Review

© Future Drugs Ltd. All rights reserved. ISSN 1473-7167 619

CONTENTS

Why it is difficult to answer the question

Expert opinion

Five-year view

Key issues

References

Affiliations

www.future-drugs.com

Therapeutic drug monitoring: is it cost-effective?Gerald E Schumacher† and Judith T Barr

During the last 30 years, therapeutic drug monitoring has evolved from an abstract consideration to a routine intervention. In this increasingly cost-conscious environment, questions are raised about the cost-effectiveness of therapeutic drug monitoring. This review presents the state of therapeutic drug monitoring today, predictions for its near future and the status of economic analyses of the intervention.

Expert Rev. Pharmacoeconomics Outcomes Res. 2(6), 619–624 (2002)

†Author for correspondenceNational Education and Research Center for Outcomes Assessment, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, MA, USATel.: +1 617 373 3203Fax: +1 617 373 2968g.schumacher@neu.edu

KEYWORDS:cost-effectiveness, outcomes, TDM, therapeutic drug monitoring

Therapeutic drug monitoring (TDM) – mean-ing the use of serum drug concentrations as anadjunct to therapeutic decision-making fordrugs with a narrow therapeutic index – wasintroduced more than 30 years ago, butachieved widespread popularity as an interven-tion in the 1980s. In the early days, TDMfocused on studying whether the interventionimproved therapeutic responses and decreasedadverse reactions. Today, in a cost-conscious eraand an evidence-based environment, the ques-tion posed in the title of this manuscript isincreasingly raised. Are the outcomes resultingfrom TDM worth the resources expended tosupport the intervention or would they be bet-ter used for other activities? Do the publishedsummaries on studies of outcomes [1–6] andcost-effectiveness [7–11] make the case that thebenefits of TDM justify the costs? Despite theprofusion of outcomes studies, the relativelysmall number of economic analyses over theyears leads us to conclude at the outset that thequestion may never be answered using strictmethodology for study design and cost-effec-tiveness analysis and that the answer in nonrig-orous analytic terms depends to a large extenton the perspective of the stakeholder [12].

Why it is difficult to answer the questionTo ask whether TDM is cost-effective requires usto analyze a body of literature or, if that is inade-quate, to resolve the question, to incept a rand-omized control trial, preferably, or cohort and/orcase-control trials, less desirably, to provide

answers. To analyze the cost-effectiveness ofTDM requires access to both noneconomic andeconomic outcomes data. However, a numberof issues cloud the rigorous consideration ofcost-justifying TDM:

• The environment in which clinicians prac-tice is quite different now than at the timeTDM was introduced. The diffusion of dataover time makes it difficult to extrapolateprevious studies to today.

• TDM encompasses a variety of activities,from extensive institution-wide monitoringservices, to targeting a very few selecteddrugs for routine monitoring, to extempora-neous application by some practitioners. Assuch, any analysis and external validity istempered by the conditions of the study.

• The majority of studies of TDM over theyears have focused on system-related ratherthan patient-centered outcomes. This hasemphasized analysis of the influence ofTDM on processes more than the evidence-based assessment of the effect of TDM onimproving patient status.

• Research on TDM has typically taken a rela-tively short time-frame for study and thenextrapolated the results to annual or longeroutcomes. The decay of intervention effectand/or the influence of study results on thesubsequent actions of practitioners is notaccounted for in these type of analyses.

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620 Expert Rev. Pharmacoeconomics Outcomes Res. 2(6), (2002)

• The literature is replete with noneconomic outcomesresulting from TDM, but the availability of rigorously andwell-designed economic studies is very limited.

• Published data have focused on an institutional perspective,but economic analyses from a societal perspective are lacking.

• The thrust of TDM research today is in specialty applica-tions. While these areas are ripe for study, it is unlikely thateconomic research time will be devoted to the TDM drugscommonly used in the general population.

• There may be specialty applications that merit TDM despitethe cost and for which humane considerations outweigheconomic factors.

