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DRAFT Guidance for individually randomised trials with usual care groups

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Who is this guidance for

This guidance is for all those who have a direct or indirect role in the funding, design, conduct, ethical review and reporting of trials with usual care groups. This includes doctors, nurses, paramedics, researchers, patient and public involvement (PPI) representatives, members of research ethics committees, funding committees, peer reviewers and Clinical Trial Unit (CTU) staff. The guidance will also be of interest to the public, trial sponsors, NHS Research and Development (R&D) staff, other members of the public and organisations that represent the interests of patients and the public.

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The guidance will include the following sections (our first drafts for each of these sections are described below)

• Need for guidance

• Guidance scope

• Alternative consent approaches

• Existing guidance

• Typology of Informed Consent for trials

• Informed consent approaches - use and acceptability.

• Guidance principles

• Guidance - Recommendations for the design and reporting of the consent process

• Recommendations for further research

• Infrastructures for trials with usual care groups

• Lexicon of consent language used in RCTs

• References

 

Need for guidance

The exchange of information between patients, medical professionals and researchers is essential for good decision-making. Good decision making is defined as decisions that are good for the patient, their clinician (and their mutual relationship) and that are aligned with/ facilitate the aims of the research. ​Good decision making requires good information. Seeking informed consent properly respects a person’s right to determine what happens to them.

We will explore How this information is offered and consent sought can be complex for trials with usual care groups. The How (what, who and when) needs to fit the patient, the clinicians, the research purpose, the trial infrastructure and be in alignment with the specific regulatory frameworks of the respective jurisdictions. 

 

 

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The How should also support the efficiency (scientific, operational, statistical and economic) of the systems and infrastructures that enable the research and the delivery of healthcare (Xie, 2024). If the 'How' is done well this will improve “appropriate access to participation in research” for potentially underrepresented groups, fostering more ethical conduct (WMA, 2024), taking EDI upstream in the research process.

 

The process of providing information and seeking consent from potential trial participants can be designed and delivered in different ways. The standard approach to informed consent uses an ‘everything to everyone up front’ approach (HRA, Example PIS for  pragmatic trial). This consent approach is well suited to explanatory trials where both trial groups’ experience of care is altered by their trial participation. However, for pragmatic trials with usual care groups (where one groups care is unaltered by the research) the standard ‘everything to everyone up front’ consent approach does not always facilitate the genuine understanding and consent of potential participants. This approach can also be challenging for clinicians and impact the generalisability of the trial results. 

 

There is a growing number of trial designs with alternative informed consent approaches e.g. Zelen, Trials within Cohorts, Random Invitation Single Arm Trials. However, these approaches are not always well known or understood in the research community. This then engenders uncertainty within researchers and regulators (Research Ethics Committees) regarding what is possible and appropriate regarding consent methods for different clinical trial designs. This is especially true for individually randomised trials with usual care groups.

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Alternative informed consent approaches

Alternative approaches can help align the consent process with (i) routine care consent processes and/or (ii) trial infrastructures that support recruitment, data collection, trial administration. 

Alternative consent approaches have the potential to reduce expectation and disappointment bias, increase generalisability of the results and enable more clinicians to take part in trials. Improved understanding of informed consent processes (the how) for alternative designs has the potential to improve trial recruitment and retention, increase equity and diversity in trials, improve participant understanding and reduce participant burden. 

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Existing guidance

There is no informed consent guidance that is specific for trials with usual care groups. There is a need to draw together existing guidance, clarify the often confusing terminology, and assimilate and share learning from trials and studies applying/ exploring these alternative approaches to informed consent for trials with usual care groups. This new guidance will bring methodological innovation in consent processes more in alignment with the technological advances that are permitting closer integration with research and standard practice.

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This guidance will build on (and be informed by) Health Research Authority (HRA) Guidance - Applying a proportionate approach to the process of seeking consent (2018) which states that the methods and procedures used to seek informed consent and the level of information provided should be proportionate to (i) the nature and the complexity of the research; (2) the risks, burdens and potential benefits (to the participants and/or society); and (iii) the ethical issues at stake.

