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Low risk pragmatic trials do not always require participants’ informed consent
... 5 Such consent approaches, while consistent with longestablished research ethics guidance, may require reconsideration in the context of low-risk pragmatic RCTs where researchers have advocated for increased use of waivers of consent. 6,7 Moreover, several groups affected by AD/ADRD research may constitute vulnerable populations-defined as those who "may have an increased likelihood of being wronged or of incurring additional harm" 8 -including those individuals with limited capacity to consent or decline to consent to research participation, and individuals living in nursing homes. 8 The inclusion of such vulnerable populations in trials brings with it an additional array of ethical and regulatory challenges, such as the need for increased protections. ...
... Finally, our finding that few pragmatic RCTs reported using a waiver of consent is in contrast to recent academic writing, and research funding in AD/ADRD, which have emphasized the use of waivers of consent. 6,7,33 Waivers of consent may be granted when risks to study participants are minimal, when the research has important social value, and where requiring consent would make it infeasible or not practicable to conduct the study. 8,34 While it may be argued that the application of a waiver of consent in minimal risk research is a way to facilitate socially important research which would be impractical to conduct if individual consent were required, 6 we do not have data regarding studies that potentially sought a waiver of consent but were refused so by a research ethics committee: our cohort consists of published trials, which potentially skews our sample toward studies that could be feasibly completed with consent. ...
... 6,7,33 Waivers of consent may be granted when risks to study participants are minimal, when the research has important social value, and where requiring consent would make it infeasible or not practicable to conduct the study. 8,34 While it may be argued that the application of a waiver of consent in minimal risk research is a way to facilitate socially important research which would be impractical to conduct if individual consent were required, 6 we do not have data regarding studies that potentially sought a waiver of consent but were refused so by a research ethics committee: our cohort consists of published trials, which potentially skews our sample toward studies that could be feasibly completed with consent. Moreover, we did not seek to examine which trials potentially could have applied for a waiver of consent. ...
Introduction:
This review aims to describe the landscape of pragmatic randomized controlled trials (RCTs) in the context of Alzheimer's disease (AD) and related dementias with respect to ethical considerations.
Methods:
Searches of MEDLINE were performed from January 2014 until April 2019. Extracted information included: trial setting, interventions, data collection, study population, and ethical protections (including ethics approvals, capacity assessment, and informed consent).
Results:
We identified 62 eligible reports. More than two-thirds (69%) included caregivers or health-care professionals as research participants. Fifty-eight (94%) explicitly identified at least one vulnerable group. Two studies did not report ethics approval. Of 57 studies in which patients were participants, 55 (96%) reported that consent was obtained but in 37 studies (67%) no mention was made regarding assessment of the patients' capacity to consent to research participation.
Discussion:
Few studies reported protections implemented when vulnerable participants were included. Shortcomings remain when reporting consent approaches and capacity assessment.
... The 3 provisions are as follows [20]: (a) the research would not be feasible or practicable to carry out without the waiver or modification, (b) the research has important social value, and (c) the research poses no more than minimal risks to participants. It is clear that these provisions are applicable to low-risk pRCTs [21]. But not all low-risk pRCTs could be candidates to fulfil the CIOMS provisions: first trials must show a high degree of pragmatism that will ensure the generalizability of the results obtained [19,21], something that is uncommon, even among those RCTs self-tagged as pragmatic [22]. ...
... It is clear that these provisions are applicable to low-risk pRCTs [21]. But not all low-risk pRCTs could be candidates to fulfil the CIOMS provisions: first trials must show a high degree of pragmatism that will ensure the generalizability of the results obtained [19,21], something that is uncommon, even among those RCTs self-tagged as pragmatic [22]. The best way to assess the degree of pragmatism of an RCT is by using specific tools such as the PRECIS-2 tool [23], which considers nine domains -from the eligibility of participants to the statistical analysis, to be individually assessed. ...
... From 420 RCTs, only 21 could be candidates to fulfil the CIOMS provisions, and only 8 (out of 15 that responded to our questionnaires) fulfilled them following the assessment of the investigators and, with inconsistent results, of members of research ethics committees and patients [24]. This type of RCT will be eased if the EU Commission amends the regulation to allow the conduct of those low-risk pRCTs that fulfil the three CIOMS provisions [21]. ...
Background:
The 2019 Science for Dialysis Meeting at Bellvitge University Hospital was devoted to the challenges and opportunities posed by the use of data science to facilitate precision and personalized medicine in nephrology, and to describe new approaches and technologies. The meeting included separate sections for issues in data collection and data analysis. As part of data collection, we presented the institutional ARGOS e-health project, which provides a common model for the standardization of clinical practice. We also pay specific attention to the way in which randomized controlled trials offer data that may be critical to decision-making in the real world. The opportunities of open source software (OSS) for data science in clinical practice were also discussed.
Summary:
Precision medicine aims to provide the right treatment for the right patients at the right time and is deeply connected to data science. Dialysis patients are highly dependent on technology to live, and their treatment generates a huge volume of data that has to be analysed. Data science has emerged as a tool to provide an integrated approach to data collection, storage, cleaning, processing, analysis, and interpretation from potentially large volumes of information. This is meant to be a perspective article about data science based on the experience of the experts invited to the Science for Dialysis Meeting and provides an up-to-date perspective of the potential of data science in kidney disease and dialysis.
Key messages:
Healthcare is quickly becoming data-dependent, and data science is a discipline that holds the promise of contributing to the development of personalized medicine, although nephrology still lags behind in this process. The key idea is to ensure that data will guide medical decisions based on individual patient characteristics rather than on averages over a whole population usually based on randomized controlled trials that excluded kidney disease patients. Furthermore, there is increasing interest in obtaining data about the effectiveness of available treatments in current patient care based on pragmatic clinical trials. The use of data science in this context is becoming increasingly feasible in part thanks to the swift developments in OSS.
... While the former is the classical RCT useful to evaluate almost all type of interventions, the latter are increasingly common beyond the typical RCTs assessing health promotion and educational interventions. The possibility of conducting ethically-sound cluster RCTs with a waiver or alteration of written consent is well established: the interventions and data collection should pose no more than minimal risk and the research will be unfeasible without a waiver or alteration of informed consent [6]; conversely, a similar approach for certain types of individual-level RCTs is less accepted [7] −although both types of trials share the same ethical requirements. Thus, for example, the EU regulation on clinical trials with drugs accepts a modified ('simplified') consent for low-risk cluster RCTs but not for low-risk trials randomizing individuals [8]; the same approach is proposed for legislative changes for clinical trials with medicines and medical devices in the UK [9]. ...
... If the research involves using identifiable private information or identifiable biospecimens, the research could not practicably be carried out without using such information or biospecimens in an identifiable format; iv. The waiver or alteration will not adversely affect the rights and welfare of the subjects; and v. Whenever appropriate, the subjects or legally authorized representatives will be provided with additional pertinent information after participation waiving or altering written consent: low-risk pragmatic RCTs (or low-intervention RCTs in the EU regulation terminology [8]) for the assessment of commercially available medicines withing the approved labels (or evidence-based), with no more risks or burdens to participants than in usual clinical practice [7]. Since randomization in these trials poses no or minimal additional risk to participants compared to usual care, the key element to consider by investigators and research ethics committees (RECs) is whether the 'impracticability' requirement is met. ...
... Increasingly, commentators have proposed that the structure and approach for consent, disclosure or participant authorization should be based on ethically relevant considerations specific to a particular study (e.g., its risk/benefit profile or patients' expectations) [9,10]. Some authors have proposed waivers of consent for some low-risk pragmatic trials [9,11,12], and in 2017 the US FDA joined the rest of the US Department of Health and Human Services (DHHS) in permitting waivers of informed consent for clinical investigations involving no more than minimal risk. Another approach that has attracted interest is streamlining, rather than waiving, consent procedures for low-risk comparative effectiveness research (CER) studies [13,14]. ...
... Another approach that has attracted interest is streamlining, rather than waiving, consent procedures for low-risk comparative effectiveness research (CER) studies [13,14]. When the additional risk of studying or learning, compared with the risk of providing the same care in ordinary clinical practice, is low, when the study compares interventions widely used in clinical practice, and where differences in interventions are unlikely to be relevant to patients' values, some argue that streamlining consent procedures is ethically acceptable [9,12,15]. Streamlining could improve the efficiency of research, while still honoring ethically important considerations for a given research context, thereby balancing ethical protection with knowledge generation to improve patient and population health. ...
Aim: Streamlining consent for low-risk comparative effectiveness research (CER) could facilitate research, while safeguarding patients' rights. Materials & methods: 2618 adults were randomized to one of seven consent approaches (six streamlined and one traditional) for a hypothetical, low-risk CER study. A survey measured understanding, voluntariness, and feelings of respect. Results: Participants in all arms had a high understanding of the trial and positive attitudes toward the consent interaction. Highest satisfaction was with a streamlined approach showing a video before the medical appointment. Participants in streamlined were more likely to mistakenly think a signature was required. Conclusion: Streamlined consent was no less acceptable than traditional, signed consent. Streamlined and traditional approaches achieved similar levels of understanding, voluntariness and a feeling that the doctor–patient interaction was respectful.
... Such trials are also key to resolving clinical uncertainty about which of multiple usual-care treatments or approaches are best, and are thus a critical component of "learning health care systems" that strive for continuous incremental improvement in medical care delivery [8]. For this reason, there have been growing calls for expanding the use of waivers or other substantive modifications of informed consent to promote and streamline these types of studies [9][10][11][12][13][14][15][16]. ...
... Most of the studies (15) in which informed consent was waived involved behavioral interventions. One trial studied attention bias modification as a treatment for PTSD. ...
Background
Pragmatic and comparative effectiveness randomized controlled trials (RCTs) aim to be highly generalizable studies, with broad applicability and flexibility in methods. These trials also address recruitment issues by minimizing exclusions. The trials may also appeal to potential subjects because of lower risk and lower burdens of participation. We sought to examine rates of refusal and uses of waivers of informed consent in pragmatic and comparative effectiveness RCTs.
Methods
A systematic review of pragmatic and comparative effectiveness RCTs performed wholely or in part in the United States and first published in 2014 and 2017.
Results
103 studies involving 105 discrete populations were included for review. Refusal data was collected for 71 RCTs. Overall, studies reported an average rate of 31.9% of potential subjects refused participation; on an individual basis, 38.4% of people asked to take part refused at some point during recruitment. 23 trials (22%) were performed, at least in part, with a waiver of informed consent, 7 (30%) of which provided any form of notice to subjects.
Conclusions
Overall refusal rates for pragmatic and comparative effectiveness RCTs appear roughly the same as other types of research, with studies reporting about a third of people solicited for participation refuse. Moreover, informed consent was waived in 22% (95% Binomial exact Confidence Interval 13.9–30.5%) of the trials, and further study is needed to understand when waivers are justified and when notice should be provided.
... This study fulfils the criteria for a low-risk intervention trial in that the study interventions, study-related assessments and follow-up pose no more than minimal additional risk or burden to the safety of the participants [20]. As such, all eligible participants will be briefly informed by their case managers about the main features of the trial during their TDTP orientation session. ...
Objectives
1) To compare the effect of the self-report distress tool (DT) and rapid mental health referral process (MH) on vocational training program attendance.
2) To compare the effect of the DT and MH on vocational training program completion.
3) To compare the effect of the DT an MH on post-vocational training program employment.
Design
Pragmatic, multi-centre, 2x2 factorial, cluster randomized, superiority study with 4 parallel groups and primary endpoints of vocational program attendance and completion at 12 weeks and post-program employment at 24 months. Cluster randomization of each training cohort will be performed with a 1:1:1:1 allocation ratio using a site stratified, permuted-block group schema. Final sample size is expected to be 400 participants (100 per group).
Participants
Students enrolled in Community Builder’s Trades & Diversity Training Program in either the city of Barrie or Sudbury (in Ontario, Canada) will be eligible for enrollment if they have an active Ontario Health Insurance Plan number and Canadian Social Insurance Number and provide written informed consent prior to Training program commencement.
