Table 1). This is
                                                           surgery in Estonia compared to Sweden during
more direct information on how hypertension is
                                                           the Soviet era. This was because of the difficul-
managed than that provided by assessing the
                                                           ties of obtaining modern anti-ulcer drugs in
overall use of the different drug groups as dis-
                                                           Estonia at that time (Fig. 3).
cussed above. In the example shown in Table 1,
the data in columns B and C are reasonably con-
                  (per 10 000 population




                                                                                   Use of hormonal
                  Nr of abortions




                                                                                   contraceptives
                                                                                   (DDD/1000/day




Figure 2 Abortion rate and use of hormonal contraceptives in Estonia in 1989-1997.
Source: Kiivet R. Drug utilization studies as support to decisions in drug policy in Estonia. [MD Thesis]
Stockholm, Karolinska Institutet, 1999.
80                                                     20

                      60                                                     16
                                                                             12
                      40
                                                                             8
                      20                                                     4
                       0                                                     0
                                     1993                  1995

                       anti-ulcer drugs, Estonia        surgery, Estonia
                       anti-ulcer drugs, Stockholm      surgery, Stockholm


     Figure 3 Treatment of ulcer disease in Estonia and in Stockholm County 1993-1995.
     Source: Kiivet R. Drug utilization studies as support to decisions in drug policy in Estonia.
     [MD Thesis] Stockholm, Karolinska Institutet, 1999.


     2.3 Patient information                                 2.4 Prescriber information
         Age; gender; ethnicity; co-morbidities;                  Demographic information - age, gender,
16   [   knowledge; beliefs and perceptions            ]          medical school, years in practice; type of
                                                                  practice (e.g. specialist or family, rural or
     Information on demographic factors and other                 urban); practice size; patient mix; knowledge
     details about the patient will often be useful.              about drugs; factors driving prescribing
     For example, the age distribution of patients may            behaviour
     be of critical importance, to assess the likelihood
     of severe adverse effects with nonsteroidal anti-       The prescriber plays a critical role in determi-
     inflammatory drugs (NSAIDs), or whether the             ning drug use. Claims have even been made that
     drug is being used to treat patients in an age          the differences between doctors are greater than
     group different from that in which the clinical         those between patients and that variations in
     trials were performed. The co-morbidities of the        drug prescribing behaviour often lack rational
     patient group may be important in determining           explanations. Dissecting the factors that deter-
     the choice of treatment and predicting possible         mine prescribing behaviour is therefore often
     adverse effects. For instance, in the manage-           central to understanding how and why drugs are
     ment of hypertension, beta-blockers should not          prescribed. Some questions that might be
     be used to treat patients with asthma, and ACE          addressed using prescriber information include
     inhibitors are the preferred treatment in patients      the following:
     with heart failure.                                     • Are prescribing profiles influenced by the
        Qualitative information relating to the know-          prescriber’s medical education?
     ledge, beliefs and perceptions of patients and          • Do the prescribing profiles of specialists differ
     their attitudes to drugs will be important in some        from those of family practitioners?
     cases, for example in assessing the pressures put       • Does the age or gender of the prescriber influ-
     by patients on their doctors to prescribe antibio-        ence the prescribing profile?
     tics, or in designing consumer information and          • Are there differences in prescribing behaviour
     education programmes.                                     between urban and rural practices or between
                                                               small and large practices? Do these variations
                                                               indicate a need to target education to particular
                                                               sectors?
• Who are those prescribers who rapidly adopt            often obtained from repeated cross-sectional sur-
recently released drugs?                                 veys (e.g. IMS (Intercontinental Medical
• In assessing rational use of medicines by a            Statistics) practice-based data are of this type).
practitioner, has the practice mix been taken into       Data collection is continuous, but the practitio-
account?                                                 ners surveyed, and therefore the patients, are
• Can the factors that determine and change pre-         continually changing. Such data give informa-
scribing behaviour be identified?                        tion about overall trends, but not about prescri-
                                                         bing trends for individual practitioners or practices.
2.5 Types of drug utilization
study                                                    Continuous longitudinal studies
Drug utilization studies can be targeted towards         In some cases continuous longitudinal data at the
any of the following links in the drug-use chain:        individual practitioner and patient level can be
                                                         obtained. Claims databases are often able to
  – the systems and structures surrounding drug          follow individual patients using a unique (but
  use (e.g. how drugs are ordered, delivered and         anonymous) identifier. These data can provide
  administered in a hospital or health care facility);   information about concordance with treatment
  – the processes of drug use (e.g. what                 based on the period between prescriptions, co-
  drugs are used and how they are used and               prescribing, duration of treatment, PDDs and so
  does their use comply with the relevant                on. As electronic prescribing becomes more               17
  criteria, guidelines or restrictions); and             common, databases are being developed to pro-
  – the outcomes of drug use (e.g. efficacy,             vide continuous longitudinal data comprising
  adverse drug reactions and the use of resour-          full medical and prescribing information at the
  ces such as drugs, laboratory tests, hospital          individual patient level. Such databases are very
  beds or procedures).                                   powerful, and can address a range of issues
                                                         including reasons for changes in therapy, adverse
Cross-sectional studies                                  effects and health outcomes.
Cross-sectional data provide a «snapshot» of
drug use at a particular time (e.g. over a year, a
month or a day). Such studies might be used for
                                                         2.6 Drug costs
making comparisons with similar data collected
over the same period in a different country,               Total drug costs; cost per prescription; cost
health facility or ward, and could be drug-, pro-          per treatment day, month or year; cost per
blem-, indication, prescriber- or patient-based.           defined daily dose (DDD); cost per prescri-
Alternatively, a cross-sectional study can be car-         bed daily dose (PDD); cost as a proportion
ried out before and after an educational or other          of gross national product; cost as a propor-
intervention. Studies can simply measure drug              tion of total health costs; cost as a propor-
use, or can be criterion-based to assess drug use          tion of average income; net cost per health
in relation to guidelines or restrictions.                 outcome (cost-effectiveness ratio); net cost
                                                           per quality adjusted life-year (cost-utility-
Longitudinal studies                                       ratio)
Public health authorities are often interested in
trends in drug use, and longitudinal data are            Data on drug costs will always be important in
required for this purpose. Drug-based longi-             managing policy related to drug supply, pricing
tudinal data can be on total drug use as obtained        and use. Numerous cost metrics can be used and
through a claims database, or the data may be            some of these are shown in the box above. For
based on a statistically valid sample of pharma-         example, the cost per DDD can usually be used
cies or medical practices. Longitudinal data are         to compare the costs of two formulations of the
same drug. However, it is usually inappropriate                     ced a marked increase in the cost of anti-psycho-
     to use this metric to compare the costs of diffe-                   tic drugs over the last 5-10 years; the data on use
     rent drugs or drug groups as the relationship bet-                  and cost for these drugs in Australia are illustra-
     ween DDD and PDD may vary.                                          ted in Fig. 4.
        Estimates of the costs at various levels and
     using data aggregated in various ways will be                       In Australia, there has been little increase in the
     required, depending on the circumstances and                        overall volume of use of antipsychotic drugs,
     the perspective taken. A government perspective                     and the cost increase has been driven by the
     might require information on drug costs and cost                    transfer from the cheap ‘classical’ agents to the
     offsets to government to be collected, whereas a                    much more expensive ‘atypical’ drugs such as
     societal perspective would require both govern-                     clozapine, olanzapine and risperidone resulting
     ment and non-government (private sector) costs                      in an increase in the average cost per prescrip-
     and cost offsets to be determined. A patient per-                   tion. In contrast, both the prescription volume of
     spective will be appropriate if questions about                     antidepressant drugs and the average cost per
     affordability and accessibility are being asked.                    prescription have increased over the same period,
     Costs may be determined at government, health                       due to an ‘add-on’ prescribing effect of the more
     facility, hospital, health maintenance organiza-                    expensive SSRIs.
     tion or other levels within the health sector.
18      Costs will often need to be broken down                          2.7 General reading
     according to drug group or therapeutic area to                      Einarsson TR, Bergman U, Wiholm BE.
     determine, for example, the reason for an increase                  Principles and practice of pharmacoepidemiology.
     in drug costs. For instance, the introduction of                    In: Speight TM, Holford NH, eds. Avery’s Drug
     new, expensive anti-cancer agents may be found                      Treatment. Place, Adis International, 1999:371-
     to be driving the increases in drug costs in a hos-                 392.
     pital. Changes in drug costs can result from
     changes in prescription volumes, quantity per                       Lee D, Bergman U. Studies of drug utilization.
     prescription or in the average cost per prescripti-                 In: Strom B. ed. Pharmacoepidemiology, 3rd ed.
     on. For example, most countries have experien-                      Chichester, J Wiley, 2000:463-481.



                             10                                                                        100
                                                community use
                                                govt cost with clozapine
                              8                                                                        80
              DDs/1000/Day




                                                                                                              $ million




                              6                                                                        60

                                                            use
                              4                                                                        40


                              2                                                                        20
                                                          cost
                              0                                                                        0
                                  1990   1991      1992    1993   1994     1995   1996   1997   1998


     Figure 4 Antipsychotic drugs - use and cost trends in Australia
2.8 Exercises                                     4. Antidepressant use
3. Amoxicillin                                      The use of antidepressant drugs (in DDDs per
  You note that amoxicillin use expressed as        1000 population per day) and their costs have
  DDDs per1000 population per day has               been increasing for at least the last five years.
  increased over the last two years. What types     What types of data would you need to deter-
  of drug utilization data would you need to        mine the reasons for the change and whether it
  evaluate the possible reasons for this?           has resulted in positive or negative health out-
                                                    comes?




