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

David J. Beard; Marion K. Campbell; Jane M. Blazeby; Andrew J. Carr; Charles Weijer; Brian H. Cuthbertson; Rachelle Buchbinder; Thomas Pinkney; Felicity L. Bishop; Jonathan Pugh; Sian Cousins; Ian Harris; L. Stefan Lohmander; Natalie Blencowe; Katie Gillies; Pascal Probst; Carol Brennan; Andrew Cook; Dair Farrar-Hockley; Julian Savulescu; Richard Huxtable; Amar Rangan; Irene Tracey; Peter Brocklehurst; Manuela L. Ferreira; Jon Nicholl; Barnaby C. Reeves; Freddie Hamdy; Samuel C. S. Rowley; Naomi Lee; Jonathan A. Cook

doi:10.3310/hta25530

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

David J. Beard^*, Marion K. Campbell, Jane M. Blazeby, Andrew J. Carr, Charles Weijer, Brian H. Cuthbertson, Rachelle Buchbinder, Thomas Pinkney, Felicity L. Bishop, Jonathan Pugh, Sian Cousins, Ian Harris, L. Stefan Lohmander, Natalie Blencowe, Katie Gillies, Pascal Probst, Carol Brennan, Andrew Cook, Dair Farrar-Hockley, Julian SavulescuRichard Huxtable, Amar Rangan, Irene Tracey, Peter Brocklehurst, Manuela L. Ferreira, Jon Nicholl, Barnaby C. Reeves, Freddie Hamdy, Samuel C. S. Rowley, Naomi Lee, Jonathan A. Cook

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Background: The use of placebo comparisons for randomised trials assessing the efficacy of surgical interventions is increasingly being considered. However, a placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges.

Objectives: To provide a summary of knowledge on placebo controls in surgical trials and to summarise any recommendations for designers, evaluators and funders of placebo-controlled surgical trials.

Design: To carry out a state-of-the-art workshop and produce a corresponding report involving key stakeholders throughout.

Setting: A workshop to discuss and summarise the existing knowledge and to develop the new guidelines.

Results: To assess what a placebo control entails and to assess the understanding of this tool in the context of surgery is considered, along with when placebo controls in surgery are acceptable (and when they are desirable). We have considered ethics arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be carried out and interpreted. The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with a high risk of bias, particularly because of the placebo effect.

Conclusions: The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. An outline for best practice was produced in the form of the Applying Surgical Placebo in Randomised Evaluations (ASPIRE) guidelines for those considering the use of a placebo control in a surgical randomised controlled trial.

Limitations: Although the workshop participants involved international members, the majority of participants were from the UK. Therefore, although every attempt was made to make the recommendations applicable to all health systems, the guidelines may, unconsciously, be particularly applicable to clinical practice in the UK NHS.

Future work: Future work should evaluate the use of the ASPIRE guidelines in making decisions about the use of a placebo-controlled surgical trial. In addition, further work is required on the appropriate nomenclature to adopt in this space.

Original language	English
Number of pages	72
Journal	Health Technology Assessment
Volume	25
Issue number	53
DOIs	https://doi.org/10.3310/hta25530
Publication status	Published - Sept 2021

Bibliographical note

Funding: Funded by the Medical Research Council UK and the National Institute for Health Research as part of the Medical Research Council–National Institute for Health Research Methodology Research programme.

Acknowledgements
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.

Keywords

GASTROESOPHAGEAL-REFLUX DISEASE
OBSTRUCTIVE SLEEP-APNEA
LASER PHOTO-COAGULATION
MAMMARY-ARTERY LIGATION
BLIND CONTROLLED-TRIAL
SHAM-CONTROLLED TRIAL
RANDOMIZED-TRIAL
ENDOSCOPIC SPHINCTEROTOMY
KNEE OSTEOARTHRITIS
GASTRIC BUBBLE