Outcomes
The primary outcome includes:
1) Difference in proportion of absence-free program days from date of randomization, where absence-free days are defined as being present in class or work setting for ≥ 8 hours from Monday to Thursday during the 12-week program duration.
Trial registration
ClinicalTrials.gov NCT05626374 (November 23, 2022).
... A learning health system features rigorous evaluation, but is primarily about programme development and evaluation and therefore some deviation from usual 'research' protocols for recruitment and consent may be reasonable. 20 Efforts to identify potential unintended consequences (eg, increased referrals to pain services or other potentially harmful prescribing) should always be incorporated, with outcomes and topics for improvement ideally co-developed by patients, clinicians and administrators. Optimisation of interventions can occur with little or no cost, starting with the 'low hanging fruit' 15 that have potential to reduce opioid prescribing but also contribute to the greater knowledge of audit and feedback science. ...
... These do not require individual consent. We were furthermore concerned that individual consent may contribute to low levels of recruitment numbers, as found in our previous work (Estcourt et al., 2015), and that this might compromise the validity and interpretation of the research (Eldridge et al., 2005;Dal-R e et al., 2019). ...
The General Data Protection Regulation (GDPR) was introduced in 2018 to harmonize data privacy and security laws across the European Union (EU). It applies to any organization collecting personal data in the EU. To date, service-level consent has been used as a proportionate approach for clinical trials, which implement low-risk, routine, service-wide interventions for which individual consent is considered inappropriate. In the context of public health research, GDPR now requires that individuals have the option to choose whether their data may be used for research, which presents a challenge when consent has been given by the clinical service and not by individual service users. We report here on development of a pragmatic opt-out solution to this consent paradox in the context of a partner notification intervention trial in sexual health clinics in the UK. Our approach supports the individual’s right to withhold their data from trial analysis while routinely offering the same care to all patients.
... The Clinical Trials Regulation's introduction of the concept of low-intervention trials could have major implications for the conduct of pragmatic clinical trials, which aim to evaluate how well a particular health technology works under real-life circumstances (Ford and Norrie, 2016). In many respects, pragmatic trials can be considered low-interventional in nature (Dal-Re et al., 2017;Dal-Re et al., 2019), since they are typically designed to measure and compare the effectiveness of already approved products that are administered within the scope of their marketing authorisations under conditions that reflect real-world clinical practice. Although patients may benefit from the outcomes of pragmatic trials, from a commercial point of view, no financial gains are to be expected as the products used in the trials are already on the market. ...
Background: Countries are struggling to provide affordable access to medicines while supporting the market entry of innovative, expensive products. This Perspective aims to discuss challenges and avenues for balancing health care system objectives of access, affordability and innovation related to medicines in Belgium (and in other countries).
Methods: This Perspective focuses on the R&D, regulatory approval and market access phases, with particular attention to oncology medicines, precision medicines, orphan medicines, advanced therapies, repurposed medicines, generics and biosimilars. The authors conducted a narrative review of the peer-reviewed literature, of the grey literature (such as policy documents and reports of consultancy agencies), and of their own research.
Results: Health care stakeholders need to consider various initiatives for balancing innovation with access to medicines, which relate to clinical and non-clinical outcomes (e.g. supporting the conduct of pragmatic clinical trials, treatment optimisation and patient preference studies, optimising the use of real-world evidence in market access decision making), value assessment (e.g. increasing the transparency of the reimbursement system and criteria, tailoring the design of managed entry agreements to specific types of uncertainty), affordability (e.g. harnessing the role of generics and biosimilars in encouraging price competition, maximising opportunities for personalising and repurposing medicines) and access mechanisms (e.g. promoting collaboration and early dialogue between stakeholders including patients).
Conclusion: Although there is no silver bullet that can balance valuable innovation with affordable access to medicines, (Belgian) policy and decision makers should continue to explore initiatives that exploit the potential of both the on-patent and off-patent pharmaceutical markets.
... [13][14][15] Many commentators have proposed that such studies require special ethical analysis, 13 14 16 17 18-20 with some arguing that PCTs comparing two standard interventions-even FDA regulated products 15 -involve no or minimal research risk. [18][19][20][21][22] Although we here leave aside the complex issues regarding the implications of research risk status on requirements for informed consent and the level of protocol review, a systematic approach to identifying PCTs' research risk is a necessary step in addressing those issues. ...
Background:
Pragmatic randomized clinical trials that compare two or more purportedly "within the standard of care" interventions attempt to provide real-world evidence for policy and practice decisions. There is considerable debate regarding their research risk status, which in turn could lead to debates about appropriate consent requirements. Yet no practical guidance for identifying the research risks of pragmatic randomized clinical trials is available.
Methods:
We developed a practical, four-step process for identifying and evaluating the research risk of pragmatic trials that can be applied to those pragmatic randomized clinical trials that compare two or more "standard of care" or "accepted" interventions.
Results:
Using a variety of examples of standard of care pragmatic randomized clinical trials (ranging from trials comparing: insurance coverage conditions, patient reminders for health screens, intensive care unit procedures, post-stroke interventions, and drugs for life-threatening conditions), we illustrate in a four-step process how any pragmatic randomized clinical trial purportedly comparing standard interventions can be evaluated for their research risks.
Conclusion:
Although determining the risk status of a standard of care pragmatic randomized clinical trial is only one necessary element in the ethical oversight of such pragmatic randomized clinical trials, it is a central element. Our four-step process of pragmatic randomized clinical trial risk determination provides a practical, transparent, and systematic approach with likely low risk of bias.
... 6 In particular, traditional written informed consent has been identified as a key topic of discussion 7 8 : some argue that standard written informed consent requirements may not be appropriate for low-risk pragmatic trials because the informed consent process may negatively impact trial recruitment, which in turn, may reduce the generalisability of the results and thereby undermine the pragmatic aim of the trial. [9][10][11][12] Accordingly, some have argued for an expanded use of waivers of consent, while others have proposed alternative approaches to standard written consent. 13 14 Regardless of the consent approaches used, the International Committee of Medical Journal Editors requires explicit reporting of this protection in reports of randomised trials. ...
Objectives
To describe reporting of informed consent in pragmatic trials, justifications for waivers of consent and reporting of alternative approaches to standard written consent. To identify factors associated with (1) not reporting and (2) not obtaining consent.
Methods
Survey of primary trial reports, published 2014–2019, identified using an electronic search filter for pragmatic trials implemented in MEDLINE, and registered in ClinicalTrials.gov.
Results
Among 1988 trials, 132 (6.6%) did not include a statement about participant consent, 1691 (85.0%) reported consent had been obtained, 139 (7.0%) reported a waiver and 26 (1.3%) reported consent for one aspect (eg, data collection) but a waiver for another (eg, intervention). Of the 165 trials reporting a waiver, 76 (46.1%) provided a justification. Few (53, 2.9%) explicitly reported use of alternative approaches to consent. In multivariable logistic regression analyses, lower journal impact factor (p=0.001) and cluster randomisation (p<0.0001) were significantly associated with not reporting on consent, while trial recency, cluster randomisation, higher-income country settings, health services research and explicit labelling as pragmatic were significantly associated with not obtaining consent (all p<0.0001).
Discussion
Not obtaining consent seems to be increasing and is associated with the use of cluster randomisation and pragmatic aims, but neither cluster randomisation nor pragmatism are currently accepted justifications for waivers of consent. Rather than considering either standard written informed consent or waivers of consent, researchers and research ethics committees could consider alternative consent approaches that may facilitate the conduct of pragmatic trials while preserving patient autonomy and the public’s trust in research.
... Scenario three provided no notification or option to opt out (ie, waiver of consent). 32 Scenarios four and five maintained the use of a waiver of consent but introduced posters as potential method of notification and an optout procedure respectively. 33 In addition, we probed alternative forms of notification, such as letters or leaflets. ...
Background:
Cluster randomized trials (CRTs) are trials in which intact groups such as hemodialysis centers or shifts are randomized to treatment or control arms. Pragmatic CRTs have been promoted as a promising trial design for nephrology research yet may also pose ethical challenges. While randomization occurs at the cluster level, the intervention and data collection may vary in a CRT, challenging the identification of research participants. Moreover, when a waiver of patient consent is granted by a research ethics committee, there is an open question as to whether and to what degree patients should be notified about ongoing research or be provided with a debrief regarding the nature and results of the trial upon completion. While empirical and conceptual research exploring ethical issues in pragmatic CRTs has begun to emerge, there has been limited discussion with patients, families, or caregivers of patients undergoing hemodialysis.
Objective:
To explore with patients and families with experience of hemodialysis research the challenges raised by different approaches to designing pragmatic CRTs in hemodialysis. Specifically, their perceptions of (1) the use of a waiver of consent, (2) notification processes and information provided to participants, and (3) any other concerns about cluster randomized designs in hemodialysis.
Design:
Focus group and interview discussions of hypothetical clinical trial designs.
Setting:
Focus groups and interviews were conducted in-person or via videoconference or telephone.
Participants:
Patient partners in hemodialysis research, defined as patients with personal experience of dialysis or a family member who had experience supporting a patient receiving hemodialysis, who have been actively involved in discussions to advise a research team on the design, conduct, or implementation of a hemodialysis trial.
Methods:
Participants were invited to participate in focus groups or individual discussions that were audio recorded with consent. Recorded interviews were transcribed verbatim prior to analysis. Transcripts were analyzed using a thematic analysis approach.
Results:
Two focus groups, three individual interviews, and one interview involving a patient and family member were conducted with 17 individuals between February 2019 and May 2020. Participants expressed support for approaches that emphasized patient choice. Disclosure of patient-relevant risks and information were key themes. Both consent and notification processes served to generate trust, but bypassing patient choice was perceived as undermining this trust. Participants did not dismiss the option of a waiver of consent. They were, however, more restrictive in their views about when a waiver of consent may be acceptable. Patient partners were skeptical of claims to impracticability based on costs or the time commitments for staff.
Limitations:
All participants were from Canada and had been involved in the design or conduct of a trial, limiting the degree to which results may be extrapolated.
Conclusions:
Given the preferences of participants to be afforded the opportunity to decide about trial participation, we argue that investigators should thoroughly investigate approaches that allow participants to make an informed choice regarding trial participation. In keeping with the preference for autonomous choice, there remains a need to further explore how consent approaches can be designed to facilitate clinical trial conduct while meeting their ethical requirements. Finally, further work is needed to define the limited circumstances in which waivers of consent are appropriate.
... 101 Numerous writers have proposed methods for reducing the burdens of having to secure written informed consent for this type of research. 102 Informed consent, instead of being the default, is at risk of being swamped by the exceptions. Nonetheless, when asked, the public largely supports informed consent, even when it makes research more expensive or difficult. ...
We examine the evolution of policies permitting exceptions to or waivers of informed consent for research in the United States. This review reveals that (1) exceptions to the duty to secure informed consent were originally quite narrow; (2) there were two alternative approaches to allowing research on human subjects without their prospective consent: (i) exceptions in which individual capacity to consent is to be assessed and consent tailored to each person’s abilities and (ii) waivers of the general requirement for a population of potential subjects, where securing prospective consent would “destroy or invalidate” critically important research; (3) waivers only appeared in the final rulemakings for research regulations issued by the National Institute of Education in 1974 and the Department of Health and Human Services in 1981, limiting the opportunity for the public to weigh in on the scope and use of waivers; and (4) rules adopted since 1981 have almost uniformly added extra requirements to justify waivers. Examples drawn from recent research show expansion of the use of waivers far beyond the bounds originally envisioned. Greater transparency about the use of waivers is needed for the public to weigh in on the standards for foregoing informed consent in human research.
... Informed consent has implications for both internal and external validity of the trial and may be seen to be at odds with the pragmatic ideal. Although some believe that low risk pragmatic trials should be permitted with waivers of consent [39], others believe that alterations such as integrated consent are more appropriate [40]. Empirical reviews indicate that the majority of pragmatic trials do obtain participant informed consent although there is limited evidence about the use of alterations of consent [41,42]. ...
