Decentralised clinical trials: ethical opportunities and challenges

Abstract

Fuelled by adaptations to clinical trial implementation during the COVID-19 pandemic, decentralised clinical trials are burgeoning. Decentralised clinical trials involve many digital tools to facilitate research without physical contact between research teams and participants at various stages, such as recruitment, enrolment, informed consent, administering study interventions, obtaining patient-reported outcome measures, and safety monitoring. These tools can provide ways of ensuring participants' safety and research integrity, while sometimes reducing participant burden and trial cost. Research sponsors and investigators are interested in expanding the use of decentralised clinical trials. The US Food and Drug Administration and other regulators worldwide have issued guidance on how to implement such adaptations. However, there has been little focus on the distinct ethical challenges these trials pose. In this Health Policy report, which is informed by both traditional research ethics and digital ethics frameworks, we group the related ethical issues under three areas requiring increased ethical vigilance: participants' safety and rights, scientific validity, and ethics oversight. Our aim is to describe these issues, offer practical means of addressing them, and prompt the delineation of ethical standards for decentralised trials.

Background

The COVID-19 pandemic and the public health measures implemented to contain it considerably impacted clinical research.1, 2 Ongoing and new clinical trials were adapted by decentralising essential elements, such as enrolment, administration of study interventions, and safety monitoring. This change involved a wide range of approaches, including the use of remote methods for consent and monitoring, and sending medications, equipment, or study staff to participants' homes to enable study continuation.

Several regulatory agencies consequently issued guidance on conducting clinical trials remotely during a pandemic. The US Food and Drug Administration (FDA) emphasised the importance of evaluating risks and benefits of continuing or discontinuing a clinical trial, noting that in some circumstances patient safety might be best preserved by study continuation. The European Medicines Agency similarly recommended a risk-based approach to study monitoring, focusing on the need for data essential to participant safety, rights, and wellbeing. The Danish Medicines Agency not only issued guidance on clinical trials during the pandemic, but also on decentralised trials in general, stating that decentralisation is a feature of clinical research that is bound to continue. The Swiss and the Swedish agencies for therapeutic products issued separate guidance on decentralised clinical trials (DCTs) unrelated to the COVID-19 pandemic (table ).

Table.

Regulatory guidance for decentralised clinical trials

	Regulatory body	Title	Year
Australia3	The Commonweath Department of Health	National principles for teletrials in Australia	2020
Canada4	Health Canada	Management of clinical trials during the COVID-19 pandemic: notice to clinical trial sponsors	2023
Denmark5	Danish Medicines Agency	The Danish Medicines Agency's guidance on the implementation of decentralised elements in clinical trials with medicinal products	2021
European Commission6	European Medicines Agency	Guidance on the management of clinical trials during the COVID-19 (coronavirus) pandemic	2022
Singapore7	Health Sciences Authority	Guidance on the conduct of clinical trials in relation to the COVID-19 situation	2020
Sweden8	Swedish Medical Products Agency	Decentralised clinical trials	2021
Switzerland9	Swissmedic and Swissethics	Position paper by Swissmedic and swissethics on decentralized clinical trials (DCTs) with medicinal products	2022
USA10	Food and Drug Administration	Conduct of clinical trials of medical products during the COVID-19 public health emergency–guidance for industry, investigators, and Institutional Review Boards	2021

Pharmaceutical companies and contract research organisations are adopting these decentralised approaches, and scholarship on the benefits of the digital components of clinical trials is emerging.¹¹ The multitude of terms used to describe these types of trials (eg, decentralised, remote, digital, virtual, and teletrials) indicates both the evolving nature of such clinical trials, and the multiplicity of ways in which decentralisation can be implemented in research. DCTs (the term that seems to be favoured by regulators) tend to mix conventional and digitally facilitated methods. However, the type and nature of such methods is rapidly expanding, as digital tools (eg, electronic consent, virtual consultations, the use of digital reporting platforms, digitally acquired endpoints, apps, and wearable technologies) prove increasingly able to replace elements of traditional clinical trials.¹²

The growing interest in DCTs by sponsors and regulators is justified for several reasons. DCTs can promote greater inclusivity, diversity, and equitable access to research participation by removing the obstacles associated with the need for proximity to clinical sites or mobility.¹³ Beyond facilitating access and participation, DCTs can ease recruitment, decrease delays, enhance participant retention, and be less costly.¹² Nevertheless, DCTs also involve distinct ethical challenges. In this Health Policy report, we identify and analyse such challenges and offer practical recommendations for addressing them.

