Placebo comparator group selection and use in surgical trials: the ASPIRE project including expert workshop

Article history

This issue of the Health Technology Assessment journal series contains a project commissioned by the MRC–NIHR Methodology Research Programme (MRP). MRP aims to improve efficiency, quality and impact across the entire spectrum of biomedical and health-related research. In addition to the MRC and NIHR funding partners, MRP takes into account the needs of other stakeholders including the devolved administrations, industry R&D, and regulatory/advisory agencies and other public bodies. MRP supports investigator-led methodology research from across the UK that maximises benefits for researchers, patients and the general population – improving the methods available to ensure health research, decisions and policy are built on the best possible evidence.

To improve availability and uptake of methodological innovation, MRC and NIHR jointly supported a series of workshops to develop guidance in specified areas of methodological controversy or uncertainty (Methodology State-of-the-Art Workshop Programme). Workshops were commissioned by open calls for applications led by UK-based researchers. Workshop outputs are incorporated into this report, and MRC and NIHR endorse the methodological recommendations as state-of-the-art guidance at time of publication.

The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Copyright statement

Copyright © 2021 Beard et al. This work was produced by Beard et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.

2021 Beard et al.

Public and patient involvement

Public and patient involvement (PPI) was important for the workshop from its inception. Following the NIHR call for a workshop, the submission team was selected from a group of appropriate international experts, scientists and clinicians. A PPI member (DF-H) was part of the submission team and contributed to all PPI work and submission documents. On award, a further PPI attendee was invited to the workshop. This PPI attendee had experience and understanding of placebo-controlled surgical trials. Both patient representatives had been involved in the CSAW (Can Shoulder Arthroscopy Work?) placebo-controlled surgical trial13 from Oxford. One patient, who had previously undergone decompression shoulder surgery, had been the patient representative on the Trial Steering Committee for CSAW. The other patient had been an enrolled patient on the same trial.

Public and patient involvement members were involved in all stages of the work. Both members attended the workshop and contributed substantially to discussions from a patient perspective and, based on their involvement in similar previous trials, also as knowledgeable individuals on aspects of the methodology. The chairperson made every effort to include the PPI members on most discussion points. The PPI members also provided a presentation alongside the other scientific presentations being delivered. Both members participated in report writing and editing content. Chapter 8, Placebo-controlled surgical trials: the patient’s perspective, has a section dedicated to the ‘patients’ perspective’, written by the PPI members. This exemplifies the impact and dissemination features of the PPI input. It may have been useful to have a further PPI representative outside the Oxford group or perhaps from overseas, but travel costs were considered in relation to the extra benefit.

The psychological aspects of placebo

Classical definitions of placebo can introduce conceptual confusion rather than clarity when considering the mechanisms underpinning placebo effects. For example, defining placebos as inert substances leads one paradoxically to define placebo effects as the effects of inert substances. These difficulties may stem from a focus on placebo as a substance rather than placebo as a process. 16 Indeed, current definitions now invoke notions of process. For example, placebo effects have been defined as changes in a person’s health status that result from the meaning and hope that the person attributes to a procedure, event or interaction in a health-care setting. 17,18 Colloca,19 a leading commentator on the placebo phenomenon, goes further in linking placebo effects to a specific mechanism, defining them as ‘powerful determinant[s] of health outcomes across many different diseases and encounters; the placebo effect is due to the expectancy of positive treatment outcomes’. 19

Two main theories dominated early work on the psychological mechanisms underpinning placebo effects: (1) learning theory, specifically conditioning (i.e. placebo effects are underpinned by associative learning when placebos are paired with an active drug that triggers a physiological response); and (2) response expectancy theory (i.e. placebo effects are underpinned by the patient’s conscious or unconscious expectation that the placebo will have a particular effect). Experiments were designed to test competing hypotheses derived from these theories and the evidence amassed suggested that both conditioning and expectancy were involved in placebo effects in different circumstances. 20

Less divisive accounts of placebo mechanisms have now been proposed. Benedetti21 emphasises the importance of considering disease- or system-specific placebo mechanisms, particularly when considering mechanisms at the physiological level. Colloca and Miller22 integrate insights from learning theory and response expectancy theory, arguing that patient expectations are the central psychological mechanism that mediates placebo effects. According to this model, the brain decodes the psychosocial context, formulating (conscious or unconscious) expectations about outcome that then trigger placebo responses.

Colloca and Miller22 drew on previous work to suggest that expectations are shaped by learning mechanisms around three types of sign (or triggers) in the psychosocial context:

1. indices, which generate expectations through sensory- or memory-based associations for individuals (e.g. tablets can be indices when patients become conditioned to expect symptomatic benefit from taking them)23

2. symbols, which generate expectations through culturally specific conventions, including language (e.g. the ritual and doctor–patient communication around surgery and the operating theatre foster particular expectations of benefit)24

3. icons, which generate expectations through perceived similarities with the object (e.g. observing a similar person with similar symptoms responding to an intervention can foster positive expectations through social learning mechanisms). 25

Understanding the influence of these different elements on placebo effects within clinical trials can then inform attempts to design, manipulate and control placebo effects in surgery trials.

Five domains of the psychosocial context of health care that may influence patient outcomes have been suggested from reviews of the literature. 26 A recent review further explored how each of the five contextual domains are at play in clinical trials and identified specific design features and methods that might shape patient expectations and, therefore, placebo effects in trials27 (Table 2).

Qualitative research methods are helpful for exploring the psychosocial context of clinical trials and understanding the myriad influences and dynamic processes involved in shaping patients’ expectations. For example, interviews in a placebo-controlled trial28 of acupuncture for osteoarthritis revealed that participants derived empathy not only from the acupuncturists themselves, but also from other trial personnel, from the friendly and polite reception staff and from the ease of making convenient appointments, all of which made the patients feel cared for.

How patients are informed about placebo surgery might be a key component of the psychosocial context of clinical trials that could shape patients’ expectations. Patient information leaflets in placebo-controlled trials typically seem to explain placebo effects in quite negative terms, if at all, with most devoting considerable space to describing the potential benefits and mechanisms of action of the trial treatment while describing placebos as ‘a ‘dummy treatment, which looks like the genuine medicine but contains no active ingredient’. 29 This is important because, arguably, it does not adequately inform patients about the potential for positive or negative outcomes from the placebo intervention. 29 Another acupuncture trial,30 this time for irritable bowel syndrome, identified four main ways that patients conceptualised placebo effects: (1) placebos are necessary for research, (2) placebo effects are fake, (3) placebo acupuncture is not real acupuncture and (4) placebos have real effects mediated by psychological mechanisms. Negative views of placebos as fakes or illusory are potentially problematic for patients who receive a placebo intervention and experience real tangible benefit from it, as they may then struggle to make sense of this and integrate it into a coherent narrative that does not entail them feeling tricked or gullible. 30,31

Patient expectations are central to placebo effects and are driven by multiple components of the psychosocial context, including interpersonal interactions with clinicians and trial personnel, and information about the trial interventions. It is important to consider this when designing and conducting placebo-controlled trials in surgery.

