Volume 11 • Number 1 • 2008
`V A L U E I N H E A L T H
`
`Medication Compliance and Persistence:
`Terminology and Definitions
`
`Joyce A. Cramer, BS,1 Anuja Roy, MBA, MSc,2 Anita Burrell, MBA,3 Carol J. Fairchild, PhD,4
`Mahesh J. Fuldeore, PhD, RPh, MBA,5 Daniel A. Ollendorf, MPH,6 Peter K. Wong, PhD, RPh, MS, MBA7
`
`1Yale University School of Medicine, New Haven, CT, USA; 2West Virginia University, Morgantown,WV, USA; 3Sanofi-Aventis, Paris, France;
`4Alcon Laboratories, Ft.Worth,TX, USA; 5TAP Pharmaceuticals, Lake Forest, IL, USA; 6PharMetrics,Watertown, MA, USA; 7Mercy Health
`Partners, Southwest Ohio, Cincinnati, OH, USA
`
`ABSTRACT
`
`Objective: The aim of the study is to provide guidance
`regarding the meaning and use of the terms “compliance”
`and “persistence” as they relate to the study of medication
`use.
`Methods: A literature review and debate on appropriate ter-
`minology and definitions were carried out.
`Results: Medication compliance and medication persistence
`are
`two different
`constructs. Medication compliance
`(synonym: adherence) refers to the degree or extent of con-
`formity to the recommendations about day-to-day treatment
`by the provider with respect to the timing, dosage, and fre-
`quency. It may be defined as “the extent to which a patient
`acts in accordance with the prescribed interval, and dose of a
`
`dosing regimen.” Medication persistence refers to the act of
`continuing the treatment for the prescribed duration. It may
`be defined as “the duration of time from initiation to discon-
`tinuation of therapy.” No overarching term combines these
`two distinct constructs.
`Conclusions: Providing specific definitions for compliance
`and persistence is important for sound quantitative expres-
`sions of patients’ drug dosing histories and their explanatory
`power for clinical and economic events. Adoption of these
`definitions by health outcomes researchers will provide a
`consistent framework and lexicon for research.
`Keywords: adherence, compliance, definitions, persistence,
`terminology.
`
`Introduction
`Inadequate medication compliance and persistence are
`age-old problems. When taken in varying degrees of
`deviation from the prescribed dosing regimen, medica-
`tions have situation-specific alterations in benefit/risk
`ratios, either because of reduced benefits, increased
`risks, or both. Numerous studies have demonstrated
`that inadequate compliance and nonpersistence with
`prescribed medication regimens result in increased
`morbidity and mortality from a wide variety of ill-
`nesses, as well as increased health-care costs [1–5].
`Factoring in actual compliance and persistence is
`central to an accurate assessment of effectiveness and
`cost-effectiveness of therapy [6]. Health outcome and
`cost-effectiveness analyses incorporating measures of
`
`Address correspondence to: Joyce A. Cramer, Department of
`Psychiatry, Yale University School of Medicine, 950 Campbell
`Avenue (151D), West Haven, CT 06516-2770, USA. E-mail:
`joyce.cramer@yale.edu
`10.1111/j.1524-4733.2007.00213.x
`Writing for the International Society for Pharmacoeconomics
`and Outcomes Research Medication Compliance and Persistence
`Special Interest Group (Joyce Cramer, Chairman), Working
`Group on Definitions (Peter Wong and Anita Burrell, Co-Chairs;
`Steven Clause, Joyce Cramer, Carol Fairchild, Mahesh Fuldeore,
`Prashant Nikam, Daniel Ollendorf, Anuja Roy, and Jianwei
`Xuan).
`
`medication usage have been hampered by the lack of
`uniformity in standards of definitions and measure-
`ments used to describe the concepts of medication
`compliance or persistence [7]. Health outcomes
`researchers need general and operationally useful defi-
`nitions that would help in standardizing the literature,
`in building a common platform for comparing and
`combining results, and for aiding in the development
`of effective and efficient intervention strategies to
`enhance medication compliance and persistence.
`The International Society for Pharmacoeconomics
`and Outcomes Research (ISPOR) Medication Compli-
`ance and Persistence Work Group developed defini-
`tions for compliance and persistence during 3 years of
`international review and discussion. The purpose of
`this article is to provide guidance regarding the
`meaning of the terms “compliance” and “persistence,”
`to define them as two separate constructs, and to
`provide some examples of how to operationalize them
`for use in research.