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This guidance will also be informed by these key documents:

• HRA Consent and Participation Guidance, 2017

• GMC Decision Making and Consent Guidance, 2020

• WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Participants

• CONSORT Pragmatic, 2008

• CONSORT ROUTINE, 2021 which describes the different types of information that should be reported in trials within cohorts and/ or routine data.

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Guidance scope

This guidance aims to assist the design, review, conduct and reporting of informed consent processes for individually randomised pragmatic trials with usual care groups. Define types of usual care groups?

 

There is a wide variety of clinical trial designs. These are chosen based on the research question and their complexity influences the design of the informed consent process. This guidance will explore the 'How (what, who and when)' of informed consent processes for these type of trials. As infrastructures strongly determine the journey of the participants (patients/ clinicians) and the journey of their data we will look at different consent approaches according to the different types of trial infrastructures and the setting.  

 

This guidance does not seek to address the issues surrounding research undertaken in an emergency context which often cannot obtain consent (or only seek consent after the trial has started). These approaches are described as 'complete waiver of consent' or 'deferred consent' and have clear HRA Guidance. 

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Typology of Informed Consent for intervention trials

A typology is a conceptual framework for grouping things based on shared characteristics. A typology is formed by grouping cases or participants into types on the basis of their common features with consideration of how each unique individual represents a particular pattern of feature. We are developing a typology which groups consent approaches for individually randomised trials according to the “what, who and when”. This typology will be informed by our findings regarding the range of informed consent approaches identified in our reviews and thinking regarding trial infrastructures.

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The two broadest/ upper level categories of this typology are described below:

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Everything to everyone up front (before randomisation) - This approach is suitable for explanatory trials including placebo controlled trials and experimental trials without usual care groups. Here is an example of the 'How' (what, who and when) of the standard 'everything to everyone up front' approach.

However, approaches are logistically demanding, requiring multiple patient contacts (with initial contact mediated by a member of the clinical team) including eligibility screening, invitation to review study information, addressing participant questions, and obtaining written consent (Wilson M et al).

​Alternative approaches modify one or more aspects of the 'everything to everyone up front' approach. There are a wide range of pragmatic trials with usual care groups which use non standard alternative approaches e.g. Zelen single/ double consent, patient centred consent, staged consent, Just in time consent, granular consent etc. These approaches all stage and/or tailor information/ consent. Here are some 'How' examples (what, who and when) of alternative (staged/ tailored) approaches used in REC approved studies in a clinical setting and in a population setting.​

 

Informed consent approaches - use and acceptability

This section will describe the wide range of informed consent approaches used for trials with usual care groups and the evidence regarding their use and acceptability. Our rapid reviews will summarise the literature regarding the use acceptability of these approaches by key stakeholder groups (patients, clinicians, ethics committees).

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Types of consent

​CONSORT ROUTINE (2021) reporting guidelines describe how informed consent could be applied at different levels and in different ways compared with conventional trial designs. Consent might be sought and obtained to use the cohort or routinely collected database and for the trial, and consent that would typically be expected to occur in conventional trials might not be done because of features of the integrated cohort or database and trial design. They list some of the different types of consent sought and obtained for the cohort or routinely collected database, and the trial:

• consent for use of health data for research from a cohort or routinely collected database

• consent to be contacted for future research purposes

• prior consent to future randomisation without explicit notice

• consent to receive a trial intervention

• conventional (everything to everyone up front) consent for participation in the trial and randomisation

• consent to no description of the experimental intervention if allocated to the control

• consent for linkage with other datasets

For each type of consent sought, they recommend that authors describe from whom consent was sought and when each type of consent was sought.

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WEBPAGE UNDER CONSTRUCTION

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Guidance principles

• Justified and proportionate - "Adopting procedures commensurate with the balance of risk and benefits, so that potential participants are not overwhelmed by unnecessarily lengthy, complex and inaccessible written information but instead are provided with succinct, relevant, truthful information in a user-friendly manner that better promotes their autonomy" (HRA Proportionate Consent, 2018).

