How Medication Non-Adherence Impacts Brand Management

Non-adherence to medication regimens is arguably the most debilitating of barriers to patient wellbeing. According to one estimate, as many as 275,000 patients die globally each year due to non-adherence. Lack of adherence is also a critical barrier to pharmaceutical business growth, costing the global pharmaceutical industry in excess of $1T annually.^6,7 This article delves into non-adherence, its causes and impact on clinical effectiveness and economic wellbeing of the healthcare ecosystem. It then provides executive guidance on strategies and tactics to tackle non-adherence based on research with key stakeholders across multiple therapy areas.

Effect on clinical effectiveness

The overarching goal of randomized control clinical trials is to establish a measure of a medicine’s safety and efficacy that can be observed with reasonable certainty in the real world. The real world, however, is fraught with complexities that make it less than certain for a medicine to realize proven clinical efficacy in the form of reliable effectiveness. Differences in patient history, demographics, co-morbidities, social, geographic and economic makeup between those who were enrolled in a successful trial and those seeking treatment in the real world are reasons why. But the most important and avoidable cause is lack of adherence to a clinically proven medication as prescribed. In the routine course of care, the decision to adhere to the regimen as prescribed rests with patients and their support net. It is no surprise then to note that:

• 41% of heart attack patients don’t take their blood pressure medications
• Half of children with asthma either don’t use their inhalers at all or use them inconsistently
• Seven out of 10 patients with depression are non-adherent to prescribed treatment

A complicating factor is the apparent disconnect between a clinician’s intent to treat with a prescribed medicine and a patient’s desire to be treated as such. Note, for example, that:

• 25% of new prescriptions written are never filled
• Of those who fill their first prescription, 40% fail to get a second refill as prescribed even after six months
• 75% of prescriptions are not taken as directed^1,2

It is thus not far fetched to believe in the notion that lack of adherence is in and of itself a preventable disease. And that for a drug to be deemed safe and effective, data collected in a randomized control trial needs to be evaluated in the larger context provided by real world evidence. The pervasive impact of non-adherence in hindering drug effectiveness in the real world calls for the design of clinical programs that integrate pre- and post-launch time frames. In such programs, the pre-launch phase would conceivably consist of designs that account for traditional variations in patient segments, histology, dosage and common, indication specific inclusion criteria across relevant geographies. The post-launch design would test for variations reflective of real-world situations—including controls for adherence, competitors, sociologic and economic factors—that reflect conditions of day to day clinical practice. In other words, a clinical program would aim to generate results that assure regulatory approval at a minimum, but also provide reliable guidance on what is necessary for wide and secure asset use in a competitive marketplace, where factors such as non-adherence adversely impact realizing the full value of a medication.³

An ineffective healthcare ecosystem

The fact that a patient does not adhere to a medication regimen as prescribed has downstream effects in the care continuum even beyond the inability to realize its clinical benefits as promised in a clinical trial. Multiple studies have established the relationship between lack of adherence and an inability to accurately assess medication effectiveness, reduced treatment response, poorer disease prognosis, higher rates of relapse, increased morbidity, additional treatment seeking behavior and lost workplace productivity. Studies have also established a relationship between lack of adherence, increased emergency room visits and higher than expected hospitalization rates. Such relationships have been found across a wide range of disease types treatable by both primary and specialty care treatments such as Type II diabetes, cardiovascular disease, ulcerative colitis, epilepsy, COPD, CML, Parkinson’s and schizophrenia. A study among patients receiving liver transplants associated lower medication adherence post transplant to serious consequences such as graft rejection and graft loss. Another study established an association between non-adherence and higher mortality rates in patients with diabetes, cardiovascular disease and hypertension. Poor adherence to oral oncology treatments (due partly to high out-of-pocket costs) is well documented; as is the impact of low adherence on cancer patient decisions to postpone or abandon care—allowing the worsening of the cancer, leading to higher rates of hospitalization and other emergency care.¹⁸

According to a literature review of 34 published studies between 2003 and 2012 measuring adherence estimates in 10 of the most prevalent therapeutic classes, the average rate of non-adherence was 48.2%, i.e. one out of every two patients on average was not adhering to a prescribed treatment regimen, and as such exposing himself/herself to the types of consequences discussed above.