The physiological aspects of placebo

The scientific overlap between the physiological and psychological aspects of placebo is significant and far from straightforward. Most work has been completed in the context of pain and pain relief, rather than methodological considerations for comparative groups in surgical trials. Therefore, direct application has limitations. However, in the context of pain modulation, it is well established that the mechanisms of placebo analgesia involve the antinociception brainstem pathway and spinal inhibition. 32 Functional magnetic resonance imaging work has also linked observed placebo effects to the anticipation of reward. 33 If these effects are substantial for an intervention such as surgery, it is critical that they are taken account of in any trial design to enable fair comparison or deeper understanding of mechanism.

Furthermore, there is evidence from investigations of the mesolimbic reward system that certain personalities are more susceptible to such analgesic responses and placebo effects. 34 Many of the more qualitative features of placebo (e.g. expectancy, prior experience and belief systems) can influence various opioid and dopamine receptor systems to produce an effect,35 giving physiological credence to centuries-old medical teaching (Galen) regarding the need for ‘confident’ physicians. The therapeutic setting can also produce very similar physiological changes using the same pathways. 35 What should not be forgotten is that the powerful antinociceptive or positive effects can also be mirrored with negative expectancy and ‘anxiety amplification’, the understanding of which continues to be driven by rapidly developing functional magnetic resonance imaging research. 36 Such nocebo or negative placebo effects also have a place in clinical trial design, depending on the research question being asked. It is likely that with large data set and machine learning input our understanding of these physiological areas will increase.

Rationale for use of a placebo intervention

Most trials did not provide an explicit rationale for using a placebo intervention. Some trials discussed the need to quantify potential placebo effects (n = 27, 28%)13,44–69 and the role of placebo interventions in reducing bias (n = 9, 9%). 13,45,50,61,65,67,70,71 Using a placebo intervention to elucidate the mechanism of treatment action was seldom explicitly reported. However, 10 articles (10%) acknowledged that there was uncertainty as to which treatment components were responsible for the mechanism of action. 13,50,53,63,69,72–76

Patient information

Eleven trials8,13,44–46,63,70,72,77–79 (11%) reported details of placebo-specific information given to patients. Three trials72,77,78 specified that the placebo surgery would not treat the patient’s condition. In contrast, one trial79 informed patients that the placebo might improve symptoms. Four trials13,44,45,63 did not use the term ‘placebo’ in patient information, with three of these trials instead describing the characteristics of both treatment and placebo procedures. 13,44,45 The remainder informed patients of the ‘blinded’ nature of the study. Two trials46,70 reported that patients were informed that they might not receive the treatment intervention.

Intervention standardisation and fidelity

Attempts to standardise interventions were reported in seven trials47,48,78,80–83 (7%). Four trials47,48,80,81 were delivered in accordance with a standardised protocol. One trial82 agreed a standard approach by consensus with participating investigators. One trial83 achieved standardisation by ensuring that all interventions were delivered by one clinician. One trial78 said that a protocol ‘was discussed in the minutest detail to ensure that it would be adhered to in a similar manner’, although no specific detail of intervention delivery was given.

Four trials47,49,78,82 (4%) reported strategies to monitor the delivery of interventions (fidelity), including videotaping (n = 3)47,49,78 and ‘monitoring of adherence to technique by the study chairman’ (no further details given). 82

Delivery of co-interventions and anaesthesia

Pre-, peri- and postoperative co-interventions were reported in 45 (47%),45,47,48,50,51,55–64,67,71,73,74,76,78,79,82,84–105 31 (32%)13,48,50,51,55–57,59,60,62,67,71,73,74,76,81,83,85,92,94,99,106–115 and 64 (67%)8,45,46,48–50,54–64,66,67,69,70,72–75,77–79,83,84,87,88,90–96,98–102,105–107,111,112,115–128 trials, respectively, with details being matched between the treatment and placebo groups in 42,45,47,48,50,51,55–63,67,71,73,74,76,78,79,82,84–93,95–102,104,105 2713,48,51,55,56,59,60,62,67,71,73,74,76,81,83,85,92,99,106,108–115 and 618,13,45,46,48–50,54–64,66,67,70,72–75,77,78,83,84,87,88,90–95,98–102,105–107,111,112,115–121,123–128 trials, respectively. Anaesthesia protocols were matched between groups in 64 (67%) RCTs. 8,13,45,46,48,50–54,56,57,59,60–62,64,66,67,69–71,73,76,78,79,81,83,84,86,88,90–95,97,98,100,102–104,106,107,109,111,112,114,116,121–124,126,127,129–135

Trials offering the treatment intervention to patients allocated to placebo

Forty-three (45%) trials45–49,51,54–56,58,59,61,62,64,66,68–71,73–75,77,78,84,85,88–90,95,97,99,107,109,111,112,114,119,121,122,124,125,132 reported that the treatment intervention was offered to patients in the placebo group. Seven trials59,73,74,85,109,112,119 were formal crossover trials and one112 had a four-group trial design that randomised the order of intervention delivery. Rationales were given by 16 (37%) trials. 48,55,56,58,61,62,64,68,69,73,75,78,85,95,112,122 This included if patients had continuing symptoms (n = 7)48,55,56,62,69,78,122 and for ethics (n = 5)62,68,75,95,122 and methodological reasons (n = 3),62,85,112 such as reducing the likelihood of patients seeking treatments outside the study.

Minimisation of risk

The degree of operator skill was reported in 22 trials (23%),13,47,50,51,55,59,69,70,74,78,79,83,85,91,94,99,100,105,110,121,123,128 independent data monitoring was reported in 28 trials (29%)13,45,46,52,55,57,60,61,68,69,71,72,78,82,84,97–100,103,104,106,113,114,121,125,128,136 and an unblinding protocol was provided in one study. 84

Ninety-six placebo-controlled surgical trials were identified. 8,13,44–79,81–83,85–138 Most were small (< 100 patients), focusing on minimally invasive endoscopic techniques. Quantifying placebo effects was the most common reason given for using placebo interventions. The information provided to patients was variable. A small number of trials reported minimal information about standardisation and fidelity of interventions. Two-thirds of trials matched anaesthesia protocols between the treatment and placebo groups and nearly half of the trials offered treatment to placebo patients.

Reporting of placebo surgical RCTs is limited. Specifically, there is a need for clearer rationales for placebo use, patient information provision, standardisation and fidelity of interventions and the use of co-interventions. Standardised reporting guidelines may be useful. In addition, consideration for how to minimise risk and whether or not patients in the placebo group should be offered the treatment intervention is necessary.