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Cite this

Beard, D. J., Campbell, M. K., Blazeby, J. M., Carr, A. J., Weijer, C., Cuthbertson, B. H., Buchbinder, R., Pinkney, T., Bishop, F. L., Pugh, J., Cousins, S., Harris, I., Lohmander, L. S., Blencowe, N., Gillies, K., Probst, P., Brennan, C., Cook, A., Farrar-Hockley, D., ... Cook, J. A. (2021). Placebo comparator group selection and use in surgical trials: the ASPIRE project including expert workshop. Health Technology Assessment, 25(53). https://doi.org/10.3310/hta25530

Beard, DJ, Campbell, MK, Blazeby, JM, Carr, AJ, Weijer, C, Cuthbertson, BH, Buchbinder, R, Pinkney, T, Bishop, FL, Pugh, J, Cousins, S, Harris, I, Lohmander, LS, Blencowe, N, Gillies, K, Probst, P, Brennan, C, Cook, A, Farrar-Hockley, D, Savulescu, J, Huxtable, R, Rangan, A, Tracey, I, Brocklehurst, P, Ferreira, ML, Nicholl, J, Reeves, BC, Hamdy, F, Rowley, SCS, Lee, N & Cook, JA 2021, 'Placebo comparator group selection and use in surgical trials: the ASPIRE project including expert workshop', Health Technology Assessment, vol. 25, no. 53. https://doi.org/10.3310/hta25530

@article{cf6f8314a093405c83db8c66606d8695,

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

abstract = "Background: The use of placebo comparisons for randomised trials assessing the efficacy of surgical interventions is increasingly being considered. However, a placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges.Objectives: To provide a summary of knowledge on placebo controls in surgical trials and to summarise any recommendations for designers, evaluators and funders of placebo-controlled surgical trials.Design: To carry out a state-of-the-art workshop and produce a corresponding report involving key stakeholders throughout.Setting: A workshop to discuss and summarise the existing knowledge and to develop the new guidelines.Results: To assess what a placebo control entails and to assess the understanding of this tool in the context of surgery is considered, along with when placebo controls in surgery are acceptable (and when they are desirable). We have considered ethics arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be carried out and interpreted. The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with a high risk of bias, particularly because of the placebo effect.Conclusions: The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. An outline for best practice was produced in the form of the Applying Surgical Placebo in Randomised Evaluations (ASPIRE) guidelines for those considering the use of a placebo control in a surgical randomised controlled trial.Limitations: Although the workshop participants involved international members, the majority of participants were from the UK. Therefore, although every attempt was made to make the recommendations applicable to all health systems, the guidelines may, unconsciously, be particularly applicable to clinical practice in the UK NHS.Future work: Future work should evaluate the use of the ASPIRE guidelines in making decisions about the use of a placebo-controlled surgical trial. In addition, further work is required on the appropriate nomenclature to adopt in this space.",

keywords = "GASTROESOPHAGEAL-REFLUX DISEASE, OBSTRUCTIVE SLEEP-APNEA, LASER PHOTO-COAGULATION, MAMMARY-ARTERY LIGATION, BLIND CONTROLLED-TRIAL, SHAM-CONTROLLED TRIAL, RANDOMIZED-TRIAL, ENDOSCOPIC SPHINCTEROTOMY, KNEE OSTEOARTHRITIS, GASTRIC BUBBLE",

author = "Beard, {David J.} and Campbell, {Marion K.} and Blazeby, {Jane M.} and Carr, {Andrew J.} and Charles Weijer and Cuthbertson, {Brian H.} and Rachelle Buchbinder and Thomas Pinkney and Bishop, {Felicity L.} and Jonathan Pugh and Sian Cousins and Ian Harris and Lohmander, {L. Stefan} and Natalie Blencowe and Katie Gillies and Pascal Probst and Carol Brennan and Andrew Cook and Dair Farrar-Hockley and Julian Savulescu and Richard Huxtable and Amar Rangan and Irene Tracey and Peter Brocklehurst and Ferreira, {Manuela L.} and Jon Nicholl and Reeves, {Barnaby C.} and Freddie Hamdy and Rowley, {Samuel C. S.} and Naomi Lee and Cook, {Jonathan A.}",