Background and objective:
Feasibility studies are increasingly being used to support the development of, and investigate uncertainties around, future large-scale trials. The future trial can be designed with either a pragmatic or explanatory mindset. Whereas pragmatic trials aim to inform the choice between different care options and thus, are designed to resemble conditions outside of a clinical trial environment, explanatory trials examine the benefit of a treatment under more controlled conditions. There is existing guidance for designing feasibility studies, but none that explicitly considers the goals of pragmatic designs. We aimed to identify unique areas of uncertainty that are relevant to planning a pragmatic trial.
Results:
We identified ten relevant domains, partly based on the PRECIS-2 framework, and describe potential questions of uncertainty within each: intervention development, research ethics, participant identification and eligibility, recruitment of individuals, setting, organisation, flexibility of delivery, flexibility of adherence, follow-up, and importance of primary outcome to patients and decision-makers. We present examples to illustrate how uncertainty in these domains might be addressed within a feasibility study.
Conclusion:
Researchers planning a feasibility study in advance of a pragmatic trial should consider feasibility objectives specifically relevant to areas of uncertainty for pragmatic trials.
... Finally, our results suggest that despite proposals for the wider application of waivers of consent with low-risk pragmatic RCTs, [67] under-accrual remains a substantial challenge for many pragmatic RCTs. One possibility is that pragmatism within different PRECIS-2 domains may both positively and negatively affect trial accrual. ...
Objective
We established a large database of trials to serve as a resource for future methodological and ethical analyses. Here, we use meta-data to describe the broad landscape of pragmatic trials including research areas, identification as pragmatic, quality of trial registry data and enrolment.
Study Design and Setting
Trials were identified by a validated search filter and included if a primary report of a health-related randomized trial published January 2014-April 2019. Data were collated from MEDLINE, Web of Science, ClinicalTrials.gov, and full text.
Results
4337 eligible trials were identified from 13,065 records, of which 1988 were registered in ClinicalTrials.gov. Research areas were diverse, with the most common being general and internal medicine; public, environmental and occupational health; and health care sciences and services. The term “pragmatic” was seldom used in titles or abstracts. Several domains in ClinicalTrials.gov had questionable data quality. We estimated that one-fifth of trials under-accrued by at least 15%.
Conclusion
There is a need to improve reporting of pragmatic trials and quality of trial registry data. Under accrual remains a challenge in pragmatic RCTs despite calls for more streamlined recruitment approaches. The diversity of pragmatic trials should be reflected in future ethical analyses.
... The concept, bypassing consent in the case of specific groups of patients or specific conditions in which patients find themselves, provides an opportunity to formulate questions on the limits of autonomy in the decisionmaking process, and ultimately its value. The Regulation clearly indicates that informed consent is unnecessary in clinical trials among particular categories of patients; such a view is also represented more extensively in other publications [27,28]. The process of ceding the possibility of expressing consent to a different entity (i.e. a legally designated representative) is to bring direct and measurable benefits for research participants in the health care sphere. ...
Introduction and Objective
For years the concept of informed consent has been gaining strength as an expression of patient and research participant’s autonomy. The interpreted Regulations allows for obtaining a substitute consent from that person’s legally designated representative which, de facto, is the decision of an authorized entity to include the participant in the study presuming that he/she would agree. The inability to consent in a specific situation and allowing for substitute consent from a different entity (a legally designated representative) is permission to participate in the proposed form of clinical trial. Through the introduced solution, the autonomy of the participant who, for various reasons, cannot consent to participate in clinical trials has been limited. The aim of the study was to analyze the concept of substitute consent in a research setting.
Brief description of the state of knowledge
The legal obligation to obtain consent originates from the early 20th century. This concept has evolved over the years and broadened in scope to increase the significance of patient autonomy. The analyzed Regulation indicates that the concept of informed consent has been redefined in the clinical research setting to incorporate those who lack the possibility to self-decide. The directive introduces the concept of substitute consent, which is an innovative solution that can affect current research protocols.
Conclusions
Traditional requirements for informed consent have been omitted (in this redefined Act), which is an innovative legislative solution that can facilitate research
... 9 10 This strategy relies on greater use of pragmatic and comparative effectiveness trials, which attempt to embed trial procedures as much as possible into routine clinical practice and often are focused on resolving latent uncertainties about optimal care. Many authors have proposed ways for streamlining or simplifying the processes of informed consent, [11][12][13][14][15][16][17] and in the limit, propose waiving consent from subjects. 18 A recent systematic review examined pragmatic and comparative effectiveness RCTs performed at least in part in the USA and first published in 2014 and 2017, finding that 23 (22%) of 103 trials were done with a waiver of individual informed consent (LY Lin, N Jochym and JF Merz, unpublished data, 2020). ...
The prevalence of randomized controlled trials (RCTs) performed without fully informed prospective consent from subjects is unknown. We performed this study to estimate the prevalence of high-impact RCTs performed without informed consent from all subjects and examine whether such trials are becoming more prevalent. We performed a systematic review of English-language RCTs published from 2014 through 2018 identified in Scopus and sorted to identify the top 100 most highly cited RCTs each year. Text search of title and abstract included terms randomized controlled or clinical trial and spelling variants thereof, and excluded metaanalyses and systematic reviews. We independently identified the most highly cited RCTs based on predefined criteria and negotiated to agreement, then independently performed keyword searches, read, abstracted and coded information regarding informed consent from each paper and again negotiated to agreement. No quality indicators were assessed. We planned descriptive qualitative analysis and appropriate quantitative analysis to examine the prevalence and characteristics of trials enrolling subjects with other than fully informed prospective consent. We find that 44 (8.8%, binomial exact 95% CI 6.5% to 11.6%) of 500 high-impact RCTs did not secure informed consent from at least some subjects. The prevalence of such trials did not change over the 5 years (OR=1.09, z=0.78, p=0.44). A majority (66%) of the trials involved emergency situations, and 40 of 44 (90.9%) of the trials involved emergency interventions, pragmatic designs, were cluster randomized, or a combination of these factors. A qualitative analysis explores the methods of and justifications for waiving informed consent in our sample of RCTs.
... 9 10 This strategy relies on greater use of pragmatic and comparative effectiveness trials, which attempt to embed trial procedures as much as possible into routine clinical practice and often are focused on resolving latent uncertainties about optimal care. Many authors have proposed ways for streamlining or simplifying the processes of informed consent, [11][12][13][14][15][16][17] and in the limit, propose waiving consent from subjects. 18 A recent systematic review examined pragmatic and comparative effectiveness RCTs performed at least in part in the USA and first published in 2014 and 2017, finding that 23 (22%) of 103 trials were done with a waiver of individual informed consent (LY Lin, N Jochym and JF Merz, unpublished data, 2020). ...
The prevalence of randomized controlled trials (RCTs) performed without fully informed prospective consent from subjects is unknown. We performed this study to estimate the prevalence of high-impact RCTs performed without informed consent from all subjects and examine whether such trials are becoming more prevalent. We performed a systematic review of English-language RCTs published from 2014 through 2018 identified in Scopus and sorted to identify the top 100 most highly cited RCTs each year. Text search of title and abstract included terms randomized controlled or clinical trial and spelling variants thereof, and excluded metaanalyses and systematic reviews. We independently identified the most highly cited RCTs based on predefined criteria and negotiated to agreement, then independently performed keyword searches, read, abstracted and coded information regarding informed consent from each paper and again negotiated to agreement. No quality indicators were assessed. We planned descriptive qualitative analysis and appropriate quantitative analysis to examine the prevalence and characteristics of trials enrolling subjects with other than fully informed prospective consent. We find that 44 (8.8%, binomial exact 95% CI 6.5% to 11.6%) of 500 high-impact RCTs did not secure informed consent from at least some subjects. The prevalence of such trials did not change over the 5 years (OR=1.09, z=0.78, p=0.44). A majority (66%) of the trials involved emergency situations, and 40 of 44 (90.9%) of the trials involved emergency interventions, pragmatic designs, were cluster randomized, or a combination of these factors. A qualitative analysis explores the methods of and justifications for waiving informed consent in our sample of RCTs.
... c There were no significant differences between STEMI and NSTEMI or in the age sub-group In the UK, where the HEAT-PPCI trial was performed, the argument for deferred consent was mainly the lifethreatening situation in combination with the minimal risk of comparing two well-established drugs [16]. The advantage of using deferred consent is a more comprehensive recruitment of an unselected study population, providing data which can be more easily generalized to everyday patient care [25]. The potential risk is to include an unwilling patient. ...
Objective:
We aimed to assess the patient experience of informed consent (IC) during acute myocardial infarction (AMI) in a sub-study of the VALIDATE-SWEDEHEART trial. The original trial compared two anticoagulant agents in patients undergoing coronary intervention. A witnessed oral IC was required prior to randomization in patients with ST-segment elevation myocardial infarction, which was subsequently complemented with a written IC after percutaneous coronary intervention. Written consent was obtained before angiography in patients with non-ST-segment elevation myocardial infarction.
Background:
The IC process in patients with AMI is under debate. Earlier trials in this population have required prospective consent before randomization. A trial published some years ago used deferred consent, but the patient experience of this process is poorly studied.
Methods:
A total of 414 patients who participated in the main trial were enrolled and asked the following questions: (1) Do you remember being asked to participate in a study? (2) How was your experience of being asked to participate; do you remember it being positive or negative? (3) Would you have liked more information about the study? (4) Do you think it would have been better if you were included in the study without being informed until a later time?
Results:
Of these patients, 94% remembered being included; 85% of them experienced this positively, 12% were neutral and 3% negative. Regarding more information, 88% did not want further information, and 68% expressed that they wanted to be consulted before inclusion. Of the patients, 5% thought it would have been better to have study inclusion without consent, and 27% considered it of no importance.
Conclusion:
It is reasonable to ask patients for verbal IC in the acute phase of AMI. Most patients felt positively about being asked to participate and had knowledge of being enrolled in a scientific study. In addition they objected to providing IC after randomization and treatment.
Trial registration:
VALIDATE-SWEDEHEART European Union Clinical Trials Register: 2012-005260-10. ClinicalTrials.gov: NCT02311231. Registered on 8 Dec 2014.
... The need to obtain participants' written informed consent in low-risk pRCTs has been shown that could jeopardize the conduct of these trials as they were conceived by the investigators. Although the CIOMS guidelines and the regulations of Canada and the USA allow for the conduct of this type of trials without seeking participants' informed consent, this approach will most likely be controversial in Europe [40,41]. However, the key issue to bear in mind is how consent is obtained by a physician that eventually prescribe a medicine in usual clinical practice, and compare it to what extent seeking written informed consent for a pRCT interferes with a real-life patient (participant)/physician (investigator) encounter [41]. ...
Introduction: An important gap within modern medicine is the lack of enough comparative effectiveness research of marketed medicines. Low-risk pragmatic randomized controlled trials (pRCTs) are those conducted resembling usual clinical practice that pose no or minimal incremental risk compared with normal clinical practice.
Areas covered: This review addresses one important hurdle in the conduct of low-risk pRCTs: the need to seek participants’ written informed consent.
Expert opinion: The CIOMS ethical guidelines consider that any research that a) would not be feasible or practicable to carry out without the waiver or modification; b) has important social value; and c) poses no more than minimal risks to participants; and that is approved by the relevant research ethics committee, could be conducted without participants’ consent. It is clear that these provisions are applicable to some low-risk RCTs. Recently a research on the EU-CTR registry showed that only 2% of all on-going phase 4 RCTs could have fulfilled the CIOMS provisions following the investigators’ assessment. The EU clinical trial regulation -and that of other jurisdictions- should be debated on the suitableness of the conduct with an alteration or waiver of participants’ consent of those low-risk pRCTs that fulfil the three CIOMS provisions.