Key ethics messages

• Placebo controls may be used in RCTs of surgical interventions provided that there is a strong scientific and ethics justification for the study.

• Clinical equipoise must be obtained among the study arms. Clinical equipoise may permit a placebo control when a surgical intervention is widely used but lacks an evidence base.

• The non-therapeutic risks of a surgical placebo can be justified only if (1) the study question cannot be answered with a different design and (2) the risks are outweighed by the importance of the knowledge to be gained.

• Generally, surgical trials with a placebo control may not enrol children or incapable adults unless the risk to the participants can be demonstrated to be minimal.

• In the informed consent process, surgical placebos should not be described in terms that may unwittingly lead participants to believe that they are clinically indicated.

• Informed consent procedures may be augmented with enhanced consent forms, additional discussion time and testing of participant understanding.

• Participants should be informed of the intervention to which they were allocated when the study is complete.

• Where a trial establishes the utility or success of a particular intervention, the intervention should be provided to all the trial participants.

Designing invasive placebo interventions: content of the intervention

The design and content of the placebo are important aspects of placebo-control methodology in surgical trials. As part of this work, we undertook an in-depth review and extension of a previously published surgical taxonomy to allow the characterisation and optimisation of a surgical placebo. The work has been written up in detail separately. 15

In summary, the process involves deciding what aspects of the treatment intervention need to be delivered as part of the placebo, providing a framework to enable its adequate description. Equally, it is important to describe what parts of the intervention can or need to be omitted (i.e. identifying and removing the ‘critical surgical element’) (see Chapter 2). The choice involves consideration of any risk to patients by addition or omission of components and any strategies required to ensure that the placebo sufficiently mimics the treatment in question.

The work, led by Cousins et al. ,15 provides a comprehensive framework to deconstruct the surgical intervention into its component elements. This allows the critical surgical element to be identified and removed to generate the placebo. The resulting DITTO framework consists of five stages (Table 3).

This newly developed framework can help in the design of high-quality RCTs and to standardise intervention content.

The intervention group should always represent the surgical procedure being studied, but the level of standardisation of the surgical technique can vary according to the aims of the study design [i.e. where the study lies on the spectrum of explanatory (tightly controlled) to pragmatic (usual care, often with some differences between surgeons, but with greater generalisability)]. The surgical intervention should also take account of adjunct treatments, such as rehabilitation and medical treatment.

Comparisons and control groups in placebo-controlled surgical trials

At its simplest level, two basic alternative trial designs have been proposed for placebo-controlled trials: (1) a two-arm comparison of placebo with active intervention and (2) a three-arm trial that has the same two arms supplemented by a third, no-treatment, arm. The surgical equivalence is illustrated by the FIMPACT (Finnish Subacromial Impingement Arthroscopy Controlled Trial)153 and CSAW trials. 13

The two-arm study is a relatively straightforward proposition and is a direct evaluation of the effect of inclusion of the critical or active surgical component of the procedure. The difficulties surrounding this comparison involve patient consent and equipoise (see Chapter 8).

The three-arm trial, with inclusion of a no-treatment arm (for a three-way comparison), does add complexity, but can be a particularly useful design to track and compare against natural history/recovery. It also can provide information for quantifying the scale of potential placebo effect for the procedure. However, the three-arm (or more) trial can be particularly challenging in terms of both analyses and trial conduct. One of the main challenges is obtaining parallel start times for the intervention in all groups. For various reasons, intervention can be delayed under some health-care systems (including routine waiting times for receiving surgery within the clinical setting in some health-care systems). By definition, ‘no treatment’ is never delayed and there is also the possibility of ‘crossover’ to a more active intervention group during the trial, either for rescue or because of lack of benefit.

In reality, placebo-controlled surgical trials offer several possibilities for the content of the control group, depending on the intervention and the research question. The pros and cons of each control group option are listed below. Although in some circumstances many comparison control groups may be desirable, this must be weighed against the logistics and cost of a multiarm trial, along with the complexity of analysis and difficulty with interpretation of multiarm studies, which may provide complex and mixed messages for the reader and, therefore, affect the ability to change practice.

Altogether, there are four possible control groups (arms) with different content for a surgical placebo trial, and each is listed below. The SUcceSS (SUrgery for Spinal Stenosis) trial,154 which tested spinal canal decompression by laminectomy (for spinal stenosis), will be used as the exemplar.

Analysis features in the design of surgical placebo-controlled trials

A further challenge related to the three-arm trial is the issue of multiplicity of comparisons. 155 Typically, pairwise comparisons would be considered the most informative (allowing direct contrasts and quantification of the treatment effect). The three-arm design, unlike the two-arm design, offers options with the associated potential for formal statistical adjustment for multiplicity (i.e. various approaches could be adopted). Some authors have provided compelling arguments not to penalise different comparisons that relate to different research questions. 155 In the context of surgical placebo control, it raises the issue of whether or not a surgical placebo intervention is considered a valid interventional option in its own right. In terms of multiplicity and wider considerations, is the contrast of the surgical placebo intervention and no treatment a valid one to undertake?

In the context of surgery, compliance with treatment allocation is another concern for placebo-controlled studies, given the potential explicit or implicit preferences of surgeons. This potential lack of equipoise and its effect on trial conduct should be considered at the design stage.

Last, a trial design issue within the context of placebo-controlled surgical trials is the legitimate concern about whether or not these trials are of sufficient size to identify the meaningful effect. A recent systematic review43 identified the median trial size to be small, with only 65% of all studies randomising > 100 patients. Only a handful of trials have had > 200 participants in the surgical arms. When such a sample size is translated to target differences that can be detected under standard conditions (i.e. two-sided significance level of 5% and statistical power of 80% or 90%), only large effects can be confidently be detected. Offsetting this concern is perhaps the general expectation that, at least for most of surgery, the benefit of the active intervention should be large enough to justify the risk. However, such considerations do reaffirm the need to for care in the choice of outcomes and the primary outcome in particular.