In a review article published in 2014, adherence rates presented averaged around 50% as well. The article further stated that there is no evidence for substantial change in medication adherence observed over the past 50 years. As of 2020, the average non-adherence rate of about 50% across chronic conditions has remained unchanged.^4,5,6

Significant avoidable costs

It is no surprise then to note that non-adherence has critical economic consequences, adding significant cost burden to an already inefficient system. Estimates of revenue loss to the pharmaceutical industry due to non-adherence in the US vary between $188B (2011) and $250B to $290B (2019), i.e. losses equivalent to approximately 50% to 60% of total US annual drug sales. The economic impact is even more pronounced when factoring for downstream, outcomes related effects of non-adherence. After including costs incurred for treatment failures, new medical problems, doctor visits, hospital admissions and the cost of new medications, a study published in 2016 estimated that total costs related to non-optimal use of medicines in the US, including non-adherence, was between $495B to $673B. Given that total US annual drug sales are approximately 48% of total global sales, the global impact of such non-optimal medication use is in excess of $1T annually.

While the economic costs of non-adherence are daunting, research has shown that much of such expense can, in principle, be controlled. For example, a study of over 300,000 patients enrolled in Medicare Advantage plans (2017-18) conducted by Prime Therapeutics analyzed claims data for diabetes medicines (n=40,407 patients), statins (n=145,038) and RAS (Renin Angiotensin System agents, i.e. high blood pressure medicines (n=132,358)). The study showed that moving someone with low adherence (<50%) to near perfect adherence (99%+) was associated with potential total cost of care savings, as follows:

• Diabetes medications were associated with $3,365 potential savings per patient per year, representing an average savings of 64%
• RAS medications were associated with $2,901 potential savings per person per year, representing an average savings of ~49%
• Statins were associated with $1,563 potential savings per person per year, representing an average savings of 29%

Even a one-point increase in adherence, the study estimated, would result in per patient per year savings of $21 to $46, depending upon treatment class. Given the substantial number of patients in the US on prescription drug treatment for diabetes, high cholesterol and high blood pressure, even small increases in adherence in such patients can mean substantial economic gains. A strategy of stressing adherence holds the twin virtues of generating healthy incremental revenue and positively impacting health care benefits and costs. Chart 1 below presents data from a study establishing a relationship between adherence and annual medical and drug related spending in the US for Type II diabetes.

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Medical spending covers costs incurred for emergency, inpatient and outpatient visits; drug spending covers costs related to medications meant to treat Type II diabetes. Note that as patients’ adherence to medication increases, medical costs decrease. Corresponding increases in drug-related costs are more than offset by substantial decreases in medical costs, resulting in net reduction in overall healthcare costs. In addition to Type II diabetes, the study focused on similar analyses of patients with hypercholesterolemia, hypertension and congestive heart failure. For each of the four conditions studied, hospitalization rates were significantly lower for patients with high medication adherence.

Even from a health economics perspective, a modest investment in reducing non-adherence has been proven to result in significant gains in the efficacy of resource utilization. A study of treatment naïve HIV patients in the US shows that just spending $1,600 per patient on interventions for increasing adherence up to ideal levels is cost effective at a total of $29,400 per QALY gained, an estimate that is 41% less than the acceptable threshold of $50,000/QALY gained.^7-10

Insights shaping brand planning

Two key dimensions of how healthcare is provided to its consumers are vital in determining patient medication adherence: communication content and style, i.e. what is discussed and how. In a study, executed with multiple sclerosis patients and their treating neurologists using custom patient chart auditing, surveys of patients and physicians, and multivariate analyses of research data, we found:

• Patient-physician interactions to be the most important drivers of treatment selection. Rather than make a treatment decision in isolation, neurologists and patients who discussed the pros and cons of specific treatment options tended to make clear, informed choices perceived to be in the best interests of the patient
• The longer a requested brand was discussed as part of a patient-physician interaction, the higher the chances were of it being prescribed and actually used as directed
• While providers focused more on the comparative treatment efficacies of competing treatment options, patients evaluated available medications on side effects such as the incidence of influenza, needle size and its impact in producing inconvenient injection site reactions. As such, treatment options that had favorable adverse event profiles had a much better chance of being prescribed and adhered to as a result of meaningful patient-physician interactions
• Not all patients were open to engaging in such a dynamic on their own. Patients who were younger, who sought more information on their own, who relied more on the experiences of other patients through informal interactions and exchanges in patient forums were more prone to discussing specific treatment options with their providers, thereby leading to the selection of specific branded products they preferred and adhered to over others
• Physicians who were more knowledgeable about a specific treatment tended to prescribe the product more as a result of a patient request during a patient–physician interaction
• Neurologists tended to discuss more treatment options requested by patients specifically. Provided the physician was convinced of the value of prescribing a particular product, more often than not patient requests for a product were granted, thereby increasing chances of higher adherence.