• Practical – doable and efficient

• Pragmatic – fits the pragmatic aims of the trial

• Relevant (timely) to participant/ patient situation and journey - easing participant burden , supporting recruitment of more representative (inclusive and diverse) trial populations - taking EDI upstream in the research process

• Protects participants and works within relevant ethical frameworks

• Fully reported (how = what, who and when)

 

Recommendations for the design of the consent process

• Where trials with usual care groups are being considered, the views of patients and clinicians regarding the design of  the consent process should be sought through substantive research at the feasibility/ pilot stage.

• Discussing research with patients who are actively seeking healthcare requires considerable care. The consent process should ensure that information offered is relevant to the patient at the time at which it is offered – and where needed the information is staged and tailored to the patients healthcare journey and the resources available to them.

• Trial protocols and results reports should describe the how (what, who and when) of the consent process  - create sample flow chart for reporting the how (what, who and when) of the informed consent process

 

 

​Infrastructure types for trials with usual care groups

Trials require an underlying framework and systems to design, implement, manage etc. and resources (human, financial, and physical) plus information systems and technologies, and healthcare data. These infrastructures are used to support the fundamental trial building blocks (e.g. recruitment, retention, data collection, analysis, trial administration). The type of infrastructure that a trial uses influences the journey of the participants (patients/ clinicians) and the data and thus how the informed consent process(es) that are implemented. 

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Trials with usual care groups can be grouped into three types of trials with usual care groups in relation to their use of infrastructures and clinical workflow.  Each type of infrastructure has a different focus (Jauniad, 2025). Each type may benefit from or require a different informed consent model:

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• Type 1 (usually intervention-focused) are independent, standalone/single-use trial structures to identify, recruit participants and collect data.

  • Examples of different types of informed consent processes

    • IC flowchart

    • information (PIS/ leaflets/ notices)

    • consent forms

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• Type 2 (usually disease-focused) have a common trial infrastructure for sharing operational elements for identifying, recruiting participants and/or collecting routine data plus a common control group e.g. Trials within Cohorts designs (Amstutz, 2023) and trials using routinely collected data sources e.g. registries, administrative databases, master protocols/ platforms.

  • Examples of different types of informed consent processes

    • IC flowchart

    • information (PIS/ leaflets/ notices)

    • consent forms

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• Type 3 (usually innovation-focused) use clinically integrated infrastructures with trials embedded within routine care workflow with the aim of supporting functioning learning health systems. Optimally clinically-integrated trials include recruitment and randomization of study subjects at their point-of-care by their usual healthcare provider e.g. Decision Architecture Randomisation Trials (DARTs), Point of Care Trials and ePOCR trials. These all embed randomisation within the Electronic Health Record architecture – but the level to which consent is embedded varies significantly.

  • Examples of different types of informed consent processes

    • IC flowchart

    • information (PIS/ leaflets/ notices)

    • consent forms

 

Recommendations for further research

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Lexicon of informed consent language in trials

The vocabulary used in the field of informed consent can often be confusing. The purpose of this lexicon is to bring together terms used. We have listed in three different groups - the components of informed consent, express vs implied consent, and other relevant consent terms.

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1. Components of Informed Consent

• Disclosure: Providing clear, comprehensive information about the procedure or study, including potential risks and benefits. 

• Understanding: Ensuring that the individual comprehends the information provided. 

• Voluntariness: Confirming that the decision to participate is made freely, without coercion or undue influence. 

• Competence: Ensuring that the individual has the capacity to make informed decisions. 

 

2. Express vs implied consent

Express consent can be oral, written or electronic

• Oral Consent: This involves obtaining a person's agreement to participate through spoken words. It's typically used for routine procedures or when written consent isn't feasible. 

• Written Consent: This is the most common form of consent, where the individual signs a document outlining the details of the procedure or study, including potential risks and benefits. 

• Electronic Consent: This involves obtaining consent through digital platforms, such as online forms or applications, and is becoming increasingly prevalent. 