Is placebo intervention risky and how to mitigate risk

The ethics arguments previously presented on the use of placebo surgical controls highlights the need for mitigation of potential risk from placebo interventions. There are opposing views on the degree of risk for surgical placebo interventions. Wartolowska et al. 5 showed that trials (albeit in endoscopic or minimal access interventions) that included a placebo surgical control had no greater risk than other treatment or control groups. Although work from the German Society of Surgery (Berlin, Germany) showed that the frequency of serious adverse events was comparable between true intervention and placebo, they expressed concern that trials of more invasive placebo interventions might entail a greater risk for study participants. 6 The ORBITA (Objective Randomised Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina) study in interventional cardiology is a good example of a study in which the frequency of adverse events was higher in the placebo group than in the normal treatment group. 45

Assessing risks of a placebo surgical control, especially in relation to fidelity, is complex and difficult to quantify. Inert treatments, such as low- or minimum-fidelity surgery, may seem to have less risk than a surgical procedure with higher fidelity (in which more tissues may be involved), but this simple model may not hold. For example, those undergoing a placebo surgical procedure, despite a priori higher risk, may still experience apparent benefit, although not achieved through any known (or theoretically causal) mechanism. Similarly, the apparent ‘safety’ of a minimum fidelity procedure, in which there is little tissue damage, is tempered by the risk of anaesthetic complications. It should be remembered that the risk of any anaesthetic complication or surgical site infection after incision will apply to all groups undergoing surgery and similar anaesthesia (including those in the placebo arm). Discussion should include the situation when the risks of a surgical treatment in a ‘low-/minimal-fidelity’ placebo surgery group can potentially outweigh the benefits of the study findings to society. This can be difficult to reconcile. It is not clear how much risk is ‘too much’ and when a placebo surgery control group trial is ‘not worth it’. It remains a complex area and will depend on individual procedure risk plus routine surgical risk (e.g. anaesthetic), with consideration of the perceived capacity to benefit from the specific surgery in question.

Previous literature has suggested various strategies for risk mitigation, including:

• restriction of eligible patients to those with a low clinical risk profile (e.g. restriction to American Society of Anesthesiologists grades 1 and 2)

• reducing the invasiveness of the surgical placebo (this forms part of the balance between fidelity and risk alluded to above)

• review of the form of anaesthesia used for the placebo procedure

• use of experienced surgeons only who are familiar with the surgical intervention under evaluation

• enhanced monitoring with oversight committees.

Therefore, it is important that all means of risk mitigation are explicitly outlined before undertaking a placebo-controlled surgical trial. When the overall risk of any placebo surgical control is deemed to be unacceptably high (despite all possible risk mitigation strategies), a placebo-controlled design should not be used. However, without a sufficiently robust trial, the surgery may continue unabated, with all patients continuing to be subjected to all risks related to the procedure. In this situation, the riskier the procedure then the more urgent the need for a sufficiently robust (placebo-controlled surgical) trial.

If the use of a placebo control is scientifically justified then the next step is to mitigate the risk of this incomplete surgery by reducing its invasiveness as far as possible. As previously stated, an unintentional unblinding should be guarded against to avoid loss of the methodological advantages of a placebo comparator (and, therefore, making its use and the whole trial futile).

Patient information for placebo-controlled surgical trials

The ethics and legal requirements for potential participants to provide informed consent for inclusion in a randomised trial are well established. These include both verbal and written information explaining the purpose of the trial, research procedures, risks and benefits, end-of-trial provisions, source of funding, conflicts of interest, and institutional affiliations. 156 Potential participants should be made aware of refusal rights and the ability to withdraw their consent at any time. 156,157 This routine regulatory guidance does not contain explicit requirements for placebo surgery trials. Both the European Medicines Agency’s Guideline for Good Clinical Practice E6 (R1)158 and the US Food and Drug Administration’s guidance for informed consent159 information sheets contain only general requirements about placebo trials, mostly designed for drug trials and not placebo-controlled surgical trials.

Section 2 in this guidance158 on the current regulatory requirements for placebo-controlled surgical trials highlights the suggestion from several medical associations that trials with a placebo surgical control arm should provide enhanced information to participants and consider any expanded consent needs. However, the details of how this should be operationalised in terms of exacting information for placebo-controlled surgical trials has not been specified. There are some broad items of content information for placebo-controlled trials than could be considered:

A full description of the placebo-surgical procedure;

A statement that although benefit might result from a surgical placebo procedure, there is no known mechanism by which the placebo surgery should result in direct benefit for the index complaint;

Recognition that the use of the procedure is for research purposes;

The need to avoid language in the consent process that might unwittingly promote any therapeutic misconception;

Possible risks or discomforts linked to both the index and the surgical placebo procedure.

Reprinted from The Lancet, vol. 395, Beard DJ, Campbell MK, Blazeby JM, Carr AJ, Weijer C, Cuthbertson BH, et al. , Considerations and methods for placebo controls in surgical trials (ASPIRE guidelines), pp. 828–38, Copyright (2020), with permission from Elsevier12

It is, however, important to recognise that these items may not be applicable to all placebo-controlled surgical trials and will be dependent on the nature of the placebo. For example, when considering a placebo with no fidelity (i.e. a sham procedure) (see Table 1), it would be necessary to inform potential participants that allocation to the placebo may not result in personal benefit. The converse, a high-fidelity placebo, may confer some potential benefit on the participant and so needs to be framed accordingly. The fidelity spectrum for placebo controls will be key in considering what information should be included in the information provided to and shared with potential trial participants. This should help to address concerns over the therapeutic misconception in trials of this type.

In addition to the information provided to potential participants on the placebo comparator in surgical trials, it is important to consider how to present information on the surgical intervention being evaluated to promote informed choice about participation. The surgical intervention will probably be the current standard of care and what the patient will receive should they chose not to participate in the trial. The information provided on the risks of the surgical intervention needs to be considered equally with regard to the placebo comparator. For example, the risk of a general anaesthetic for both the surgical intervention and the placebo should be considered alongside the risk of surgical site infection, especially when the placebo comparator is of low fidelity.

Methods to specify core content for patient information for trials while working with potential participants are available. 160 These opportunities for the co-production of information in advance of the trial will be key for developing patients’ information for placebo-controlled surgical trials that is fit for purpose. In addition to the core content, considering how the information is provided to enable support for decision-making is also important. Rogers et al. 161 have proposed the use of decision support tools (namely decision aids) to help potential participants deliberate over their participation in placebo-controlled surgical trials by improving research literacy and attending to potential concerns over therapeutic misconceptions. There is preliminary evidence that the medium (e.g. verbal, written, audiovisual) and who (e.g. the surgeon) presents the information may also make a difference to potential trial participants in placebo-controlled surgical trials. 162

As well as information provided to potential trial participants at the point of considering participation in a trial, written (and often verbal) information is provided throughout the trial in the form of follow-up questionnaires, newsletters and trial results. Each interaction with a participant requires consideration regarding the information being shared with them and how that may have an impact on aspects of the placebo-controlled surgical trial that are important for conduct and analysis (i.e. considering the information continuum across the lifetime of the trial).

Maximising recruitment

Overestimation of the pool of available eligible patients is common, and especially true for placebo-controlled surgery trials. A systematic review7 of placebo surgery trials (63 studies published between 1959 and 2014) found that slow recruitment that was directly attributable to eligibility was a substantial barrier to trial completion. It was found that approximately five people needed to be screened to identify one eligible person. In an Australian placebo-controlled trial50 of vertebroplasty, performed before the procedure was widely available in that setting, only 34% (of 468 people screened) were eligible. Almost half (49%) of those found to be eligible agreed to participate. 50 A recruitment strategy that included direct-to-consumer adverts using a range of media failed to substantially improve the pool of eligible people. A more focused approach to doctors who manage vertebral fractures across primary to tertiary care was more successful.