The evolving environment of TDM practiceWhat practitioners knew in the early days of TDM is differentfrom what they know today. Early on, when TDM was a newintervention with a sparse database, it was understood andapplied by a small number of clinical pharmacists, clinical labo-ratorians and physicians. Today, the principles and applicationsof TDM are taught to physicians, pharmacists and nurses andthe use of serum drug levels in decision-making is widespread.Furthermore, as the principles and applications of TDM havebecome increasingly well understood, the awareness of the datapublished from TDM studies pervades the thoughts andactions of practitioners, leading to more savvy, prudent andimproved drug therapy practices with or without the use ofserum drug levels. As a result it would be a challenge to isolateTDM practices from general practitioner knowledge today instudying the cost-effectiveness of TDM. This makes it difficultto devise prospective studies in which the ‘test’ practitionersmake decisions using TDM as an adjunct while ‘control’ practi-tioners do not use TDM advice even though the information tobe gained may have already been a requisite part of the deci-sion-making process of some members of the control group.Retrospective studies become even more difficult to interpret.

Somewhat unrelated to the above considerations, yet still ger-mane to the changing environment of TDM practice, is theperceived movement away from TDM-dependent drugs in thedevelopment of recent new drugs for general use. Some of themainstay TDM drugs of the past (e.g., theophylline, procaina-mide, digoxin) have been supplanted or downgraded by neweragents that appear not to require TDM.

The variety of TDM activitiesTDM as a verb or noun is not monolithic. As such, it is difficultto generalize results from one type of study to other approachesto TDM. In a very few cases, TDM is a health system-wide,proactive unit responsible for monitoring many drugs with nar-row therapeutic indices used by patients in the institution andassociated clinics. In more situations, there is a system-wide pol-icy to monitor a very few selected drugs. In some cases, patientsin specialty practices have some drugs monitored as policy, whileother commonly monitored drugs are left up to individual prac-titioners to decide. Most commonly, the decision of TDM or notfor applicable drugs is the province of the practitioner, varying

from one practitioner and patient to another. In addition,some health systems routinely publish TDM information, dataand ‘pearls’ for practitioners, while others institutions do not.External validity of published studies becomes an issue.

System-related compared with patient-centered TDM outcomesThe majority of studies of TDM over the years have focused onsystem-related rather than patient-centered outcomes[1,2,5,12,13]. We evaluated 247 study citations over the period of1974–1994, as aggregated from eight summary studies [1,2].

Nearly 75% of the studies reported outcomes from TDMthat were system-related rather than patient-centered. System-related outcomes deal with the results of the intervention proc-ess or procedure itself (e.g., timing of obtaining drug levels, fre-quency of obtaining drug levels) – patient-centered outcomesreport the result of the intervention on the patient specifically(e.g., cure rate, rate of adverse reactions).

Similarly, nearly 75% of the studies reported process ratherthan outcome measures. Process measures assess various activi-ties in the procedures for providing TDM as an intervention.Outcome measures, in this context, assess the end result of theintervention in the patient.

For system-related measures, studies comparing TDM withnonTDM populations generally revealed that TDM reducedthe rate of undesirable system-related outcomes by 50%(outcomes relating to the intervention itself and not thepatient) and increased the rate of desirable system-relatedoutcomes by 100%. For patient-centered measures, forwhich there were many less studies to review, TDM reducedthe rate of undesirable outcomes by 15–50%.

As a result, the pattern is clear. TDM improves the structureand process for monitoring therapy and that is an importantobservation. However, the data are limited and less persuasivethat TDM actually enhances patient-centered outcomes. Whileit is likely that TDM improves patient care and we expect thatmost well-constructed studies would show that, the publishedpatient-centered data are not extensive and the external validityof the results is in question. No studies of the effect of TDM onpatient health-related quality of life have been reported.

Extrapolating TDM studies of limited duration to longer time-framesTDM is not alone in extrapolating studies of limited durationto longer time-frames. We find no reports in the literaturedocumenting TDM interventions that were conducted andanalyzed for intervals that justify the effects of a real-timeapplication of the intervention. A few studies have been eval-uated over a short duration and have been reported as such or,alternately, as results extrapolated to yearly savings [11,14–23].This approach restricts the full usefulness of cost-effectivenessanalyses because factors may change over time and thus mod-ify the extrapolation, there may be a decay of effect over timeafter exposure to an intervention (TDM in this case), or thediffusion of information to practitioners from short studiesmay confound the results when applied to real-time.

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The limited availability of TDM economic outcome dataCost-effective analyses require access to economic and noneco-nomic outcome data and while access to noneconomic data arelikely adequate for some retrospective studies of TDM, there islittle access to parallel economic outcomes. A few well-con-structed prospective economic analyses have been published andthe results are persuasive that TDM in the limited situationsstudied is not only cost-effective, but also cost-beneficial[15,17,20,22]. However, most of the economic analyses of TDMhave been constrained by limitations in methodology, includingthe lack of appropriate controls, failure to account for all rele-vant direct and indirect costs not only within the time-frame ofthe study, but downstream, limited study duration and the useof system-related rather than patient-centered outcome data.

