Defining and Measuring Primary Medication Nonadherence: Development of a Quality Measure

Poor medication adherence has been increasingly recognized as a major public health issue and a priority for health care reform. Primary medication nonadherence (PMN) is a subset of this broader subject and occurs when a new medication is prescribed for a patient, but the patient does not obtain the medication, or an appropriate alternative, within an acceptable period of time after it was prescribed. It is increasingly evident that the public health problem of PMN is widespread. However, the lack of standardized definitions and measures inhibits the ability to establish the true incidence of this problem or to track changes in PMN rates over time. Given the limitations of current measures, the Pharmacy Quality Alliance (PQA) convened an expert working group to set parameters for a new industry measure. That new measure, which links electronic prescribing and pharmacy dispensing databases and was developed and approved by the PQA, is described here. PMN literature from 1990 to June 2015 is also reviewed, and existing PMN measures are summarized.


V I E W P O I N T S
Primary and secondary nonadherence are distinct subsets of medication nonadherence. 8 Primary medication nonadherence (PMN) occurs when a new medication is prescribed for a patient, but the patient does not obtain the medication or an appropriate alternative within an acceptable period of time after it was prescribed. This includes prescriptions that patients actually present (or are electronically prescribed), as well as those that never reach the pharmacy. Secondary nonadherence measures prescription refills among patients who previously filled their first prescriptions.
Secondary nonadherence has emerged as a major target of quality improvement initiatives. The Centers for Medicare & Medicaid Services, for example, has adopted secondary adherence-related measures as part of its star ratings program for Medicare Advantage plans and stand-alone prescription drug plans. Secondary adherence rates are publicly reported for these plans, and incentives, including quality bonus payments, are tied in part to performance on secondary nonadherence measures. 7 These secondary nonadherence measures are likely to underestimate the true rate of nonadherence, however, since their method for calculation is to use prescription claims data to identify patients who filled a prescription at least 2 times in the measurement period but then did not refill the medication regularly. Because a patient needs to fill the prescription twice to be included in the adherence measure, this would mean that the method thus misses instances of PMN when the medication never reaches the patient in the first instance.
With most medication adherence research to date focused on secondary nonadherence, PMN has been identified as a major research gap. 6,9,10 The few studies on PMN have differed in operational definition and methods of measurement. The lack of standardized measures for PMN has limited the understanding of its true extent and the ability to compare PMN rates across the health care system. One reason for the challenge in measuring PMN is the difficulty in linking prescriptions that are written with those that are dispensed. Many written prescriptions for new medications never make it to the pharmacy, so there are difficulties in calculating an accurate denominator. Growth in electronic prescribing has partially resolved this issue, and new measures have emerged linking electronic prescribing databases with pharmacy dispensing databases. 8 This method for capturing PMN may lead to more standardized PMN measures, which may prove useful for benchmarking and quality improvement initiatives.

PMN Operational Definition
While the extant literature on PMN generally defines PMN as an instance in which a patient does not fill a newly prescribed medication, variation exists with respect to (a) the definition of "new prescription"; (b) the number of days that elapse after a prescription is ordered before a medication is considered to be not filled; and (c) the types of medications included in the measure. To determine if a prescription is new, measures traditionally had a look-back period of 6-24 months to determine if the medication had been previously dispensed. The length of time that previous studies gave patients to fill a prescription before classifying it as PMN had the greatest variation, spanning from 48 hours to 12 months; some studies did not even offer a time limitation. Studies generally limited the measure to chronic medications, while some were specific to individual medication classes (e.g., statins or bisphosphonates). Acute medications, such as antibiotics or antivirals, were generally excluded, since these medications may sometimes be written by prescribers for patients to fill on an as needed basis.

Method of Measurement
The PMN studies we assessed varied widely in their methods of measurement. Early PMN studies generally employed laborintensive methods such as random digit dialing, pharmacistdelivered questionnaires, or patient self-reports. These methods are unlikely to yield objective data or to be scalable for the purposes of benchmarking across the health care system.
Newer studies have used electronic prescribing records linked with pharmacy dispensing databases. For example, Fischer et al. (2011) linked e-prescribing transactions and pharmacy claims files. 33 New prescriptions were defined as those that had not been filled in the previous 12 months. PMN was defined as "the number of prescriptions filled divided by the total number of prescriptions written." Patients were given up to 12 months to fill a prescription before it was classified as PMN. 33 Studies such as that from Fischer et al. have been enabled by working with integrated health systems and national pharmacy chains/pharmacy benefit managers, since these agencies capture robust information on prescriptions written and prescriptions dispensed. Similarly, international studies within single-payer health care systems have leveraged government databases that record all prescriptions ordered and link these with comparable government databases that contain complete prescription dispensing records. 12,14 The broad reproducibility of such methods in multipayer health care systems such as those in the United States is difficult given the lack of comprehensive government prescription ordering and dispensing datasets.