Recruitment into placebo-controlled trials testing treatments that are already widely accepted, available and affordable, despite an absence of high certainty evidence supporting their use, is especially challenging. Both surgeons and patients may be reluctant to accept a 50% chance of placebo, particularly when placebo involves invasive surgery. In any case, recruitment planning of both surgeons and participants must necessarily start early, as it is essential to determining the feasibility of the trial.

Several recent initiatives have developed frameworks for strategic recruitment planning, and these highlight the need for realistic budgets and resources to support recruitment. 163 At the trial design and protocol development phase, Huang et al. 163 have highlighted that it is essential to identify and engage all stakeholders, ensure the relevance of the scientific question and have realistic eligibility criteria. Trial feasibility requires evidence-based feasibility analyses, having realistic metrics and milestones, and ensuring appropriate site selection and performance monitoring.

Recruitment communication planning can strongly facilitate a trial. It involves identification and engagement of all relevant stakeholders, clarifying treatment pathways, developing and testing tailored and creative messages/materials, and monitoring and evaluating process and performance. The QuinteT Recruitment Intervention system for optimising recruitment and informed consent pioneered by Donovan et al. 164 has been very successful and is based on identification of the motivators of and barriers to trial participation.

Increasingly, business models and modern marketing theory and techniques have also been used to inform strategies for recruitment. 165–167 For example, McDonald et al. 166 recommends developing and building brand values that gain prestige and legitimacy and signal worthiness of the trial; developing an explicit market plan, including strategies for overcoming resistance; making the ‘sale’ through achieving public buy-in, delivery of a multiaudience, multilevel message and engaging champions and change agents; and maintaining engagement via provision of frequent positive reinforcement and facilitating incorporation of recruitment into usual routines. 166,168

Embedding recruitment intervention studies and sharing the results will also ensure advancements in trial recruitment for placebo surgery trials, but there is currently a paucity of data in this space. For example, a 2018 Cochrane review168 investigating strategies to improve recruitment into clinical trials included 68 RCTs; however, none of the RCTs was a placebo surgery trial. Likewise, a review published in 2015 included 17 trials investigating training programmes for recruiters to RCTs also failed to identify any programmes specifically for recruiters of placebo surgery trials. 169 The latter review found that, although training increased recruiters’ self-confidence in communicating key trial concepts to potential participants, there was little evidence that it increased recruitment rates.

Furthering our knowledge about how to optimise recruitment into placebo surgery trials, including the information that is provided for potential trial participants and who should provide that information, is crucial. It is well known that the preferences of patients, as well as health professionals, including surgeons who provide the treatment, can have a decisive influence on trial recruitment:170

These questions include whether transmission of preference can be mitigated if consent is obtained by a trained and ideally neutral recruiters; whether well-informed patients are more or less likely to accept random assignment to; and whether or not surgeons should be allowed to restrict random assignment to eligible patients only when personally uncertain as to which intervention would be the best option.

Reprinted from The Lancet, vol. 395, Beard DJ, Campbell MK, Blazeby JM, Carr AJ, Weijer C, Cuthbertson BH, et al. , Considerations and methods for placebo controls in surgical trials (ASPIRE guidelines), pp. 828–38, Copyright (2020), with permission from Elsevier12

Placebo-controlled surgical trials: the patient’s perspective

The patient’s perspective is crucial to the design, conduct and analysis of placebo-controlled surgical trials. The patients’ partners gave this critical reflection:

As patients and patient representatives, it was a privilege for us to be invited to the Workshop; to contribute but also to learn more about the fascinating world of placebo surgery trials.

The patient follows a journey: through development of symptoms, to medical consultation, enrolment in the trial, treatment (or pseudo treatment), follow-ups, recovery (or not) and ultimately ‘unblinding’. Patients join clinical trials for a variety of reasons and for each there may be a mixture of altruism, self-interest and curiosity. Many patients will have reached a point where they feel desperate to find a solution to their symptoms. Any observations about the process of recruitment are necessarily personal and anecdotal. This said, clear and simple explanations of what participation will involve answering questions, enabling a dialogue and, significantly, clarifying what options are open to the patient during the trial. It is obvious that at no point should the participant feel that they were deceived about any aspect of the trial.

All patients benefit from being informed, supported and having a good relationship with their clinicians. It is the same for participants in clinical trials and perhaps not more or less for those in placebo surgery trials. There must be trust and confidence not only in the lead clinician, but in the whole team administering the trial. Some patients felt that, having had potential participation broached to them by their surgeon, it was helpful for more detailed discussions and decision-making to take place separately, with a different member of the team.

The ‘unblinding’ stage is a key one and it is important that patients know both when and how they can access this information. Not all will be familiar with electronic communication and more traditional methods, such as letters, should be offered. This also applies to the published results of their trial. This is of great importance to participants and so it must be presented in an easily digestible form.

Any participants whose symptoms are persisting will need continued treatment and support.

Friends and family tend to be very interested in the experiences of participants and favourable reports to them may open the door to future volunteers.

These reflections echo the conclusions from the ethics and trial literature that communication is key, and that potential risks and benefits of participation need to be clearly laid out (as identified in Chapter 4). Timely and direct feedback of trial results is also crucial.

Placebo-controlled surgical trials: the surgeon’s perspective

The surgeon’s position with regard to a placebo trial can be a difficult one. Surgeons who are investigators for the study and fully believe in the utility of the placebo-control methodology often have different perspectives from those who are simply recruiting to the trial. The recruiting surgeons must explore and satisfy their own position of equipoise. This is not straightforward, as surgeons have been trained to make clear-cut decisions and, as a rule, do not sit easily in a landscape of uncertainty, especially the uncertainty that a postulate of a placebo-controlled surgical trial brings. The patient is expecting their surgeon to express confidence and reassurance about the operation they are about to perform, and the reason for doing it, but is told that they can be recruited to a study that questions the very benefit of the proposed treatment. Both surgeon and patient are asked to accept that the evidence for the treatment is insufficient and this can generate concerns for both groups. The explanation of a control treatment of surgery that may have some risk without necessarily any benefit is an added layer of complication to convey to a vulnerable patient.

