Adherence FAQ

What is adherence?

The WHO defines adherence as the extent to which a person’s behavior – taking medication, following a diet, and/or executing lifestyle changes – corresponds with agreed recommendations from a health care provider.1 Beyond that definition, adherence can be understood in three categories:2

  1. Initiation – occurs when the patient takes the first dose of a prescribed medication
  2. Execution – is the extent to which a patient’s actual dosing corresponds to the prescribed dosing regimen, from initiation until the last dose
  3. Discontinuation – occurs when the patient stops taking the prescribed medication for whatever reason(s)

Researchers have used the terms compliance and persistence amongst others in the past, but the term adherence is now widely accepted.3

  1. "What Is Adherence?". Adherence to Long-Term Therapies - Evidence for Action. WHO, 2003. Web. 1 Aug. 2012.
  2. Ascertaining Barriers for Compliance: Policies for Safe, Effective and Cost-effective Use of Medicines in Europe. Vol. 7.1: ABC Project, 2012. Print.
  3. Vrijens, B. A New Taxonomy for Describing and Defining Adherence to Medications. Br J Clin Pharmacol 73.5 (2012): 691-705.
How does non-adherence affect clinical trials ?

Non-adherence is a significant confounder that affects data interpretation and trial results in the following ways:

  1. Inaccurate and usually underestimated efficacy of new drugs1-4
  2. Trial failure5,6
  3. Distorted pharmacoeconomic analyses7,8
  4. Limited accuracy and cost-effectiveness of pharmacokinetic and pharmacodynamics analysis
  5. Overestimated dosing requirements when brought to market9,10
  6. Limited accuracy in modeling or simulations of following trials

Non-adherence ultimately creates ambiguity around data collected during trials the decisions concerning the next phase of drug development.

  1. Lipid Res. Clin. Progr. 1984. The Lipid Research Clinics Coronary Primary Prevention Trial results: II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 251:365–74
  2. Lipid Res. Clin. Progr. 1984. The Lipid Research Clinics Coronary Primary Prevention Trial results: I. Reduction in incidence of coronary heart disease. JAMA 251:351–64
  3. Manninen V, Elo MO, Frick MH, Haapa K, Heinonen OP, et al. 1988. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA 260:641–51
  4. Kastrissios H, Blaschke TF. 1997. Medication compliance as a feature in drug development. Annu. Rev. Pharmacol. Toxicol. 37:451–75
  5. Urquhart J. 1991. Patient compliance as an explanatory variable in four selected cardiovascular studies. See Reference 50, pp. 301–22
  6. Fischer K, Goetghebeur E. 2004. Structural mean effects of noncompliance: estimating interaction with baseline prognosis and selection effects. J. Am. Stat. Assoc. 99:918–28
  7. UrquhartJ.1999.Pharmacoeconomic consequences of variable patient compliance with prescribed drug regimens. Pharmacoeconomics 15:217–28
  8. Roebuck MC, Liberman JN, Gemmill-Toyama M, Brennan TA. 2011. Medication adherence leads to lower health care use and costs despite increased drug spending. Health Aff. 30:91–99
  9. Cross J, Lee H, Westelinck A, Nelson J, Grudzinskas C, Peck C. 2002. Postmarketing drug dosage changes of 499 FDA-approved new molecular entities, 1980–1999. Pharmacoepidemiol. Drug Saf. 11:439– 46
  10. Heerdink ER, Urquhart J, Leufkens HG. 2002. Changes in prescribed drug doses after market intro- duction. Pharmacoepidemiol. Drug Saf. 11:447–53
The importance of real-time data
  1. Current methods that don’t utilize real-time data collection fall short. They are mostly crude approximations that underestimate adherence and collect no data on the timing of dosing histories.1-3 Retroactive counts of untaken pills, questionnaires, histories, diaries, assays of drug concentration in plasma, and tracking of prescription refills, seem archaic in the data age.4
  2. Pharmaceuticals are dosed to maintain continuous therapeutic action. Effective therapy ceases not just when dosing is discontinued, but sometimes only hours after a missed dose. Therefore, precise calculations of drug action time-course and concentration in the human body can only be realized with real-time data on drug intake history.5,6
  3. For clinical trial supervisors, real-time drug dosing data allows for timely management of adherence and improved decision-making during drug development, regulatory review, and health-economic review. Specifically, real-time data allows for:
    1. Faster decisions on whether to proceed to the next phase of drug development
    2. Accurate and cost-effective analysis of pharmacodynamics and pharmacokinetics
    3. A more robust data foundation for modeling new trials
    4. The option to intervene and manage non-adherence at the moment it occurs
  4. Without data, we can’t answer the following questions7
    1. How often does clinically unrecognized non-adherence masquerade as drug resistance?
    2. How often does partial execution of dosing regimens mislead drug research strategies because of unrecognized type II errors in trial results?
    3. How often and by how much are therapeutic and pharmacoeconomic benefits compromised by under-dosing?
    4. To what extent do current or new management methods improve adherence?

