Applicants for the commission were Professor David Beard, Associate Professor Jonathan Cook, Professor Marion Campbell, Professor Jane Blazeby, Professor Andrew Carr, Associate Professor Thomas Pinkney, Professor Brian Cuthbertson, Professor Irene Tracey, Professor Rachelle Buchbinder, Professor Julian Savulescu, Mr Dair Farrah-Hockley and Dr Natalie Blencowe.
As part of the process of developing the ASPIRE guidelines, a 2-day workshop was held in St Anne’s College (Oxford, UK) in December 2018. In addition to the applicants, the academic workshop participants were Dr Jonathan Pugh, Dr Felicity Bishop, Dr Sian Cousins, Professor Charles Weijer, Prof Richard Huxtable, Professor Jon Nicholl, Professor Pascal Probst, Professor Peter Brocklehurst, Dr Andrew Cook, Dr Katie Gillies, Professor Freddie Hamdy, Professor Ian Harris, Dr Naomi Lee, Professor Stefan Lohmander, Professor Amar Rangan, Professor Barney Reeves and Dr Sam Rowley.
Dr Carol Brennan and Mr Dair Farrah-Hockley kindly attended as patient representatives.
Dr Sian Cousins and Dr Natalie Blencowe kindly took detailed cross-referenced notes throughout and recorded the workshop discussions.
Ms Katie Chegwin was responsible for the administration and organisation of the workshop, editing of the manuscript and is thanked for her assistance.
Near-complete versions of the report were also sent to Professor Marion Campbell, Professor Jonathan Cook and Professor Manuela Ferreira for additional review, comment and edit.
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.
ASPIRE checklist for the design and conduct of placebo surgical controls in randomised trials
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.