In our analysis of 247 citations over the 20 years, only 8% ofthe reports included economic evaluations [1,2]. Nine cost-effec-tiveness studies reported savings resulting from TDM. How-ever, these studies involved TDM-influenced changes in proc-ess not patient-centered outcome variables, the average studywas 4 months in length, but data were then projected to anaverage annual savings of $37,000/year. Three cost-benefitstudies of aminoglycoside TDM, of 4–6 months duration,reaped 4:1, 9:1 and 52:1 benefit-to-cost ratios.

We recently perused the entire inventory of three journals inwhich economic analyses of TDM would likely be published:Therapeutic Drug Monitoring, PharmacoEconomics and ClinicalPharmacokinetics. Although a few review articles appeared, lessthan ten prospective or retrospective cost-effectiveness or cost-benefit (not cost-utility) studies were published over the life ofthe journals. Remove aminoglycoside monitoring, usuallystudied for relatively short intervals, from the publications andprecious little has been reported.

Even given the above limitations, the pattern develops thatTDM, at least for single drug-specific monitoring, is likely tobe cost-effective, generally the result of reduced length of stayand/or decreased incidence of TDM drug-related adverse reac-tions. Whether a full-blown program of TDM, monitoringmany drugs over a long period of time, would be cost-effectiveor cost-beneficial is unresolved. A few published studies, how-ever, do provide the reader with a sound approach to analyzingthe economic impact of TDM [15,18,20,23–25].

The perspective of TDM analysesEconomic analyses of TDM to date have taken the institutionalperspective. In this era of increasing third-party reimburse-ment, the institutional viewpoint is not necessarily the same asthat of the insurer/payer. Nor is it the same as a societal per-spective. It is important for users of TDM economic data to beclear on the stakeholder perspective being reported.

Specialty applications as the thrust of TDM research todayThe 1996 survey of the American Society of Health-SystemPharmacists, the most reliable and current data, reported that60 and 80% of all TDM activities involved aminoglycosidesonly and aminoglycosides plus vancomycin assays, respectively[26]. Therefore, it is not surprising that the published analyses ofTDM cost-effectiveness deal with these drugs.

Yet, the real enthusiasm and activity in TDM today stemsfrom studies of specialty drugs, TDM in various subpopulationsand refining complex aspects of interpreting and applying TDMresults. The pharmacokinetic, pharmacodynamic and TDMmethodological aspects of antiretrovirals [27,101–105], antineoplas-tics [29] and immunosuppressants [30–32] are aggressively investi-gated. Comparison of various analytic methods, especially forthe specialty drugs, is common. Evaluating patients at extremesof age continues to be an important activity [33,34]. Evaluatingbound and unbound fractions of TDM drugs where applicable,in terms of determining the fraction with the greatest predictivevalue for monitoring, is still an important subject.

Therefore, it is unlikely that a full-plate, prospective study ofTDM will be initiated. TDM as an intervention was well inplace before pharmacoeconomic analysis became popular, so thebloom for such investigations is off the rose. Cost-effectivenessanalyses of TDM specialty drugs should be expected, especiallysince economic analyses are now more common.

Expert opinionDespite numerous monographs questioning the routine appli-cation of TDM over the years – pondering its value, excessivecosts, improper use and overuse – it has become a well-acceptedand commonplace intervention [35–40].

Our assessment of the published literature suggests that it isnot possible to answer the question of whether TDM is cost-effective, if a profuse body of rigorous analyses using standardmethodology is expected, if TDM in its various guises is con-sidered and if external validity is important. However, a patternof data does exist and it portends that rigorous studies, werethey to be performed, would show that TDM does increasedrug effectiveness, reduce drug-induced toxicity, produce cost-effectiveness analyses within commonly accepted thresholdsand may be cost-beneficial. Nonetheless, the proof of the pud-ding is unlikely because the cost, interest and enthusiasm arelikely to be in very short supply for conducting the variousstudies necessary to resolve the question in general terms.

We are aware of no cost-utility analyses of TDM performedto date, but given current recommendations for this as thefavored form of economic analysis, cost-utility analyses shouldbe performed [41].