`
`Methods
`Terminology
`Selection of “compliance” as the primary term and
`“adherence” as a synonym was based on similar usage
`by indexing services (e.g., MEDLINE, PubMed). We
`
`44
`
`© 2007, International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 1098-3015/08/44 44–47
`
`Novo Nordisk Exhibit 2388
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`

`

`Compliance and Persistence Terminology
`
`45
`
`found no authoritative support for the assumption that
`“adherence” is a less derogatory term or whether it is
`preferred by patients. Commenting on the prolifera-
`tion of terms representing compliance, Feinstein [8]
`described reasons why such synonyms were not supe-
`rior terms: “Adherence seems too sticky; Fidelity has
`too many connotations; and Maintenance suggests a
`repair crew. Although Adherence has its adherents,
`Compliance continues to be the most popular term.”
`
`Literature Review of Definitions
`We reviewed English-language reports of compliance,
`adherence, or persistence during the period from 1966
`to 2005. Investigations have also used disease-specific
`or study-specific operational definitions, sometimes
`mixing the terms compliance, adherence, and persis-
`tence without adequate delineation. Some authors
`carefully separate compliance data from persistence
`data but use the term adherence to combine the two
`sets of results without a rationale or stated metric. The
`use of arbitrary categories of good and poor compli-
`ance (often set at 80%) usually was unsupported by
`research documenting the appropriateness of the cutoff
`for a specific medication class or disease (e.g., lack of
`sensitivity testing or link to outcome) [9]. Reports
`rarely document that lower compliance might be a
`more precise cutoff point (e.g., 50% or 75%).
`Most of the suggested definitions offered no con-
`crete guidance to researchers in methodological or
`operational approaches. The result has been a series of
`general reviews over the past 30 years, revealing the
`difficulty of presenting a composite view of compli-
`ance, other than to say that patients take less medica-
`tion than prescribed [10–15]. The development of
`electronic monitors to assess compliance improved the
`reliability of the data but did little to address the
`confusion created by variations in operational defini-
`tions [16,17].
`
`Similarly, a review of the persistence literature
`revealed that, although different aspects or constructs
`have generally been measured under the heading “per-
`sistence,” it was not uncommon to have the same
`measures referred to by different names (e.g., persis-
`tency, continuous adherence, and discontinuation
`rates). “Persistence” has been reported in chronic pre-
`vention therapies and described as the time of continu-
`ous therapy, demarcated by the time from initiation of
`therapy to discontinuation of therapy [18–20]. Persis-
`tence was found to be operationally defined alterna-
`tively as the time between refills, number of refills,
`renewal of prescription with an allowance for a pre-
`specified gap [21,22], the proportion of patients dis-
`pensed a certain number of days’ supply of medication
`[23,24], as well as the proportion of patients continu-
`ing to refill prescriptions after a specified time interval.
`Some arbitrary measures such as longer duration of
`therapy or greater number of patients completing the
`therapy, or the proportion of patients receiving some
`kind of therapy after commencement of treatment
`have also been used to define persistence [25,26].
`Many reports measure persistence but call it compli-
`ance and vice versa [27].
`
`Results
`The ISPOR Work Group completed 3 years of review
`and discussion at five international conferences, as well
`as review and response to drafts on the website. We
`propose definitions for two discrete terms to describe
`two aspects of medication-taking behavior (Fig. 1).
`Conceptually, compliance and persistence represent
`two constructs that are based on one’s belief in the
`efficacy of the medication, the severity of their illness,
`and their ability to control it with medication. Com-
`pliance follows the initial appraisal of the health threat
`and behavioral changes to develop the habit of taking
`
`COMPLIANCE
`
`% of doses taken as prescribed
`
`Days taking medication
`
`(without exceeding permissible gap)
`
`Start Medication
`or
`Observation
`
`Start Medication
`or
`Observation
`
`Stop Medication
`or End
`Observation
`
`Stop Medication
`or End
`Observation
`
`Figure 1 Definitions of compliance and persis-
`tence.
`
`PERSISTENCE
`
`Novo Nordisk Exhibit 2388
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`

`

`46
`
`Cramer et al.
`
`Table 1 Compliance rates by time period. Compliance for the
`first 4 weeks was 100% (28/28 days), declining to 36% (10/
`28 days) in the second month, or 68% overall
`for 2 months
`(28 + 10/56 days)
`
`Sun
`
`Mon
`
`Tue
`
`Wed
`
`Thu
`
`1
`1
`1
`1
`1
`1
`
`1
`
`1
`1
`1
`1
`
`1
`
`1
`1
`1
`1
`
`1
`
`1
`1
`1
`1
`
`1
`
`1
`1
`1
`1
`1
`1
`
`1
`
`Fri
`
`1
`1
`1
`1
`
`Sat
`
`1
`1
`1
`1
`
`1
`
`medication in accordance with the physician’s pre-
`scription (time, quantity, and frequency).