Ethical considerations for DCTs

Our analysis draws on both clinical research ethics and digital ethics frameworks, which are premised on substantive principles (eg, respect for persons, beneficence, and justice)14, 15 and incorporate procedural values (eg, ensuring responsiveness, sound research design, and transparency).16, 17 Although elaborating on the conceptual foundations for these frameworks is beyond the scope of this Health Policy report, we use these frameworks to help identify and evaluate the ethical issues associated with DCTs. We describe three broad areas requiring increased ethical vigilance: participants' safety and protection of their rights, scientific validity, and ethical oversight mechanisms.

Advancing participants' safety and protecting their rights

Advancing participants' safety and protecting their rights includes consideration of physical safety, privacy, informed consent, and wellbeing.

Physical safety

In conventional research settings, study personnel (eg, physicians and nurses) help ensure safe handling and administration of investigational products, which is more challenging in DCTs. DCT protocols should specify how safety and risk mitigation conditions for the delivery, storage, use, disposal, and return of medicinal products and devices are met. If DCTs require decentralised collection of biological specimens from participants, investigators and sponsors should ensure appropriate hygienic conditions and that the risks linked to the sampling procedure do not affect participants' safety. To mitigate such risks, self-collection might have to be restricted to simple, non-invasive procedures, or be done by specialised personnel. With respect to both product handling and biological samples, participants should be provided with comprehensive instructions, for instance, through dedicated apps or websites, with user-friendly communication tools, such as visual aids, infographics, and videos.

Participants' safety is also dependent on careful monitoring for adverse reactions. DCTs generally offer fewer opportunities for direct interaction between participants and study personnel than conventional trials. However, this restricted physical contact should not affect the robustness of safety monitoring. Therefore, participants in DCTs could be given access to a digital platform to register adverse reactions, receive medical advice in real time, and automatically trigger a request for in-person visits at home or a nearby clinical centre in case of severe adverse reactions. It might be feasible to analyse safety issues more continuously than in conventional trials, and possibly protect participants more effectively.

Privacy

The use of digital tools and data infrastructures to support DCTs entails data protection challenges. Trials using wearables, apps, and web-based interactions might increase cybersecurity risks. Although conventional trials have substantial data security risks as well, distributed networks might increase system vulnerabilities. Appropriate safeguards should be adopted to protect participants' privacy. Privacy impact assessment¹⁸ can be useful to identify technical vulnerabilities and tailor safeguards to the kind of data collected, especially for participants from social groups facing specific privacy-related risks such as discrimination and stigmatisation due to social perceptions about certain health conditions or behaviours.

Pseudonymisation and anonymisation—together with data minimisation and privacy-preserving technologies19, 20—can offer additional safeguards in DCTs. Although adhering to the data minimisation principle in DCTs might be challenging, efforts should be made to explicitly justify the types of data collected and how they will be used. Privacy-by-design and privacy-by-default approaches²¹ should be followed to prevent risks linked to excessive data collection and unauthorised data uses. Data protection safeguards should be adopted across all technical components and data processing activities, and the most stringent privacy-preserving setting should be adopted.

Special consideration should be given to the protection of identifiable personal data and information. When digital devices are used to verify the identity of enrolled participants, monitor intended use of medicinal products, or communicate adverse reactions, state-of-the-art encryption should be used to minimise the risk of breaches.²² Such safeguards should be clearly described in the study protocol to be assessed by research ethics committees (eg, Institutional Review Boards and their equivalents).