Lastly and apart from the economic considerations, TDM,while often indicated and useful as an intervention, is probablyused excessively for commonly monitored drugs. Too often it isa reflex intervention that substitutes for good judgment alonein daily management of routine cases. However, for targetedpopulations and specialty drugs with a narrow therapeuticindex, TDM is almost always justified and often essential. Inthese cases, TDM improves decision-making, is part of humanecare and is a critical intervention regardless of cost.

Five-year viewWidespread cost-effectiveness, cost-benefit, or cost-utilityanalyses of TDM, even in this increasingly cost consciousenvironment, are unlikely to occur in the next 5 years, if ever.We conclude this for three reasons:

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622 Expert Rev. Pharmacoeconomics Outcomes Res. 2(6), (2002)

• Active TDM, in terms of applying serum drug concentra-tions as an adjunct to therapeutic decision-making, hasbecome a well-accepted staple of drug management, be it forthe commonplace drugs like the aminoglycosides, or theinvestigation into application for specialty drugs, like theantiretrovirals and immunosuppressants.

• Passive TDM, implying the use of pharmacokinetic/pharma-codynamic concepts in prescribing and monitoring applicabledrugs, whether drug levels are invoked or not, has increasinglybecome commonplace in the actions of practitioners.

• There is a perceived movement away from TDM-dependentdrugs in the development of recent new drugs for general use.Some of the commonplace TDM drugs of the past (theo-phylline and older antiarrhythmics are good examples) havebeen reduced in favor by newer agents that appear to notrequire TDM.

Some have suggested that future applications will embracepharmacogenetic-oriented TDM [42]. Traditional TDM occursafter a drug is administered to a patient, whereas pharmacoge-netic-oriented TDM will be applicable as a screening adjunctbefore drug therapy begins. This is an exciting prospect that islikely to be realized, for therapeutic as well as economic reasons,but it is unlikely to be achieved in the next 5 years.

The active application of traditional TDM for ambulatorypatients has never been a widespread practice [43]. In thefuture, we envision that its use may grow in this setting due tothe financial pressures to deinstitutionalize many clinicalpractices. As a result, drugs like the aminoglycosides, immu-nosuppressants and antineoplastics may increase in ambula-tory TDM applications. Furthermore, some types of specialtydrugs (e.g., antiretrovirals) may turn out to benefit fromTDM and this would expand the application of the TDM tocommunity patients.

Key issues

• During the last 30 years, therapeutic drug monitoring (TDM) has evolved from a notion to a routine intervention for drugs with a narrow therapeutic index. Nonetheless, the present cost-conscious environment leads many to urge evaluations of the cost-effectiveness of TDM.

• Although some limited economic analyses of TDM have been performed, the prospective, rigorous, widespread economic analysis of TDM is unlikely, due to lack of interest, acceptance of the intervention as a staple of drug decision-making and the realization that external validity of individual economic studies is unlikely.

• Historical data on TDM, as well as some of the published economic analyses, have limitations that constrain application to the present.

• The majority of TDM studies over the years have focused on system-related rather than patient-centered outcomes. This approach has emphasized how effectively TDM enhances monitoring practices rather than an evidence-based approach to how effectively TDM improves patient outcomes.

• Research on TDM has taken a relatively short time-frame for study and extrapolated the results to annual or longer economic outcomes. This ignores the decay of intervention and effect and the influence of study results on the subsequent actions of practitioners.

• The availability of published economic analyses of TDM that are rigorous and well designed is very limited.

• TDM represents a variety of activities, from institution-wide units responsible for monitoring all applicable drugs, to targeting selected drugs, to casual use of the intervention. This limits the external validity of studies.

• The status of TDM for traditionally monitored drugs is stable. Increasing study of these drugs is rather stagnant, however. The most active interest in TDM today and for the near future is in investigating and/or refining the application for specialty drugs, like the antiretrovirals and immunosuppressants.

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Websites

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Affiliations• Gerald E Schumacher, PharmD, PhD, National

Education and Research Center for Outcomes

Assessment, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, MA, USA, Tel.: +1 617 373 3203, Fax: +1 617 373 2968, g.schumacher@neu.edu

• Judith T Barr, ScD, National Education and Research Center for Outcomes Assessment, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, MA, USA, Tel.: +1 617 373 4188, Fax: +1 617 373 2968, j.barr@neu.edu