`
`Proposed Definitions
`
`compliance
`compliance. Medication
`Medication
`(synonym: adherence) refers to the act of conforming
`to the recommendations made by the provider with
`respect to timing, dosage, and frequency of medication
`taking. Therefore medication compliance may be
`defined as “the extent to which a patient acts in accor-
`dance with the prescribed interval and dose of a dosing
`regimen.” Compliance is measured over a period of
`time and reported as a percentage (Fig. 1). This defi-
`nition is operationalized in prospective assessments as
`dose taking in relation to what was prescribed. Table 1
`shows compliance patterns for a patient prescribed a
`once-daily medication. Electronic monitoring provides
`sufficient details to calculate the number of doses taken
`daily as well as whether the doses were taken at appro-
`priate intervals (e.g., approximately 12 hours apart
`for a twice-daily dosing). Additional details can be
`obtained as number of days with extra doses or
`without any doses. The definition is operationalized in
`retrospective assessments as the number of doses dis-
`pensed in relation to the dispensing period, often called
`the “medication possession ratio (MPR)” [28]. Com-
`pliance with the prescription is assumed when the
`medication is dispensed. Retrospective prescription
`claims database analyses lack the details of daily
`dosing that are available with prospective electronic
`monitoring; however, as these tools are often the only
`sources available for assessing compliance, it is sug-
`gested that this caveat is noted when describing com-
`pliance in these instances.
`
`Medication persistence. Medication compliance refers
`to the act of conforming to a recommendation of con-
`tinuing treatment for the prescribed length of time.
`Therefore, medication persistence may be defined as
`“the duration of time from initiation to discontinua-
`tion of therapy” (Fig. 1). Continuing to take any
`amount of the medication is consistent with the defi-
`
`nition of persistence. This definition can be opera-
`tionalized in both prospective and retrospective assess-
`ments by determining the initiation of treatment, or a
`point in time during chronic treatment, to a point in
`time defined as the end of the observation period.
`Persistence analyses must include a prespecified limit
`on the number of days allowed between refills, consid-
`ered the “permissible gap.” Methods for gap deter-
`mination should be based on the pharmacologic
`properties of the drug and the treatment situation (i.e.,
`the maximum allowable period until when patients
`could go without a dose and not anticipate reduced or
`suboptimal outcomes) [29,30]. By definition, persis-
`tence is reported as a continuous variable in terms of
`number of days for which therapy was available. Per-
`sistence may also be reported as a dichotomous vari-
`able measured at the end of a predefined time period
`(e.g., 12 months), considering patients as being “per-
`sistent” or “nonpersistent.”
`
`Conclusions
`Clinical outcomes of treatment are affected not only by
`how well patients take their medications but also by
`how long they take their medications. Thus, compli-
`ance and persistence should be defined and measured
`separately to characterize medication-taking behavior
`comprehensively. Addressing both compliance and
`persistence provides
`a
`richer understanding of
`medication-taking behavior. Determining the clinical
`sequelae of being fully or partially compliant or per-
`sistent is necessary before dichotomous declarations
`about “good” or “poor” compliance and persistence
`can be made.
`The proposed definitions are focused on promoting
`consistency in terminology and methodology to aid in
`the conduct, analysis, and interpretation of scientific
`studies of medication compliance. The definitions
`are geared toward future standardization in medical
`research to allow for comparisons among reports, and
`use of compliance and persistence data for pharmaco-
`economic evaluations. They will also assist researchers
`in re-evaluating both the earlier literature and its appli-
`cation in practice, with a better understanding of the
`differences between compliance and persistence mea-
`sures. Standardization will facilitate health policy deci-
`sions based on consistent evidence. The adoption of
`these definitions will also help standardize the medical
`literature.
`
`References
`
`1 DiMatteo MR, Giordani PJ, Lepper HS, Croghan
`TW. Patient adherence and medical treatment out-
`comes: a meta-analysis. Med Care 2002;40:794–811.
`2 Cramer
`JA. Partial medication compliance:
`the
`enigma in poor medical outcomes. Am J Manag Care
`1995;1:45–52.
`
`Novo Nordisk Exhibit 2388
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

`Compliance and Persistence Terminology
`
`47
`
`3 Zyczynski TM, Coyne KS. Hypertension and current
`issues in compliance and patient outcomes. Curr
`Hypertens Rep 2000;2:510–14.
`4 Avorn J, Monette J, Lacour A, et al. Persistence of use
`of lipid-lowering medications: cross-national study.
`JAMA 1998;279:1458–62.
`5 Howell N, Trotter R, Mottram DR, Rowe PH. Com-
`pliance with statins
`in primary care. Pharm J
`2004;272:1–40.
`6 Urquhart J. Defining the margins for errors in patient
`compliance with prescribed drug regimens. Pharma-
`coepidemiol Drug 2000;9:565–8.