Reconciliation of these positions can take substantial consideration. Ultimately, as the ethics literature in Chapter 2 highlighted, the surgeon has to believe that the evidence for the intervention under assessment is insufficient and that a placebo design is the best, or the only, way of providing the evidence. Only then can surgeons discuss the merits and issues with a patient and recruitment be successful and fully informed. Qualitative research in these areas can help considerably with this process, as has been seen in the ProtecT (Prostate Testing for Cancer and Treatment) study in urology,171 the CSAW study13 and the wider area of trials recruitment involving surgeons. 164,172

There is an increasing acceptance among the surgical community that surgery and surgical intervention requires more comprehensive and rigorous evaluation, and this is helping surgeons become familiar with the needs for involvement and recruitment to surgical trials. It is essential that surgeons involved in placebo-controlled trials are fully knowledgeable of the rationale, conduct and implications of these types of studies, especially the teachings on community equipoise and uncertainty.

Placebo-controlled surgical trials: the anaesthetist’s perspective

A theme that appeared in this previous work in this field was the identification that key stakeholder groups for such trials are broader than previously understood and that previously less prominent stakeholder groups are very influential. An important example of this is anaesthetists.

Anaesthetists do not necessarily have major involvement in the diagnosis, prognostication or identification of treatment trajectories and outcomes in patient groups that may be considered for such trial methodologies (e.g. patients with osteoarthritis), but are key clinical stakeholders when it comes to patient safety around the perioperative period. Importantly, the perioperative period is where the greatest risk to patients lies in placebo trials and, therefore, the area where the greatest focus comes from clinical, ethics, regulatory and other risk management stakeholders.

An interesting example of this comes from the KORAL study. 38 It might be thought that anaesthetists would consider sedation and local anaesthesia, or perhaps regional anaesthesia, to be the safest anaesthetic techniques to use when delivering a trial intervention, as these appear on the face of it to be relatively low-risk techniques. However, when asked, a significant majority of anaesthetists taking part in a focus group thought that general anaesthesia with full control of the airway was the safest procedure, and, importantly, they also pointed out that general anaesthesia would supply the highest fidelity placebo for the proposed study intervention. According to the anaesthetists, intravenous sedation techniques have been reported in the medical literature to be unsafe, and their own experience showed that local anaesthesia techniques are often insufficient for surgery, with implications for both patients and control group fidelity. These conclusions were the opposite to those drawn by the lay reviewer and by trial team members from medical backgrounds other than anaesthesia (e.g. the surgeons), showing the benefit of such expert engagement. Conversely, if anaesthetists are to assess the risk-to-benefit ratio in proposed placebo surgery trials, they need to understand the potential benefit of the proposed surgical procedures so that they can weigh this against the risks of anaesthesia from the perspective of their own clinical expertise.

To allow such high-level engagement, anaesthetists must be integrally involved in the acceptability phases of future proposed studies (e.g. in the design and piloting of the intervention, as well as informing the ethics and regulatory decision-making from the perspective of patient safety). Anaesthetists are identified as key stakeholders in all future research involving local or general anaesthesia, as well as intravenous sedation, for placebo trials.

The statistical analysis plan and potential results scenarios

All clinical trials should have a statistical analysis plan. This gives an a priori opportunity to review potential scenarios for the results of the trial, what the results might mean and how this is translated into clinical interpretation. This process is especially important for placebo-controlled trials. The complexity of a multigroup design, perhaps with a no-treatment arm, brings about many possible interpretation permutations (see Chapter 3, The physiological aspects of placebo). The surgery can be shown to have more benefit than placebo or no treatment, or maybe no added benefit. A hierarchy of benefit may be proposed perhaps with surgery being more beneficial than both placebo and no treatment.

One of the advantages of outlining the various possible results scenarios is to prepare for any clinical conclusions and potential obstructions to change of practice (outlined below). Early consideration of difficult commissioning decisions can be shared upfront with the surgical community conducting the trial if the options are reported. Sudden realisation from surgical personnel that they have been involved in a study that questions the value of an established procedure can be alarming and have negative influences on any change of practice and acceptance of that change.

A further stage for the future might be to fully explore what the trial results might mean with all parties before the trial has even started. The discussion around whether or not a placebo treatment still has sufficient benefit or merit to be commissioned or provided as a treatment in itself could also be had at this time.

Translation into change of policy and practice

Many of the placebo-controlled trials of surgery reported to date have shown no benefit of the definitive procedure over the placebo-controlled intervention. The design is popular and used frequently to explore treatments with suspicious efficacy and effectiveness. Bearing in mind the ethics and academic justifications required (see Chapters 6 and 7) for a surgical placebo control, reasonable preliminary evidence is, therefore, required to show that part or all the treatment effect of the surgical procedure under investigation might be due to the placebo effect. As previously reported, investigation of a treatment that has no such placebo component, or even a general belief that surgery has no placebo effect at all (Dr Teemu V Karjalainen, Central Hospital, Finland, 2020, personal communication), would not require a placebo-controlled evaluation.

With this backdrop and focus on established, if questionable, procedures, investigators responsible for undertaking such trials must anticipate that any ‘no difference’ results of the trial will be disruptive to accepted clinical care pathways and guidelines. Investigators should also expect, and be prepared for, resistance from clinicians and patients whose beliefs and convictions are being challenged by the findings. Such trials will also generate interest from payers (state and insurance based), press and media.

Once change is indicated, there can be a long lag between research findings and change in practice, as exampled by trials of knee arthroscopy. In the case of knee arthroscopy for osteoarthritis, although the original publication was in 2002,72 it took 15 years for the findings to be partially adopted, despite several other high-quality studies replicating the findings. Similar resistance from the clinical community has been encountered with trials of vertebroplasty for osteoporosis50 and subacromial decompression for shoulder pain. 13 There are consistent features of the resistance and these include a belief by the surgical community that the patients in the trial do not represent the usual population undergoing the procedure. It is also suggested that the surgeons involved in the trial may not be sufficiently expert in the procedure. In other words, a feeling that the trial results ‘do not apply to me and my practice’ is commonplace. This sentiment is highlighted by the expressed views of 15 combined surgical associations of one European country. These associations have advised that, contrary to previous reports, the CSAW trial does not provide any new insights and there are no consequences from the CSAW study for this country’s health system. The response in the UK was starkly different with NHS England moving to de-implement subacromial decompression surgery by placing it on a list of ‘ineffective’ treatments. 173

The question then becomes ‘How can the challenge of effective and timely change of policy and practice be improved?’. There are ways to facilitate, and ideally consideration of any impact should be included in the design phase and conduct of the trial. Most importantly, this should include key leaders in the patient groups, professional associations and clinical communities involved in delivering the investigated treatment. If the results are likely to have global impact then consideration should be given to involving international investigators. There should be ‘buy-in’ from patients and professionals. As soon as results are known, further discussions and the production of joint statements are necessary. If the implications are that the procedure will likely be performed less frequently then advice for patients about alternative treatment is essential.