Implied Consent: This type of consent is inferred from a person's actions or behaviour, suggesting their agreement to participate. For example, showing up for a scheduled appointment could be considered implied consent for a routine examination. 

 

3. Other Relevant Terms

• Broad consent: refers to a staged-informed consent procedure , specifically within the Trials within Cohorts (TwiCs) design, where participants give broad consent for potential future randomization to study arms at the start of their involvement in a cohort. This initial consent allows them to be assigned to intervention or control groups in future trials without further specific notification, though they are contacted again if selected for an intervention to provide additional consent for that specific trial (Young -Afat, 2016). 

• Broadcast Consent (or Opt-out Consent): This model involves broad notification to a group of potential participants (e.g., through flyers, brochures, or online announcements) about the research study. Participants are then given the option to "opt-out" or decline participation if they do not wish to be involved. This method can be helpful in large-scale trials where it may be impractical to obtain individual consent from every participant. 

• Deferred consent: also known as research without prior consent, is a process where participants are enrolled in a research study without obtaining their consent beforehand, and consent is sought later. This is typically used in emergency research situations where it's not feasible to get consent before the research intervention due to the patient's condition (e.g., unconsciousness, severe illness). The idea is to get consent from the patient or their legal representative as soon as practically possible after the initial intervention. 

• Dynamic Consent: a new approach to consent where participants have more autonomy over the use of their personal information by allowing for alterations in their consent choices in real time, developed as a response to evolving data protection frameworks resulting in greater trust in researchers and new legislation.

• Fully informed consent: A commonly used phrase to denote the 'everything to everyone up front' consent approach (although there is no formal definition of this phrase or any mention in ICH-GCP guidelines).

• General approval consent: light touch, consisting of passive information about study participation (e.g. leaflets, posters), without routine explanation of the studies by clinicians, and no specific opportunity to opt-out of participation. Patients are given information through institutional policies, newsletters, posters, and information sheets about routinely conducted lower risk research in their care setting that the institution thinks will not adversely affect patient care to ultimately learn which care is most effective (Kass et al, 2016). Clinicians do not routinely explain the study to the patient during appointments, and there are no study-specific opportunity to opt-out of participation.

• Granular consent: giving individuals the ability to choose what specific aspects of data processing they consent to, rather than a single, broad agreement. Instead of a single "yes" or "no" for all data processing, users are given separate options for different purposes and types of processing.  

• Integrated Consent: combines the consent process for the clinical intervention with the consent for research participation. The patient provides consent for their clinical care, and this consent also covers their participation in the research study, as the research is integrated into their routine care. This model aims to reduce the burden on participants and streamline the process, particularly in settings where research is closely intertwined with clinical practice. 

• Just in time consent: Consent discussions take place in two stages: an initial consent to research from all participants, and a later specific consent to randomized treatment only from those assigned to the experimental intervention (Vickers et al, 2018). Also known as two-stage consent.

• Layered consent: Participants choose how much information they want. Key information for decision-making is provided in a short patient information sheet (layer 1) with additional optional information that is accessed separately (layer 2) - being developed by Leeds CTU.

• Opt-in Consent: Individuals must actively agree to participate, often by actively selecting an option to indicate their consent – classical/ standard consent approach. 

• Opt-out Consent: Individuals are included in a study or process unless they actively choose to withdraw. 

• Patient-centred informed consent: The process of obtaining patient information and consent aims to replicate that in real world routine health care. All cohort patients consent to provide observational data at the outset; however, consent to “try” a particular intervention is sought only from those offered that intervention, thus replicating the patient-centred information and consent procedures that exist in routine health care, where clinicians provide patients with the information they need, at the time they need it. The rationale for this approach is twofold. Firstly, the primary motive for patients to enter clinical trials is not altruism, but their own direct benefit as patients. Clinical trial informed consent procedures should, therefore, put the needs of the patient at the centre; that is, patients should not be told about treatments that they might not then receive, nor should they be told that their treatment will be allocated by chance. Secondly, the greater the similarity between patients’ experiences in trials and their experiences in routine health care, then the greater the generalisability of the trial results to patients in routine health care.