Reported PMN Rates
Given the variation in PMN definition and methods of measurement across the 35 studies, it is of little surprise that This commentary reviews the literature on PMN, summarizes existing PMN measures, and describes a new PMN quality measure, which was developed and approved by the Pharmacy Quality Alliance, a national measure development organization.

■■ Methods
To assess the published data on PMN, a literature review was conducted using Google Scholar and PubMed databases, covering the time period from 1990 to June 2015. Search terms included "primary non-adherence," "primary medication non-adherence," "medication non-redemption," "medication non-fulfillment," "primary non-compliance," "first-fill prescriptions," and "newly initiated drug therapy." The bibliographies of identified articles were examined to identify additional relevant literature. We excluded non-English articles, as well as letters, editorials, comments, and review articles. Selected articles were reviewed, and the key elements were extracted for comparison and synthesis.

■■ Literature Review Findings
The literature review produced 35 articles that were included for further analyses. Table 1 provides an overview of key elements from these studies.  The majority of the studies (77%) have been published since 2010, indicating recent momentum in research for this subset of medication adherence.
It is important to distinguish PMN from prescription abandonment. "Prescription abandonment" is traditionally used in studies as a broader term than PMN and occurs whenever a prescription is filled by a pharmacy but not claimed by the patient. This umbrella term thus includes instances of first-fill abandonment, which is PMN, as well as the abandonment of refilled prescriptions, which is not PMN but, rather, secondary nonadherence. Further, abandonment rates are generally calculated based on prescriptions that reach the pharmacy and, thus, miss the significant portion of prescriptions written but never filled at a pharmacy. For these reasons, abandonment measures contain elements of PMN but are imperfect proxies for PMN. While abandonment rates may be useful for pharmacy self-assessment to track the impact of operation changes, they are separate and distinct from PMN.

Primary medication nonadherence
Patients failed to fill prescription provided by practitioner (in the past 12 months).

Retrospective study
Random digit dialing telephone patient-reported survey.

21.60
Mcaffrey et al. 44 Initial noncompliance Patients failed of their own accord to receive intended medications within 48 hours.

Prospective observational study
Audit of unclaimed prescription information and patient data from 3 pharmacies and tracking logged prescriptions for 4 weeks.

1.94
Beardon et al.  membership. Based on the recommendation from the QMEP, the measure was endorsed in November 2013 by a vote of the PQA membership. 46 According to the PQA quality measure, "PMN occurs when a new medication is prescribed for a patient, but the patient does not obtain the medication, or appropriate alternative, within an acceptable period of time after it was prescribed." 46

Key Elements of the PMN Measure
Given the areas of variation identified in the literature review, the following elements were considered for the consensus PMN measure: 1. A new prescription is described as one where the same drug or its generic equivalent had not been filled during the prior 180 days. 2. The measurement period of time is 12 months. This is the time when the prescription medication fill pattern is assessed. Thus, the measurement period will require 19 months of pharmacy prescription dispensing data, including 6 months before the measurement period premeasurement period) and 1 month following the measurement period (postmeasurement period). 3. Focus is on chronic medications that fall within measurement priorities outlined in the National Quality Strategy, which sets standards and regulations to measure the quality of health care and its impact on public health. Priority is given for chronic obstructive pulmonary disease, diabetes, dyslipidemia, and hypertension.
A full listing of medication classes that count toward the PQA PMN measure is available in Table 2. 46 The expert panel also excluded instances where an "appropriate alternative medication" was dispensed. The panel noted that formularies may require a switch to a preferred medica-tion and, thus, did not classify an instance as PMN if a drug product was dispensed that appears in the same medication class as the product that was e-prescribed. For example, if a statin was e-prescribed, and a separate statin was dispensed, it would not be classified as an instance of PMN. Without exempting appropriate alternative medications, measures are likely to overestimate the extent of PMN.