Privacy issues might also arise not directly for the participants but for others living or closely interacting with them. For example, family members or caregivers might be present during study-related activities and virtual interactions. Investigators should be aware of such risks and, depending on the type of activity or circumstances, consider mitigation strategies.23, 24

Informed consent

DCTs face several ethical and practical challenges related to the process of obtaining informed consent. First, electronic consent approaches must incorporate measures to verify the identity of the person giving consent. Second, remotely ensuring that consent is voluntary and free from undue influence or coercion can be difficult. Third is the challenge of providing comprehensive information about the research in an easy to understand manner by use of digital technologies. Nonetheless, electronic consent designed appropriately can promote improved understanding and meaningful autonomous decision making, despite no physical interaction between study personnel and participants.²⁵

Outside the research context, important information such as online privacy notices are notoriously ineffective at informing users and enabling them to make informed decisions.²⁶ This type of outcome should be avoided in the case of electronic consent for DCTs. Emerging standards about the most appropriate ways to use novel approaches to consent (ie, interaction design and choice architecture approaches) can make electronic consent a preferred choice to fulfil the ethical aims of informed consent—conveying the necessary information to enable free and autonomous decision making regarding enrolment.27, 28 Finally, an additional concern for electronic consent is its legal permissibility and acceptability in various jurisdictions. Although several countries have issued clear guidance regarding the legality of electronic informed consent (eg, the UK, Belgium, and the USA), others only accept a wet ink or in-person signature.

Wellbeing

Although digital tools offer convenient means of communication between study teams and participants, excessive reminders and requests can be unnecessarily intrusive. To promote participants' wellbeing, the number of digitally mediated interactions in DCTs should be kept to a minimum. Qualitative studies regarding DCTs show that participants can feel overburdened by many technologies and devices.²⁹ Due consideration should also be given to the subtle intrusiveness of data collection practices taking place in the background, such as through wearables and other connected devices that might leave participants with the impression of being constantly surveilled.³⁰

In conventional research, participants generally get financially reimbursed for the expenses they incur due to trial participation, such as transportation costs. Direct costs of trial participation are arguably reduced in DCTs. However, as participants will be asked to complete several actions related to the study on their own, a shift in labour might occur from the study personnel to the participants themselves. To avoid exploitation of participants' time and resources, an assessment of direct and indirect costs for participants should be done.

Ensuring scientific validity

The scientific value of a clinical trial is a precondition to justify the enrolment of participants.¹⁵ Therefore, a decentralised approach should not be chosen solely because it is more convenient or less expensive than an in-person study. DCTs, like conventional trials, should address important evidence gaps and be designed rigorously, prospectively registered, and comprehensively reported. Inclusion criteria should be clearly defined and their clinical relevance to the study aims must be justified. Study endpoints must be clinically meaningful to enable the robust assessment of the safety and efficacy of the planned intervention. Investigators should thus justify the choice of study endpoints and related measurements if they propose to replace endpoints typically assessed with physical examinations in conventional trials. The choice of study endpoints (including digitally acquired ones) should be justified as scientifically valid alternatives to endpoints that would be adopted in the context of conventional clinical trials.

Adverse events might be more easily reported in decentralised than in conventional trials. Measures taken to minimise the biases and inconsistencies potentially introduced by self-reporting should be clearly described in the study protocol for appropriate ethical assessment. The adoption of digital devices and an auditable adverse event reporting (digital) platform following specific standards could facilitate safety assessment and improve accountability of sponsors and investigators. Reporting standards that can be adapted to DCTs are emerging.³¹

DCTs can reduce some barriers to participation, such as distance from a clinical site or absence of transportation. In a DCT, however, self-selection bias is a risk because of the influence of the digital divide on the composition of the trial population. Individuals who might meet inclusion criteria could feel discouraged to enrol due to unfamiliarity with the digital tools that typically have a key role in DCTs, or due to restricted access to adequate internet connectivity. However, digital proficiency assessment tools (eg, DigiComp2.1³²) can allow investigators and research ethics committees to predict the level of digital proficiency needed for participation and to take corrective or mitigating actions if necessary. Systematic exclusion of participants from some demographic groups from clinical research results in what has been termed health data poverty³³—impairing what we know about the safety and efficacy of new drugs for populations not included in clinical trials, which deprives people from the excluded groups of the benefits of biomedical knowledge.

Enhanced ethics oversight

The issues identified in this Health Policy report (panel ) and their respective mitigation strategies should be included in risk–benefit assessments determining the ethical acceptability of DCTs. Investigators and research ethics committees will have to increase their vigilance when identifying the novel risks raised in DCTs. Despite the promise of DCTs to address many of the deficits in conventional clinical trials, not all trials will be suitable for such an approach. Therefore, the choice of decentralising requires careful consideration (panel).