                                                                                                        19
Chapter 3: Sources of data on drug utilization


         Drug-use chain; large databases; other sour-       drug distribution chain, pharmaceutical and
     [   ces; drug use evaluation; pharmacoeconomics   ]    medical billing or samples of prescriptions. The
                                                            databases may be international, national or local
     The drug-use chain includes the processes of           in scope. They may be diagnosis-linked or non-
     drug acquisition, storage, distribution, prescri-      diagnosis-linked. Diagnosis-linked data enable
     bing, patient compliance and the review of out-        drug use to be analysed according to patient cha-
     come of treatment. Each of these events is an          racteristics, therapeutic groups, diseases or con-
     important aspect of drug utilization, and most         ditions and, in the best of cases, clinical out-
     countries have regulations to cover these aspects.     come. A useful analysis requires an understand-
     Data are collected, or are available, at national,     ing of the sources and organization of the data.
     regional and local health facility or household
     level and may be derived from quantitative or          3.2 Data from drug regulatory
     qualitative studies. Quantitative data may be          agencies
     used to describe the present situation and the
                                                                Drug registration; drug importation
     trends in drug prescribing and drug use at vari-       [                                                ]
     ous levels of the health care system.
                                                            Drug regulatory agencies have the legal respon-
     Quantitative data may be routinely collected data
                                                            sibility of ensuring the availability of safe, effi-
     or obtained from surveys. Qualitative studies
20   assess the appropriateness of drug utilization and
                                                            cacious and good-quality drugs in their country.
                                                            They are thus the repositories of data on which
     generally link prescribing data to reasons (indi-
                                                            drugs have been registered for use, withdrawn or
     cations) for prescribing. Such studies have been
                                                            banned within a country. Regulatory agencies
     referred to as «drug utilization review» or «drug
                                                            also have inspection and enforcement functions,
     utilization evaluation». The process is one of a
                                                            and are responsible for supervising the importa-
     «therapeutic audit» based on defined criteria and
                                                            tion of drugs and for the issuance of permits for
     is intended to improve the quality of therapeutic
                                                            drug registration.
     care. There is an increasing interest in the evalu-
                                                               It is possible, therefore, to obtain data on the
     ation of the economic impact of clinical care and
                                                            number of drugs registered in a country from
     medical technology. This has evolved into a dis-
                                                            such agencies. Where the agency issues import
     cipline dedicated to the study of how pharma-
                                                            permits and supervises drug importation, data on
     cotherapeutic methods influence resource utili-
                                                            product type (i.e. generic or branded), volume,
     zation in health care known as pharmacoeco-
                                                            port of origin, country of manufacture, batch
     nomics (see chapter 4).
                                                            number and expiry date may be collected.
        The sources of drug utilization data vary from
                                                            Where the data reflect total national imports,
     country to country depending on the level of
                                                            estimates of quantities of drugs in circulation
     sophistication of record keeping, data collection,
                                                            can be obtained for defined periods and for
     analysis and reporting and the operational consi-
                                                            various therapeutic groups
     derations of the health care system.
                                                               It may be difficult to obtain true estimates if
                                                            documentation is incomplete and not all trans-
     3.1 Large databases
                                                            actions are recorded. Information on smuggled
     The increasing interest in efficient use of health
                                                            goods or goods entering the country through ille-
     care resources has resulted in the establishment
                                                            gal routes will not be captured by these data.
     of computer databases for studies on drug utili-
     zation. Some of the databases can generate sta-
     tistics for patterns of drug utilization and adverse
                                                            3.3 Supplier (distribution) data
     drug reactions. Data may be collected on drug              Drug importation; local manufacture; cus-
     sales, drug movement at various levels of the          [   toms service                                 ]
Data on suppliers may be obtained from drug           motivate health care providers to adhere to esta-
importers, wholesalers or local manufacturers.        blished health care standards.
In countries where permits or licences are
required from drug regulatory authorities and         3.4.1 Prescribing data
ministries of health before importation of drugs,     Prescribing data are usually extracted from out-
data may be available from such sources.              patient and inpatient prescription forms. Such
Customs services, in the process of clearing          data may be easily retrieved where records are
imports from the ports of entry, may collect data     computerized and computerized data also facili-
on drugs. However, the codes used by customs          tate trend analysis. In the absence of electronic
services are not detailed enough to capture all       databases, prescribing data are usually extracted
relevant information. National agencies respon-       from patient records or from patient intercept
sible for the collection of excise duty can also      studies or retrieved at dispensing points.
provide information on the volume of production          Information that may be obtained from pre-
and on distribution of drugs from local manufac-      scriptions includes patient demography, drug
turers.                                               name, dosage form, strength, dose, frequency of
   Data from these sources can generally be used      administration and duration of treatment. Where
to describe total quantities of specific drugs or     diagnoses are noted on prescriptions, and parti-
drug groups, origins of supplies and type (i.e.       cularly for inpatient prescription, it is possible to
branded or generic).                                  link drug use to indications. Trends in utilization     21
   In the absence of a national mechanism for the     for specific drugs and diseases can also be esta-
direct capture of data on drug production or          blished. As an example, inpatient data may pro-
importation, wholesalers become an important          vide a link to empirical treatment of infections as
source of information on drug acquisition. Such       opposed to treatment based on microbiological
data are reliable insofar as wholesalers are the      assessment. This may be achieved by extracting
only legal entity able to import drugs. In some       relevant data from the patient records, but requi-
countries, medical, dental and veterinary practiti-   res that the records be of good quality.
oners, as well as pharmacists, can import phar-          Prescriptions are a good source of information
maceutical products. It is usually very difficult     for determining some of the indicators of drug
to collect comprehensive data from such sources       use recommended by WHO including the:
even if there are regulatory requirements about
submitting reports. Public sector procurement         – average number of drugs per prescription
practices, however, have reasonable documen-            (encounter);
tation but provide data only on that sector.          – percentage of drugs prescribed by generic
                                                        name;
Practice setting data                                 – percentage of encounters resulting in prescrip-
                                                        tion of an antibiotic;
    Prescribing data; dispensing data; drug use       – percentage of encounters resulting in prescrip-
[   indicators; facility data (aggregate)         ]     tion of an injection;
                                                      – percentage of drugs prescribed from essential
Data from health facilities may be used to evalu-       drugs list or formulary, and
ate specific aspects of health provision and drug     – average drug cost per encounter.
use and to generate indicators that provide infor-
                                                      Prescribing data allow the determination of the
mation on prescribing habits and aspects of pati-
                                                      PDD which may differ from the DDD. While
ent care. These indicators can be used to deter-
                                                      the DDD is based on the dosages approved in
mine where drug use problems exist, provide a
                                                      standard product characteristics with clinical out-
mechanism for monitoring and supervision and
                                                      come data from controlled clinical trials, the
PDD is variable and dependent on factors such       can be used to obtain information on various
     as severity of illness, body weight, interethnic    aspects of drug use including:
     differences in drug metabolism and the prescri-     – the cost of individual drugs and classes of
     bing culture of the health provider. Using DDDs       drug;
     enables comparison to be made between drug          – the most frequently or infrequently used drugs;
     groups as the influences of prescribing culture     – the most expensive drugs;
     and available dosage strengths are eliminated.      – the per capita consumption of specific pro-
        In some countries, it is a legal requirement       ducts;
     that prescriptions dispensed by pharmacies and      – comparisons of two or more drugs used for the
     drug outlets are kept for a minimum period before     same indication;
     disposal. Where these regulations are adhered       – the prevalence of adverse drug reactions;
     to, prescription data may be obtainable from        – the prevalence of medication errors; and
     pharmacies. However, in many developing             – the percentage of the budget spent on specific
     countries the rule is not generally followed. In      drugs or classes of drug.
     countries where computerized records of prescri-
     bing data are kept, they may be readily retriev-    Aggregate data are often useful for comparing
     able depending on the depth of the database.        the utilization of a particular drug to that of
                                                         other drugs and to utilization in other hospitals,
22   3.4.2 Dispensing data                               regions or countries.
     Drug dispensing is a process that ends with a
     client leaving a drug outlet with a defined quan-   3.4.4 Over-the-counter and
     tity of medication(s) and instructions on how to    pharmacist-prescribed drugs
     use it (them). The quantity of drugs dispensed      Pharmacists and other drug outlet managers may
     depends on their availability. Thus information     prescribe over-the-counter preparations or phar-
     available from dispensers may include:              macist-prepared drugs that do not require pre-
     – drug(s) prescribed;                               scription by a physician. Data on such medica-
     – dose(s) prescribed;                               tions may be difficult to obtain especially in
     – average number of items per prescription;         environments with weak drug regulation and
     – percentage of items prescribed that were actu -   poor record keeping, but when such information
        ally supplied (an indicator of availability);    is available from stock or dispensing records, it
     – percentage of drugs adequately labelled;          broadens the understanding of drug utilization
     – quantity of medications dispensed; and            patterns.
     – cost of each item or prescription.
                                                         3.4.5. Telephone and Internet
     These data may be obtained from records kept at     prescribing
     the drug outlet either in electronic or manual      Physicians in certain countries may prescribe
     form.                                               over the telephone. Prescribing and dispensing
                                                         using the Internet also occurs, especially in deve-
     3.4.3 Aggregate data                                loped countries. Most Internet prescriptions are
     A number of data sources within the health faci-    for nutritional supplements and herbal preparati-
     lity or hospital setting can provide aggregate      ons. However, as exemplified by sildenafil
     data on drug utilization. These sources include     (Viagra®), other medicines are also increasingly
     procurement records, warehouse drug records,        being sold on the Internet. Innovative ways have
     pharmacy stock and dispensing records, medica-      to be devised to collect information on this type
     tion error records, adverse drug reaction records   of transaction.
     and patient medical records. These data sources
3.5 Community setting data                             Drug use evaluation can assess the actual pro-
                                                       cess of administration or dispensing of a medica-
    Household survey; compliance (adherence            tion (including appropriate indications, drug
[   to treatment); drug utilization               ]    selection, dose, route of administration, duration
                                                       of treatment and drug interactions) and also the
The drugs available in households have either          outcomes of treatment (e.g. cured disease condi-
been prescribed or dispensed at health facilities,     tions or decreased levels of a clinical parameter).
purchased at a pharmacy (with or without a pre-        The objectives of drug use evaluation include:
scription) or are over-the-counter medications.
The drugs may be for the treatment of a current        – ensuring that drug therapy meets current stan--
illness or are left over from a previous illness. It     dards of care
is not uncommon for patients to adhere poorly to       – controlling drug cost;
the instructions given for taking their dispensed      – preventing problems related to medication;
medicines. Thus dispensing data and utilization        – evaluating the effectiveness of drug therapy; and
data may not be equivalent because they have           – identification of areas of practice that require
not been corrected for non-compliance.                   further education of practitioners.
   Drug utilization by outpatients is best assessed
by performing household surveys, counting left-        The problems to be addressed by drug use evalu-
                                                       ation may be identified from any of the data des-
over pills or using special devices that allow
                                                       cribed in section 3.4 (including prescription indi-
                                                                                                             23
electronic counting of the number of times a par-
ticular drug is administered. Drug utilization by      cators, dispensing data and aggregate data). The
inpatients can be determined by reviewing treat-       main source of data for drug use evaluation is
ment sheets or orders.                                 the patient records. An identifiable authoritative
   For both outpatients and inpatients, the data       group, such as the drugs and therapeutic com-
on the utilization of a particular drug can be         mittee, usually carries out reviews of drug use in
aggregated for a defined population in DDDs.           a hospital or health facility. This group has the
Using DDDs has the advantage of allowing com-          responsibility for drawing up the guidelines, cri-
parison for example between inpatients and out-        teria, indicators and thresholds for the evaluati-
patients. Data on various dosage forms and             on. Drug use evaluation may be based on data
generic equivalents of the same medication can         collected prospectively (as the drug is being dis-
also be aggregated.                                    pensed or administered) or retrospectively (based
                                                       on chart reviews or other data sources).
3.6 Drug use evaluation
                                                       • Typical criteria reviewed in prospective studies
    Drugs and therapeutic committee; prospec-          include the following
    tive evaluation; retrospective evaluation;         – indications;
    criteria setting                                   – drug selection;
                                                       – doses prescribed;
Drug use evaluation, sometimes referred to as          – dosage form and route of administration;
drug utilization review, is a system of continu-       – duration of therapy;
ous, systematic, criteria-based drug evaluation        – costs;
that ensures the appropriate use of drugs. It is a     – therapeutic duplication;
method of obtaining information to identify pro-       – quantity dispensed;
blems related to drug use and if properly develo-      – contraindications;
ped, it also provides a means of correcting the        – therapeutic outcome
problem and thereby contributes to rational drug       – adverse drug reactions; and
therapy.                                               – drug interactions.
• In retrospective studies, the criteria             source that could help you understand the situa-
     reviewed include:                                    tion, and (2) some possible advantages and/or
        – evaluation of indications;                      limitations of each of the sources of data you
        – monitoring use of high-cost medicines;          have listed.
        – comparison of prescribing between physicians;
        – cost to patient;                                When evaluating the advantages and
        – adverse drug reactions; and                     limitations of the data, consider the ans-
        – drug interactions.                              wers to the following questions:
                                                             • How relevant are the data for
     It is possible to incorporate some of the above           learning about antibiotics?
     criteria into databases thus allowing drug experts      • How easy is it to collect these
     to evaluate any items that do not meet establis-          types of data in your country?
     hed criteria. For meaningful results to be obtai-       • How much will it cost to collect
     ned from drug use evaluation a reasonable num-            and process the data and how
     ber of records need to be assessed. A minimum             long will it take?
     of 50 to 75 records per health care facility is         • How reliable are these data?
     considered adequate. However, the number of
     records sampled would depend on the size of the      For example, from data from previous
24   facility and the number of prescribers.
                                                          surveys, we might obtain the following
                                                          useful information: historical utilization
     3.7 General reading
                                                          rates by facility or geographical area, and
     How to investigate drug use in health facilities:
                                                          possibly utilization by type of antibiotic,
     Selected drug use indicators. Geneva,World
                                                          health problem or age. The advantages
     Health Organization, 1993 (unpublished docu-
                                                          of using historical survey data are that
     ment WHO/DAP/93.1; available on request from
                                                          they have already been collected and
     Department of Essential Drugs and Medicines
                                                          carry no additional cost. However, their
     Policy, World Health Organization, 1211
                                                          limitations include not being able to con-
     Geneva, 27, Switzerland).
                                                          trol exactly which data have been collec-
                                                          ted or from where, not knowing whether
     3.8 Exercises
                                                          current practices reflect those of the past,
     Examine the sources of data listed in the
                                                          and having no patient-specific or provi-
     Worksheet. Imagine that you want to learn
                                                          der-specific information. It would also
     about the utilization of antibiotics in your coun-
                                                          usually not be possible to find informa-
     try. In the spaces provided in the right-hand
                                                          tion on dosing of antibiotics.
     columns of the worksheet, write down (1) what
     kinds of useful data you might gather from each
Worksheet for section 3.8
                        Sources of data on drug utilization