`7 Hasford J. Biometric issues in measuring and analyz-
`ing partial compliance in clinical trials. In: Cramer,
`JA, Spilker, B, eds. Compliance in Medical Practice
`and Clinical Trials. New York: Raven Press, 1991.
`8 Feinstein AR. On white coat effects and the electronic
`monitoring of
`compliance. Arch Intern Med
`1990;150:1377–8.
`9 Caro JJ, Ishak KJ, Huybrechts KF, et al. The impact of
`compliance with osteoporosis therapy on fracture
`rates
`in
`actual
`practice. Osteoporos
`Int
`2004;15:1003–8.
`10 Sackett DL, Haynes RB. Compliance with Therapeu-
`tic Regimens. Baltimore, MD: The Johns Hopkins
`University Press, 1976.
`11 Sabate E. Adherence to Long-Term Therapies: Evi-
`dence for Action. Geneva: World Health Organiza-
`tion, 2003. Available from: http://www.who.int/
`chronic_conditions/en/adherence_report.pdf
`[Accessed July 2, 2006].
`12 Cramer JA. Relationship between medication compli-
`ance and medical outcomes. Am J Health Syst Pharm
`1995;52(Suppl.):S52–9.
`13 Lopatriello S, Berto P, Cramer JA, et al. Different
`aspects of adherence to antihypertensive treatments.
`Exp Rev Pharmacoeconom Res 2004;4:317–3.
`14 Roter DL, Hall JA, Rolande M, et al. Effectiveness
`of
`interventions to improve patient adherence: a
`metaanalysis. Med Care 1998;36(8):1138–61.
`15 Eisen SA, Miller DK, Woodward RS, et al. The effect
`of prescribed daily dose frequency on patient medica-
`tion compliance. Arch Intern Med 1990;150:1881–4.
`16 Cramer JA, Mattson RH, Prevey ML, et al. How
`often is medication taken as prescribed? A novel
`assessment technique. JAMA 1989;261:3273–7.
`17 Claxton AJ, Cramer JA, Pierce C. Medication compli-
`ance: the importance of the dosing regimen. Clin Ther
`2001;23:1296–310.
`
`18 Catalan VS, LeLorier J. Predictors of long term per-
`sistence on statins in a subsidized clinical population.
`Value Health 2000;3:417–26.
`19 Yanni F, Nichol MB, Yu AP, Ahn J. Persistence and
`adherence of medication for chronic overactive
`bladder/urinary incontinence in the California Medic-
`aid program. Value Health 2005;8:495–505.
`20 Cramer JA, Amonkar MM, Hebborn A, Altman RD.
`Compliance and persistence with bisphosphonate
`dosing regimens among women with postmenopausal
`osteoporosis. Curr Med Res Opin 2005;21:1453–
`60.
`21 White TJ, Chang E, Leslie S, et al. Patient adherence
`with HMG reductase inhibitor therapy among users
`of two types of prescription services. J Manag Care
`Pharm 2002;8:186–91.
`22 Mauskopf JA, Paramore C, Lee WC, Snyder EH.
`Drug persistency patterns for patients treated with
`rivastigmine or donepezil
`in usual care settings. J
`Manag Care Pharm 2005;11:231–9.
`23 Grant RW, O’Leary KM, Weilburg JB, et al. Impact
`of concurrent medication use on statin adherence
`and refill persistence. Arch Intern Med 2004;164:
`2343–8.
`24 Cramer JA, Sernyak M. Results of a naturalistic study
`of treatment options: switching atypical antipsychotic
`drugs or augmenting with valproate. Clin Ther
`2004;26:905–14.
`25 Malone M, Alger-Mayer SA. Pharmacist intervention
`enhances adherence to Orlistat therapy. Ann Pharma-
`cother 2003;37:1598–602.
`26 Carswell JL, Beard KA, Chevrette MM, et al. Track-
`ing trends in secondary stroke prevention strategies.
`Ann Pharmacother 2004;38:215–19.
`27 Sikka R, Xia F, Aubert RE. Estimating medication
`persistency using administrative claims data. Am J
`Manag Care 2005;11:449–57.
`28 Steiner JF, Prochazka AV. The assessment of refill
`compliance using pharmacy records. Methods, valid-
`ity, and applications. J Clin Epidemiol 1997;50:105–
`16.
`29 Peterson AM, Nau DP, Cramer JA, et al. A checklist
`for medication compliance and persistence studies
`using
`retrospective
`databases. Value Health
`2007;10:3–12.
`30 Burrell A, Wong P, Ollendorf D, et al. Defining
`compliance/adherence and persistence: ISPOR Special
`Interest Working Group. Value Health 2005;
`8:A194–5.
`
`Novo Nordisk Exhibit 2388
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
`
`