Patient Compliance in Clinical Trials

What is compliance in a clinical study?

Compliance in clinical trials refers to the extent to which participants adhere to the study protocol and follow the instructions provided by the researchers/investigators. Complying with the study protocol means that participants acknowledge and follow through with what is expected of them, doing what they are asked to (such as taking a medication or answering a survey), at the appropriate time (a specific time point, range of time, etc.), and in the correct way, as outlined in the study description. Compliance involves closely following medication administration schedules, attending scheduled appointments, completing required assessments, and following any other specific requirements outlined in the clinical trial protocol.

Patient compliance vs regulatory compliance

Note that compliance also refers to the compliance of the clinical research team and the conduct of the study with applicable rules and regulations, which are in place to safeguard participant safety and ensure integrity and quality in clinical research. We write about HIPAA compliance, FDA compliance, GDPR compliance, data privacy compliance, and other forms of regulatory compliance in a separate article, which can be found here. This article is focused on patient compliance with the study protocol and intervention.

What does adherence in clinical trials mean?

We can define adherence as the timely fulfillment of the tasks and actions that are expected of the clinical research participant. Adhering to the study protocol involves taking medications in the correct dosage and on time, answering questions or surveys, showing up to study visits (including follow-up visits), sticking to any specific diet, habits, or restrictions outlined in the study protocol, etc. For the purposes of this article, adherence is the same as compliance in clinical trials, when speaking about patient adherence to protocol.

Patient adherence vs compliance

In contrast to compliance, which can refer to patient adherence to protocol as well as regulatory compliance of the study overall, adherence is mostly used when speaking about patient adherence to the trial protocol. While compliance and adherence are often used interchangeably, compliance typically focuses on the act of following the specific procedures outlined in the study protocol, whereas adherence could be thought of as placing more emphasis on the participant's commitment to their overall treatment plan or intervention. For the purposes of this article, we will assume there is no difference between patient adherence vs compliance; adherence and compliance are essentially the same term when it comes to the patient’s follow through with expectations of the clinical trial.

Why is compliance important in clinical research?

Participant compliance plays a critical role in ensuring the validity and reliability of clinical trial results. Each clinical trial goes through a lengthy trial design stage, wherein every detail of the study methodology is decided upon intentionally such that the study is set up to generate reliable and accurate data that allows the researchers to answer the research question. The ability of a trial design to demonstrate an effect of the intervention under study is referred to as its power, and that metric is directly tied to the number of participants involved. If a participant does not follow the treatment/intervention regime exactly as outlined in the protocol, it means that he/she has effectively undergone a different treatment, and the results for that person are no longer valid for comparison to the other study participants. Thus, non-adherence to the treatment protocol effectively reduces the valid sample size, which in turn reduces the power of the study and the ability of researchers to make a scientifically valid conclusion about the safety and/or efficacy of the study treatment.

Participant compliance is also important for ensuring patient safety and that they receive appropriate care. Drug dosages and administration schedules are determined based on specific aspects of drug metabolism, toxicity, clearance, etc. It’s important to stick to the prescribed dosing regimen in order for the drug to work as intended, and to limit the risk of side effects. Similarly for non-medicinal and behavioral interventions, the timing, frequency, and other details are also determined intentionally and according to specific factors that could have implications for patient safety and well-being. Particularly in phase III trials (once the dosages and basic safety information have been established), there is a hope that the study treatment will lead to improved health outcomes, and thus adherence to treatment regimens can maximize the chances of benefitting from the study intervention, such as experiencing an improvement symptoms or getting the condition under better control.

Patient non-compliance, or non-adherence, to the study protocol can introduce bias and affect the interpretation of trial outcomes. When participants do not adhere to the prescribed intervention regimen, it becomes challenging to determine whether the observed effects are truly due to the intervention being tested or other factors. We will explore non-compliance in further detail below.

Who is ultimately responsible for compliance to a clinical trial?

In a clinical trial, both participants and researchers share responsibility for compliance. Researchers are responsible for clearly outlining study expectations and objectives, while also maintaining consistent and effective communication with participants.

Participants, on the other hand, as part of the consenting process, make a commitment to following the guidance provided by researchers and adhering to the prescribed treatment regimen throughout the trial duration. Although patients are not legally obligated to follow through (they can leave the study at any point, which is part of their basic rights as clinical research participants), they should be reminded that adherence is essential for data integrity and optimizing the scientific and medical value of the study results

Reasons for and types of non-compliance in clinical trials

Non-compliance is a common issue faced in clinical trials. It can stem from various factors, such as forgetfulness, lack of understanding, or unwillingness to adhere to the study protocol. Non-compliance introduces challenges in data interpretation, possibly introducing bias into the findings, and may impact statistical analyses and compromise the integrity of research outcomes. Poor compliance can thus limit our understanding of how safe and/or effective an intervention or treatment may be.