Data source                Type of information available   Advantages and limitations


Drug import records


Drug supply to health
facility
Orders and/or
delivery receipts


Previous reports of
surveys
                                                                                        25
Pharmacy stock cards/
pharmacy ledger book


Pharmacy sales
receipts


Large hospital or
insurance databases


Private
drug outlet sales
records


Community
or household surveys


Drug manufacturing
records


Other sources
Chapter 4: Economic aspects of drug
     use (pharmacoeconomy)

       Pharmacoeconomics; types of cost; cost-mini-           4.2 Cost-minimization analysis
       mization analysis; cost-effectivness analysis;         Cost-minimization analysis is a method of calcu-
       cost-benefit analysis; cost-utility analysis           lating drug costs to project the least costly drug
                                                              or therapeutic modality. Cost minimization also
     4.1 Introduction                                         reflects the cost of preparing and administering a
     Drug costs per se are important, as they account for     dose. This method of cost evaluation is the one
     a substantial part of the total cost of health care -    used most often in evaluating the cost of a speci-
     typically 10-15% in developed countries and up to        fic drug. Cost minimization can only be used to
     30-40% in some developing countries. However,            compare two products that have been shown to
     drug costs usually need to be interpreted in the con-    be equivalent in dose and therapeutic effect.
     text of the overall (net) costs to the health system.    Therefore, this method is most useful for compa-
     Drugs cost money to buy, but their use may also          ring generic and therapeutic equivalents or «me
     save costs in other areas. For example, the purchase     too» drugs. In many cases, there is no reliable
     of one specific type of drug may lead to reductions      equivalence between two products and if thera-
     in the following:                                        peutic equivalence cannot be demonstrated, then
     – use of other drugs;                                    cost-minimization analysis is inappropriate.
     – the number of patients requiring hospitalization          If a new therapy were no safer or more effecti-
        or in the length of stay in hospital;                 ve than an existing therapy (i.e. there is no incre-
26   – the number of doctor visits required;                  mental benefit), it would normally justify the
     – administration and laboratory costs compared           same price as the existing therapy. An example
        with those incurred by using another drug to treat    would be the introduction of a new ACE inhibi-
        the same condition.                                   tor with essentially the same properties as exis-
        Assessing the true cost to a health system of         ting members of the class; the price would be
     using a specific drug will therefore require the cost    equivalent to that of the existing drug(s). This is
     of acquisition of the drug to be balanced against        often not as simple as it may seem, as it requires
     both any cost savings resulting from the use of that     sound trial-based information on the doses of the
     drug and the extra health benefits it may produce.       two drugs required for equivalent efficacy. An
     On the other hand, costs may arise from adverse          alternative is to use the PDDs for the two drugs
     drug reactions both in the short- and particularly the   in the marketplace to determine the relative pri-
     long-term.                                               ces. This is a pragmatic approach, but assumes
        Assessing the value for money of using a drug         that the two drugs are actually used at equiva-
     requires the extra health benefits achieved to be        lently effective doses, and this may not always
     weighed against the extra net cost. This compari-        be the case.
     son is usually expressed as an incremental cost-
     effectiveness ratio (ICER) which is the net incre-       4.1 Cost-effectiveness analysis
     mental cost (costs minus cost offsets) of gaining an     Cost-effectiveness analysis involves a more com-
     incremental health benefit over another therapy.         prehensive look at drug costs. While cost is
        Concerns about the cost of medical care in gene-      measured in monetary terms, effectiveness is
     ral, and pharmaceuticals in particular, are currently    determined independently and may be measured
     being expressed by all health systems. There is a        in terms of a clinical outcome such as number of
     general focus on providing quality care within limi-     lives saved, complications prevented or diseases
     ted financial resources. Decision-makers are increa-     cured.
     singly dependent on clinical economic data to guide         Cost-effectiveness analysis thus measures the
     policy formulation and implementation. Some of           incremental cost of achieving an incremental
     the concepts used in making such decisions include:      health benefit expressed as a particular health
     cost-minimization, cost-effectiveness,                   outcome that varies according to the indication
     cost-benefit, and cost-utility.                          for the drug. Examples of ICERs using this
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Due