Panel. Questions to consider in decentralised clinical trials.

Several specific issues across different ethics domains need to be addressed to advance participants' safety, protect their rights, and ensure scientific validity.

Physical safety

• •Is it safe to deliver the investigational product or intervention remotely?
• •Can the investigational product or intervention be self-administered?
• •Has comprehensive safety-related information been provided to participants?
• •Is there timely online help available for participants?
• •Can specimens be collected safely by non-specialised personnel?
• •Can specimens be stored safely by the participants?
• •Is there sufficient information and assistance regarding specimen and data collection available to participants?
• •Are wearable devices, apps, and other digital equipment used by participants in the study validated for clinical use?
• •Is there a system in place for efficient monitoring of adverse reactions?
• •Do participants have easy access to medical consultation in case of adverse reactions?

Privacy

• •Do digital devices such as wearables and apps used by participants for the purposes of the study carry specific data security risks?
• •Are stopping rules and other harm mitigation mechanisms in place in case of data breaches or other technical failure affecting data security?
• •Has a privacy impact assessment been done?
• •Have data encryption approaches been considered in relation to actual privacy risks?
• •Have privacy-preserving approaches such as data minimisation, privacy-by-design, and privacy-by-default been taken into account?
• •Have appropriate measures been taken to minimise the intrusiveness of data collection and communication activities?

Informed consent

• •Is the electronic consent process based on accepted standards?
• •What is the process of identity verification of electronic consent?
• •What measures are in place to ascertain voluntary participation?
• •Are electronic consents and signatures accepted in the jurisdiction of the trial?
• •Is the information provided to potential participants through informed consent comprehensive and understandable?

Wellbeing

• •Does the study rely on reasonable and justifiable amounts of active engagement of research participants (eg, data collection tasks)?
• •Have direct and indirect costs of participation been assessed?
• •Will direct and indirect costs of participation be compensated?

Scientific validity

• •Are inclusion criteria and study endpoints scientifically sound compared with those that would be adopted in conventional trials?
• •Has the risk of self-reporting bias for adverse events been assessed?
• •Has a digital proficiency assessment been done?
• •Has the risk of self-selection bias been assessed?

Concerns have been raised about the ability of investigators and research ethics committees to competently evaluate research projects involving big data analytics and other digital elements.³⁴ Specifically, the types of risks that digital approaches might pose for participants' informational privacy, their communities, and society might be difficult to recognise and consider in conventional risk–benefit assessments.³⁵

To ensure that DCTs receive the necessary ethical scrutiny, we recommend a three-pronged approach. First, those engaged in DCTs (including investigators, sponsors, research institutions, and contract research organisations) should consider that participant safety includes protection of their informational privacy and make use of the tools that are available for assessing information privacy risks in the digital environment. Privacy impact assessments and digital proficiency assessment tools can assist with identifying the hidden risks including those arising from the persisting digital divide. Stopping rules and contingency plans should cover data breaches and other possible technical issues. Second, the safeguards in place to help ensure that DCTs are done ethically should be transparently reported. Open reporting about such safeguards is particularly useful in this evolving area. ³⁶ Finally, independent oversight bodies, such as research ethics committees, and Data and Safety Monitoring Boards, should ensure they have adequate expertise in digital health and DCTs. The guidance issued by drug regulators can serve as a basis for clarifying some of the ethical criteria for DCTs, but additional deliberation by national ethics bodies about these issues would be welcome.

Conclusions

DCTs will continue to evolve and are likely to become a common approach to clinical research. To ensure that this evolution results in robust scientific evidence, while protecting the rights and wellbeing of research participants, adherence to clear ethical standards is essential.

Declaration of interests

JS is a member of Merck KGaA's Ethics Advisory Panel and Stem Cell Research Oversight Committee, IQVIA's Ethics Advisory Panel, Aspen Neurosciences Clinical Advisory Panel, and Merck Data Monitoring Committee; and a consultant to Biogen. EV is a member of IQVIA's Ethics Advisory Panel and a member of Merck KGaA's Digital Ethics Advisory Panel. EV co-chaired the WHO expert group on Ethics and Governance for AI in Health. This work was supported by the Swiss National Science Foundation, NRP77 research grant number 407740_187356.