Informed Engagement: Unpacking and Addressing Patients' Reasons for Nonadherence

There is no one-size-fits-all solution to the problem of medication nonadherence.

If the problem of patient medication nonadherence has just as many complexities as any other human behavioral challenge, why have we attempted to address it as a systems efficiency issue? I would argue that we’ve done so for many reasons that are grounded in the economics of health care, an approach that inadvertently does a grave disservice to patients. Clearly, on an academic level, we have for decades taken a more reasonable and sound approach to understanding and addressing patient medication nonadherence. That individualized care, however, has often failed to translate into overarching policy and thus, reimbursement practices.

The past decade has seen broadscale health care decision making and policy driven purely by economic considerations— enlightened by neither medicine nor pharmacy. During this period, we have measured adherence in the United States predominantly in terms of pharmacy efficiency (ie, scripts leaving the building). Accordingly, it makes perfect sense that we have addressed nonadherence as a systems efficiency problem. If, for example, retrospective pharmacy claims analyses tell us that the problem is one of “a quota not being filled,” then business logic would argue that increased dispensing rates equals problem solved. We know better, however. A world of automatic refills does not equate to medication taken correctly, or at all. Common sense tells us that availability is but one hurdle to medication adherence.

The systems built to address the problem are likewise complicated. The time lag and lack of direct correlation between nonadherence and negative health outcomes hinder enlightened policy making, and the fragmentation and discord between pharmacy, medical practice, and benefit design have chilled the collaboration necessary to make sense out of this mess. Large health systems and payer organizations have suffered and, to a certain extent, continue to suffer from the delusion that an elusive one-size-fitsall solution to medication nonadherence exists. Alignment across stakeholders is not always collaborative, with payers, providers, and health policy groups working alongside one another, relatively uninformed by each other’s advances and failures. As a result, resources pour into familiar and scalable practices that we know do not work.

Even where the importance of consistency in the care continuum is obvious to all players, tactical implementation across that same continuum has proven to be daunting. Only organizations less encumbered by the pressures of segmentation and scalability (namely, the few larger “closed” health care systems, the Centers for Medicare & Medicaid Services—driven innovation pilots, and the very small number of truly innovative systems working in the space) have recognized and honored the values that come from delivering health care services in an interdependent manner— and at the individual level. These success stories, albeit few and far between, remind us that the key to success lies with informed patient engagement: when innovation is focused squarely at the individual patient the problem of nonadherence becomes entirely solvable.

There is brilliance in C. Everett Koop’s simple reduction of the adherence problem to “Drugs don’t work in patients who don’t take them.” It was only an introduction, however, to the problem at a national level in a form digestible to the masses. We’re beyond that now. We know from behavioral economics research that people make decisions in the face of incomplete information, limited cognitive resources, and decision biases. Decision-making research tells us that people do not always act in their own best interest. While it is true that there are arguably more drivers than ever calling upon patients to take charge of their own well-being and pressuring health systems and payer organizations to improve quality and efficacy, we see no meaningful trend toward improved medication adherence.

Pharmacists are in a unique position to inform today’s much-needed health care transformation. As the true meaning of health care innovation begins to permeate systems practice, pharmacists are returning to the basics of patient engagement to effectively inform adherence intervention plans.

Human Behavioral Complexities Require an Individualized Approach

When patient medication nonadherence first began to emerge as a recognized public health issue, inconsistent terminology existed, with terms such as “compliance” carrying negative connotations and translational challenges that led to confusion and impeded research and practical application.¹ Evaluation of a problem as complex as nonadherence requires effective communication among all stakeholders to deliver solutions that align to individual patient needs.

Recognizing the importance of establishing a common language that could support such an individualized approach, the European consensus meeting on taxonomy and terminology of patient compliance convened in 2009 to propose a new taxonomy based on behavioral and pharmacological science. This taxonomy has become almost universally adopted, promoting consistency, aiding in adherence-related research, and helping define the complexities of the problem:

• Adherence to medication is the process by which patients take their medications as prescribed, composed of initiation, implementation, and discontinuation.
• Initiation occurs when the patient takes the first dose of a prescribed medication.
• Implementation is the extent to which a patient’s actual dosing corresponds to the prescribed dosing regimen, from initiation until the last dose.
• Discontinuation occurs when the patient stops taking the prescribed medication, for whatever reason(s).
• Persistence is the length of time between initiation and the last dose, which immediately precedes discontinuation.
• Management of adherence is the process of monitoring and supporting patients’ adherence to medications by health care systems, providers, patients, and their social networks.
• Adherence-related sciences are the disciplines that seek understanding of the causes or consequences of the differences between prescribed (ie, intended) and actual exposures to medicines.²

Once adopted, the common language not only advanced a public dialogue on (and thus recognition of) the myriad of costs associated with nonadherence, but also made evident the need to consider carefully the method by which adherence is assessed. A market driven by pharmacy claims data metrics began to wake up to the fact that while available and convenient, these measures told only part of the story. True, script abandonment and refill rates provided some insight into the problems of noninitiation and discontinuation; however, they told us almost nothing about comprehensive individual implementation patterns.