... The current studies used retrospective, anonymised data extracted from medical records without the need for patient consent. This ethical method of data collection [14] was appropriate as there was virtually no influence on inclusion eligibility by the sites, no effect from patient behaviour, and clinical care was not disrupted by any discussion or administration of the trial allowing the usual standard of diabetes care to be maintained [15]. The entry of changing to a flash sensor monitoring method in the medical record suggests that this decision was likely a result of clinical review and discussion between patient and physician. ...
Introduction:
The impact of flash glucose monitoring technology on HbA1c in type 2 diabetes managed by basal bolus insulin is uncertain. Three parallel European retrospective non-interventional chart review studies collected data reported in medical records. Each country's study aim was to determine the effectiveness of the device on HbA1c when used by their population for 3-6 months as their standard of care for management of glycaemia in a real-world setting.
Methods:
Medical records were eligible for adult patients with type 2 diabetes, on a basal bolus insulin regimen for 1 year or more, device use for 3 months or more before the start of the study, an HbA1c concentration up to 3 months prior to starting device use (patients were using blood glucose monitoring for self-management) between 64 and 108 mmol/mol (8.0-12.0%) plus an HbA1c determination 3-6 months after commencing flash glucose monitoring use.
Results:
Records were analysed from 18 medical centres in Austria (n = 92), France (n = 88) and Germany (n = 183). Baseline HbA1c results, recorded up to 90 days before the start of device use, were comparable across the three countries and were reduced significantly by 9.6 ± 8.8 mmol/mol mean ± SD (Austria [0.9 ± 0.8%], p < 0.0001), 8.9 ± 12.5 mmol/mol (France [0.8% ± 1.1], p < 0.0001) and 10.1 ± 12.2 mmol/mol (Germany [0.9% ± 1.1], p < 0.0001). No significant differences were detected between age group, sex, BMI or duration of insulin use.
Conclusions:
Three European real-world, chart review studies in people with type 2 diabetes managed using basal bolus insulin therapy each concluded that HbA1c was significantly reduced after changing to use of flash glucose monitoring for 3-6 months in a real-world setting.
... 4 Pragmatic trials evaluate interventions as prescribed, managed and used in routine clinical practice. 5 We used the UK recommended colchicine dose, 6 consistent with the British Society for Rheumatology gout management guideline. 7 Furthermore, the EULAR recommendations advocate a loading dose of colchicine of 1 mg followed by 0.5 mg 1 hour later in patients presenting within 12 hours of flare onset, 4 as per the Acute Gout Flare Receiving Colchicine Evaluation (AGREE) trial, 8 without making a dose recommendation for patients with longer flare durations. ...
... The second design feature worth highlighting is the approach to individual consents. The IRB permitted the waiver of informed consent based on federal regulations [54], an approach increasingly used in pragmatic trails [55]. Such a waiver increases recruitment and avoids unnecessary administrative procedures for participants and the research team. ...
Background:
Infections are common in nursing home (NH) residents with advanced dementia but are often managed inappropriately. Antimicrobials are extensively prescribed, but frequently with insufficient evidence to support a bacterial infection, promoting the emergence of multidrug-resistant organisms. Moreover, the benefits of antimicrobials remain unclear in these seriously ill residents for whom comfort is often the goal of care. Prior NH infection management interventions evaluated in randomized clinical trials (RCTs) did not consider patient preferences and lack evidence to support their effectiveness in 'real-world' practice.
Methods:
This report presents the rationale and methodology of TRAIN-AD (Trial to reduce antimicrobial use in nursing home residents with Alzheimer's disease and other dementias), a parallel group, cluster RCT evaluating a multicomponent intervention to improve infection management for suspected urinary tract infections (UTIs) and lower respiratory tract infections (LRIs) among NH residents with advanced dementia. TRAIN-AD is being conducted in 28 facilities in the Boston, USA, area randomized in waves using minimization to achieve a balance on key characteristics (N = 14 facilities/arm). The involvement of the facilities includes a 3-month start-up period and a 24-month implementation/data collection phase. Residents are enrolled during the first 12 months of the 24-month implementation period and followed for up to 12 months. Individual consent is waived, thus almost all eligible residents are enrolled (target sample size, N = 410). The intervention integrates infectious disease and palliative care principles and includes provider training delivered through multiple modalities (in-person seminar, online course, management algorithms, and prescribing feedback) and an information booklet for families. Control facilities employ usual care. The primary outcome, abstracted from the residents' charts, is the number of antimicrobial courses prescribed for UTIs and LRIs per person-year alive.
Discussion:
TRAIN-AD is the first cluster RCT testing a multicomponent intervention to improve infection management in NH residents with advanced dementia. Its findings will provide an evidence base to support the benefit of a program addressing the critical clinical and public health problem of antimicrobial misuse in these seriously ill residents. Moreover, its hybrid efficacy-effectiveness design will inform the future conduct of cluster RCTs evaluating nonpharmacological interventions in the complex NH setting in a way that is both internally valid and adaptable to the 'real-world'.
Trial registration:
ClinicalTrials.gov, NCT03244917 . Registered on 10 August 2017.
Introduction
Acute febrile illness (AFI), traditionally attributed to malaria, is a common reason for seeking primary healthcare in rural South and Southeast Asia. However, malaria transmission has declined while health workers are often poorly equipped to manage non-malarial AFIs. This results in indiscriminate antibiotic prescribing and care escalation, which promotes antibiotic resistance and may increase healthcare costs. To address this problem, an electronic clinical decision support algorithm (eCDSA) called ‘Electronic clinical Decision support for Acute fever Management (EDAM)’ has been developed for primary health workers which integrates clinical, epidemiological and vital sign data with simple point-of-care tests to produce a diagnosis and management plan.
Methods and analysis
This is a pragmatic cluster-randomised trial aiming to assess the effect of EDAM and related training on antibiotic prescribing rates in rural Cambodian primary health centres (PHCs) as the primary outcome, along with a range of secondary outcomes including safety. Patients with AFI are eligible for recruitment if they are aged ≥1 year. A cluster is defined as a PHC and PHCs will be randomised to control (standard of care) and intervention (EDAM and associated training) arms, with 15 PHCs per arm. Patients will be followed up after 7 days to ascertain the safety profile of EDAM. Each PHC will recruit 152 patients (total 4560), based on a baseline antibiotic prescription rate of 25% and expected reduction to 17.5% with EDAM.
Ethics and dissemination
Results will be published in international peer-reviewed journals to inform the design of future versions of EDAM and of future trials of similar eCDSAs and other digital health interventions targeted towards rural populations. This study was approved by the Oxford University Tropical Research Ethics Committee (550-23) and the Cambodian National Ethics Committee for Health Research (395-NECHR).
Trial registration number
International Standard Randomized Controlled Trial Number Registry ( ISRCTN15157105 ).
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Objective
Randomized trials labelled as “pragmatic” are attractive to funders, patients, and clinicians as the label implies that the results are directly applicable to clinical care. We examined how authors justify use of the label (e.g., by referring to one or more PRECIS (PRagmatic Explanatory Continuum Indicator Summary)-2 domains).
Study design and setting
We reviewed primary trial reports published 2014-2019, registered in ClinicalTrials.gov and using the pragmatic label anywhere in the report.
Results
Among 415 trials, the label was justified by reference to at least one design element in 282 (68.0%): of these, 240 (85.1%) referenced trial characteristics that can be mapped to one or more of the PRECIS-2 domains, most commonly eligibility (91, 32.3%), setting (90, 31.9%), flexibility-delivery (89, 31.6%) and organization (75, 26.6%); 42 (14.9%) referenced characteristics that are not PRECIS-2 domains, most commonly type of intervention/comparator (48, 17%), recruitment without consent (22, 7.8%), routinely collected data (22, 7.8%) and cluster randomization (20, 7.1%). Most reports referenced only one or two design elements. Overall, 9/415 (2.2%) provided PRECIS wheels.
Conclusions
Current use of pragmatic labels is uninformative. Authors should clarify the decision the trial is intended to support and include a PRECIS-2 table to make the design transparent.
Radiation-induced heart disease (RIHD) is a recent concern in patients with lung cancer after being treated with radiotherapy. Most of information we have in the field of cardiac toxicity comes from studies utilizing real-world data (RWD) as randomized controlled trials (RCTs) are generally not practical in this field. This article is a narrative review of the literature using RWD to study RIHD in patients with lung cancer following radiotherapy, summarizing heart dosimetric factors associated with outcome, strength, and limitations of the RWD studies, and how RWD can be used to assess a change to cardiac dose constraints.
The General Data Protection Regulation (GDPR) was introduced in 2018 to harmonize data privacy and security laws across the European Union (EU). It applies to any organization collecting personal data in the EU. To date, service-level consent has been used as a proportionate approach for clinical trials, which implement low-risk, routine, service-wide interventions for which individual consent is considered inappropriate. In the context of public health research, GDPR now requires that individuals have the option to choose whether their data may be used for research, which presents a challenge when consent has been given by the clinical service and not by individual service users. We report here on development of a pragmatic opt-out solution to this consent paradox in the context of a partner notification intervention trial in sexual health clinics in the UK. Our approach supports the individual’s right to withhold their data from trial analysis while routinely offering the same care to all patients.
Learning health systems and rapid-learning are well developed at the conceptual level. The promise of rapidly generating and applying evidence where conventional clinical trials would not usually be practical is attractive in principle. The connectivity of modern digital healthcare information systems and the increasing volumes of data accrued through patients’ care pathways offer an ideal platform for the concepts. This is particularly true in radiotherapy where modern treatment planning and image guidance offers a precise digital record of the treatment planned and delivered. The vision is of real-world data, accrued by patients during their routine care, being used to drive programmes of continuous clinical improvement as part of standard practice. This vision, however, is not yet a reality in radiotherapy departments. In this article we review the literature to explore why this is not the case, identify barriers to its implementation, and suggest how wider clinical application might be achieved.
We examine the evolution of policies permitting exceptions to or waivers of informed consent for research in the United States. This review reveals that (1) exceptions to the duty to secure informed consent were originally quite narrow; (2) there were two alternative approaches to allowing research on human subjects without their prospective consent: (i) exceptions in which individual capacity to consent is to be assessed and consent tailored to each person’s abilities and (ii) waivers of the general requirement for a population of potential subjects, where securing prospective consent would “destroy or invalidate” critically important research; (3) waivers only appeared in the final rulemakings for research regulations issued by the National Institute of Education in 1974 and the Department of Health and Human Services in 1981, limiting the opportunity for the public to weigh in on the scope and use of waivers; and (4) rules adopted since 1981 have almost uniformly added extra requirements to justify waivers. Examples drawn from recent research show expansion of the use of waivers far beyond the bounds originally envisioned. Greater transparency about the use of waivers is needed for the public to weigh in on the standards for foregoing informed consent in human research.
Importance
Nimodipine is a highly prescribed drug for the treatment of cognitive impairment and dementia in Argentina. There is little evidence to support the use of nimodipine for cognitive impairment and dementia.
Objective
To test the effectiveness of a behavioral intervention based on social norm feedback to reduce prescription of nimodipine for cognitive impairment in Argentina.
Design, Setting, and Participants
This pragmatic parallel-group randomized clinical trial included 2 arms with a 1:1 allocation ratio. General practitioner physicians in the national health care system for older adults in Argentina (INSSJP-PAMI) with history of high nimodipine prescription rate were enrolled. The study was conducted from May 2019 to October 2019, and data were analyzed from November 2019 to February 2020.
Interventions
The treatment group received 2 emails with evidence-based information about nimodipine plus the individual’s level of nimodipine prescription compared with their peers. The control group received 2 emails with general information about the risks of overprescription in older adults.
Main Outcomes and Measures
The primary outcome was the cumulative number of nimodipine prescriptions per 1000 prescriptions of all drugs made by the targeted physicians during the 6 months of the study. Secondary outcomes included annual monetary savings attributable to the intervention and physicians’ qualitative perceptions of the acceptability of the procedure.