  • 1. Introduction to Drug Utilization Research 2003 Introduction to Drug Utilization Research Tittel: Introduction to Drug Utilization Research Opplag: 2 500 Design: Grete Søimer Foto: Photo Alto/Laurent Hamels Trykk: Nordberg Aksidenstrykkeri AS ISBN 82-8082-039-6 IN 0000-2069 2003
  • 2. Introduction to Drug Utilization Research World Health Organization WHO International Working Group for Drug Statistics Methodology WHO Collaborating Centre for Drug Statistics Methodology WHO Collaborating Centre for Drug Utilization Research and Clinical Pharmacological Services
  • 3. WHO Library Cataloguing-in-Publication Data Introduction to drug utilization research / WHO International Working Group for Drug Statistics Methodology, WHO Collaborating Centre for Drug Statistics Methodology, WHO Collaborating Centre for Drug Utilization Research and Clinical Pharmacological Services. 1. Drug utilization 2. Research 3. Manuals I.WHO International Working Group for Drug Statistics Methodology II.WHO Collaborating Centre for Drug Statistics Methodology III.WHO Collaborating Centre for Drug Utilization Research and Clinical Pharmacological Services ISBN 92 4 156234 X (NLM classification: WB 330) 2 © World Health Organization 2003 All rights reserved. Publications of the World Health Organization can be obtained from Marketing and Dissemination, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel: +41 22 791 2476; fax: +41 22 791 4857; email: bookorders@who.int). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to Publications, at the above address (fax: +41 22 791 4806; email: permissions@who.int). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The World Health Organization does not warrant that the information contained in this publication is complete and correct and shall not be liable for any damages incurred as a result of its use. Printed in Oslo, Norway, 2003
  • 4. 3
  • 5. Contents Preface: Drug utilization research - the early work ...........................................................................6 Chapter 1: What is drug utilization research and why is it needed? ...............................................8 1.1 Definition and domains............................................................................................................8 1.2 Why drug utilization research? ................................................................................................9 1.2.1 Description of drug use patterns ....................................................................................9 1.2.2 Early signals of irrational use of drugs .......................................................................10 1.2.3 Interventions to improve drug use - follow-up ............................................................10 1.2.4 Quality control of drug use...........................................................................................10 1.3 Drug utilization studies and drug policy decisions................................................................11 1.4 General reading ......................................................................................................................12 Chapter 2: Types of drug use information ........................................................................................13 2.1 Drug-based information .........................................................................................................13 2.1.1 Level of drug use aggregation .....................................................................................13 2.1.2 Indication .....................................................................................................................13 2.1.3 Prescribed daily doses .................................................................................................14 2.2 Problem or encounter-based information ..............................................................................15 2.3 Patient information.................................................................................................................16 2.4 Prescriber information ...........................................................................................................16 2.5 Types of drug utilization study ..............................................................................................17 2.6 Drug costs ..............................................................................................................................17 2.7 General reading ......................................................................................................................18 2.8 Exercises ................................................................................................................................19 Chapter 3: Sources of data on drug utilization ................................................................................20 3.1 Large databases ......................................................................................................................20 3.2 Data from drug regulatory agencies ......................................................................................20 3.3 Supplier (distribution) data ....................................................................................................20 3.4 Practice setting data ...............................................................................................................21 3.4.1 Prescribing data ............................................................................................................21 3.4.2 Dispensing data ............................................................................................................22 3.4.3 Aggregate data .............................................................................................................22 3.4.4 Over-the-counter and pharmacist-prescribed drugs ....................................................22 3.4.5 Telephone and Internet prescribing .............................................................................22 3.5 Community setting data .........................................................................................................23 3.6 Drug use evaluation ...............................................................................................................23 3.7 General reading ......................................................................................................................24 3.8 Exercises ................................................................................................................................24 Chapter 4: Economic aspects of drug use (pharmacoeconomy) ....................................................26 4.1 Introduction ............................................................................................................................26 4.2 Cost-minimization analysis....................................................................................................26 4.3 Cost-effectiveness analysis ....................................................................................................26 4.4 Cost-utility analysis ...............................................................................................................27 4.5 Cost-benefit analysis ..............................................................................................................27 4.6 General reading ......................................................................................................................28 4.7 Exercises ................................................................................................................................28
  • 6. Chapter 5: Drug classification systems..............................................................................................33 5.1 Different classification systems .............................................................................................33 5.2 The ATC classification system...............................................................................................33 5.3 Ambivalence towards an international classification system ................................................35 5.4 Implementation of the ATC/DDD methodology ...................................................................36 5.5 General reading ......................................................................................................................36 5.6 Exercises ................................................................................................................................37 Chapter 6: Drug utilization metrics and their applications ............................................................38 6.1 The concept of the defined daily dose (DDD).......................................................................38 6.2 Prescribed daily dose and consumed daily dose....................................................................39 6.3 Other units for presentation of volume..................................................................................39 6.4 Cost ......................................................................................................................................39 6.5 General reading .....................................................................................................................40 6.6 Exercises ...............................................................................................................................41 Chapter 7: Solutions to the exercises .................................................................................................74 Acknowledgements...............................................................................................................................84
  • 7. Preface: Drug utilization research - the early work The development of drug utilization research became clear that we need to know the answers was sparked by initiatives taken in Northern to the following questions: Europe and the United Kingdom in the mid- • why drugs are prescribed; 1960s (1, 2). The pioneering work of Arthur • who the prescribers are; Engel in Sweden and Pieter Siderius in Holland • for whom the prescribers prescribe; (3) alerted many investigators to the importance • whether patients take their medicines correctly; of comparing drug use between different count- • what the benefits and risks of the drugs are. ries and regions. Their demonstration of the remarkable differences in the sales of antibiotics The ultimate goal of drug utilization research in six European countries between 1966 and must be to assess whether drug therapy is rational 1967 inspired WHO to organize its first meeting or not. To reach this goal, methods for auditing on «Drug consumption» in Oslo in 1969 (4). drug therapy towards rationality are necessary. This led to the constitution of the WHO The early work did not permit detailed compa- European Drug Utilization Research Group risons of the drug utilization data obtained from (DURG). different countries because the source and form The pioneers of this research understood that a of the information varied between them. To correct interpretation of data on drug utilization overcome this difficulty, researchers in Northern requires investigations at the patient level. It Ireland (United Kingdom), Norway and Sweden 6 Figure 1 Utilization of insulin and oral antidiabetic drugs in seven European countries from 1971-1980 expressed in defined daily doses (DDDs) per 1000 inhabitants per day. For comparison the prescribed daily doses (PDD) per 1000 inhabitants per day of oral antidiabetic drugs are given for Northern Ireland (UK) and Sweden for 1980 (indicated with an asterisk).
  • 8. developed a new unit of measurement, initially Scandinavica, 1984, Suppl. 683:7-9. called the agreed daily dose (5) and later the 2. Dukes MNG. Development from Crooks to the defined daily dose (DDD) (6). This unit was nineties. In: Auditing Drug Therapy. defined as the average maintenance dose of Approaches towards rationality at reasonable the drug when used on its major indication in costs. Stockholm, Swedish Pharmaceutical adults. The first study used antidiabetic drugs Press, 1992. as an example: it was found that the sum of the 3. Engel A, Siderius P. The consumption of drugs. DDDs of insulin and oral antidiabetic drugs Report on a study 1966-1967. Copenhagen, (about 20 DDDs per1000 inhabitants per day) WHO Regional Office for Europe, 1968 (EURO roughly corresponded to the morbidity due to 3101). diabetes after correction for the number of pati- ents treated with dietary regimens alone. Among 4. Consumption of drugs. Report on a symposium in Oslo 1969. Copenhagen, WHO Regional the first countries to adopt the DDD methodo- Office for Europe, 1970 (EURO 3102). logy was the former Czechoslovakia (7) and the first comprehensive national list of DDDs was 5. Bergman U, et al. The measurement of drug published in Norway in 1975 (8). Another consumption. Drugs for diabetes in Northern important methodological advance was the adop- Ireland, Norway, and Sweden. European Journal of Clinical Pharmacology, 1975,8:83- tion of the uniform anatomical therapeutic che- 89. mical (ATC) classification of drugs (see chapter 7 5.2). The use of standardized methodology allo- 6. Bergman U et al., eds. Studies in drug utilizati- wed meaningful comparisons of drug use in on. Methods and applications. Copenhagen, different countries to be made (Fig. 1). WHO Regional Office for Europe, 1979 (WHO Regional Publications, European Series No. 8). Drug utilization research developed quickly during the following 30 years and soon became a 7. Stika L et al. Organization of data collection in respectable subject for consideration at inter- Czechoslovakia. In: Bergman U et al., eds. national congresses in pharmacology, pharmacy Studies in drug utilization. Methods and appli- and epidemiology. Particularly rapid develop- cations. WHO Regional Office for Europe, Copenhagen, 1979 (WHO Regional Publications ments were seen in Australia (9) and Latin European Series No. 8) pp.125-136. America (10). The number of English-language papers on the subject listed in the Cumulative 8. Baksaas Aasen I et al. Drug dose statistics, list index medicus rose from 20 in 1973 (when the of defined daily doses for drugs registered in term «drug utilization« first appeared) to 87 in Norway. Oslo, Norsk Medicinal Depot, 1975. 1980, 167 in 1990, and 486 in 2000. 9. Hall RC. Drug use in Australia. In: Sjöqvist F, History has taught us that successful research Agenäs I, eds. Drug utilization studies: in drug utilization requires multidisciplinary col- Implications for medical care. Acta Medica laboration between clinicians, clinical pharmaco- Scandinavica, 1983, Suppl. XXX:79-80. logists, pharmacists and epidemiologists. 10. Drug Utilization Research Group, Latin Without the support of the prescribers, this rese- America. Multicenter study on self-medication arch effort will fail to reach its goal of facilita- and self-prescription in six Latin American ting the rational use of drugs. countries. Clinical Pharmacology and Therapeutics, 1997, 61:488-493. References 11. Bergman U, Sjöqvist F. Measurement of drug 1. Wade O. Drug utilization studies - the first utilization in Sweden: methodological and clini- attempts. Plenary lecture. In: Sjöqvist F, cal implications. Acta Medica Scandinavica, Agenäs I. eds. Drug utilization studies: implica- 1984, Suppl 683:15-22. tions for medical care. Acta Medica