Consensus PMN Measurement
Denominator. The denominator consists of the number of e-prescriptions for newly initiated drug therapy for chronic medications listed in Table 2 during the measurement period and for patients aged 18 and older. Thus, when using e-prescribing data, all newly initiated prescriptions transmitted through an e-prescribing portal for any medication in Table 2 should be identified and counted. 46 Several instances are excluded from the denominator. To winnow out medications that are not new, prescriptions dispensed in the preceding 180 days for the same drug were excluded. Similarly, any over-the-counter medication that is e-prescribed was excluded, and duplicate medications, defined as any medication that has been e-prescribed twice in a 30-day period with no prescription fill in between the e-prescriptions, was also excluded. Lastly, pharmacies must have 30 or more e-prescriptions for newly initiated medications in the denominator in order to ensure an adequate sample size for appropriate comparison. 46 Numerator. The numerator consists of the number of e-prescribing transactions in the denominator where there is no pharmacy dispensing event that matches the patient and the prescribed drug or appropriate alternative drug within 30 days following the e-prescribing event. Thus, patients are given 30 days before being classified as primary nonadherent. If a prescription is reversed and not collected by the patient, it is not considered a dispensing event.
The measure level for the current PMN metric is a pharmacy or network of pharmacies. At this time, the PMN measure is not intended for use by pharmacy benefit managers or health plans, since the required e-prescribing data are not available in administrative prescription drug claims. 46 Testing Results Based on the rates calculated in testing, PMN is a significant problem in the community pharmacy setting, with rates varying among pharmacies. In a study by the University of Mississippi, testing revealed that of the e-prescriptions received during the 1-year observation period, an average of 12.2% of new prescriptions (or drug alternatives) were not claimed within the 30-day period. 15 There was significant variability among pharmacies (ranging from 4.9% to 78.6%), as well as among classes of drugs, suggesting that significant opportunities exist for quality improvement. 15 Based on scientific

Medication Classes
Angiotensin-converting enzyme (ACE) inhibitors, plus combination products Angiotensin II receptor blockers (ARBs), plus combination products Biguanides (plus combination products) Chronic obstructive pulmonary disease (COPD) medications Direct renin inhibitors, plus combination products Dipeptidyl peptidase 4 (DPP-IV) inhibitors, plus combination products Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, plus combination products Incretin mimetic agents Inhaled corticosteroids Meglitinides, plus combination products Sulfonylureas, plus combination products Thiazolidinediones, plus combination products Sodium-glucose co-transporter type 2 (SGLT2) inhibitors PMN = primary medication nonadherence. Notably, the average PMN rate calculated from the consensus measure (12.2%) was lower than many rates observed in the literature review. 15 This lower rate is likely because of the measure's exclusion criteria, which do not count scenarios in which an appropriate alternative medication is dispensed, among other scenarios. In addition, previous studies have shown that e-prescriptions are more likely to be picked up than hard copy prescriptions. Given that the consensus measure is limited to e-prescriptions, this is likely another reason for lower rates than when including hard copy prescriptions. 47,48

Measure Limitations
There are several potential limitations to the PMN measure. PMN is only feasible with combined data from e-prescribing transactions and prescription dispensing data because of the need to link prescriptions written with those dispensed. Changes in pharmacy benefit coverage during the measurement period may confound the PMN rates. In addition, the measure is dependent on e-prescribing and does not account for hard copy prescriptions that do not make it to pharmacies. While growing, e-prescribing rates vary regionally, and areas with low current uptake may not prove as useful for measurement. Given the 30-day time frame in which a prescription needs to be filled, the measure assumes that the patient did not receive a medication sample from the physician that would prevent pickup during the measurement period. Lastly, because the unit of analysis is the pharmacy, the measure assumes that the patient did not receive the medication at another pharmacy than the pharmacy it was e-prescribed to.

■■ Conclusions
It is increasingly evident that the public health problem of PMN is widespread. However, the lack of standardized definitions and measures inhibits the ability to establish the true incidence of this problem or to track changes in PMN rates over time. The effort to develop a consensus-based definition and quality measure of PMN is an important step towards consistent measurement of this phenomenon. Because e-prescribing is becoming the leading mode of prescription transmission, it is important to have standardized methods of tracking PMN in order to study the effectiveness of interventions to reduce PMN. Further research should evaluate clinical scenarios in which improvements of PMN is most linked to improved patient outcomes. One scenario in which the PMN measure may be specifically considered is that of hospital discharges, since adherence to discharge medications is an important consideration for hospital readmissions. The endorsed PQA measure outlined in this manuscript provides a consensus-based, tested, and validated method to calculate PMN using pharmacy dispensing data linked to an e-prescribing system.