Results
Of 1811 physicians enrolled, 906 physicians (354 [39.1%] women; mean [SD] age, 57.10 [10.73] years) were randomized to treatment and 905 participants (331 [36.6%] women; mean [SD] age, 56.49 [10.47] years) to the control group. Physicians in the treatment group wrote a mean of 93.25 (95% CI, 89.27 to 97.24) prescriptions of nimodipine, compared with 98.99 (95% CI, 95.00 to 102.98) prescriptions among practitioners in the control group during the half-year of the intervention (mean difference, –5.73 [95% CI, –11.38 to –0.10] prescriptions; P = .046), which meant a 5.79% reduction. Regression analysis revealed a significant association of the group condition with number of prescriptions per 1000 total prescriptions when controlling for baseline prescriptions (B = –0.312 [95% CI, –0.465 to –0.160]; P < .001). The observed difference corresponds to a 4.48% reduction in nimodipine prescriptions per 1000 prescriptions of all drugs made by physicians in the treated group compared with the control group. Physicians who effectively opened the email in the treatment group (427 physicians [47.1%]) prescribed the drug 11.3% less compared with the control group (426 physicians) (mean difference, –10.78 [95% CI, –18.53 to –3.03] prescriptions; P = .006). Expenditures were 7.18% lower in the treatment group, resulting in an estimated annual net cost benefit of US 225 565.35 to $237 112.30).
Conclusions and Relevance
In this randomized clinical trial, the social norm email feedback program showed an effect on curbing the nonrecommended prescription of nimodipine. It was highly cost-effective and well accepted by participants.
Trial Registration
ISRCTN.org identifier: ISRCTN17823729
To the Editor: Collins et al. (Feb. 13 issue)¹ set up a false dichotomy in presenting real-world evidence (RWE) as an “unreliable” substitute for findings from randomized, controlled trials (RCTs). While the “magic” of randomization ensures balance between groups in RCTs, it cannot ensure that outcomes are representative of a given population. In the United States, RCTs involving patients with cancer represent less than 5% of U.S. adults with cancer. Patients in RCTs are also younger, healthier, and less diverse than the other 95% of patients with cancer.² Because it is not always feasible to conduct an RCT, particularly among . . .
Objectives:
European regulations do not allow modification or waiver of informed consent for medicines randomized controlled trials (RCTs) where the three 2016 Council for International Organizations of Medical Sciences (CIOMS) provisions are met (consent would be impractical or unfeasible, yet the trial would have high social value and pose no or minimal risk to participants). We aimed to identify whether any such trials of medicines were being conducted in Europe.
Study design and setting:
This is a survey of all phase 4 "ongoing" RCTs on the EU clinical trial register between July 1, 2016 and June 30, 2018, to identify those with potentially high levels of pragmatism. Trials that were excluded were as follows: those conducted on rare diseases; conducted on healthy volunteers (except those assessing vaccines); masked (single-, double-blind) trials; single-center trials; those where one could expect to lead patients to prefer one intervention over the other; and miscellaneous reasons. The degree of pragmatism of the RCTs was self-assessed by trials' investigators by means of the PRECIS-2 tool. Investigators of those trials considered to be highly pragmatic assessed the fulfillment of the three CIOMS provisions. Seven patients assessed the social value of the RCTs. Finally, 33 members of 11 research ethics committees (RECs) assessed the social value of the trials and whether they posed no more than minimal risk to participants. Investigators, patients, and REC members assessed the fulfillment of the CIOMS provisions as "yes," "not sure" or "no."
Results:
Of the 638 phase 4 trials, 420 were RCTs, and 21 of these (5%) were candidates to be pragmatic. Investigators of 15 of these 21 RCTs self-assessed their trial's degree of pragmatism: 14 were highly pragmatic. Of these 14, eight fulfilled the three CIOMS provisions. Assessments by patients and RECs were inconsistent for several trials.
Conclusions:
We found few low-risk participant-level pragmatic RCTs that could be suitable for modified or waived participants' informed consent. European regulators should consider amending the current regulation and encouraging the conduct of such trials.
Pragmatic randomised clinical trials could use existing electronic health records (EHRs) to identify trial participants, perform randomisation, and to collect follow-up data. Achieving adequate informed consent in routine care and clinician recruitment have been identified as key barriers to this approach to clinical trials. We propose a model where written informed consent for a pragmatic comparative effectiveness trial is obtained in advance by the research team, recorded in the EHR, and then confirmed by the general practitioner (GP) at the time of enrolment. The EHR software then randomly assigns a patient to one of two treatments. Follow-up data is collected in the EHR. Twenty-two of 23 GPs surveyed (96%) were ‘definitely’ or ‘probably’ comfortable with confirming consent. Twenty-one out of 23 GPs (91%) were ‘definitely’ or ‘probably’ comfortable with a patient being randomised to one of two comparable drugs during a routine consultation. Twenty-two out of 23 GPs (96%) were ‘definitely’ or ‘probably’ comfortable with allowing the electronic system to randomise a patient to drug A or drug B and generate a prescription. Ten out of 23 GPs (43%) identified time constraints as the main hurdle to conducting this sort of research in the primary care setting. On average, it was felt that 6.5 min, in addition to a usual consult, would be acceptable to complete enrolment. Our survey found this model of a comparative effectiveness trial to be acceptable to the majority of GPs.
Electronic supplementary material
The online version of this article (10.1186/s13063-018-2658-8) contains supplementary material, which is available to authorized users.
Plain English summary
Including patient and public involvement (PPI) in health research is thought to improve research but it is hard to be clear exactly how it helps. This is because PPI takes many forms, is sometimes only token and is not always reported clearly. This makes it difficult to combine the evidence so that clear conclusions can be reached about the ingredients of successful PPI and what PPI achieves. Previous research that has tried to combine the evidence has led to several guidelines for researchers to use in setting up and reporting PPI.
This paper was written jointly by researchers and PPI contributors as a reflection on our experiences. The aim was to add to the evidence, by giving detail about the use of PPI in a large randomised controlled trial and the effect it had. We were guided by published PPI reporting guidelines. The effects on the trial are shown in a table of changes made because of suggestions from the PPI group. A survey was used to ask PPI contributors and researchers about their experience and effects they had noticed. Three themes were noted: impact on the trial, the effect of involvement on individual researchers and group members, and group environment. The PPI work affected the trial in many ways, including changes to documents used in the trial and advice on qualitative data collection methods and analysis. Individuals reported positive effects, including enjoying being in the group, gaining confidence, and learning how to share views.
Abstract
Background
Patient and public involvement (PPI) is believed to enhance health care delivery research, and is widely required in research proposals. Detailed, standardised reporting of PPI is needed so that strategies to implement more than token PPI that achieves impact can be identified, properly evaluated and reproduced. Impact includes effects on the research, PPI contributors and researchers. Using contributor and researcher perspectives and drawing on published guidelines for reporting PPI, we aimed to reflect on our experience and contribute evidence relevant to two important questions: ‘What difference does PPI make?’ and ‘What’s the best way to do it?’
Methods
Fourteen people living with multiple long-term conditions (multimorbidity) were PPI contributors to a randomised controlled trial to improve care for people with multimorbidity. Meetings took place approximately four times a year throughout the trial, beginning at grant application stage. Meeting notes were recorded and a log of PPI involvement was kept. At the end of the trial, seven PPI contributors and four researchers completed free-text questionnaires about their experience of PPI involvement and their perception of PPI impact. The responses were analysed thematically by two PPI contributors and one researcher. The PPI group proposed writing this report, which was co-authored by three PPI contributors and two researchers.
Results
Meeting attendance averaged nine PPI contributors and three to four researchers. The involvement log and meeting notes recorded a wide range of activities and impact including changes to participant documentation, advice on qualitative data collection, contribution to data analysis and dissemination advice. Three themes were identified from the questionnaires: impact on the study, including keeping the research grounded in patient experience; impact on individuals, including learning from group diversity and feeling valued; and an environment that facilitated participation. The size of the group influenced impact. Researchers and PPI contributors described a rewarding interaction that benefitted them and the research.
Conclusions
PPI was wide-ranging and had impact on the trial, contributors and researchers. The group environment facilitated involvement. Feedback and group interactions benefitted individuals. The insights gained from this study will postitively influence the researchers’ and contributors’ future involvement with PPI.
Introduction:
Pragmatic randomized controlled trials (RCTs) mimic usual clinical practice and they are critical to inform decision-making by patients, clinicians and policy-makers in real-world settings. Pragmatic RCTs assess effectiveness of available medicines, while explanatory RCTs assess efficacy of investigational medicines. Explanatory and pragmatic are the extremes of a continuum. This debate article seeks to evaluate and provide recommendation on how to characterize pragmatic RCTs in light of the current landscape of RCTs. It is supported by findings from a PubMed search conducted in August 2017, which retrieved 615 RCTs self-labeled in their titles as "pragmatic" or "naturalistic". We focused on 89 of these trials that assessed medicines (drugs or biologics).
Discussion:
36% of these 89 trials were placebo-controlled, performed before licensing of the medicine, or done in a single-center. In our opinion, such RCTs overtly deviate from usual care and pragmatism. It follows, that the use of the term 'pragmatic' to describe them, conveys a misleading message to patients and clinicians. Furthermore, many other trials among the 615 coined as 'pragmatic' and assessing other types of intervention are plausibly not very pragmatic; however, this is impossible for a reader to tell without access to the full protocol and insider knowledge of the trial conduct. The degree of pragmatism should be evaluated by the trial investigators themselves using the PRECIS-2 tool, a tool that comprises 9 domains, each scored from 1 (very explanatory) to 5 (very pragmatic).
Conclusions:
To allow for a more appropriate characterization of the degree of pragmatism in clinical research, submissions of RCTs to funders, research ethics committees and to peer-reviewed journals should include a PRECIS-2 tool assessment done by the trial investigators. Clarity and accuracy on the extent to which a RCT is pragmatic will help understand how much it is relevant to real-world practice.
Background:
Recruiting participants to trials can be extremely difficult. Identifying strategies that improve trial recruitment would benefit both trialists and health research.
Objectives:
To quantify the effects of strategies for improving recruitment of participants to randomised trials. A secondary objective is to assess the evidence for the effect of the research setting (e.g. primary care versus secondary care) on recruitment.
Search methods:
We searched the Cochrane Methodology Review Group Specialised Register (CMR) in the Cochrane Library (July 2012, searched 11 February 2015); MEDLINE and MEDLINE In Process (OVID) (1946 to 10 February 2015); Embase (OVID) (1996 to 2015 Week 06); Science Citation Index & Social Science Citation Index (ISI) (2009 to 11 February 2015) and ERIC (EBSCO) (2009 to 11 February 2015).
Selection criteria:
Randomised and quasi-randomised trials of methods to increase recruitment to randomised trials. This includes non-healthcare studies and studies recruiting to hypothetical trials. We excluded studies aiming to increase response rates to questionnaires or trial retention and those evaluating incentives and disincentives for clinicians to recruit participants.
Data collection and analysis:
We extracted data on: the method evaluated; country in which the study was carried out; nature of the population; nature of the study setting; nature of the study to be recruited into; randomisation or quasi-randomisation method; and numbers and proportions in each intervention group. We used a risk difference to estimate the absolute improvement and the 95% confidence interval (CI) to describe the effect in individual trials. We assessed heterogeneity between trial results. We used GRADE to judge the certainty we had in the evidence coming from each comparison.
Main results:
We identified 68 eligible trials (24 new to this update) with more than 74,000 participants. There were 63 studies involving interventions aimed directly at trial participants, while five evaluated interventions aimed at people recruiting participants. All studies were in health care.We found 72 comparisons, but just three are supported by high-certainty evidence according to GRADE.1. Open trials rather than blinded, placebo trials. The absolute improvement was 10% (95% CI 7% to 13%).2. Telephone reminders to people who do not respond to a postal invitation. The absolute improvement was 6% (95% CI 3% to 9%). This result applies to trials that have low underlying recruitment. We are less certain for trials that start out with moderately good recruitment (i.e. over 10%).3. Using a particular, bespoke, user-testing approach to develop participant information leaflets. This method involved spending a lot of time working with the target population for recruitment to decide on the content, format and appearance of the participant information leaflet. This made little or no difference to recruitment: absolute improvement was 1% (95% CI -1% to 3%).We had moderate-certainty evidence for eight other comparisons; our confidence was reduced for most of these because the results came from a single study. Three of the methods were changes to trial management, three were changes to how potential participants received information, one was aimed at recruiters, and the last was a test of financial incentives. All of these comparisons would benefit from other researchers replicating the evaluation. There were no evaluations in paediatric trials.We had much less confidence in the other 61 comparisons because the studies had design flaws, were single studies, had very uncertain results or were hypothetical (mock) trials rather than real ones.