  • 9. Chapter 1: What is drug utilization research and why is it needed? 1.1. Definition and domains not. Sophisticated utilization-oriented pharma- coepidemiology may focus on the drug (e.g. Drug utilization; pharmacoepidemiology; dose-effect and concentration-effect relationships), [ pharmacosurveillance; pharmacovigilance ] the prescriber (e.g. quality indices of the prescrip- tion), or the patient (e.g. selection of drug and • Drug utilization research was defined by dose, and comparisons of kidney function, drug WHO in 1977 as «the marketing, distribution, metabolic phenotype/genotype, age, etc.). prescription, and use of drugs in a society, with Drug utilization research is thus an essential special emphasis on the resulting medical, social part of pharmacoepidemiology as it describes the and economic consequences». Since then, a extent, nature and determinants of drug exposure. number of other terms have come into use and it Over time, the distinction between these two is important to understand the interrelationships terms has become less sharp, and they are some- of the different domains. times used interchangeably. However, while • Epidemiology has been defined as «the study drug utilization studies often employ various of the distribution and determinants of health- sources of information that focus on drugs (e.g. related states and events in the population, and aggregate data from wholesale and prescription the application of this study to control of health registers) the term epidemiology implies defined problems». populations in which drug use can be expressed 8 • Pharmacoepidemiology applies epidemiologi- in terms of incidence and prevalence (see cal methods to studies of the clinical use of chapter 1.2.1). drugs in populations. A modern definition of Together, drug utilization research and pharma- pharmacoepidemiology is: «the study of the use coepidemiology may provide insights into the fol- and effects/side-effects of drugs in large numbers lowing aspects of drug use and drug prescribing. of people with the purpose of supporting the rational and cost-effective use of drugs in the • Pattern of use: This covers the extent and pro- population thereby improving health outcomes». files of drug use and the trends in drug use and • Pharmacosurveillance and pharmacovigi- costs over time. lance are terms used to refer to the monitoring • Quality of use: This is determined using audits of drug safety, for example, by means of spon- to compare actual use to national prescription taneous adverse-effect reporting systems, case- guidelines or local drug formularies.1 Indices of control and cohort studies. quality of drug use may include the choice of drug (compliance with recommended assort- Pharmacoepidemiology may be drug-oriented, ment), drug cost (compliance with budgetary emphasizing the safety and effectiveness of indi- recommendations), drug dosage (awareness of vidual drugs or groups of drugs, or utilization- inter-individual variations in dose requirements oriented aiming to improve the quality of drug and age-dependence), awareness of drug inter- therapy through pedagogic (educational) inter- actions and adverse drug reactions, and the pro- vention. Drug utilization research may also be portion of patients who are aware of or unaware divided into descriptive and analytical studies. of the costs and benefits of the treatment. The emphasis of the former has been to describe • Determinants of use: These include user cha- patterns of drug utilization and to identify pro- racteristics (e.g. sociodemographic parameters blems deserving more detailed studies. and attitudes towards drugs), prescriber characte- Analytical studies try to link data on drug utili- ristics (e.g. speciality, education and factors zation to figures on morbidity, outcome of treat- influencing therapeutic decisions) and drug cha- ment and quality of care with the ultimate goal racteristics (e.g. therapeutic properties and affor- of assessing whether drug therapy is rational or dability). 1 An audit in drug use was defined by Crooks (1979) as an examination of the way in which drugs are used in clinical practice carried out at intervals frequent enough to maintain a generally accepted standard of prescribing.
  • 10. • Outcomes of use: These are the health out price. Without a knowledge of how drugs are comes (i.e. the benefits and adverse effects) and being prescribed and used, it is difficult to initiate the economic consequences. a discussion on rational drug use or to suggest measures to improve prescribing habits. The initial focus of pharmacoepidemiology was Information on the past performance of prescri- on the safety of individual drug products (phar- bers is the linchpin of any auditing system. macosurveillance), but it now also includes stu- Drug utilization research in itself does not dies of their beneficial effects. The driving force necessarily provide answers, but it contributes to behind this development was a growing awa- rational drug use in important ways as described reness that the health outcomes of drug use in below. the rigorous setting of randomized clinical trials are not necessarily the same as the health outco- 1.2.1 Description of drug mes of drug use in everyday practice. The clini- use patterns cal trials needed to obtain marketing authori- Drug utilization research can increase our under- zation for new drugs involve limited numbers of standing of how drugs are being used as follows. carefully selected patients, who are treated and followed-up for a relatively short time in strictly • It can be used to estimate the numbers of pati- controlled conditions. As a result, such trials do ents exposed to specified drugs within a given not accurately reflect how drug use will affect time period. Such estimates may either refer to 9 health outcomes in everyday practice under every- all drug users, regardless of when they started to day circumstances. Pharmacoepidemiological use the drug (prevalence), or focus on patients studies often make useful contributions to our who started to use the drug within the selected knowledge about effectiveness and safety, because, period (incidence). unlike clinical trials, they assess drug effects in • It can describe the extent of use at a certain large, heterogeneous populations of patients over moment and/or in a certain area (e.g. in a coun- longer periods. try, region, community or hospital). Such des- Drug utilization research also provides insight criptions are most meaningful when they form into the efficiency of drug use, i.e. whether a part of a continuous evaluation system, i.e. when certain drug therapy provides value for money the patterns are followed over time and trends in and the results of such research can be used to drug use can be discerned. help to set priorities for the rational allocation of • Researchers can estimate (e.g. on the basis of health care budgets. epidemiological data on a disease) to what extent drugs are properly used, overused or underused. 1.2 Why drug utilization • It can determine the pattern or profile of drug research? use and the extent to which alternative drugs are Description of drug use pattern; early signals being used to treat particular conditions. of irrational use of drugs; interventions to • It can be used to compare the observed patterns improve drug use; quality control cycle; of drug use for the treatment of a certain disease continuous quality improvement with current recommendations or guidelines. • It can be used in the application of quality indi- The principal aim of drug utilization research is cators to patterns of drug utilization. An exam- to facilitate the rational use of drugs in popu- ple is the so-called DU90% (drug utilization lations. For the individual patient, the rational 90%), a further development of the «top-ten» use of a drug implies the prescription of a well- list. documented drug at an optimal dose, together The DU90% segment reflects the number of with the correct information, at an affordable drugs that account for 90% of drug prescriptions
  • 11. and the adherence to local or national prescrip- mal practice, whether pedagogic interventions tion guidelines in this segment. This general (education) are required or whether the guide- indicator can be applied at different levels (e.g. lines should be reviewed in the light of actual individual prescriber, group of prescribers, hos- practice. These hypotheses should apply to both pitals, region or county) to obtain a rough esti- under use and over use of drugs. mate of the quality of prescribing. • Drug utilization data can be fed back to pre- 1.2.3 Interventions to improve scribers. This is particularly useful when the drug use - follow-up drug prescribing by a particular individual can Drug utilization research undertaken in the follo- be compared with some form of «gold standard» wing ways may enable us to assess whether or best practice, and with the average prescrip- interventions intended to improve drug use have tions in the relevant country, region or area. had the desired impact. • The number of case reports about a drug pro- • The effects of measures taken to ameliorate blem or adverse effects can be related to the undesirable patterns of drug use (e.g. provision number of patients exposed to the drug to assess of regional or local formularies, information the potential magnitude of the problem. If it is campaigns and regulatory policies) should be possible to detect that the reaction is more com- monitored and evaluated. The researchers mon in a certain age group, in certain conditions should bear in mind that prescribers may have 10 or at a given dose level, improving the informa- switched to other drugs that are equally undesi- tion on indications, contraindications and rable. These potential alternative drugs should appropriate dosages may be sufficient to ensure be included in the survey to assess the full safer use and avoid withdrawal of the drug from impact of the measure. the market. • The impact of regulatory changes or changes in insurance or reimbursement systems should 1.2.2 Early signals of irrational use be assessed using a broad survey. This is neces- of drugs sary because the total cost to society may remain Drug utilization research may generate hypothe- the same or may even increase if more expen- ses that set the agenda for further investigations sive drugs are used as alternatives. as outlined below, and thus avoid prolonged irra- • The extent to which the promotional activities tional use of drugs. of the pharmaceutical industry and the educatio- • Drug utilization patterns and costs between nal activities of the society affect the patterns of different regions or at different times may be drug use should be assessed. compared. Hypotheses can be generated to form the basis for investigations of the reasons for, 1.2.4 Quality control of drug use and health implications of, the differences Drug use should be controlled according to a found. Geographical differences and changes in quality control cycle that offers a systematic drug use over time may have medical, social and framework for continuous quality improve- economic implications both for the individual ment. The components of such a cycle are illu- patient and for society, and should therefore be strated on the next page. identified, explained and, when necessary cor- rected. After step 4, the cycle begins again with new • The observed patterns of drug use can be com- analyses, the setting of new targets, and so on. pared with the current recommendations and The quality control cycle can be applied at guidelines for the treatment of a certain disease. many levels, ranging from local or regional dis- Hypotheses can then be generated to determine cussion groups consisting of physicians, clinical whether discrepancies represent less than opti- pharmacologists or pharmacists to national and
  • 12. Step 1. Plan. Analyse current situation to Step 2. Do. Implement the plan on a small establish a plan for improvment (e.g. analyse scale (e.g. provide feedback on possible current prescription patterns of individual overuse, underuse or drug misuse of prescribers, groups of prescribers, or health individual drugs or therapeutic groups). facilities). Step 4. Act Revise plan or implement plan Step 3. Check Check to see if expected on large scale (e.g. guide national imple- results are obtained (e.g. evaluate whether mentation of plan). prescription patterns really improve). international initiatives. An important technique and validated from 1992-1994. Since then, that can be used in conjunction with this cycle annual reviews of drug utilization have been is benchmarking. By comparing drug utiliza- used to provide background information for tion data from different localities, it is often decisions on regulatory and reimbursement poli- possible to detect substantial differences that cies in Estonia; two examples are described require further evaluation, which may then lead below. to the identification and promotion of best prac- If physicians have high rates of inappropriate tice. Such comparisons will be accurate and prescribing, drug regulatory authorities can 11 truthful provided that the data are collected and require educational intervention or impose aggregated in a standardized, uniform way (see restrictions on specific drugs or on practitioners. chapter 5). In Estonia, it was decided to stop the import and use of some hazardous products, such as phena- 1.3 Drug utilization studies and cetine, older sulphonamides and pyrazolones, drug policy decisions after clarifying and explaining the reasons for Many of the questions asked in drug utilization this in the national Drug information bulletin, research and the answers obtained are important which is distributed free by the drug regulatory for initiating and modifying a rational drug poli- authority to all prescribers in Estonia. cy at both national and local levels. Two suc- In planning the reimbursement policies, the cessful examples of the use of such research are total volume of drug use in DDDs was monito- given below. red carefully. During the 1990s, the use of pre- scription-only medicines measured as number of Drug use in Estonia DDDs per capita was less than one third of that An important reason for undertaking studies of reported from the Nordic countries. This proved drug use in Estonia after its independence was to be the result of under-treatment of certain the need to make decisions on drug policy. At chronic diseases (i.e. hypertension and schizo- the time, no information was available in the phrenia), and therefore the decision was to incre- country on which drugs were used (sold), or on ase the availability and use of cardiovascular and the quantities and there was therefore no rationale neuroleptic drugs. Thus, the national drug use for regulating the drug market. Moreover, in the surveys in Estonia have been used to monitor the absence of any feedback system it was impos- impact of drug regulatory activities as well as to sible to gauge the impact of possible future follow the increase in drug expenditure. interventions. A national drug classification Because data on drug use are only part of the system was therefore developed for Estonia, and background material relevant to the discussions a reporting system from wholesalers, based on and decisions on therapeutic strategies - at both this classification, was implemented, checked the local and national levels - it is difficult to