The value of such insight in shaping effective brand planning is self-evident. A wide variety of strategy options that put patients at the center of marketing efforts can be expected to make marketing more patient-centric and encourage better adherence. For instance, considerable value exists in:

• Evaluating options to enhance the quality and frequency of patient information seeking behaviors—including providing more information about other patients’ experiences, more avenues for self-expression in a formal forum where other similar patients can share experiences, proven data on available treatment options and their pros and cons compared to what they have been prescribed
• Thinking through marketing levers that encourage patient–physician dialogue; including presenting vignettes of productive dialogues through advertisements, developing direct-to-patient marketing materials focused on encouraging such dialogue—while presenting brand-specific data that would provide the patient with relevant content
• Designing product messages that address similar and distinct specific physician and patient needs in ways that encourage interactions about relevant information
• Finding ways to encourage physicians to spend more time engaging patients in productive discussions about the marketed brand in the context of its patient-related benefits compared to its competition
• Embedding in market research projects objectives that divine reasons behind physician decisions to prescribe specific products and patient decisions to comply with them, also understanding social and emotional reasons behind behaviors so that better, patient-centric decisions can be made.

An equally critical, albeit under-recognized driver of quality treatment is physicians’ inherent style of communication. Consider the following facts:

• The most common cause of physician malpractice suits is failed communication of physicians with patients and their families.
• In a survey, 83% of MDs believed communication was as important as technical skills in patient outcomes; however, only 18% believed they had had good training in patient communication.
• In a large-scale patient study, a person-focused interaction style appeared to be the most congruent with patient-reported quality of primary care. Physicians with the person-focused style rated highest on four of five measures of the quality of the physician–patient relationship and patient satisfaction. In contrast, physicians with the high-control style were lowest or next to lowest on the outcomes. Physicians with a person-focused style granted the longest visits, while high-control physicians held the shortest visits—a difference of two minutes per visit on average. The associations were not explained by patient and physician age and gender.

Taking a patient-centric view in two-way communications related to evaluation, diagnosis and treatment holds the promise of enhancing the quality of patient interactions, treatment decisions and subsequent patient outcomes such as ensuring adherence.

Designing cancer product marketing programs that emphasize the use of effective patient-provider communication can benefit cancer patients, their care providers and the manufacturers of cancer-treating medications. There is considerable social and business value in reducing avoidable uncertainty about information patients care about, identifying and explicating the worth of a course of treatment over available alternatives, justifying product and regimen choices and emphasizing the importance of receiving continual patient and caregiver feedback.^11-14

Address latent patient needs

Strategies to address patient non-adherence can benefit by understanding latent, often unstated, patient needs that inadvertently impact behavior. A key such need is the desire for kinship, psychological and social support, particularly from similar other sufferers. Studies have consistently proven the value of psychosocial support for cancer patients in offsetting medical costs and freeing up resources in terms of reduced office visits, medical procedures, diagnostic tests and hospital admissions.

Access and control over personal information is another key motive likely to improve patient empowerment and subsequent behavior that improves care quality. In an online survey of 8,411 cancer patients administered by LIVESTRONG (the Lance Armstrong Foundation) and the National Cancer Institute's Health Information National Trends Survey, 80%-87% of respondents indicated it was very important for them to be able to obtain their own medical records electronically, since it would improve their care. Respondents who were survivors (on or post-treatment) comprised the greatest proportion of those who believed this was important.

