Heródoto, I, 5-7.

This project provided several lessons with respect to the opportunities and challenges of research using routinely collected data (Table 30). Routinely collected data can provide detailed information on medical and prescribing histories of trial participants and allow long-term follow-up for major clinical outcomes, even after completion of the trial. Data on trial participants and sites can be compared with data from those not participating in the trial. Retropro has shown that a trial can be conducted without site visits and with minimal interference by the research team providing opportunities for more representative trial settings. The challenges in conducting point-of-care trials relate to the complexities in obtaining research governance approvals, recruitment and retainment of GPs and consent procedures for recruiting patients. There are many uncertainties about the relative merits of alternative treatments already in wide use and who to treat with these interventions. Even for statins that have been evaluated in a large number of trials, there are important outstanding research questions. Even small differences in the relative merits of alternative treatments could translate to a substantial number of lives saved if the suboptimal treatment is being widely used. A learning health-care system should consider the continuous optimisation of routinely used interventions as a key task. Clinicians should consider it as their duty to help resolve uncertainties about the effects of their treatments. There is increasing recognition that patients have suffered and died unnecessarily because doctors have failed to recognise and confront uncertainties about the effects of

their treatments and to support the research needed to reduce these.156_{The challenge will be to embed}

research into clinical practice and engender a culture of continuous testing with routinely used treatments in order to find out what works in whom. This will require different models of organising and conducting

these trials and of involving patients and seeking consent. Faden et al.157_{recently proposed that a trial like}

Retropro may be allowed under certain conditions to proceed without consent of patients at the time of randomisation. Patients could be regularly informed about randomisation activities in the clinic and be allowed to opt out from future randomisation. There should be engagement with patients and clinicians

about the proper role for randomisation and consent in a learning health-care system.157_{Randomised trials}

of routinely used treatments should be simple to conduct and conducted as a matter of routine. Clinicians and patients should set the priorities for these trials and conduct them, with researchers merely providing the infrastructure for design and analysis.

This project has shown that electronic point-of-care trials are feasible, although the recruitment of clinicians is a major challenge owing to the complexity in the trial approvals and diverse barriers to recruitment (as outlined in Chapter 8). However, these trials will contribute substantially to the quality improvement only if interventions, clinicians and participants of these trials are representative and if trials are simple to conduct. The current research governance system mandates special requirements and conditions to trials, even those that aim to evaluate interventions in routine use. As a consequence, only a selective minority of clinicians participate and trial interventions may no longer reflect usual care (e.g. due to lengthy consent procedures or requirements to switch trial medication for administrative convenience). Point-of-care trials will have limited scientific value if the trial setting or participants are artificial. These trials aim to compare actual clinical decisions (rather than testing biological effects of a molecule) and, thus, will need to replicate these clinical decisions. The concept and practice of research exceptionalism are a fundamental and critical challenge to the use of point-of-care trials.

TABLE 30 Main lessons of this project with respect to opportunities and challenges for point-of-care trials

Area Lesson Comment

Opportunity Clinicians showed interest in participating in

simple trials

Two-thirds of practices that were contacted expressed interest; qualitative research also indicated support in principle

Patients showed interest in participating in simple trials

Qualitative research indicated support and patient representatives on the Trial Steering Committee advocate further progress (see Appendix 5) Routinely collected EHRs can provide long-term

information on major clinical outcomes; linked databases enhance the capture of major clinical outcomes

Data quality can be measured in EHR databases prior to start of trial; end points in trials should be simple to define; linkages can be important in enhancing capture of end points

Feasible to conduct simple trials without site visits and with minimal interference by research team

Central monitoring techniques are valuable especially if data are available on

non-trial participants IT system can facilitate simple recruitment

procedures including flagging

Clinicians found the technical procedures for recruitment simple, having done it once; interest was expressed in tailoring flagging to individual preferences of clinicians

IT system can facilitate central control of recruitment Patients_{’ eligibility can be controlled centrally}

(subject to data availability) and the number of trial participants at a site can be managed

Fraud may be less likely because of the greater chance of detection, greater technical challenges for the fraudulent researcher and ease of routine audit

Availability of EHRs before and after the trial plus information on non-trial participants/sites simplify fraud detection

Challenge Research governance procedures are complex,

leading to substantial attrition of clinicians

Trials of routinely used interventions should be considered quality improvement, regulated under

Good Medical Practice guidelines155

Informed consent procedures are legalistic and complex, based on the unsubstantiated belief that long paper forms are more informative

Consent procedures should be informed by preferences of patients; alternative models of consent (of content and timing) should be developed and evaluated

Trial recruitment during an unscheduled consultation is difficult for clinicians

Simplification of trial recruitment procedures is required (including consent procedures and collection of study-specific data)

Study interventions are already well established in routine clinical practice or subjected to treatment guidelines

Trials need to be conducted earlier

Protocols and study procedures should be simple and consistent with routine clinical practice

Collection of eDiaries, for example, should be limited to selected sites that have dedicated research staff

Bias in the measurement of more subjective end points due to preferences (such as patient-reported outcomes)

Placebo-controlled trial should be considered in a subset of sites only

DISCUSSION, RECOMMENDATIONS AND GUIDANCE

NIHR Journals Library www.journalslibrary.nihr.ac.uk

Several authors have advocated large simple point-of-care trials with minimal study-specific data collection, inclusion criteria consistent with normal clinical practice and collection of information on major clinical

outcomes.158–161_{As succinctly put by Tognoni et al.,}162_{truly important questions need only simple protocols}

and data collection. Unfortunately, these trials are currently rarely done although the recent TASTE trial

provides an example how simple trials can be done.25_{The call for making trials much simpler and larger}

clearly has not been heeded.163

An important limitation of this project was that the study setting was restricted to primary care and that simple pharmacological interventions were evaluated. The GPs in the UK have been using EHRs for over two decades. Secondary care in the UK has had a lower uptake of EHRs. The recent experiences in Sweden

of the TASTE trial, conducted in secondary care,25_{do support the notion that point-of-care trials do not}

need to be limited to primary care. Our project was developed and based in CPRD, which currently contains the EHRs of about 8% of the UK population. However, many of the issues raised are likely to apply more generically to EHRs.