  • 13. evaluate the specific influence of drug utilization rent social-class districts in the catchment areas research on developments in drug policies. It is, of 11 health centres.1 however, reasonable to assume that such studies have contributed to a more rational use of drugs 1.4 General reading in Estonia.1 Bergman U et al. Drug utilization 90% - a sim- ple method for assessing the quality of drug pre- Drug use in Latin America scribing. European Journal of Clinical The second example is the successful work within Pharmacology, 1998, 54:113-118. the Latin American DURG, in association with Crooks J. Methods of audit in drug use. In: the WHO Collaborating Centre of Pharmaco- Duchene-Marulla ZP, ed. Advances in pharma- epidemiology in Barcelona, Spain. cology and therapeutics. Proceedings of 7th In September 1991, health professionals from International Congress of Pharmacology, Paris, Spain and eight Latin American countries met in 1978. Oxford, Pergamon Press, 1979:189-195. Barcelona for the «First Meeting of Latin Diogène E et al. The Cuban experience in American Groups for Drug Epidemiology». It focusing pharmaceuticals policy to health popu- was made clear that in most of the countries lation needs: initial results of the National taking part, data on drug utilization were scarce Pharmacoepidemiology Network (1996-2001). and fragmentary. Some national drug regulatory European Journal of Clinical Pharmacology, 12 authorities had no access to either quantitative or 2002, in press. qualitative data on drug consumption and reali- Drug Utilization Research Group, Latin zed that information on patterns of drug utili- America. Multicenter study on self-medication zation would be useful for designing drug policy and self-prescription in six Latin American and educational programmes about drugs. countries. Clinical Pharmacology and It was agreed at this meeting to set up a Latin Therapeutics, 1997, 61:488-493. American network (later called DURG-LA), Dukes MNG, ed. Drug Utilization Studies: with the following aims: Methods and Uses. Copenhagen, WHO Regional – to promote drug utilization research in Latin Office for Europe, 1993 (WHO Regional American countries; Publications European Series No. 45) – to exchange experiences and information Einarson TR, Bergman U, Wiholm BE. between the participating groups; Principles and practice of pharmacoepidemiolo- – to use the knowledge generated to give techni- gy. In: Avery’s Drug Treatment, 4th ed. Adis cal advice to drug regulatory authorities and to International:371-392. guide teaching of pharmacology; Figueras A et al. Health need, drug registration – to write and disseminate information aimed at and control in less developed countries - the improving drug use, and Peruvian case. Pharmacoepidemiology and Drug – to participate in the training of health pro- Safety, 2001, 10:1-2. fessionals in pharmacoepidemiology and thera- Laporte JR, Porta M, Capella D. Drug utiliza- peutics. tion studies: a tool for determining the effecti- veness of drug use. British Journal of Clinical Seven further DURG-LA meetings have been Pharmacology, 1983, 16:301-304. held over the subsequent ten years to promote McGavock H. Handbook of drug use research drug utilization research. Part of the initial core methodology 1st ed. Newcastle upon Tyne, group participated in a first multicentre study in United Kingdom Drug Utilization Research six Latin American countries to examine self- Group, 2000. medication and self-prescription. The study was Strom BL. Pharmacoepidemiology, 3rd ed. carried out in a sample of pharmacies from diffe- New York, J Wiley, 2000. 1 The information about DURG-LA was provided in a personal communication by Dr Albert Figueras and Professor Joan-Ramon Laporte, Barcelona, Spain.
  • 14. Chapter 2: Types of drug use information Different types of drug use information are 2.1.2 Indication required depending on the problem being exami- For drugs with multiple indications, it will usually ned. These include information about the overall be important to divide data on use according to use of drugs, drug groups, individual generic indication to allow a correct interpretation of the compounds or specific products. Often, infor- overall trends. An example is the relative use of mation about the condition being treated, the drug groups in treating hypertension. The over- patient and the prescriber is also required. In all data might suggest that the relative use of addition, data on drug costs will be important in diuretics is comparable to that of ACE inhibitors ensuring that drugs are used efficiently and eco- and higher than the use of calcium channel bloc- nomically. These types of drug information are kers (column A in Table 1). However, analysis described in detail below, together with exam- of the data according to indication may reveal ples to illustrate the ways in which the informa- that 75% of ACE inhibitors are used to treat tion can be used to promote the rational use of hypertension whereas only 43% of diuretics are drugs. used for this indication (most of the high-ceiling diuretics used are for treating heart failure). The 2.1 Drug-based information picture that emerges of the use of the two drug Knowledge of the trends in total drug use may groups in the treatment of heart failure is mar- be useful, but more detailed information invol- kedly altered when use according to indication is ving aggregation of data on drug use at various taken into account (column B of Table 1). 13 levels, and information on indications, doses and dosage regimens is usually necessary to answer Table 1 Relative use of drug groups in the treatment clinically important questions. of hypertension in Australia in 1998a 2.1.1 Level of drug use aggregation Drug group Ab Bc Cd The level at which data on drug use are aggrega- ted will depend on the question being asked. ACE inhibitors (C09A) 31.80 36.6 34.8 For example, the question might concern the Calcium channel blockers relative use of drug groups in the treatment of (C08C) 24.50 28 26.7 hypertension. It would then be appropriate to Diuretics (C03) 29.60 19.4 15.9 aggregate data on diuretics, beta-blockers and Beta-blockers angiotensin-converting enzyme (ACE) inhibitors, (C07AA, C07AB) 11.20 11.5 15.7 etc. If, however, the question concerns the rela- tive use of beta-blockers in hypertension, data at ATII antagonists the substance (generic drug) level would be nee- (C09CA) 3.00 4.6 6.9 ded. Information on the relative scale of use of individual products will sometimes be required, for example to find the market leader or to Source: Australian Drug Utilization assess the relative use of generic versus branded Subcommittee and BEACH Survey April- or innovator products. Information down to the December 1998, Sydney University, GPSCU level of dose strength will be necessary, for 1999. example, to determine whether there is a trend a Values are the use of the drug group expressed as a percenta towards use of higher strengths of antibiotics, or ge of the total use for these drug groups. to determine the relative use of strengths of anti- b Based on total use. depressants to assess whether they are being c Adjusted for the percentage of total use of each group for the used at effective doses. treatment of hypertension. d Relative prescribing of these drug groups in hypertension community practice patient encounters.
  • 15. Another example of a situation in which the when making such comparisons. The PDDs dif- indication is important is antibiotic utilization. fer between countries and ethnic groups, and In determining whether the use of a particular even between areas or health facilities within the antibiotic, for example, amoxicillin, is rational, it same country. The PDD will also often differ will usually be necessary to know what infecti- for different indications of the same drug, so it ons or problems it is being used to treat. It will sometimes be necessary to reach this level would therefore be necessary to break down data of detail to interpret overall use data. on amoxicillin use into indications and compare Data on the use of tricyclic antidepressants these uses with the appropriate guidelines. If it and selective serotonin reuptake inhibitors were found that there was substantial use of (SSRIs) in Australia are shown in Table 2 as amoxicillin to treat acute sore throat, for exam- both DDDs and prescription volumes. ple, this finding would indicate a problem that The two metrics give different results for the needed to be addressed. This is because a nar- relative use of the two groups of antidepressant row-spectrum agent (or no drug) would be a drugs because of the different relationship bet- more appropriate treatment for a sore throat, and ween the PDDs and the DDDs for the two drug if amoxicillin is used to treat mononucleosis, groups. On average, the PDD is lower than the which can present as a sore throat, there is a DDD for the tricyclics and higher for the SSRIs. high incidence of rash. In this case, knowledge of the PDDs is necessary 14 for clinical interpretation of the data. 2.1.3 Prescribed daily doses The DDD per 1000 inhabitants per day is The prescribed daily dose (PDD) is the average often used to derive a rough estimate of the pre- daily dose prescribed, as obtained from a repre- valence of use in the population being studied, sentative sample of prescriptions. The use of and for chronic diseases it may even be used to DDD per 1000 inhabitants per day allows aggre- assess the prevalence of a disease when the drug gation of data across drug groups and compari- is prescribed for a single indication. Such esti- sons between countries, regions and health faci- mates are valid only if the DDDs and the PDDs lities. However, the DDD metric may not reflect are similar. the actual PDDs, and this needs to be considered Table 2 Relative use of antidepressants in Australia in 1998 Prescription % of total DDD/1000 % of total DDD/1000 volume prescription population/day population/day (millions)a volume Tricyclics (N06AA) 3.53 48.82 8.40 28.09 SSRI (N06AB) 3.09 42.74 17.20 57.53 Moclobemide (N06AG02) 0.61 8.44 4.30 14.38 Total 7.23 100.00 29.90 100.00 Source: Australian Drug Utilization Subcommittee, Department of Health & Aged Care, Commonwealth of Australia, http://www.health.gov.au:80/haf/docs/asm.htm
  • 16. 2.2 Problem or encounter-based sistent. This consistency between data using two information different approaches (i.e. drug and problem- based) gives confidence in the result. Reason for the encounter (the problem); Other questions that might be addressed using drug treatment versus non-drug treatment; a problem-based approach include the following: other problems managed; severity of the pro- blem managed; new or continuing presenta- • Does the severity of hypertension influence the tion; duration of consultation; medications choice of single or combination therapy? prescribed for the problem; how the medica- • Is the management of newly-presenting pati- tions were supplied; other medications pre- ents different to that of patients already receiving scribed treatment? • Are there likely to be any drug interactions with co-prescribed treatments? Rather than asking how a particular group of • Is the choice of drug influenced by evidence- drugs is used, it may be useful to address the based outcome data? question of how a particular problem (e.g. sore throat, hypertension or gastric ulcer) is managed. For some diseases it may be important to study The different types of information that may be the relative use of drug treatment and other the- required are listed in the box above. As an example, consider how problem-based rapeutic approaches to map out and understand 15 pharmacotherapeutic traditions and other thera- information about the management of hyperten- peutic approaches. As an example, drug utiliza- sion might be used. Initially, concordance with tion research in Estonia has shown that there was guidelines for drug treatment or non-drug mana- a reciprocal relationship between the use of hor- gement of blood pressure and other risk factors monal contraceptives and the abortion rate might be assessed. Where drug treatment is from1989-1997 (Fig. 2). used, the proportion of patients treated with each of the drug groups gives an overall picture of Another example was the excessive use of ulcer management (column C of Table 1). This is surgery in Estonia compared to Sweden during more direct information on how hypertension is the Soviet era. This was because of the difficul- managed than that provided by assessing the ties of obtaining modern anti-ulcer drugs in overall use of the different drug groups as dis- Estonia at that time (Fig. 3). cussed above. In the example shown in Table 1, the data in columns B and C are reasonably con- (per 10 000 population Use of hormonal Nr of abortions contraceptives (DDD/1000/day Figure 2 Abortion rate and use of hormonal contraceptives in Estonia in 1989-1997. Source: Kiivet R. Drug utilization studies as support to decisions in drug policy in Estonia. [MD Thesis] Stockholm, Karolinska Institutet, 1999.