This new taxonomy also made clear that successful management of nonadherence was a shared responsibility, involving not only players in the health care system but also patient social networks. The recognized extension beyond the patient—provider relationship reminded us that as we considered the causes of nonadherence, a holistic approach would help us understand the real world challenges faced by individual patients and permit us to capitalize on the value of secondary caregivers.

Understanding the Etiology of Nonadherence

In the context of drug development, researchers have long recognized the importance of understanding adherence patterns. Consequently, adherence measurement methodologies have been most extensively evaluated based upon their usefulness and reliability in light of researcher and clinician goals.³ Most indirect measures of adherence (eg, selfreporting, pill count) have been discounted as unreliable⁴ and most direct measures (eg, drug assays, drug markers, direct observation) are considered to be somewhat impractical outside of limited high-value research design.^5,6

Special drug packaging with electronic monitoring has become the norm in drug development clinical trials due to its substantiated reliability⁷ and scalability. For years, the Medication Event Monitoring System (MEMS; commonly referred to as the MEMS cap) has been the standard for drug packaging in phase 1, 2, and 3 drug development trials. These electronic caps record, store, and wirelessly transfer hour-by-hour drug-dosing histories over extended periods so researchers can obtain a comprehensive picture of each subject’s complete dosing history and compare a subject’s adherence to the patterns of other trial participants.

From a reliability standpoint, research has substantiated that a less than 2% discrepancy exists between MEMSgenerated data and therapeutic monitoring. Data gathered by electronic monitors, therefore, can be used to inform protocol design based upon insights into drug tolerance, safety and efficacy issues, and appropriate dosing levels. Used with more than 500,000 subjects, data from MEMS have been published in more than 650 peer-reviewed articles and have been cited more than 47,000 times.

As we consider the relevance of these concepts to clinical practice, perhaps one of most interesting insights gained is that the term “fully adherent patient” (defined as medication possession ratio of at least 80%) actually represents a vast array of adherence behaviors. While some fully adherent patients may indeed execute perfectly, others discontinue therapy early, take drug holidays, or take their medications at varying times of day—all of which could be missed completely as false positives under current claimsbased adherence classification.

Patient medication nonadherence is really more akin to a syndrome than a disease state, with no approved treatment available to address the problem. “Diagnosis” of nonadherence is simply the first step, with a follow-on analysis to provide comprehensive understanding of the etiology necessary for adequate care planning.

This etiology is best determined through adherence pattern analysis and patient engagement. With a more accurate picture of each individual’s adherence patterns, physicians, nurses, pharmacists, and others can engage in an informed manner and identify root causes of nonadherence. Together with the patient, the provider can use these informed insights to deliver more effective coaching and make more sophisticated recommendations specific to each individual user.⁸

Such a compelling value proposition leaves one wondering why this standard in clinical research is not the standard in clinical care. As with so many promising technologies, uptake has been slowed by several factors, including an unclear FDA regulatory landscape; cost relative to doing the “same things” or worse, doing nothing; change inertia; and resistance to the still novel concept of patient population segmentation, otherwise known as “differentiated patient management.”

On an optimistic note, recent FDA guidance indicating a “light touch” approach toward a number of health technology issues,^9,10 increasing product offerings,¹¹ better affordability, and market leader—driven innovation have resulted in a recent uptick in pilot projects at the pharmacy, health system, and drug manufacturer levels. These pilot projects promise to spur scalable innovation across the industry.

Informed Adherence Intervention Plans

Patient medication nonadherence is unlikely to be adequately addressed by a single intervention or intervener. This complicated problem must be addressed with multilayer, multifaceted, multisystem approaches designed in response to post engagement evaluation and collaboration.¹² Components of the adherence plan will be as diverse as the nonadherence causes themselves.

Grounded in experience drawn from decades of MEMS-generated data, Bernard Vrijens¹³ et al have identified the most effective interventions to be: (1) broad involvement of the patient’s health care ecosystem; (2) multifaceted interventions that are well targeted to address the specific causes of nonadherence (eg, if forgetfulness is a key barrier, then interventions such as the use of calendars and similar reminders are well targeted); (3) data-driven feedback and counseling for the patient; and (4) specific techniques or counseling that tend to promote healthy medication-taking habits.