Non-compliance issues can arise during a clinical trial despite efforts made by researchers. It is important to address these challenges promptly to maintain data quality and minimize biases introduced by non-compliance.

Some common non-compliance issues faced in clinical trials include:

- Missed doses or treatments

- Inaccurate self-reporting of symptoms or side effects

- Failure to attend scheduled visits or follow-up assessments

- Improper storage or handling of medications

- Use of prohibited medications concurrently with the trial intervention

- Failure to stick to behavioral guidelines, such as avoiding specific foods, following an exercise program, or performing tasks required by the study protocol

Participant non-compliance issues can skew statistical analyses, diminish statistical power, introduce bias into results interpretation, decrease the generalizability of findings, and could eventually negatively affect patient outcomes in real-world settings if an investigational product is approved based on inaccurate data.

How do you ensure compliance in a clinical trial?

Ensuring participant compliance during a clinical trial might involve a variety of strategies aimed at improving adherence rates among participants. This can be done through facilitating adherence (i.e., making it easier for the patient to follow the treatment regimen) and/or encouraging adherence (supporting them, following-up, offering incentives, etc.). Techniques for improving compliance include fostering clear communication about expectations from both sides, educating participants on the importance of adherence, using reminder systems, and fostering trusting relationships with participants through regular contact and support throughout the duration of the trial.

Solutions for improving compliance in clinical trials

Some specific measures that can be implemented to facilitate, encourage, and maximize participant compliance in a clinical trial include:

1. Design simplified, patient-centric protocols

In line with the increasingly popular and relevant topic of patient centricity in clinical research, adherence can be made easier for patients by designing protocols that are as uncomplicated as possible while still being scientifically robust. Protocols, including intervention and treatment schedules and other details, should be clear, legible (using simple terminology), and simple to follow. Minimize particularly burdensome procedures that are likely to bring about compliance issues wherever possible. Researchers can consider design aspects such as remote or decentralized clinical trials, direct-to-patient trials or drug distribution, wearable devices, and remote monitoring,, all of which have strong potential for limiting compliance deviations by making trials smoother to navigate and more connected, which facilitates real-time monitoring of compliance issues. When designing protocols, consider the daily routine of a typical participant, and try to make their study-related duties manageable within that context. Capture essential data points only – those that are directly related to study endpoints – and avoid the desire to capture all the data possible just because current technologies make it relatively easy. Patient-centricity is about the sponsors and investigators putting themselves in the patients’ shoes to make trials more comfortable.

2. Prioritize clear communication

Providing clear, detailed, understandable information about the clinical trial's objectives and the intervention under study is mandatory as part of the informed consent process, but it also helps establish clear expectations. Participants should be allowed to ask for clarification on any doubts they have during the informed consent process, which fosters open dialogue between researchers and participants and helps to establish a trusting relationship.

3. Leverage technological tools and solutions

Technological advancements have made significant changes to the possibilities for conducting and monitoring clinical trials. From the patient side, mobile applications, wearables, or remote monitoring devices can offer convenience and can be set up to send reminders or alerts to take medications, collect data in an automated/passive manner, and enable real-time communication between researchers and participants.

From the researcher's side, there is a huge variety of end-to-end digital trial solutions available, connecting nearly every aspect of the trial from consenting through to data collection and monitoring. These systems can be leveraged to support real-time monitoring from a remote or centralized location in multi-center and even international trials, enabling rapid identification of compliance issues. Wearable or connected devices can be connected to central monitoring systems and alert researchers if a data collection point is missed, further connecting a support person to the participant to check if everything is alright and remind them about the missed event. Data can even be collected remotely and automatically, for example by taking period readings from a wearable blood pressure sensor or blood glucose monitoring device, without requiring the participant to move a finger, let alone visit a study site. With the proper pre-trial setup and customization, eClinical software solutions can facilitate patient compliance by automating many aspects of reminders or even data collection, reducing the need for constant manual oversight and worries about non-compliance.

Nonetheless, some trials will require that participants take medications, which can be tricky to verify, especially remotely. An interesting technological solution to this is the use of “smart pills,” which have microchips that register when a patient consumes it, or “smart bottles,” which can transmit data about when the bottle was opened and the medication removed. Other sensors can be utilized which would tell researchers other details, such as whether the person was sitting or standing when they took the medication.