  • 17. 80 20 60 16 12 40 8 20 4 0 0 1993 1995 anti-ulcer drugs, Estonia surgery, Estonia anti-ulcer drugs, Stockholm surgery, Stockholm Figure 3 Treatment of ulcer disease in Estonia and in Stockholm County 1993-1995. Source: Kiivet R. Drug utilization studies as support to decisions in drug policy in Estonia. [MD Thesis] Stockholm, Karolinska Institutet, 1999. 2.3 Patient information 2.4 Prescriber information Age; gender; ethnicity; co-morbidities; Demographic information - age, gender, 16 [ knowledge; beliefs and perceptions ] medical school, years in practice; type of practice (e.g. specialist or family, rural or Information on demographic factors and other urban); practice size; patient mix; knowledge details about the patient will often be useful. about drugs; factors driving prescribing For example, the age distribution of patients may behaviour be of critical importance, to assess the likelihood of severe adverse effects with nonsteroidal anti- The prescriber plays a critical role in determi- inflammatory drugs (NSAIDs), or whether the ning drug use. Claims have even been made that drug is being used to treat patients in an age the differences between doctors are greater than group different from that in which the clinical those between patients and that variations in trials were performed. The co-morbidities of the drug prescribing behaviour often lack rational patient group may be important in determining explanations. Dissecting the factors that deter- the choice of treatment and predicting possible mine prescribing behaviour is therefore often adverse effects. For instance, in the manage- central to understanding how and why drugs are ment of hypertension, beta-blockers should not prescribed. Some questions that might be be used to treat patients with asthma, and ACE addressed using prescriber information include inhibitors are the preferred treatment in patients the following: with heart failure. • Are prescribing profiles influenced by the Qualitative information relating to the know- prescriber’s medical education? ledge, beliefs and perceptions of patients and • Do the prescribing profiles of specialists differ their attitudes to drugs will be important in some from those of family practitioners? cases, for example in assessing the pressures put • Does the age or gender of the prescriber influ- by patients on their doctors to prescribe antibio- ence the prescribing profile? tics, or in designing consumer information and • Are there differences in prescribing behaviour education programmes. between urban and rural practices or between small and large practices? Do these variations indicate a need to target education to particular sectors?
  • 18. • Who are those prescribers who rapidly adopt often obtained from repeated cross-sectional sur- recently released drugs? veys (e.g. IMS (Intercontinental Medical • In assessing rational use of medicines by a Statistics) practice-based data are of this type). practitioner, has the practice mix been taken into Data collection is continuous, but the practitio- account? ners surveyed, and therefore the patients, are • Can the factors that determine and change pre- continually changing. Such data give informa- scribing behaviour be identified? tion about overall trends, but not about prescri- bing trends for individual practitioners or practices. 2.5 Types of drug utilization study Continuous longitudinal studies Drug utilization studies can be targeted towards In some cases continuous longitudinal data at the any of the following links in the drug-use chain: individual practitioner and patient level can be obtained. Claims databases are often able to – the systems and structures surrounding drug follow individual patients using a unique (but use (e.g. how drugs are ordered, delivered and anonymous) identifier. These data can provide administered in a hospital or health care facility); information about concordance with treatment – the processes of drug use (e.g. what based on the period between prescriptions, co- drugs are used and how they are used and prescribing, duration of treatment, PDDs and so does their use comply with the relevant on. As electronic prescribing becomes more 17 criteria, guidelines or restrictions); and common, databases are being developed to pro- – the outcomes of drug use (e.g. efficacy, vide continuous longitudinal data comprising adverse drug reactions and the use of resour- full medical and prescribing information at the ces such as drugs, laboratory tests, hospital individual patient level. Such databases are very beds or procedures). powerful, and can address a range of issues including reasons for changes in therapy, adverse Cross-sectional studies effects and health outcomes. Cross-sectional data provide a «snapshot» of drug use at a particular time (e.g. over a year, a month or a day). Such studies might be used for 2.6 Drug costs making comparisons with similar data collected over the same period in a different country, Total drug costs; cost per prescription; cost health facility or ward, and could be drug-, pro- per treatment day, month or year; cost per blem-, indication, prescriber- or patient-based. defined daily dose (DDD); cost per prescri- Alternatively, a cross-sectional study can be car- bed daily dose (PDD); cost as a proportion ried out before and after an educational or other of gross national product; cost as a propor- intervention. Studies can simply measure drug tion of total health costs; cost as a propor- use, or can be criterion-based to assess drug use tion of average income; net cost per health in relation to guidelines or restrictions. outcome (cost-effectiveness ratio); net cost per quality adjusted life-year (cost-utility- Longitudinal studies ratio) Public health authorities are often interested in trends in drug use, and longitudinal data are Data on drug costs will always be important in required for this purpose. Drug-based longi- managing policy related to drug supply, pricing tudinal data can be on total drug use as obtained and use. Numerous cost metrics can be used and through a claims database, or the data may be some of these are shown in the box above. For based on a statistically valid sample of pharma- example, the cost per DDD can usually be used cies or medical practices. Longitudinal data are to compare the costs of two formulations of the
  • 19. same drug. However, it is usually inappropriate ced a marked increase in the cost of anti-psycho- to use this metric to compare the costs of diffe- tic drugs over the last 5-10 years; the data on use rent drugs or drug groups as the relationship bet- and cost for these drugs in Australia are illustra- ween DDD and PDD may vary. ted in Fig. 4. Estimates of the costs at various levels and using data aggregated in various ways will be In Australia, there has been little increase in the required, depending on the circumstances and overall volume of use of antipsychotic drugs, the perspective taken. A government perspective and the cost increase has been driven by the might require information on drug costs and cost transfer from the cheap ‘classical’ agents to the offsets to government to be collected, whereas a much more expensive ‘atypical’ drugs such as societal perspective would require both govern- clozapine, olanzapine and risperidone resulting ment and non-government (private sector) costs in an increase in the average cost per prescrip- and cost offsets to be determined. A patient per- tion. In contrast, both the prescription volume of spective will be appropriate if questions about antidepressant drugs and the average cost per affordability and accessibility are being asked. prescription have increased over the same period, Costs may be determined at government, health due to an ‘add-on’ prescribing effect of the more facility, hospital, health maintenance organiza- expensive SSRIs. tion or other levels within the health sector. 18 Costs will often need to be broken down 2.7 General reading according to drug group or therapeutic area to Einarsson TR, Bergman U, Wiholm BE. determine, for example, the reason for an increase Principles and practice of pharmacoepidemiology. in drug costs. For instance, the introduction of In: Speight TM, Holford NH, eds. Avery’s Drug new, expensive anti-cancer agents may be found Treatment. Place, Adis International, 1999:371- to be driving the increases in drug costs in a hos- 392. pital. Changes in drug costs can result from changes in prescription volumes, quantity per Lee D, Bergman U. Studies of drug utilization. prescription or in the average cost per prescripti- In: Strom B. ed. Pharmacoepidemiology, 3rd ed. on. For example, most countries have experien- Chichester, J Wiley, 2000:463-481. 10 100 community use govt cost with clozapine 8 80 DDs/1000/Day $ million 6 60 use 4 40 2 20 cost 0 0 1990 1991 1992 1993 1994 1995 1996 1997 1998 Figure 4 Antipsychotic drugs - use and cost trends in Australia
  • 20. 2.8 Exercises 4. Antidepressant use 3. Amoxicillin The use of antidepressant drugs (in DDDs per You note that amoxicillin use expressed as 1000 population per day) and their costs have DDDs per1000 population per day has been increasing for at least the last five years. increased over the last two years. What types What types of data would you need to deter- of drug utilization data would you need to mine the reasons for the change and whether it evaluate the possible reasons for this? has resulted in positive or negative health out- comes? 19
  • 21. Chapter 3: Sources of data on drug utilization Drug-use chain; large databases; other sour- drug distribution chain, pharmaceutical and [ ces; drug use evaluation; pharmacoeconomics ] medical billing or samples of prescriptions. The databases may be international, national or local The drug-use chain includes the processes of in scope. They may be diagnosis-linked or non- drug acquisition, storage, distribution, prescri- diagnosis-linked. Diagnosis-linked data enable bing, patient compliance and the review of out- drug use to be analysed according to patient cha- come of treatment. Each of these events is an racteristics, therapeutic groups, diseases or con- important aspect of drug utilization, and most ditions and, in the best of cases, clinical out- countries have regulations to cover these aspects. come. A useful analysis requires an understand- Data are collected, or are available, at national, ing of the sources and organization of the data. regional and local health facility or household level and may be derived from quantitative or 3.2 Data from drug regulatory qualitative studies. Quantitative data may be agencies used to describe the present situation and the Drug registration; drug importation trends in drug prescribing and drug use at vari- [ ] ous levels of the health care system. Drug regulatory agencies have the legal respon- Quantitative data may be routinely collected data sibility of ensuring the availability of safe, effi- or obtained from surveys. Qualitative studies 20 assess the appropriateness of drug utilization and cacious and good-quality drugs in their country. They are thus the repositories of data on which generally link prescribing data to reasons (indi- drugs have been registered for use, withdrawn or cations) for prescribing. Such studies have been banned within a country. Regulatory agencies referred to as «drug utilization review» or «drug also have inspection and enforcement functions, utilization evaluation». The process is one of a and are responsible for supervising the importa- «therapeutic audit» based on defined criteria and tion of drugs and for the issuance of permits for is intended to improve the quality of therapeutic drug registration. care. There is an increasing interest in the evalu- It is possible, therefore, to obtain data on the ation of the economic impact of clinical care and number of drugs registered in a country from medical technology. This has evolved into a dis- such agencies. Where the agency issues import cipline dedicated to the study of how pharma- permits and supervises drug importation, data on cotherapeutic methods influence resource utili- product type (i.e. generic or branded), volume, zation in health care known as pharmacoeco- port of origin, country of manufacture, batch nomics (see chapter 4). number and expiry date may be collected. The sources of drug utilization data vary from Where the data reflect total national imports, country to country depending on the level of estimates of quantities of drugs in circulation sophistication of record keeping, data collection, can be obtained for defined periods and for analysis and reporting and the operational consi- various therapeutic groups derations of the health care system. It may be difficult to obtain true estimates if documentation is incomplete and not all trans- 3.1 Large databases actions are recorded. Information on smuggled The increasing interest in efficient use of health goods or goods entering the country through ille- care resources has resulted in the establishment gal routes will not be captured by these data. of computer databases for studies on drug utili- zation. Some of the databases can generate sta- tistics for patterns of drug utilization and adverse 3.3 Supplier (distribution) data drug reactions. Data may be collected on drug Drug importation; local manufacture; cus- sales, drug movement at various levels of the [ toms service ]
  • 22. Data on suppliers may be obtained from drug motivate health care providers to adhere to esta- importers, wholesalers or local manufacturers. blished health care standards. In countries where permits or licences are required from drug regulatory authorities and 3.4.1 Prescribing data ministries of health before importation of drugs, Prescribing data are usually extracted from out- data may be available from such sources. patient and inpatient prescription forms. Such Customs services, in the process of clearing data may be easily retrieved where records are imports from the ports of entry, may collect data computerized and computerized data also facili- on drugs. However, the codes used by customs tate trend analysis. In the absence of electronic services are not detailed enough to capture all databases, prescribing data are usually extracted relevant information. National agencies respon- from patient records or from patient intercept sible for the collection of excise duty can also studies or retrieved at dispensing points. provide information on the volume of production Information that may be obtained from pre- and on distribution of drugs from local manufac- scriptions includes patient demography, drug turers. name, dosage form, strength, dose, frequency of Data from these sources can generally be used administration and duration of treatment. Where to describe total quantities of specific drugs or diagnoses are noted on prescriptions, and parti- drug groups, origins of supplies and type (i.e. cularly for inpatient prescription, it is possible to branded or generic). link drug use to indications. Trends in utilization 21 In the absence of a national mechanism for the for specific drugs and diseases can also be esta- direct capture of data on drug production or blished. As an example, inpatient data may pro- importation, wholesalers become an important vide a link to empirical treatment of infections as source of information on drug acquisition. Such opposed to treatment based on microbiological data are reliable insofar as wholesalers are the assessment. This may be achieved by extracting only legal entity able to import drugs. In some relevant data from the patient records, but requi- countries, medical, dental and veterinary practiti- res that the records be of good quality. oners, as well as pharmacists, can import phar- Prescriptions are a good source of information maceutical products. It is usually very difficult for determining some of the indicators of drug to collect comprehensive data from such sources use recommended by WHO including the: even if there are regulatory requirements about submitting reports. Public sector procurement – average number of drugs per prescription practices, however, have reasonable documen- (encounter); tation but provide data only on that sector. – percentage of drugs prescribed by generic name; Practice setting data – percentage of encounters resulting in prescrip- tion of an antibiotic; Prescribing data; dispensing data; drug use – percentage of encounters resulting in prescrip- [ indicators; facility data (aggregate) ] tion of an injection; – percentage of drugs prescribed from essential Data from health facilities may be used to evalu- drugs list or formulary, and ate specific aspects of health provision and drug – average drug cost per encounter. use and to generate indicators that provide infor- Prescribing data allow the determination of the mation on prescribing habits and aspects of pati- PDD which may differ from the DDD. While ent care. These indicators can be used to deter- the DDD is based on the dosages approved in mine where drug use problems exist, provide a standard product characteristics with clinical out- mechanism for monitoring and supervision and come data from controlled clinical trials, the