Rather than leave patients to fend for themselves efforts to provide sustained, customized care coordinated with healthcare providers has also shown notable results. Community Care of North Carolina, a group of 14 physician networks serving Medicaid patients, paid physicians a monthly fee for care coordination; collected data on patients’ prescription-filling rates; and had clinical pharmacists reach out to patients, explain the need for the medications, and often reduce a regimen’s complexity. This approach led to a 5%-7% improvement in adherence in the patient group.⁴

The ability to afford prescribed medications has long been a known and obvious driver of lower than expected adherence. Among patients with diabetes or hypertension, cost is the most common reason for medication non-adherence, with more than two-thirds of patients skipping or delaying medication. A National Health Interview Survey project established that cost related non-adherence in the US was associated with 15% to 22% higher all-cause mortality rates for all conditions.¹⁵

As is well known to pharmaceutical marketers and economists, however, higher prices do not have to imply lower usage. Interventions that represent higher value to patients at the same list price can generate a lot more intent to purchase resulting in higher than expected volume. It behooves a marketer to study patient behaviors at the pharmacy in order to determine the key economic and marketing levers that are likely to increase product purchase rates above the norm under the status quo. Chart 2 below presents data from a willingness-to-pay experiment conducted with patients for a new drug slated for launch in the US market. The experiment sought to measure patient reactions to a range of possible copayments at the pharmacy in terms of four alternate behaviors and an undecided/don’t know option. Note that while patient intent to purchase a product drops significantly as co-pay increases, the proportion of patients who intend to refuse purchasing the prescribed product outright does not. The desire to initiate dialogue with the prescribing physician overrides any such knee jerk reaction. Needless to say, this represents excellent opportunity for the marketer.

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Patients need rationale to buy into the value provided by the product at a cost perceived to be higher than what they are used to. Physicians need information to resolve the patient–physician dialogue in favor of a product, especially of the type that establishes the product’s holistic value proposition, rather than one that focuses on its cost alone. Focusing on the unstated, latent needs for convincing rationale is usually the better strategic goal, more so than offering short term cost incentives in the form of co-pay cards or temporary one time cost reductions.

Whatever the form of the incentive, sufficient marketing of the product’s total value proposition to payers, patients and physicians alike is essential in sustaining and reinforcing the more desired dynamic whereby payers are incentivized to increase access to the product for reasons that are much more than cost related, physicians are convinced the product has differentiated value and is easy to access, and patients believe the product is relatively more valuable than what they are used to and worth purchasing at the price incurred—so as to maintain adherence as prescribed and realize health benefits as promised.

Leverage technology innovations

The vital challenges to patient health care posed by lack of adherence to clinically proven medicines can conceivably be tackled by a range of evolving innovations. Key examples are as follows:

• Disseminating direct-to-patient materials that contain product information on correct administration, dosing, storage, clinical safety, efficacy and use that clear misconceptions and increase confidence in matters such as product safety and efficacy
• Funding cognitive behavioral psychosocial groups for patients with chronic conditions, particularly those who are terminally ill
• Building into marketing and medical affairs initiatives provider programs that aim to improve provider-patient communication, particularly stressing the importance of collaborative discussion (as opposed to transactional interaction), treatment option comparisons (as opposed to favored treatment selection), longer duration of interactions, and a person focused style (as opposed to a controlling one)
• Emphasizing customer marketing initiatives that stress a total medication value proposition, which rationally balances cost with accrued benefit to patients and payer; supporting it with proof of accretive value realization over a finite time due to sustained adherence, rather than overemphasizing short term benefits of marginal co-pay reductions
• Offering patient friendly insurance benefit designs that remove affordability as a barrier to improving adherence. For example, custom designing value-based plans for specific patient segments that offer reduced cost sharing for conditions that need increased adherence for maximizing health benefit, while increasing cost sharing for conditions that are not relevant or unnecessary.16
• Devising creative branded and unbranded tools that use technology to facilitate patient engagement and involvement specific to their condition, such as patient engagement portals that facilitate patient interaction with other sufferers and health care providers while simultaneously allowing self-directed monitoring, access and control of personal information
• Spreading use of technology and telecommunication-based innovations, including:
  • Mobile platform apps for retaining medication storage and intake logs, providing alerts/reminders, communicating with healthcare providers, monitoring adherence and compliance through inbuilt metrics
  • Digital and video enabled systems for recording or real time observance of treatment that allow patients and their health care providers to remotely monitor adherence as prescribed
  • Telecom based systems that require patients / caregivers to call in to pre-specified call centers or autopilot receptors each time a medication is ingested¹⁷

Medication non-adherence is a serious and endemic barrier to realizing the inherent value of pharmaceutical innovation, its purpose and societal rationale. It behooves executives to recognize it as such, and harness reliable research, ensuing strategy and technology to design and execute progressive brand plans that alleviate its silent and detrimental consequences to patients. The fact that encouraging adherence has clear implications on revenue and profits is a welcome corollary.