Authors' conclusions:
The literature on interventions to improve recruitment to trials has plenty of variety but little depth. Only 3 of 72 comparisons are supported by high-certainty evidence according to GRADE: having an open trial and using telephone reminders to non-responders to postal interventions both increase recruitment; a specialised way of developing participant information leaflets had little or no effect. The methodology research community should improve the evidence base by replicating evaluations of existing strategies, rather than developing and testing new ones.
Aims:
Pragmatic randomized clinical trials (pRCTs) collect data that have the potential to significantly improve medical care. However, these trials may be undermined by the requirement to obtain written informed consent, which can decrease accrual and increase selection bias. Recent data suggest that the majority of the U.S. public endorses written consent for low risk pRCTs. This study was designed to assess whether this view is specific to the US.
Methods:
Cross-sectional, probability-based survey, with a 2x2 factorial design, assessing support for written informed consent versus verbal consent or general notification for two low-risk pRCTs in hypertension, one comparing 2 drugs with similar risk/benefit profiles and the other comparing the same drug being taken in the morning or at night. The primary outcome measures were respondents' personal preference and hypothetical recommendation to a research ethics committee regarding the use of written informed consent versus the alternatives.
Results:
2008 adults sampled from a probability-based online panel responded to the web-based survey conducted in May 2016 (response rate: 61%). Overall, 77% of respondents endorsed written consent. In both scenarios, the alternative of general notification received significantly more support (28.7%-37.1%) than the alternative of verbal consent (12.7%-14.0%) (p = 0.001). 40% of respondents preferred and/or recommended general notification rather than written consent.
Conclusions:
This resuts suggests that, rather than attempting to waive written consent, current pRCTs should focus on developing ways to implement written consent that provide sufficient information without undermining recruitment or increasing selection bias. The finding that some 40% of respondents endorsed general notification over written consent raises the posibility that, with educational efforts, a majority of Spaniards might accept general notification for low risk pRCTs.
Objectives:
To systematically assess registration details of ongoing randomised controlled trials (RCTs) targeting 10 common chronic conditions and registered at ClinicalTrials.gov and to determine the prevalence of (1) trial records excluding patients with concomitant chronic condition(s) and (2) those specifically targeting patients with concomitant chronic conditions.
Design:
Systematic review of trial registration records.
Data sources:
ClinicalTrials.gov register.
Study selection:
All ongoing RCTs registered from 1 January 2014 to 31 January 2015 that assessed an intervention targeting adults with coronary heart disease (CHD), hypertension, heart failure, stroke/transient ischaemic attack, atrial fibrillation, type 2 diabetes, chronic obstructive pulmonary disease, painful condition, depression and dementia with a target sample size ≥100.
Data extraction:
From the trial registration records, 2 researchers independently recorded the trial characteristics and the number of exclusion criteria and determined whether patients with concomitant chronic conditions were excluded or specifically targeted.
Results:
Among 319 ongoing RCTs, despite the high prevalence of the concomitant chronic conditions, patients with these conditions were excluded in 251 trials (79%). For example, although 91% of patients with CHD had a concomitant chronic condition, 69% of trials targeting such patients excluded patients with concomitant chronic condition(s). When considering the co-occurrence of 2 chronic conditions, 31% of patients with chronic pain also had depression, but 58% of the trials targeting patients with chronic pain excluded patients with depression. Only 37 trials (12%) assessed interventions specifically targeting patients with concomitant chronic conditions; 31 (84%) excluded patients with concomitant chronic condition(s).
Conclusions:
Despite widespread multimorbidity, more than three-quarters of ongoing trials assessing interventions for patients with chronic conditions excluded patients with concomitant chronic conditions.
Clinical trials represent the best source of evidence on which to base treatment decisions. For such evidence to be utilized meaningfully, however, it is essential that results are interpreted correctly. This requires a good understanding of strengths and weaknesses of the adopted design, the clinical relevance of the outcome measures, and the many factors that could affect such outcomes. As a general rule, uncontrolled studies tend to provide misleading evidence as a result of the impact of confounders such as regression to the mean, patient-related bias, and observer bias. On the other hand, although randomized controlled trials (RCTs) are qualitatively superior, aspects of their execution may still decrease their validity. Bias and decreased validity in RCTs may occur by chance alone (for example, treatment groups may not necessarily be balanced for important variables despite randomization) or because of specific features of the trial design. In the case of industry-driven studies, bias often influences the outcome in favor of the sponsor's product. Factors that need to be carefully scrutinized include (1) the purpose for which the trial is conducted; (2) potential bias due to unblinding or lack of blinding; (3) the appropriateness of the control group; (4) the power of the study in detecting clinically relevant differences; (5) the extent to which eligibility criteria could affect outcomes and be representative of routine clinical practice; (6) whether the treatments being compared are used optimally in terms of dosing, duration of treatment, and other variables; (7) the appropriateness of the statistical comparisons; (8) the clinical relevance of the outcome measures and whether all key outcome information is reported (for example, responder rates in completers); and (9) potential bias in the way results are presented and discussed. This article discusses each of these aspects and illustrates the discussion with examples taken from published antiepileptic drug trials.
Coronary artery disease (CAD) is the underlying cause of death in one out of seven deaths in the USA. Aspirin therapy has been proven to decrease mortality and major adverse cardiovascular events in patients with CAD. Despite a plethora of studies showing the benefit of aspirin in secondary prevention of cardiovascular events, debate remains regarding the optimal dose due to relatively small studies that had disparate results when comparing patients taking different aspirin dosages. More recently, aspirin dosing has been thoroughly studied in the CAD population with concomitant therapy (such as P2Y12 inhibitors); however, patients in these studies were not randomized to aspirin dose. No randomized controlled trial has directly measured aspirin dosages in a population of patients with established coronary artery disease. In 2015, the Patient-Centered Outcomes Research Institute (PCORI) developed a network, called PCORnet, that includes patient-powered research networks (PPRN) and clinical data research networks (CDRN). The main objective of PCORnet is to conduct widely generalizable observational studies and clinical trials (including large, pragmatic clinical trials) at a low cost. The first clinical trial, called Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-term Effectiveness (ADAPTABLE), will randomly assign 20,000 subjects with established coronary heart disease to either low dose (81 mg) or high dose (325 mg) and should be able to finally answer which dosage of aspirin is best for patients with established cardiovascular disease.
Background/aims:
In the context of research on medical practices, which includes comparative effectiveness research and pragmatic clinical trials, empirical studies have begun to raise questions about the extent to which institutional review boards' interpretations and applications of research regulations align with patients' values. To better understand the similarities and differences between these stakeholder groups, we compare and contrast two surveys: one of institutional review board professionals and one of patients, which examine views on consent for research on medical practices.
Methods:
We conducted online surveys of two target populations between July 2014 and March 2015. We surveyed 601 human subjects research professionals out of 1500 randomly selected from the Public Responsibility in Medicine and Research membership list (40.1% response rate), limiting analysis to 537 respondents who reported having had institutional review board experience. We also surveyed 120 adult patients out of 225 approached at subspecialty clinics in Spokane, Washington (53.3% response rate). Our survey questions probed attitudes about consent in the context of research on medical practices using medical record review and randomization. The patient survey included three embedded animated videos to explain these concepts.
Results:
A majority of institutional review board professionals distinguished between consent preferences for medical record review and randomization, ranked clinicians as the least preferred person to obtain participant consent (54.6%), and viewed written or verbal permission as the minimum acceptable consent approach for research on medical practices using randomization (87.3%). In contrast, most patients had similar consent preferences for research on medical practices using randomization and medical record review, most preferred to have consent conversations with their doctors rather than with researchers for studies using randomization (72.6%) and medical record review (67.0%), and only a few preferred to see research involving randomization (16.8%) or medical record review (13.8%) not take place if obtaining written or verbal permission would make the research too difficult to conduct. Limitations of our post hoc analysis include differences in framing, structure, and language between the two surveys and possible response bias.
Conclusion:
Our findings highlight a need to identify appropriate ways to integrate patient preferences into prevailing regulatory interpretations as institutional review boards increasingly apply research regulations in the context of research on medical practices. Dialogue between institutional review boards and research participants will be an important part of this process and should inform future regulatory guidance.
Objective To assess differences in estimated treatment effects for mortality between observational studies with routinely collected health data (RCD; that are published before trials are available) and subsequent evidence from randomized controlled trials on the same clinical question.
Design Meta-epidemiological survey.
Data sources PubMed searched up to November 2014.
Methods Eligible RCD studies were published up to 2010 that used propensity scores to address confounding bias and reported comparative effects of interventions for mortality. The analysis included only RCD studies conducted before any trial was published on the same topic. The direction of treatment effects, confidence intervals, and effect sizes (odds ratios) were compared between RCD studies and randomized controlled trials. The relative odds ratio (that is, the summary odds ratio of trial(s) divided by the RCD study estimate) and the summary relative odds ratio were calculated across all pairs of RCD studies and trials. A summary relative odds ratio greater than one indicates that RCD studies gave more favorable mortality results.
Results The evaluation included 16 eligible RCD studies, and 36 subsequent published randomized controlled trials investigating the same clinical questions (with 17 275 patients and 835 deaths). Trials were published a median of three years after the corresponding RCD study. For five (31%) of the 16 clinical questions, the direction of treatment effects differed between RCD studies and trials. Confidence intervals in nine (56%) RCD studies did not include the RCT effect estimate. Overall, RCD studies showed significantly more favorable mortality estimates by 31% than subsequent trials (summary relative odds ratio 1.31 (95% confidence interval 1.03 to 1.65; I²=0%)).
Conclusions Studies of routinely collected health data could give different answers from subsequent randomized controlled trials on the same clinical questions, and may substantially overestimate treatment effects. Caution is needed to prevent misguided clinical decision making.
Institutional review boards, which are charged with overseeing research, must classify the riskiness of proposed research according to a federal regulation known as the Common Rule (45 CFR 46, Subpart A) and by regulations governing the US Food and Drug Administration codified in 21 CFR 50. If an institutional review board determines that a clinical trial constitutes "minimal risk," there are important practical implications: the institutional review board may then allow a waiver or alteration of the informed consent process; the study may be carried out in certain vulnerable populations; or the study may be reviewed by institutional review boards using an expedited process. However, it is unclear how institutional review boards should assess the risk levels of pragmatic clinical trials. Such trials typically compare existing, widely used medical therapies or interventions in the setting of routine clinical practice. Some of the therapies may be considered risky of themselves but the study comparing them may or may not add to that pre-existing level of risk. In this article, we examine the common interpretations of research regulations regarding minimal-risk classifications and suggest that they are marked by a high degree of variability and confusion, which in turn may ultimately harm patients by delaying or hindering potentially beneficial research. We advocate for a clear differentiation between the risks associated with a given therapy and the incremental risk incurred during research evaluating those therapies as a basic principle for evaluating the risk of a pragmatic clinical trial. We then examine two pragmatic clinical trials and consider how various factors including clinical equipoise, practice variation, research methods such as cluster randomization, and patients' perspectives may contribute to current and evolving concepts of minimal-risk determinations, and how this understanding in turn affects the design and conduct of pragmatic clinical trials.
Significant debate surrounds the issue of whether written consent is necessary for pragmatic randomized, controlled trials (RCTs) with low risk.
To assess the U.S. public's views on alternatives to written consent for low-risk pragmatic RCTs.
National experimental survey (2 × 2 factorial design) examining support for written consent versus general notification or verbal consent in 2 research scenarios.