  • 23. PDD is variable and dependent on factors such can be used to obtain information on various as severity of illness, body weight, interethnic aspects of drug use including: differences in drug metabolism and the prescri- – the cost of individual drugs and classes of bing culture of the health provider. Using DDDs drug; enables comparison to be made between drug – the most frequently or infrequently used drugs; groups as the influences of prescribing culture – the most expensive drugs; and available dosage strengths are eliminated. – the per capita consumption of specific pro- In some countries, it is a legal requirement ducts; that prescriptions dispensed by pharmacies and – comparisons of two or more drugs used for the drug outlets are kept for a minimum period before same indication; disposal. Where these regulations are adhered – the prevalence of adverse drug reactions; to, prescription data may be obtainable from – the prevalence of medication errors; and pharmacies. However, in many developing – the percentage of the budget spent on specific countries the rule is not generally followed. In drugs or classes of drug. countries where computerized records of prescri- bing data are kept, they may be readily retriev- Aggregate data are often useful for comparing able depending on the depth of the database. the utilization of a particular drug to that of other drugs and to utilization in other hospitals, 22 3.4.2 Dispensing data regions or countries. Drug dispensing is a process that ends with a client leaving a drug outlet with a defined quan- 3.4.4 Over-the-counter and tity of medication(s) and instructions on how to pharmacist-prescribed drugs use it (them). The quantity of drugs dispensed Pharmacists and other drug outlet managers may depends on their availability. Thus information prescribe over-the-counter preparations or phar- available from dispensers may include: macist-prepared drugs that do not require pre- – drug(s) prescribed; scription by a physician. Data on such medica- – dose(s) prescribed; tions may be difficult to obtain especially in – average number of items per prescription; environments with weak drug regulation and – percentage of items prescribed that were actu - poor record keeping, but when such information ally supplied (an indicator of availability); is available from stock or dispensing records, it – percentage of drugs adequately labelled; broadens the understanding of drug utilization – quantity of medications dispensed; and patterns. – cost of each item or prescription. 3.4.5. Telephone and Internet These data may be obtained from records kept at prescribing the drug outlet either in electronic or manual Physicians in certain countries may prescribe form. over the telephone. Prescribing and dispensing using the Internet also occurs, especially in deve- 3.4.3 Aggregate data loped countries. Most Internet prescriptions are A number of data sources within the health faci- for nutritional supplements and herbal preparati- lity or hospital setting can provide aggregate ons. However, as exemplified by sildenafil data on drug utilization. These sources include (Viagra®), other medicines are also increasingly procurement records, warehouse drug records, being sold on the Internet. Innovative ways have pharmacy stock and dispensing records, medica- to be devised to collect information on this type tion error records, adverse drug reaction records of transaction. and patient medical records. These data sources
  • 24. 3.5 Community setting data Drug use evaluation can assess the actual pro- cess of administration or dispensing of a medica- Household survey; compliance (adherence tion (including appropriate indications, drug [ to treatment); drug utilization ] selection, dose, route of administration, duration of treatment and drug interactions) and also the The drugs available in households have either outcomes of treatment (e.g. cured disease condi- been prescribed or dispensed at health facilities, tions or decreased levels of a clinical parameter). purchased at a pharmacy (with or without a pre- The objectives of drug use evaluation include: scription) or are over-the-counter medications. The drugs may be for the treatment of a current – ensuring that drug therapy meets current stan-- illness or are left over from a previous illness. It dards of care is not uncommon for patients to adhere poorly to – controlling drug cost; the instructions given for taking their dispensed – preventing problems related to medication; medicines. Thus dispensing data and utilization – evaluating the effectiveness of drug therapy; and data may not be equivalent because they have – identification of areas of practice that require not been corrected for non-compliance. further education of practitioners. Drug utilization by outpatients is best assessed by performing household surveys, counting left- The problems to be addressed by drug use evalu- ation may be identified from any of the data des- over pills or using special devices that allow cribed in section 3.4 (including prescription indi- 23 electronic counting of the number of times a par- ticular drug is administered. Drug utilization by cators, dispensing data and aggregate data). The inpatients can be determined by reviewing treat- main source of data for drug use evaluation is ment sheets or orders. the patient records. An identifiable authoritative For both outpatients and inpatients, the data group, such as the drugs and therapeutic com- on the utilization of a particular drug can be mittee, usually carries out reviews of drug use in aggregated for a defined population in DDDs. a hospital or health facility. This group has the Using DDDs has the advantage of allowing com- responsibility for drawing up the guidelines, cri- parison for example between inpatients and out- teria, indicators and thresholds for the evaluati- patients. Data on various dosage forms and on. Drug use evaluation may be based on data generic equivalents of the same medication can collected prospectively (as the drug is being dis- also be aggregated. pensed or administered) or retrospectively (based on chart reviews or other data sources). 3.6 Drug use evaluation • Typical criteria reviewed in prospective studies Drugs and therapeutic committee; prospec- include the following tive evaluation; retrospective evaluation; – indications; criteria setting – drug selection; – doses prescribed; Drug use evaluation, sometimes referred to as – dosage form and route of administration; drug utilization review, is a system of continu- – duration of therapy; ous, systematic, criteria-based drug evaluation – costs; that ensures the appropriate use of drugs. It is a – therapeutic duplication; method of obtaining information to identify pro- – quantity dispensed; blems related to drug use and if properly develo- – contraindications; ped, it also provides a means of correcting the – therapeutic outcome problem and thereby contributes to rational drug – adverse drug reactions; and therapy. – drug interactions.
  • 25. • In retrospective studies, the criteria source that could help you understand the situa- reviewed include: tion, and (2) some possible advantages and/or – evaluation of indications; limitations of each of the sources of data you – monitoring use of high-cost medicines; have listed. – comparison of prescribing between physicians; – cost to patient; When evaluating the advantages and – adverse drug reactions; and limitations of the data, consider the ans- – drug interactions. wers to the following questions: • How relevant are the data for It is possible to incorporate some of the above learning about antibiotics? criteria into databases thus allowing drug experts • How easy is it to collect these to evaluate any items that do not meet establis- types of data in your country? hed criteria. For meaningful results to be obtai- • How much will it cost to collect ned from drug use evaluation a reasonable num- and process the data and how ber of records need to be assessed. A minimum long will it take? of 50 to 75 records per health care facility is • How reliable are these data? considered adequate. However, the number of records sampled would depend on the size of the For example, from data from previous 24 facility and the number of prescribers. surveys, we might obtain the following useful information: historical utilization 3.7 General reading rates by facility or geographical area, and How to investigate drug use in health facilities: possibly utilization by type of antibiotic, Selected drug use indicators. Geneva,World health problem or age. The advantages Health Organization, 1993 (unpublished docu- of using historical survey data are that ment WHO/DAP/93.1; available on request from they have already been collected and Department of Essential Drugs and Medicines carry no additional cost. However, their Policy, World Health Organization, 1211 limitations include not being able to con- Geneva, 27, Switzerland). trol exactly which data have been collec- ted or from where, not knowing whether 3.8 Exercises current practices reflect those of the past, Examine the sources of data listed in the and having no patient-specific or provi- Worksheet. Imagine that you want to learn der-specific information. It would also about the utilization of antibiotics in your coun- usually not be possible to find informa- try. In the spaces provided in the right-hand tion on dosing of antibiotics. columns of the worksheet, write down (1) what kinds of useful data you might gather from each
  • 26. Worksheet for section 3.8 Sources of data on drug utilization Data source Type of information available Advantages and limitations Drug import records Drug supply to health facility Orders and/or delivery receipts Previous reports of surveys 25 Pharmacy stock cards/ pharmacy ledger book Pharmacy sales receipts Large hospital or insurance databases Private drug outlet sales records Community or household surveys Drug manufacturing records Other sources
  • 27. Chapter 4: Economic aspects of drug use (pharmacoeconomy) Pharmacoeconomics; types of cost; cost-mini- 4.2 Cost-minimization analysis mization analysis; cost-effectivness analysis; Cost-minimization analysis is a method of calcu- cost-benefit analysis; cost-utility analysis lating drug costs to project the least costly drug or therapeutic modality. Cost minimization also 4.1 Introduction reflects the cost of preparing and administering a Drug costs per se are important, as they account for dose. This method of cost evaluation is the one a substantial part of the total cost of health care - used most often in evaluating the cost of a speci- typically 10-15% in developed countries and up to fic drug. Cost minimization can only be used to 30-40% in some developing countries. However, compare two products that have been shown to drug costs usually need to be interpreted in the con- be equivalent in dose and therapeutic effect. text of the overall (net) costs to the health system. Therefore, this method is most useful for compa- Drugs cost money to buy, but their use may also ring generic and therapeutic equivalents or «me save costs in other areas. For example, the purchase too» drugs. In many cases, there is no reliable of one specific type of drug may lead to reductions equivalence between two products and if thera- in the following: peutic equivalence cannot be demonstrated, then – use of other drugs; cost-minimization analysis is inappropriate. – the number of patients requiring hospitalization If a new therapy were no safer or more effecti- or in the length of stay in hospital; ve than an existing therapy (i.e. there is no incre- 26 – the number of doctor visits required; mental benefit), it would normally justify the – administration and laboratory costs compared same price as the existing therapy. An example with those incurred by using another drug to treat would be the introduction of a new ACE inhibi- the same condition. tor with essentially the same properties as exis- Assessing the true cost to a health system of ting members of the class; the price would be using a specific drug will therefore require the cost equivalent to that of the existing drug(s). This is of acquisition of the drug to be balanced against often not as simple as it may seem, as it requires both any cost savings resulting from the use of that sound trial-based information on the doses of the drug and the extra health benefits it may produce. two drugs required for equivalent efficacy. An On the other hand, costs may arise from adverse alternative is to use the PDDs for the two drugs drug reactions both in the short- and particularly the in the marketplace to determine the relative pri- long-term. ces. This is a pragmatic approach, but assumes Assessing the value for money of using a drug that the two drugs are actually used at equiva- requires the extra health benefits achieved to be lently effective doses, and this may not always weighed against the extra net cost. This compari- be the case. son is usually expressed as an incremental cost- effectiveness ratio (ICER) which is the net incre- 4.1 Cost-effectiveness analysis mental cost (costs minus cost offsets) of gaining an Cost-effectiveness analysis involves a more com- incremental health benefit over another therapy. prehensive look at drug costs. While cost is Concerns about the cost of medical care in gene- measured in monetary terms, effectiveness is ral, and pharmaceuticals in particular, are currently determined independently and may be measured being expressed by all health systems. There is a in terms of a clinical outcome such as number of general focus on providing quality care within limi- lives saved, complications prevented or diseases ted financial resources. Decision-makers are increa- cured. singly dependent on clinical economic data to guide Cost-effectiveness analysis thus measures the policy formulation and implementation. Some of incremental cost of achieving an incremental the concepts used in making such decisions include: health benefit expressed as a particular health cost-minimization, cost-effectiveness, outcome that varies according to the indication cost-benefit, and cost-utility. for the drug. Examples of ICERs using this