The policy-maker’s perspective

Policy-makers consist of two broad groups: (1) those who issue guidance about how health-care interventions should be used and (2) those who commission and pay for services. In most health systems, those who make decisions about service provision attempt to maximise the health returns obtained for the investment [e.g. by maximising the quality-adjusted life-year (QALY) output of any health services provided]. Evidence of value from studies employing a placebo control and the value of any placebo effect itself may be viewed differently by each side.

Payers (e.g. commissioners in the English NHS and insurance companies in many European countries) tend to value a QALY gain, regardless of its origin. If a policy provides a net health gain for a reasonable price and is acceptable to patients and society, then the mechanism by which that gain occurs may not be considered important. The health-care system is a mechanism for turning money into QALYs, and exactly how that occurs may not be important.

Guideline generators see things differently. Producers of guidelines tend to pursue the understanding of how a health gain is generated. There can be unease when a gain occurs through a non-specific placebo mechanism, rather than the anatomical, physiological and psychological processes that the intervention’s logic model presupposes. For interventions that may have a significant placebo effect, a guideline producer would like to see robust studies that explore that effect and enable them to separate out any placebo benefit. Therefore, the guideline producer tends to value more comparative studies with active control or placebos, whichever is clinically more appropriate.

There are potential impacts of establishing that an intervention has a significant placebo component contributing to the effect. First, there may be downgrading of any recommendation to use the procedure, as it has been shown not to ‘work’. Second, the payer who may have previously willingly paid for the procedure now follows the downgraded recommendation and declines to fund an intervention that may be effective, albeit with a large placebo component (an unanticipated mechanism).

The journal’s perspective

The view expressed by journals may be best conveyed by the editorial accompanying the placebo surgery methods paper in The Lancet:174

Writing in today’s The Lancet, David Beard and colleagues review the role of placebo controls in surgical trials and present recommendations for their use. Over the past 10 years there has been increasing recognition of the importance of the placebo effect, particularly how strong this effect could be for a surgical procedure that involves high-intensity medical care, strong analgesia, and often physiotherapy. The growing use of placebo-controlled surgical trials to re-examine common surgical procedures that have a biologically convincing mechanism and a long history of use has led to a wave of unexpected results. Of surgical procedures examined with this rigorous method, half were proven to be no more effective than placebo.

The systematic debunking of many well established, definitive operations has become perhaps the biggest story in surgical research this decade. Common procedures such as vertebroplasty and subacromial decompression have been shown to be largely ineffective, but these procedures continue to be in common use. Challenging current practice is difficult in many areas of medicine, particularly where there are potential personal and commercial vested interests, including private practice. Stopping the use of a common but debunked surgical intervention will be especially tough because the alternative is not a newer or better intervention but often a continuation of the patient’s current treatment course. For some of these procedures, where insurers or care commissioners have prevented surgeons from doing them, the discourse has often centred erroneously on rationing. The argument is not really about cost-effectiveness but rather that when robustly assessed, these procedures have been found to not be effective at all and still risk adverse effects.

Beard and colleagues discuss the need to plan for a negative result at the outset of a trial, anticipating the disruption that such a result produces, and creating processes to allow a transition of practice. The responsibility for doing this lies not only with surgical researchers, but also with the wider medical community. It is only by having the tenacious drive to question and critically assess with the most robust studies that we can leave behind ineffective procedures and concentrate on the many areas where surgery cures and heals.

Reprinted from The Lancet, vol. 395, Editorial. Gaining control: placebos in surgery trials, p. 756, Copyright (2020), with permission from Elsevier174

ASPIRE recommendation summary

A practical checklist that summarises the learning points from the ASPIRE guidelines and represents a minimum standard that researchers should attain and demonstrate when designing a placebo-controlled surgical trial is presented in Box 1.

Example of using the guidelines

An example is given of how the guidelines may be useful in the development and conduct of a placebo-controlled surgical trial.

A researcher is considering a study to assess the efficacy of a new surgical treatment for knee pain in patients with osteoarthritis of the knee (prior to arthroplasty). The team wish to demonstrate fundamental efficacy for the treatment and are aware of the potential non-specific effects and placebo effects of undergoing a surgical treatment. Therefore, as one option, they consider a placebo surgical control design. They familiarise themselves by reading the background sections on placebo definitions, placebo effect and design in these NIHR/Medical Research Council (MRC) guidelines. If the study can be answered without a placebo surgical control, or the question does not involve fundamental efficacy (perhaps comparative effectiveness) or lack of efficacy is already evident from studies not using placebo (Dr Teemu V Karjalainen, personal communication), then no further placebo involvement is needed.

If placebo control remains an option, then researchers can check through the ASPIRE guidelines to assist their decision-making. An important aspect is justification for using a placebo control, as such designs are complex and have an ethics aspect (see Chapter 6). The team agree that the placebo and non-specific effects are potentially large for the new intervention and may need to be accounted for by a placebo control. Before confirming this design, other designs are considered for answering the set research question. One alternative for exploring efficacy is a two-armed study comparing the treatment against ‘no treatment’ (natural history). A further option is a three-armed study with both placebo and ‘no treatment’ controls. After considering the trial conduct and recruitment aspect of placebo designs and the ethics implications (see Chapter 8), it is felt that not offering any treatment would be inappropriate and unsuccessful for this particular trial. Therefore, a two-armed surgical intervention compared with placebo surgical intervention is decided.

The content of the placebo surgical intervention is then decided by breaking the surgical procedure down into component constituents, as per the DITTO framework. A decision on the level of fidelity of the intervention to the definitive surgery is made. This is contingent on the research question, the type of surgery and practicalities of the surgery.

The ethics of the trial and treatment are considered, and clear patient information leaflets/consent forms are designed on this basis, again with reference to the ASPIRE guidelines.

The conduct of the trial is designed using information and assistance highlighted in the ASPIRE guidelines. In particular, aspects of equipoise (patient and clinician) are explored. The trial is submitted for funding. Funding bodies may use the ASPIRE guidelines to check thoroughness and understanding of placebo control in surgery by the research team. The trial is funded (if appropriate) and delivered.

Interpretation of the results can be made with reference to recommendations provided in the ASPIRE guidelines. Change of practice resulting from placebo-controlled surgical trials can also be pre-empted by reference to this document.

Submitted manuscripts for journals can be checked for completeness and understanding by editors and reviewers using these guidelines.

Further research priorities

• Evaluation of use of the ASPIRE guidelines in making decisions about the use of a placebo-controlled surgical trial.

• Use of the ASPIRE guidelines to assess the quality and comprehensiveness of pre-existing placebo-controlled surgical trials.

• Usability of the ASPIRE guidelines and evaluating their comprehensiveness.

• Further consideration of nomenclature in this area.

• Further work to establish when a placebo-controlled trial is warranted and necessary.

Contributions of authors

David J Beard (https://orcid.org/0000-0001-7884-6389) led the development of the submission, chaired the workshop, and led production of the initial and final version of the manuscript.