4. Offer education on the importance of adherence

It’s important that participants understand their role within the trial and the importance of their individual contribution. They should also understand that the value of their contribution depends on adhering strictly to the study protocol, in all its aspects. Educational materials, individual counseling/discussion sessions, or group discussions can be provided to help emphasize the importance of adherence and reinforce the idea that participants can come to the study staff with any concerns or doubts they are experiencing. By knowing that they can speak openly about their concerns, patients are less likely to skip treatments or deviate from the study protocol due to doubts or uncertainties. Providing regular updates and opportunities for participants to ask questions can foster a sense of engagement and commitment, and dedicated helplines can empower participants to voice their concerns in a timely manner and receive ongoing guidance and support throughout the trial.

5. Regular monitoring

Thorough monitoring practices, which could include maintaining regular contact with participants and implementing follow-up procedures, can facilitate assessment of compliance levels. Consistent contact allows researchers to openly inquire about an individual’s adherence to the study intervention and quickly identify any difficulties or barriers that participants may be experiencing. Simple follow-up about medication schedules (i.e., “have you found it easy to remember to take your study medication this week?”) is an easy way to ensure that participants have taken their medication, and can also elicit feedback about how it could be made even easier for participants in future studies.

6. Employ a methodology for verifying compliance

There are also dedicated techniques for verifying compliance, such as:

• Tablet counting, where participants are asked to bring in the leftover study drug at given time points, allowing clinical trial investigators to check that the right number of pills have been taken. However, this method has been shown to be notoriously unreliable.
• Measuring levels of the investigational product in the bloodstream or urine. This may even be an important part of routine monitoring, in some studies.
• Patient diaries, where patients are asked to record the time and place each time they take the study medication or perform a study-related task.
• Directly observing participants taking the study drug. This is limited to studies with in-person site visits, and would not be feasible for daily medication regimes. This setup may be inherent in some studies involving regulated drugs which cannot be given to the participant to take home.

7. Use personalized reminders

Utilizing reminders in the form of text messages, phone calls, or notifications in digital applications can help prompt participants when it is time to take their medication, take a measurement, or answer questions about their symptoms. These reminders can be personalized on an individual patient basis, and they can usually be automated quite easily using common software, or through dedicated functions that may be found in many clinical trial management systems (CTMS) or other eClinical software.

Dealing with non compliance in clinical trials

Compliance-related issues in clinical trials are best managed by preventing or limiting non-compliance in the first place. However, even when the strategies described above in the section “How do you ensure compliance in a clinical trial?” have been applied, some degree of non-compliance is likely to occur.

When issues of participant non-compliance are identified, it is the responsibility of the investigator to duly record the issue, in patient case report forms (CRFs) and any other study records. Depending on the severity of the non-compliance, different approaches might be taken. It is important that the protocol for dealing with non-compliance be outlined in the study protocol itself and any pertinent standard operating procedures.

If the instance of non-compliance is something as simple as a participant missing a study dose, in some cases it may be permissible to simply take the dose late. This should be done within a reasonable window, such that the outcomes will not be significantly different as they would have been had the participant taken the medication on time. For example, if a treatment is administered monthly, it could be acceptable to take the dose a single day late. However, for medications administered with a greater frequency, a missed dose may need to be skipped and recorded as such.

Depending on the severity and type of non-adherence to protocol, the investigator may be obligated to report the non-compliance event to the sponsor and/or regulatory bodies. The consequences of non-compliance for the patient, in more extreme cases, could include exclusion from the study. This situation could result in significant setbacks for the sponsor, who may have to enroll further patients to make up for the missing data and reduced sample size, and thus best efforts should be made to avoid such situations by implementing techniques focused on facilitating and optimizing adherence.

At the very least, the patient should be notified about the consequences of the non-compliance event, which could even include potential dangers to their health or well-being, besides detrimental effects on the quality of research results. Research participants are human and often are transiting tough moments in their lives. By being firm yet understanding/forgiving, open and honest communication may go a long way in encouraging them to be more careful and avoid subsequent compliance deviations.

Conclusion

Participant adherence, or compliance in clinical trials, refers to the patient’s follow-through with the actions expected of them, as outlined in the trial protocol. Adherence to protocol is important for patient safety, data accuracy and quality, and research integrity. Patients may be non-compliant for various reasons, from simple forgetfulness to an intentional unwillingness to continue with the study. Compliance deviations have consequences related to potential bias in results or inaccurate study data and conclusions about the safety and/or efficacy of the investigational product or intervention under study. Limiting non-compliance involves designing non-burdensome, patient-centric protocols, supporting open communication and patient engagement, identifying barriers to adherence, providing additional education or support if or when needed, and implementing appropriate measures for preventing compliance deviations as well as dealing with non-compliance issues/participants in the trial.