Web-based survey conducted in December 2014.
2130 U.S. adults sampled from a nationally representative, probability-based online panel (response rate, 64.0%).
Respondent's recommendation to an ethics review board and personal preference as a potential participant for how to obtain consent or notification in the 2 research scenarios.
A majority of respondents in each of the 4 groups (range, 60.3% to 71.5%) recommended written informed consent, and personal preferences were generally in line with that advice. Most (78.9%) believed that the pragmatic RCTs did not pose additional risks, but 62.5% of these respondents would still recommend written consent. In contrast, a substantial minority in all groups (28.5% to 39.7%) recommended the alternative option (general notification or verbal consent) over written consent.
Framing effects could have impacted respondents' attitudes, and nonrespondents may have differed in levels of trust toward research or health care institutions.
A majority of the public favored written informed consent over the most widely advocated alternatives for low-risk pragmatic RCTs; however, a substantial minority favored general notification or verbal consent.
Time-sharing Experiments for the Social Sciences and Intramural Research Program of the National Institutes of Health Clinical Center.
PRECIS is a tool to help trialists make design decisions consistent with the intended purpose of their trial. This paper gives guidance on how to use an improved, validated version, PRECIS-2, which has been developed with the help of over 80 international trialists, clinicians, and policymakers. Keeping the original simple wheel format, PRECIS-2 has nine domains-eligibility criteria, recruitment, setting, organisation, flexibility (delivery), flexibility (adherence), follow-up, primary outcome, and primary analysis-scored from 1 (very explanatory) to 5 (very pragmatic) to facilitate domain discussion and consensus. It is hoped PRECIS-2 will be valuable in supporting the explicit matching of design decisions to how the trial results are intended to be used
Randomized clinical trials provide the foundation of clinical evidence to guide physicians in their selection of treatment options. Importantly, randomization is the only reliable method to control for confounding factors when comparing treatment groups. However, randomized trials have limitations, including the increasingly prohibitive costs of conducting adequately powered studies. Local and national regulatory requirements, delays in approval, and unnecessary trial processes have led to increased costs and decreased efficiency. Another limitation is that clinical trials involve selected patients who are treated according to protocols that might not represent real-world practice. A possible solution is registry-based randomized clinical trials. By including a randomization module in a large inclusive clinical registry with unselected consecutive enrolment, the advantages of a prospective randomized trial can be combined with the strengths of a large-scale all-comers clinical registry. We believe that prospective registry-based randomized clinical trials are a powerful tool for conducting studies efficiently and cost-effectively.
Objective To conduct a systematic review and meta-analysis to assess the level of participants’ understanding of all components of informed consent in clinical trials.
Methods Relevant studies were identified by a search of PubMed, Scopus, Google Scholar, and manual approach with data up to October, 2013. The event rate was pooled using a random-effects model.
Findings One hundred and three studies evaluating 135 populations were included. Correct understanding of the freedom to withdraw from the study at any time, nature of study, voluntary nature of participation, understanding of benefit, purpose, awareness of potential risks and side effects, confidentiality, alternative treatment if withdrawn from the study, recognizing the comparator (treatment or placebo), and no therapeutic misconception, was noted in 75.8% (95% CI: 70.6-80.3), 74.7% (68.8-79.8), 74.7% (67.9-80.5), 74.0% (65.0-81.3), 69.6% (63.5-75.1), 67.0% (57.4-75.4), 66.2% (55.3-75.7), 64.1% (53.7-73.4), 62.9% (45.5-77.5), and 62.4% (50.1-73.2), respectively. The figures for comprehension of randomization, comprehension of placebo, and naming at least one risk were 52.1% (41.3-62.7), 53.3% (38.4-67.6), and 54.9% (43.3-65.0), respectively. Subgroup and meta-regression analyses identified some co-variates significantly affecting the results and revealed no change in the understanding of all components over a 30 – year period.
Conclusion: Mixed levels of correct understanding of components of informed consent were recorded in this meta-analysis. There is still much to be done to assist research participants achieve a comprehensive and complete understanding of informed consent, so that meaningful decision-making can be made and their best interest is protected.
Background:
Pragmatic trials compare the effects of different decisions in usual clinical practice.
Objectives:
To develop and evaluate methods to implement simple pragmatic trials using routinely collected electronic health records (EHRs) and recruiting patients at the point of care; to identify the barriers and facilitators for general practitioners (GPs) and patients and the experiences of trial participants.
Design:
Two exemplar randomised trials (Retropro and eLung) with qualitative evaluations.
Setting:
Four hundred and fifty-nine English and Scottish general practices contributing EHRs to a research database, of which 17 participated in the trials.
Participants:
Retropro aimed to recruit 300 patients with hypercholesterolaemia and high cardiovascular risk and eLung aimed to recruit 150 patients with a chronic obstructive pulmonary disease exacerbation.
Interventions:
Retropro randomised between simvastatin and atorvastatin and eLung between immediate antibiotics and deferred or non-use. eLung recruited during an unscheduled consultation using EHR flagging.
Main outcome measure:
Successful trial completion with implementation of information technology (IT) system for flagging and data processing and documentation of operational and scientific experiences.
Data sources:
EHR research database.
Results:
The governance approval process took over 3 years. A total of 58.8% of the practices (n = 270) expressed interest in participating. The number of interested practices dropped substantially with each stage of the governance process. In Retropro, 6.5% of the practices (n = 30) were eventually approved and 3.7% (n = 17) recruited patients; in eLung, these numbers were 6.8% (n = 31) and 1.3% (n = 6) respectively. Retropro successfully completed recruitment (301 patients) whereas eLung recruited 31 patients. Retropro recruited 20.6% of all statin starters in recruiting practices and 1.1% in the EHR database; the comparable numbers for eLung were 32.3% and 0.9% respectively. The IT system allowed for complex eligibility criteria with central on and off control of recruitment and flagging at a practice. Good Clinical Practice guidelines, governance and consent procedures were found to have substantially affected the intended simple nature of the trials. One qualitative study of 13 clinicians found that clinicians were generally positive about the principle of computerised trial recruitment (flagging during consultation). However, trials which did not include patients with acute illness were favoured. The second qualitative process evaluation interviewed 27 GPs about their actual experiences, including declining, recruiting and non-recruiting GPs. Opportunistic patient recruitment during a routine GP consultation was found to be the most controversial element. The actual experiences of recruiting patients during unscheduled consultation were generally more positive than the hypothetical views of GPs. Several of the recruiting GPs reported the process took 5 minutes and was straightforward and feasible on most occasions. Almost all GPs expressed their strong support for the use of EHRs for trials. Ten eLung participants were interviewed, all of whom considered it acceptable to be recruited during a consultation and to use EHRs for trials.
Conclusions:
EHR point-of-care trials are feasible, although the recruitment of clinicians is a major challenge owing to the complexity of trial approvals. These trials will provide substantial evidence on clinical effectiveness only if trial interventions and participating clinicians and patients are typical of usual clinical care and trials are simple to initiate and conduct. Recommendations for research include the development of evidence and implementation of risk proportionality in trial governance and conduct.
Trial registration:
Current Controlled Trials ISRCTN33113202 and ISRCTN72035428.
Funding:
This project was funded by the NIHR Health Technology Assessment programme and the Wellcome Trust and will be published in full in Health Technology Assessment; Vol. 18, No. 43. See the NIHR Journals Library website for further project information.
The authors argue that informed consent is ethically necessary in pragmatic trials that randomly assign individual patients to treatments, even when treatment options are within the standard of care. They propose integration of a streamlined consent process into routine practice.
Informed consent is regarded as a cornerstone of ethical healthcare research and is a requirement for most clinical research studies. Guidelines suggest that prospective randomised controlled trial (RCT) participants should understand a basic amount of key information about the RCTs they are being asked to enrol in in order to provide valid informed consent. This information is usually provided to potential participants in a patient information leaflet (PIL). There is evidence that some trial participants fail to understand key components of trial processes or rationale. As such, the existing approach to information provision for potential RCT participants may not be optimal. Decision aids have been used for a variety of treatment and screening decisions to improve knowledge, but focus more on overall decision quality, and may be helpful to those making decisions about participating in an RCT. We investigated the feasibility of using a tool to identify which items recommended for good quality decision making are present in UK PILs.
PILs were sampled from UK registered Clinical Trials Unit websites across a range of clinical areas. The evaluation tool, which is based on standards for supporting decision making, was applied to 20 PILs. Two researchers independently rated each PIL using the tool. In addition, word count and readability were assessed.
PILs scored poorly on the evaluation tool with the majority of leaflets scoring less than 50%. Specifically, presenting probabilities, clarifying and expressing values and structured guidance in deliberation and communication sub-sections scored consistently poorly. Tool score was associated with word count (r = 0.802, P <0.01); there was no association between score and readability (r = -0.372, P = 0.106).
The tool was feasible to use to evaluate PILs for UK RCTs. PILs did not meet current standards of information to support good quality decision making. Writers of information leaflets could use the evaluation tool as a framework during PIL development to help ensure that items are included which promote and support more informed decisions about trial participation. Further research is required to evaluate the inclusion of such information.
After identification of an important research question and selection of an appropriate study design, waste can arise from the regulation, governance, and management of biomedical research. Obtaining regulatory and governance approval has become increasingly burdensome and disproportionate to the conceivable risks to research participants. Regulation and governance involve interventions that are assumed to be justified in the interests of patients and the public, but they can actually compromise these interests. Inefficient management of the procedural conduct of research is wasteful, especially if it results in poor recruitment and retention of participants in well designed studies addressing important questions. These sources of waste can be minimised if the following four recommendations are addressed. First, regulators should use their influence to reduce other causes of waste and inefficiency in research. Second, regulators and policy makers should work with researchers, patients, and health professionals to streamline and harmonise the laws, regulations, guidelines, and processes that govern whether and how research can be done, and ensure that they are proportionate to the plausible risks associated with the research. Third, researchers and research managers should increase the efficiency of recruitment, retention, data monitoring, and data sharing in research through use of research designs known to reduce inefficiencies, and further research should be done to learn how efficiency can be increased. Finally, everyone, particularly those responsible for health-care systems, should promote integration of research into everyday clinical practice. Regulators and researchers should monitor adherence to each of these recommendations and publish metrics.
Pragmatic randomised controlled trials are often used in primary care to evaluate the effect of a treatment strategy. In these trials it is difficult to achieve both high internal validity and high generalisability. This article will discuss several methodological challenges in designing and conducting a pragmatic primary care based randomised controlled trial, based on our experiences in the DIAMOND-study and will discuss the rationale behind the choices we made. From the successes as well as the problems we experienced the quality of future pragmatic trials may benefit.
The first challenge concerned choosing the clinically most relevant interventions to compare and enable blinded comparison, since two interventions had very different appearances. By adding treatment steps to one treatment arm and adding placebo to both treatment arms both internal and external validity were optimized. Nevertheless, although blinding is essential for a high internal validity, it should be warily considered in a pragmatic trial because it decreases external validity. Choosing and recruiting a representative selection of participants was the second challenge. We succeeded in retrieving a representative relatively large patient sample by carefully choosing (few) inclusion and exclusion criteria, by random selection, by paying much attention to participant recruitment and taking the participant's reasons to participate into account. Good and regular contact with the GPs and patients was to our opinion essential. The third challenge was to choose the primary outcome, which needed to reflect effectiveness of the treatment in every day practice. We also designed our protocol to follow every day practice as much as possible, although standardized treatment is usually preferred in trials. The aim of this was our fourth challenge: to limit the number of protocol deviations and increase external validity.
It is challenging to design and conduct a pragmatic trial. Thanks to thorough preparation, we were able to collect highly valid data. To our opinion, a critical deliberation of where on the pragmatic--explanatory spectrum you want your trial to be on forehand, in combination with consulting publications especially on patient recruitment procedures, has been helpful in conducting a successful trial.