Marion K Campbell (https://orcid.org/0000-0001-5386-4097) contributed to the development of the submission, attended and presented a theme at the workshop, attended the workshop, led and produced the initial version of the manuscript, and read and approved the final version.

Jane M Blazeby (https://orcid.org/0000-0002-3354-3330) contributed to the development of the submission document, commented on the draft manuscript, and read and approved the final version. (Jane M Blazeby was unable to attend the workshop because of unforeseen circumstances.)

Andrew J Carr (https://orcid.org/0000-0001-5940-1464) contributed to the development of the submission document, attended and presented a theme at the workshop, commented on the draft manuscript, and read and approved the final version.

Charles Weijer (https://orcid.org/0000-0002-5510-1074) contributed to the development of the submission document, attended and presented a theme at the workshop, commented on the draft manuscript, and read and approved the final version.

Brian H Cuthbertson (https://orcid.org/0000-0003-4174-9424) contributed to the development of the submission document, attended and presented a theme at the workshop, commented on the draft manuscript, and read and approved the final version.

Rachelle Buchbinder (https://orcid.org/0000-0002-0597-0933) contributed to the development of the submission document, attended and presented a theme at the workshop, commented on the draft manuscript, and read and approved the final version.

Thomas Pinkney (https://orcid.org/0000-0001-7320-6673) contributed to the development of the submission document, attended and contributed to the workshop, commented on the draft manuscript, and read and approved the final version.

Felicity L Bishop (https://orcid.org/0000-0002-8737-6662) attended and presented a theme at the workshop, commented on the draft manuscript, and read and approved the final version.

Jonathan Pugh (https://orcid.org/0000-0003-4944-406X) attended and presented a theme at the workshop, commented on the draft manuscript, and read and approved the final version.

Sian Cousins (https://orcid.org/0000-0003-0088-841X) attended and presented a theme at the workshop, commented on the draft manuscript, and read and approved the final version.

Ian Harris (https://orcid.org/0000-0003-0887-7627) attended and presented a theme at the workshop, commented on the draft manuscript, and read and approved the final version.

L Stefan Lohmander (https://orcid.org/0000-0002-5424-9448) attended and presented a theme at the workshop, commented on the draft manuscript, and read and approved the final version.

Natalie Blencowe (https://orcid.org/0000-0002-6111-2175) contributed to the development of the submission document, attended and contributed to the workshop, commented on the draft manuscript, and read and approved the final version.

Katie Gillies (https://orcid.org/0000-0001-7890-2854) attended and presented a theme at the workshop, commented on the draft manuscript, and read and approved the final version.

Pascal Probst (https://orcid.org/0000-0002-0895-4015) attended and presented a theme at the workshop, commented on the draft manuscript, and read and approved the final version.

Carol Brennan (https://orcid.org/0000-0002-2356-6379) attended and presented a theme at the workshop, commented on the draft manuscript, and read and approved the final version.

Andrew Cook (https://orcid.org/0000-0002-6680-439X) attended and presented a theme at the workshop, commented on the draft manuscript, and read and approved the final version.

Dair Farrar-Hockley (https://orcid.org/0000-0002-5034-1669) contributed to the development of the submission document, attended and presented a theme at the workshop, commented on the draft manuscript, and read and approved the final version.

Julian Savulescu (https://orcid.org/0000-0003-1691-6403) contributed to the development of the submission document, commented on the draft manuscript, and read and approved the final version. (Julian Savulescu was unable to attend the workshop because of unforeseen circumstances.)

Richard Huxtable (https://orcid.org/0000-0002-5802-1870) attended and presented a theme at the workshop, commented on the draft manuscript, and read and approved the final version.

Amar Rangan (https://orcid.org/0000-0002-5452-8578) attended and contributed to the workshop, commented on the draft manuscript, and read and approved the final version.

Irene Tracey (https://orcid.org/0000-0003-4134-6115) contributed to the development of the submission document, attended and presented a theme at the workshop, commented on the draft manuscript, and read and approved the final version.

Peter Brocklehurst (https://orcid.org/0000-0002-9950-6751) attended and presented a theme at the workshop, commented on the draft manuscript, and read and approved the final version.

Manuela L Ferreira (https://orcid.org/0000-0002-3479-0683) was unable to attend the workshop, but contributed to manuscript preparation, commented on the draft manuscript, and read and approved the final version.

Jon Nicholl (https://orcid.org/0000-0001-5436-1264) attended and contributed to the workshop, commented on the draft manuscript, and read and approved the final version.

Barnaby C Reeves (https://orcid.org/0000-0002-5101-9487) attended and presented a theme at the workshop, commented on the draft manuscript, and read and approved the final version.

Freddie Hamdy (https://orcid.org/0000-0003-2627-2154) attended and presented a theme at the workshop, commented on the draft manuscript, and read and approved the final version.

Samuel CS Rowley (https://orcid.org/0000-0002-2468-801X) attended and contributed to the workshop, commented on the draft manuscript, and read and approved the final version.

Naomi Lee (https://orcid.org/0000-0003-0100-9659) attended and presented a theme at the workshop, commented on the draft manuscript, and read and approved the final version.

Jonathan A Cook (https://orcid.org/0000-0002-4156-6989) led the development of the submission, attended and presented a theme at the workshop, contributed to the initial version of the manuscript, and read and approved the final version.

Dissemination

The findings from the work have been presented in this report to the MRC/NIHR.

The findings were presented at the Society for Clinical Trials 2020 Annual Meeting [originally due to be in Baltimore, MD, USA (17–20 May 2020), but was converted to an online virtual conference on the same date because of the COVID-19 pandemic].

Publications

Beard DJ, Campbell MK, Blazeby JM, Carr AJ, Weijer C, Cuthbertson BH, et al. Considerations and methods for placebo controls in surgical trials (ASPIRE guidelines). Lancet 2020;395:828–38.

Cousins S, Blencowe NS, Tsang C, Chalmers K, Mardanpour A, Carr AJ, et al. Optimizing the design of invasive placebo interventions in randomized controlled trials. Br J Surg 2020;107:1114–22.

Cousins S, Blencowe NS, Tsang C, Lorenc A, Chalmers K, Carr AJ, et al. Reporting of key methodological issues in placebo-controlled trials of surgery needs improvement: a systematic review. J Clin Epidemiol 2020;119:109–16.

Data-sharing statement

All data requests should be submitted to the corresponding author for consideration. Access to anonymised data may be granted following review.

Disclaimers

This report presents independent research funded under a MRC–NIHR partnership. The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, the MRC, NETSCC, the HTA programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, the MRC, NETSCC, the HTA programme or the Department of Health and Social Care.

6 and 7 December 2018 at St Anne’s College, 56 Woodstock Road, Oxford, OX2 6HS, UK