As pharmacists consider practice-level implementation of adherence programs, real-world issues associated with scalability and affordability must be considered. Depending upon practice type, varying degrees of flexibility will be available for investment and design choices. Clearly, informed patient engagement should be within the purview of all providers. At the foundation level, a platform of low-cost, proven solutions that is broadly implemented on a population level could significantly leverage therapeutic effect and provide substantial cumulative public health benefits.¹⁴

When considering more intensive, more effective, and/or more expensive interventions, pharmacists must determine whether those costs are warranted and whether responsible disproportionate allocation of patient management resources is an option. It is likely that increased technology uptake and accelerated economic drivers will continue to foster an environment where pharmacist input will be pivotal in redesigning patient care to achieve the best use, by patients, of appropriately prescribed medicine to maximize the potential for benefit and minimize the risk of harm.

Liz received her BSN from Boston College School of Nursing and earned her MBA in executive management from St. John’s University. After extensive careers in clinical nursing and big pharma, she obtained a JD in health law and economics from George Mason University School of Law. She practiced food and drug, fraud and abuse, insurance and privacy law at Wiley, Rein LLP in DC. In 2003, Liz joined Altria Client Services, managing the legal and health ethics considerations associated with clinical research and new product development activities undertaken in pursuit of tobacco harm reduction. Liz joined MWV Healthcare in 2009 as vice president of global quality, regulatory and external affairs. Her responsibilities include health care—specific legal issues and global health care regulatory support for innovation, development, and commercialization of products and services that address emerging patient needs, particularly patient medication nonadherence. Most recently, Liz headed a consultancy exploring novel health innovation opportunities including Virginia’s first Pay for Success Social Impact Financing project and the use of technology-enabled adherence interventions as a replacement for/supplement to directly observed therapy, short course, in the treatment of drug-resistant tuberculosis and HIV in India, China, and sub-Saharan Africa.

References

• Steiner JF, Earnest MA. The language of medication-taking. Ann Intern Med. 2000;132(11): 926-930.
• Vrijens, B, deGeest S, Hughes D, et al. A new taxonomy for describing and defining adherence to medications. Brit J Clin Pharmacol. 2012;73(5):691-705. doi: 10.1111/j.1365-2125.2012.04167.x.
• Farmer KC. Methods for measuring and monitoring medication regimen adherence in clinical trials and clinical practice. Clin Ther. 1999;21(6):1074-1090.
• Levine AJ, Hinkin CH, Marion S, et al. Adherence to antiretroviral medications in HIV: differences in data collected via self-report and electronic monitoring. Health Psychol. 2006;25:329-335.
• Lehmann A, Aslani P, Ahmed R, et al. Assessing medication adherence: options to consider. Int J Clin Pharm. 2014;36(1);55-69.
• Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353(5):487-497.
• Vrijens B, Tousset E, Rode R, Bertz R, Mayer S, Urquhart J. Successful projection of the time course of drug concentration in plasma during a 1-year period from electronically compiled dosing-time data used as input to individually parameterized pharmacokinetic models. J Clin Pharmacol. 2005;45(4):461-467.
• Vrijens B, Vincze G, Kristanto P, Urquhart J, Burnier M. Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ. 2008; 336(7653):1114—1117.
• US Department of Health and Human Services. Docket No FDA-2012-D-1145. Draft Guidance for Industry on Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products, 77 Fed Reg 74670. December 17, 2012.
• US Department of Health and Human Services. Mobile Medical Applications; Guidance for Industry and Food and Drug Administration. 80 Fed Reg 6996. February 9, 2015.
• Market entrants include “real-time” self-reporting (eg, mHealth), “smart” bottles (eg, MEMSCAP), “smart” blisters (eg, Helping Hand), “smart” pill organizers, “smart” boxes/containers, ingestible sensors.
• Vrijens B, De Geest S, Hughes DA, et al. A new taxonomy for describing and defining adherence to medication. Brit J Clin Pharm. 2012;73(5):691-705.
• Bernard Vrijens, PhD, chief science officer at MWV Healthcare, former general manager of the AARDEX Group, associate professor of biostatistics at the University of Liège, Belgium.
• Zedler BK, Joyce A, Murrelle L, Kakad P, Harpe SE. A pharmacoepidemiologic analysis of the impact of calendar packaging on adherence to self-administered medications for long-term use. Clin Ther. 2011;33(5):581-597. doi: 10.1016/j.clinthera.2011.04.020.