References

1. Interventions to Improve Adherence to Self-administered Medications for Chronic Diseases in the United States: A Systematic Review (2012); Meera Viswanathan, Carol E Golin, Christine D Jones, Mahima Ashok, Susan J Blalock, Roberta C M Wines, Emmanuel J L Coker-Schwimmer, David L Rosen, Priyanka Sista & Kathleen N Lohr; Annals of Internal Medicine; 157: 785:789
2. The Cost of Not Taking Your Medicine (2017); Jane Brody; The New York Times; April 17
3. Strategic Priorities for Specialty Care Products (2011); Sanjay K. Rao; PM360; August 1
4. Interventions For Enhancing Medication Adherence (2014); Nieuwlaat R, Wilczynski N, Navarro T, Hobson N, Jeffery R, Keepanasseril A, Agoritsas T, Mistry N, Iorio A, Jack S, Sivaramalingam B, Iserman E, Mustafa RA, Jedraszewski D, Cotoi C, Haynes RB; The Cochrane Collaboration; Issue 11
5. Prevalence and Cost of Non-adherence with Antiepileptic Drugs in an Adult Managed Care Population (2007); Keith L. Davis, Sean D. Candrilli, and Heather M. Edin; Epilepsia, 49(3):446–454, 2008 doi: 10.1111/j.1528-1167.2007.01414.x
6. Estimated Annual Pharmaceutical Revenue Loss Due to Medication Non-Adherence (2012); Thomas Forisser & Katrina Firlik; Capgemini Consulting & Health Prize
7. Cost of Prescription Drug-Related Morbidity & Mortality (2018); Watanabe JH, Mcinnis T, Hirsch JD; Annals of Pharmacotherapy; 1060028018765159. doi: 10
8. Impact of Medication Adherence on Hospitalization (2005); Sokol MC, McGuigan KA, Verbrugge RR, Epstein RS; Med Care June 43(6) 521-30
9. Therapy in Patients With Human Immunodeficiency Virus (2006); Julie MS; Benner, Joshua S; Becker, Stephen; Dezii, Christopher M., Hazard, Elisabeth H.; Tierce, Jonathan C; Medical Care: October, Volume 44 - Issue 10 - p 893-899
10. Is Medicare Star Category Medication Adherence Associated with Lower Total Cost of Care and Medical Events? (2020); Y. Qiu, P. Karaca Mandic, P. P. Gleason, Poster, Academy of Managed Care Pharmacy (AMCP Nexus 2020 virtual event, October
11. Battling Non-Adherence: What Actually Works? (2019); James Sweeney, Medscape, May
12. A Patient Centric Commercial Model For Cancer Care (2013); Sanjay K. Rao, The Journal Of Commercial Biotechnology, 19(2) 40-48, April
13. Generating Growth Through Patient-Centered Commercial Strategies (2012); Sanjay K. Rao; Journal of Medical Marketing; September
14. Teaching Physician-Patient Communication (AIDET) for Results in all Pillars. What’s Right in Healthcare (2015); Putnam JB Jr, Kennedy J; Studer Group Website
15. Cost-Related Non-adherence and Mortality in Patients With Chronic Disease: A Multiyear Investigation, National Health Interview Survey, 2000–2014 (2020); Sarah C. Van Alsten, Jenine K. Harris; Preventing Chronic Disease, CDC, v17, December
16. Health Insurance and Managed Care: What They Are and How They Work (2015); Peter R. Kongstvedt, Burlington, MA; Jones & Bartlett Learning
17. Breaking Treatment Barriers with Tech (2019), Deepak Batra & Raj Sevilimedu, BioVoice, April 9
18. Impact of Increasing Out-of-Pocket Costs for Insured Cancer Patients (2019), Diane Blum; Drug Benefits Trend. May 17

Sanjay K. Rao, PhD is vice president at SRI Inc. of Princeton, NJ.