Physician and patient adherence in hypertension trials: a point of view on an important issue to resolve

Figures & data

Table 1. Methods used to assess drug adherence in randomized control studies (RCTs) and observational studies (OS).

	Pill count	Self-report	Drug levels in blood or urine	Electronic monitoring packages	Smart pills	Direct observed treatment	Administrative and pharmacy claims	New technologies (biosensors, implantable devices)
Frequency of use in RCTs or OS	++++	+++	++	++	±	+	++ in OS Not in RCTs	+ in OS Not in RCTs
Advantages	Simple, cheap	Simple, cheap	Ascertain drug intake May support adherence	Provide a dosing history May support adherence	Ascertain intake Provide dosing history	Ascertain drug intake	Cheap Possible dosing history	Continuous monitoring
Limits	Counting errors Desirability bias No defined threshold Possible manipulation	Desirability and acquiescence bias Recall bias High variability	Ability to measure drugs and metabolites Impact of PK Punctual white coat adherence Cost	No proof of drug intake Availability Reconditioning of drugs in OS Cost	Very high cost Tolerance of external patch Acceptance by patients	Cumbersome method Need staff Costly Use mainly with small number of participants	Not available in all countries Ethical aspects (confidentiality) Multiple sources (pharmacies) Not objective	Acceptance by patients Technical and ethical acceptability need to be validated Cost?
Overall reliability	Low Overestimate adherence	Low Overestimate adherence	High Overestimate adherence	High Recommended by FDA	High	High	Medium Underestimate adherence Need validation	Unknown, possibly high

Figure 1. Relation between adherence levels in the placebo group and the improvement in adherence induced by electronic monitoring packaging systems in the interventional group. This figure has been created de novo based on data collected in a recent review by Checchi et al. [32].

EM: electronic monitoring.

Table 2. Some possible unwanted consequences of non-adherence in clinical trials.

	Unwanted consequences
Scientific: Efficacy	Inability to reach valid study conclusions
	Production of outcomes on study endpoints unrelated to treatment assignment
	Falsely negative or inconclusive results
	Inaccurate determination of the optimal dosing in drug development studies leading to overestimation of dose requirements
Scientific: Safety	Inappropriate assessment of drug safety
Statistics	Adverse impact on sample size and statistical power
	Increase patient withdrawal and the need for new patients’ recruitment
Economic	Increased costs
	Delay in drug registration

Table 3. Suggested ways to mitigate the impact of non-adherence in randomized controlled trial.

Identify adherence issues in the trial preparation and run-in phases Identify approaches to directly improve adherence to the trial protocol and/or the investigational drug. Identify and select patients who are likely to adhere to treatment, but only prior to randomization, not afterward. Use subject registries if available. Prespecify who will be included in the final analysis based on information available on subjects prior to randomization. Consider performing pharmacokinetic sampling on background treatments and consider a biomarker or medication adherence technology during the run-in phase. Provide standard adherence monitoring and support to all participants in both active and placebo arms. Monitor individual subject adherence with a medication adherence technology, not pill counts alone; when appropriate, provide subjects and investigators with prompt feedback when nonadherence is detected. Discontinue promptly subjects who are deceptive, duplicate, or egregiously nonadherent. This may be desirable to minimize the negative impact of these subjects’ data. Include a prespecified analysis of adherence data in the statistical plan. Consider stratification of subpopulations based on adherence and behavior. Utilize known adherence data when designing a new protocol and taking go/no-go decisions in later studies.

Checchi KD, Huybrechts KF, Avorn J, et al. Electronic medication packaging devices and medication adherence: a systematic review. JAMA. 2014;312(12):1237–1247. doi: 10.1001/jama.2014.10059

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