• Proportionate consent: refers to adopting procedures and practice appropriate with the balance of risk and benefits so that potential participants are not burdened by unnecessarily complex information sheets, but rather provided with information in a succinct and user-friendly manner, often times verbally. Current HRA guidance recognises the importance of proportionate approach to research and states researchers and Research Ethics Committees (RECs) should always ensure research procedures should be justified and proportionate. 

• Staged consent:  This involves breaking down the informed consent process into separate, sequential stages to provide information and gain agreement at different points, rather than all at once. Participants can first consent to participate in the study's procedures and then separately consent to the randomized intervention itself. Staged consent aims to improve understanding and engagement by allowing information to be presented and absorbed in manageable parts, promoting a more ongoing and meaningful dialogue with the individual. Also known as "just-in-time consent" or tiered consent.

• Staged & Tailored consent: This is the same as staged consent - i.e. information is tailored to the needs of each group at each stage in the research. 

• Targeted Consent: researchers focus on obtaining consent for specific aspects of the research that pose potential risks or require specific procedures. For example, if a trial involves only minimal risk interventions, consent might be targeted to those specific procedures, rather than requiring a blanket consent for the entire trial. This approach can be particularly useful when some aspects of the trial are more routine than others. 

• Two-stage consent: an informed consent method that splits the traditional consent process into two phases, separating information about research procedures from details on the experimental intervention itself.  Originally known as Just in Time consent.

• Waiver of Consent: In certain situations, a waiver of consent may be granted by an Institutional Review Board (IRB) or ethics committee. This means that participants are not required to provide explicit consent before participating in the research. Waivers are typically granted when the research involves minimal risk, the waiver is necessary to conduct the research, and there is no way to obtain consent without compromising the study's objectives. Examples might include research using existing medical records or data where obtaining consent would be extremely burdensome or impractical.

• Withdrawable Consent: Individuals have the right to revoke their consent at any time.

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References

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Amstutz A, Schönenberger CM, Speich B, et al. Characteristics, consent patterns, and challenges of randomized trials using the Trials within Cohorts (TwiCs) design: a scoping review. Journal of Clinical Epidemiology 2024;174:111469. doi: https://doi.org/10.1016/j.jclinepi.2024.111469

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Flory J. Ancker JS. Ho SY. et al. et al. Decision architecture randomisation (DARTs): extremely efficient clinical trials that preserve clinician and patient choice? BMJ Evidence Based Medicine 2023;29:71-74. bmjebm-2023-112386

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GMC Guidance on Decision Making and Consent 9 November 2020 https://www.gmc-uk.org/-/media/documents/gmc-guidance-for-doctors---decision-making-and-consent-english_pdf-84191055.pdf

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Health Research Authority (HRA) Guidance - Applying a proportionate approach to the process of seeking consent (2018) https://www.hra.nhs.uk/planning-and-improving-research/best-practice/informing-participants-and-seeking-consent/

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​Health Research Authority (HRA). 2023 [cited 2025 Jun 20]. Putting People First: Embedding public involvement in health and social care research. Available from: https://www.hra.nhs.uk/planning-and-improving-research/best-practice/public-involvement/putting-people-first-embedding-public-involvement-health-and-social-care-research/

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James Lind Alliance (JLA) Priority Setting Partnership PRioRiTy (Prioritising Recruitment in Randomised Trials) https://www.jla.nihr.ac.uk/priority-setting-partnerships/recruitment-to-clinical-trials

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Janiaud P, Ioannidis JP, Kasenda B, Fretheim A, Goodman SN, Hemkens LG. Single-arm trials can provide randomized real-world evidence: the random invitation single-arm trial (RISAT) design. Annals of Internal Medicine. 2025 Jul 15. doi: 10.7326/ANNALS-24-02979

 

Kalkman S et al, Series: Pragmatic trials and real-world evidence: Paper 4. Informed consent, Journal of Clinical Epidemiology. 2017;89:181-187. https://doi.org/10.1016/j.jclinepi.2017.03.019.