  1. Osterberg L, Blaschke T. 2005. Adherence to medication. N. Engl. J. Med. 353:487–97
  2. Daniels T, Goodacre L, Sutton C, Pollard K, Conway S, Peckham D. 2011. Accurate assessment of adherence: self and clinician report versus electronic monitoring of nebulizers. Chest 140(2):425–32
  3. Sajatovic M, Velligan DI, Weiden PJ, Valenstein MA, Ogedegbe G. 2010. Measurement of psychiatric treatment adherence. J. Psychosom. Res. 69:591–99
  4. Podsadecki TJ, Vrijens BC, Tousset EP, Rode RA, Hanna GJ. 2008. “White coat compliance” limits the reliability of therapeutic drug monitoring in HIV-1-infected patients. HIV Clin. Trials 9:238–46
  5. Rubio A, Cox C, Weintraub M. 1992. Prediction of diltiazem plasma concentration curves from limited measurements using compliance data. Clin. Pharmacokinet. 22:238–46
  6. Vrijens B, Tousset E, Rode R, Bertz R, Mayer S, Urquhart J. 2005. 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. 45:461–67
  7. Blaschke T, Osterberg L, Vrijens B, Urquhart J. Feb 2012. Adherence to medications: insights arising from studies on the unreliable link between prescribed and actual drug dosing histories. Annu Rev Pharmacol Toxicol. 10;52:275-301.
What are the drivers of patient non-adherence?
Reasons for non-adherence according to patients:1
  1. Forgetfulness (30%)
  2. Other priorities (16%)
  3. Decision to omit doses (11%)
  4. Lack of information (9%)
  5. Emotional factors (7%)
  6. Did not provide a reason (27%)

Major predictors of poor adherence to medication, according to studies of predictors.2
  1. Presence of psychological problems, particularly depression3-5
  2. Presence of cognitive impairment5,6
  3. Treatment of asymptomatic disease7
  4. Inadequate follow-up or discharge planning7,8
  5. Side effects of medication3
  6. Patient’s lack of belief in benefit of treatment6,8
  7. Patient’s lack of insight into the illness8,9
  8. Poor provider–patient relationship6,8
  9. Presence of barriers to care or medications3,9
  10. Missed appointments3,10
  11. Complexity of treatment regimen4,11
  12. Cost of medication, copayment, or both12,13

  1. Cramer J. Identifying and improving compliance patterns. In: Cramer JA, Spilker B, eds. Patient compliance in medical practice and clinical trials. New York: Raven Press, 1991:387-92
  2. Osterberg L, Blaschke T. Adherence to Medication. N Engl J Med 2005;353:487-97
  3. Van Servellen G, Chang B, Garcia L, Lombardi E. Individual and system level factors associated with treatment nonadherence in human immunodeficiency virus- infected men and women. AIDS Patient Care STDS 2002;16:269-81
  4. Ammassari A, Trotta MP, Murri R, et al. Correlates and predictors of adherence to highly active antiretroviral therapy: overview of published literature. J Acquir Immune Defic Syndr 2002;31:Suppl 3:S123-S127
  5. Stilley CS, Sereika S, Muldoon MF, Ryan CM, Dunbar-Jacob J. Psychological and cognitive function: predictors of adherence with cholesterol lowering treatment. Ann Behav Med 2004;27:117-24
  6. Okuno J, Yanagi H, Tomura S. Is cognitive impairment a risk factor for poor compliance among Japanese elderly in the community? Eur J Clin Pharmacol 2001;57: 589-94
  7. Sewitch MJ, Abrahamowicz M, Barkun A, et al. Patient nonadherence to medication in inflammatory bowel disease. Am J Gastroenterol 2003;98:1535-44
  8. Lacro JP, Dunn LB, Dolder CR, Leck- band SG, Jeste DV. Prevalence of and risk factors for medication nonadherence in patients with schizophrenia: a comprehensive review of recent literature. J Clin Psychiatry 2002;63:892-909
  9. Perkins DO. Predictors of noncompliance in patients with schizophrenia. J Clin Psychiatry 2002;63:1121-8
  10. Farley J, Hines S, Musk A, Ferrus S, Tepper V. Assessment of adherence to antiviral therapy in HIV-infected children using the Medication Event Monitoring System, pharmacy refill, provider assessment, caregiver self-report, and appointment keeping. J Acquir Immune Defic Syndr 2003;33:211-8
  11. Saini SD, Schoenfeld P, Kaulback K, Dubinsky MC. Effect of medication dosing frequency on adherence in chronic diseases. Am J Manag Care. 2009 Jun 1;15(6):e22-33
  12. Balkrishnan R. Predictors of medication adherence in the elderly. Clin Ther 1998;20: 764-71
  13. Ellis JJ, Erickson SR, Stevenson JG. Sub- optimal statin adherence and discontinuation in primary and secondary prevention populations. J Gen Intern Med 2004;19:638- 45
What are some good adherence information resources?
  1. The ABC project (Ascertaining Barriers for Compliance) is an international collaboration of experts in adherence research with the specific aims of identifying methods for promoting adherence, and assessing their clinical and cost-effectiveness.(
  2. The Pharmionic Knowledge Centre (PKC®) Database - the largest open source database of drug dosing histories. (
  3. European Society for Patient Adherence, Compliance and Persistence (http:/ /