Vitamin K antagonists (VKAs) are effective antithrombotic agents and advocated in guidelines for the management of cardiovascular disease. However, in the trials underlying these guidelines, many patients were excluded. We performed a case-control study in 993 patients receiving VKAs, who required hospitalization for bleeding, and contrasted them to 993 matched control patients on VKAs, who were hospitalized for an infection. We analyzed whether patients and controls would have been eligible for the clinical trials on which their indication for anticoagulation was based, and estimated the risk of hemorrhage associated with exclusion criteria as applied in those trials. Approximately one quarter (23% [95% CI: 21%-26%]) of controls had one or more exclusion criteria for the trials, supporting the use of anticoagulation for their condition. Forty percent of patients presenting with bleeding had one or more exclusion criteria (95% CI: 37%-43%). Having one exclusion criterion resulted in a 2.9-fold increased risk of bleeding (95% CI: 2.2-3.9), and this risk increased sharply when more than one exclusion criterion was present. VKAs are often prescribed to patients who would not have qualified for clinical trials, and in these patients a careful consideration should be made regarding the expected efficacy and the risk of bleeding.
Pragmatic randomized clinical trials (pRCTs) are considered a highly valuable design, providing evidence for clinical decisions in real-world settings.¹ The conduct and setting of pRCTs mimic the usual practice of care while trying to maintain the internal validity of randomization,² and they are becoming increasingly common.³ Their perceived and documented strengths and weaknesses need to be empirically studied beyond the theoretical expectations. In this study, we assessed the main characteristics among numerous recently published RCTs tagged as pragmatic, how the authors supported their claims for pragmatism, and whether major limitations stemming from the pragmatic design were noted in the articles.
After identifi cation of an important research question and selection of an appropriate study design, waste can arise from the regulation, governance, and management of biomedical research. Obtaining regulatory and governance approval has become increasingly burdensome and disproportionate to the conceivable risks to research participants. Regulation and governance involve interventions that are assumed to be justifi ed in the interests of patients and the public, but they can actually compromise these interests. Ineffi cient management of the procedural conduct of research is wasteful, especially if it results in poor recruitment and retention of participants in well designed studies addressing important questions. These sources of waste can be minimised if the following four recommendations are addressed. First, regulators should use their infl uence to reduce other causes of waste and ineffi ciency in research. Second, regulators and policy makers should work with researchers, patients, and health professionals to streamline and harmonise the laws, regulations, guidelines, and processes that govern whether and how research can be done, and ensure that they are proportionate to the plausible risks associated with the research. Third, researchers and research managers should increase the effi ciency of recruitment, retention, data monitoring, and data sharing in research through use of research designs known to reduce ineffi ciencies, and further research should be done to learn how effi ciency can be increased. Finally, everyone, particularly those responsible for health-care systems, should promote integration of research into everyday clinical practice. Regulators and researchers should monitor adherence to each of these recommendations and publish metrics.
Background
Individual informed consent from all participants is required for most randomized clinical trials (RCTs). However, some exceptions—for example, emergency research—are widely accepted.
Methods
The literature on various approaches to randomization without consent (RWOC) has never been systematically reviewed. Our goal was to provide a survey and narrative synthesis of published proposals for RWOC. We focused on proposals to randomize at least some participants in a study without first obtaining consent to randomization. This definition included studies that omitted informed consent entirely, omitted informed consent for selected patients (e.g., the control group), obtained informed consent to research but not to randomization, or only obtained informed consent to randomization after random assignment had already occurred. It omitted oral and staged consent processes that still obtain consent to randomization from all participants before randomization occurs.
Results
We identified ten different proposals for RWOC: two variants of cluster randomization, two variants of the Zelen design, consent to postponed information, two-stage randomized consent, cohort multiple RCT, emergency research, prompted optional randomization trials, and low-risk pragmatic RCTs without consent.
Conclusion
Of all designs discussed here, only cluster randomized designs and emergency research are routinely used, with the justification that informed consent is infeasible in those settings. Other designs have raised concerns that they do not appropriately respect patient autonomy. Recent proposals have emphasized the importance for RWOC of demonstrating such respect through systematic patient engagement, transparency, and accountability, potentially in the context of learning health care systems.
Using the best quality of clinical research evidence is essential for choosing the right treatment for patients. How to identify the best research evidence is, however, difficult. In this narrative review we summarise these threats and describe how to minimise them. Pertinent literature was considered through literature searches combined with personal files. Treatments should generally not be chosen based only on evidence from observational studies or single randomised clinical trials. Systematic reviews with meta-analysis of all identifiable randomised clinical trials with Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment represent the highest level of evidence. Even though systematic reviews are trust worthier than other types of evidence, all levels of the evidence hierarchy are under threats from systematic errors (bias); design errors (abuse of surrogate outcomes, composite outcomes, etc.); and random errors (play of chance). Clinical research infrastructures may help in providing larger and better conducted trials. Trial Sequential Analysis may help in deciding when there is sufficient evidence in meta-analyses. If threats to the validity of clinical research are carefully considered and minimised, research results will be more valid and this will benefit patients and heath care systems.
Reporting adverse events (AEs) and serious AEs (SAEs) are practical steps to ensure safety for volunteers and patients in medical research involving medications, treatments and devices. However, the burden and cost of reporting should be proportionate with the public health benefit of this information. Unfortunately, in Australia there is clear evidence of ever-increasing requirements from sponsors and ethics committees to report AEs and SAEs unnecessarily, leading to a decrease in the uptake of research, particularly less well funded investigator-initiated trials. We believe that individual AE reports to ethics committees serve no useful purpose, because in most cases the study group identity (drug exposure) is not known in studies with blinded treatment arms and their value is limited. Pragmatic, investigator-initiated Phase IV clinical trials of post-marketed drugs or devices are needed to understand their role in everyday clinical practice. In this setting, the workload and costs of systematic, complete reporting of all AEs and SAEs (independent of whether these are treatment-related) is wasteful, and mostly unnecessary. A trial data safety and monitoring committee is in the unique position of being able to review safety information according to the blinded treatment arms of the study. This enables safety data to be analysed appropriately and a summary report provided to the trial steering committee, principal investigators and the relevant ethics committees in a meaningful way. Defined trial endpoints do not need to be reported as safety events (because they are being properly monitored and analysed).
Pragmatic clinical trials can help answer questions of comparative effectiveness for interventions routinely used in medical practice. Pragmatic clinical trials may examine outcomes of one or more marketed medical products, and they are heterogeneous in design and risk. The Food and Drug Administration is charged with protecting the rights, safety, and welfare of individuals enrolled in clinical investigations, as well as assuring the integrity of the data upon which approval of medical products is made. The Food and Drug Administration has broad jurisdiction over drugs and medical devices (whether or not they are approved for marketing), and as such, clinical investigations of these products are subject to applicable Food and Drug Administration regulations. While many pragmatic clinical trials will meet the criteria for an exemption from the requirements for an investigational new drug application or investigational device exemption, in general, all clinical investigations of medical products that fall under Food and Drug Administration jurisdiction must adhere to regulations for informed consent and review by an institutional review board. We are concerned that current Food and Drug Administration requirements for obtaining individual informed consent may deter or delay the conduct of pragmatic clinical trials intended to develop reliable evidence of comparative safety and effectiveness of approved medical products that are regulated by the Food and Drug Administration. Under current regulations, there are no described mechanisms to alter or waive informed consent to make it less burdensome or more practicable for low-risk pragmatic clinical trials. We recommend that the Food and Drug Administration establish a risk-based approach to obtaining informed consent in pragmatic clinical trials that would facilitate the conduct of pragmatic clinical trials without compromising the protection of enrolled individuals or the integrity of the resulting data.
There are situations in which the requirement to obtain conventional written informed consent can impose significant or even insurmountable barriers to conducting pragmatic clinical research, including some comparative effectiveness studies and cluster-randomized trials. Although certain federal regulations governing research in the United States (45 CFR 46) define circumstances in which any of the required elements may be waived, the same standards apply regardless of whether any single element is to be waived or whether consent is to be waived in its entirety. Using the same threshold for a partial or complete waiver limits the options available to institutional review boards as they seek to optimize a consent process. In this article, we argue that new standards are necessary in order to enable important pragmatic clinical research while at the same time protecting patients' rights and interests.
In the United States, doctors generally develop new cancer chemotherapy for
children by testing innovative chemotherapy protocols against existing
protocols in prospective randomized trials. In the Netherlands, children with
leukemia are treated by protocols that are agreed upon by the Dutch
Childhood Oncology Group. Periodically, the Dutch Childhood Oncology
Group revises its protocols. Sometimes, these revisions are categorized as
research, sometimes as treatment. In this Ethics Rounds, we analyze whether
enrollment in a new protocol ought to be considered research and, if so, we
discuss the implications of that designation. Our discussion highlights the
different ways different countries approach complex issues of research
ethics.
The U.S. Office for Human Research Protections has proposed that end points of randomized trials comparing the effectiveness of standard medical practices are risks of research that would require disclosure and written informed consent, but data are lacking on the views of potential participants.
To assess attitudes of U.S. adults about risks and preferences for notification and consent for research on medical practices.
Cross-sectional survey conducted in August 2014.
Web-based questionnaire.
1095 U.S. adults sampled from an online panel (n = 805) and an online convenience river sample (n = 290).
Attitudes toward risk, informed consent, and willingness to participate in 3 research scenarios involving medical record review and randomization of usual medical practices.
97% of respondents agreed that health systems should evaluate standard treatments. Most wanted to be asked for permission to participate in each of 3 scenarios (range, 75.2% to 80.4%), even if it involved only medical record review, but most would accept nonwritten (oral) permission or general notification if obtaining written permission would make the research too difficult to conduct (range, 70.2% to 82.7%). Most perceived additional risk from each scenario (range, 64.0% to 81.6%).
Use of hypothetical scenarios and a nonprobability sample that was not fully representative of the U.S. population.
Most respondents preferred to be asked for permission to participate in observational and randomized research evaluating usual medical practices, but they are willing to accept less elaborate approaches than written consent if research would otherwise be impracticable. These attitudes are not aligned with proposed regulatory guidance.
National Center for Advancing Translational Sciences at the National Institutes of Health.
Calls are increasing for American health care to be organized as a learning health care system, defined by the Institute of Medicine as a health care system “in which knowledge generation is so embedded into the core of the practice of medicine that it is a natural outgrowth and product of the healthcare delivery process and leads to continual improvement in care.” We applaud this conception, and in this paper, we put forward a new ethics framework for it. No such framework has previously been articulated. The goals of our framework are twofold: to support the transformation to a learning health care system and to help ensure that learning activities carried out within such a system are conducted in an ethically acceptable fashion.
The authors argue that in a learning health care system with ethically robust oversight policies, a streamlined consent process could replace formal written informed-consent procedures for many studies, and patient consent would not be required at all for some trials.
To assess patient recruitment and quality of data in a randomized database study.
A randomized database study was conducted in the Integrated Primary Care Information (IPCI) general practice research database. Software was built to allow for automated patient identification and recruitment, and randomization. As an application, we compared gastrointestinal tolerability in persons treated with diclofenac and celecoxib for osteoarthritis. The outcomes were assessed in the IPCI database. To assess accuracy of exposure and outcome, we also collected information by self-administrated patient questionnaires. For all eligible subjects, we assessed the main reason for noninclusion. Physicians were interviewed to evaluate the study and to identify the major obstacles.
Forty-two general practice physicians collaborated with the study and 7,127 potential study subjects were identified. Among these subjects, 170 were eligible for recruitment and 20 (11.8%) were randomized. Of the eligible patients, 96 (56.5%) were not recruited because the physician was too busy or the patient was treated by another healthcare provider and 54 (31.8%) were not recruited because of exclusion criteria.
Concordance between questionnaires and IPCI data and the outcome was good (kappa=0.7; SD=0.14). The physicians reported that recruitment during routine visits was too time-consuming, in particular because of the need for informed consent. Although a randomized database study is feasible, patient recruitment during routine consultations should be avoided.
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Is a new protocol for acute lymphoblastic leukemia research or standard therapy?
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