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Kim SY, Flory J, Relton C. Ethics and practice of Trials within Cohorts: An emerging pragmatic trial design. Clinical Trials. 2018;15(1):9-16

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Kirsten Bibbins-Domingo, Editor in Chief, JAMA and the JAMA Network, Talk at ICTMC 2024 on the JAMA Summit on the Clinical Trials Enterprise: The Gap Between Clinical Research and Practice https://inconference.eventsair.com/ictmc-2024.

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Love SB, Cafferty F, Snowdon C, et al. Practical guidance for running late-phase platform protocols for clinical trials: lessons from experienced UK clinical trials units. Trials. 2022;23(1):757. doi: 10.1186/s13063-022-06680-4.

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Neves JB, Warren H, Santiapillai J, Rode N, Cullen D, Pavlou M, et al. Nephron Sparing Treatment (NEST) for Small Renal Masses: A Feasibility Cohort-embedded Randomised Controlled Trial Comparing Percutaneous Cryoablation and Robot-assisted Partial Nephrectomy. European Urology. 2024;85(4):333-6.

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Nickolls BJ, Relton C, Hemkens L, et al. Randomised trials conducted using cohorts: a scoping review. BMJ Open 2024;0:e075601. doi:10.1136/ bmjopen-2023-075601

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Nickolls BJ. Understanding staged informed consent in the Trials within Cohorts design: a mixed methods study. PhD thesis (for submission October 2025)

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NIHR Clinical Trials Toolkit Trial Recruitment Phase webpage.

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Relton C, Nickolls B, Griffin X, Sohanpal R (2025) Staged and Tailored Informed Consent with Usual Care Groups: Developing Guidance, Society for Clinical Trials Annual Meeting, Vancouver, Canada. https://www.sctweb.org/meeting/

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Verweij ME, Gal R, Burbach JPM, Young-Afat DA, Van Der Velden JM, Van Der Graaf R, et al. Most patients reported positively or neutrally of having served as controls in the trials within cohorts design. Journal of Clinical Epidemiology. 2022;148:39-47.

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Vickers AJ, Young-Afat DA, Ehdaie B, et al. Just-in-time consent: the ethical case for an alternative to traditional informed consent in randomized trials comparing an experimental intervention with usual care. Clin Trials. 2018;15:3-8. [PMID: 29224379] doi:10.1177/ 1740774517746610

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Wilson, M.G., Palmer, E., Asselbergs, F.W. and Harris, S.K., 2023. Integrated rapid-cycle comparative effectiveness trials using flexible point of care randomisation in electronic health record systems. Journal of Biomedical Informatics, 137, p.104273.

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Wilson MG, Asselbergs FW, Saleem N, et al Digital integration of research conduct into clinical care: results of the PROSPECTOR randomised feasibility study. BMJ Evidence-Based Medicine Published Online First: 10 May 2025. doi: 10.1136/bmjebm-2024-113081

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World Medical Association. WMA Declaration of Helsinki – ethical principles for medical research involving human subjects. Accessed at www.wma.net/policies-post/wma-declaration-of-helsinkiethical-principles-for-medical-research-involving-human-subjects on 3 May 2024

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Xie CX, De Simoni A, Eldridge S, Pinnock H, Relton C (2024) Development of a conceptual framework for defining trial efficiency. PLoS ONE 19(5): e0304187. https://doi.org/10.1371/journal.pone.0304187

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Young-Afat DA, Gal R, Gerlich S, Burbach JPM, Van Der Velden JM, Van Den Bongard DHJG, et al. Oncology patients were found to understand and accept the Trials within Cohorts design. Journal of Clinical Epidemiology. 2021;130:135-42

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Zelen M. A new design for randomized clinical trials. New England Journal of Medicine. 1979;300(22):1242-5.

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Zwarenstein M, Treweek S, Gagnier JJ, Altman DG, Tunis S, Haynes B, et al. Improving the reporting of pragmatic trials: an extension of the CONSORT statement. BMJ. 2008;337:a2390.

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