note = "Funding: Funded by the Medical Research Council UK and the National Institute for Health Research as part of the Medical Research Council–National Institute for Health Research Methodology Research programme. Acknowledgements 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{\textquoteright}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.",

year = "2021",

month = sep,

doi = "10.3310/hta25530",

language = "English",

volume = "25",

journal = "Health Technology Assessment",

issn = "1366-5278",

publisher = "National Co-ordinating Centre for HTA",

number = "53",

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TY - JOUR

T1 - Placebo comparator group selection and use in surgical trials

T2 - the ASPIRE project including expert workshop

AU - Beard, David J.

AU - Campbell, Marion K.

AU - Blazeby, Jane M.

AU - Carr, Andrew J.

AU - Weijer, Charles

AU - Cuthbertson, Brian H.

AU - Buchbinder, Rachelle

AU - Pinkney, Thomas

AU - Bishop, Felicity L.

AU - Pugh, Jonathan

AU - Cousins, Sian

AU - Harris, Ian

AU - Lohmander, L. Stefan

AU - Blencowe, Natalie

AU - Gillies, Katie

AU - Probst, Pascal

AU - Brennan, Carol

AU - Cook, Andrew

AU - Farrar-Hockley, Dair

AU - Savulescu, Julian

AU - Huxtable, Richard

AU - Rangan, Amar

AU - Tracey, Irene

AU - Brocklehurst, Peter

AU - Ferreira, Manuela L.

AU - Nicholl, Jon

AU - Reeves, Barnaby C.

AU - Hamdy, Freddie

AU - Rowley, Samuel C. S.

AU - Lee, Naomi

AU - Cook, Jonathan A.

N1 - Funding: Funded by the Medical Research Council UK and the National Institute for Health Research as part of the Medical Research Council–National Institute for Health Research Methodology Research programme. Acknowledgements 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.

PY - 2021/9

Y1 - 2021/9

N2 - Background: The use of placebo comparisons for randomised trials assessing the efficacy of surgical interventions is increasingly being considered. However, a placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges.Objectives: To provide a summary of knowledge on placebo controls in surgical trials and to summarise any recommendations for designers, evaluators and funders of placebo-controlled surgical trials.Design: To carry out a state-of-the-art workshop and produce a corresponding report involving key stakeholders throughout.Setting: A workshop to discuss and summarise the existing knowledge and to develop the new guidelines.Results: To assess what a placebo control entails and to assess the understanding of this tool in the context of surgery is considered, along with when placebo controls in surgery are acceptable (and when they are desirable). We have considered ethics arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be carried out and interpreted. The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with a high risk of bias, particularly because of the placebo effect.Conclusions: The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. An outline for best practice was produced in the form of the Applying Surgical Placebo in Randomised Evaluations (ASPIRE) guidelines for those considering the use of a placebo control in a surgical randomised controlled trial.Limitations: Although the workshop participants involved international members, the majority of participants were from the UK. Therefore, although every attempt was made to make the recommendations applicable to all health systems, the guidelines may, unconsciously, be particularly applicable to clinical practice in the UK NHS.Future work: Future work should evaluate the use of the ASPIRE guidelines in making decisions about the use of a placebo-controlled surgical trial. In addition, further work is required on the appropriate nomenclature to adopt in this space.

AB - Background: The use of placebo comparisons for randomised trials assessing the efficacy of surgical interventions is increasingly being considered. However, a placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges.Objectives: To provide a summary of knowledge on placebo controls in surgical trials and to summarise any recommendations for designers, evaluators and funders of placebo-controlled surgical trials.Design: To carry out a state-of-the-art workshop and produce a corresponding report involving key stakeholders throughout.Setting: A workshop to discuss and summarise the existing knowledge and to develop the new guidelines.Results: To assess what a placebo control entails and to assess the understanding of this tool in the context of surgery is considered, along with when placebo controls in surgery are acceptable (and when they are desirable). We have considered ethics arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be carried out and interpreted. The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with a high risk of bias, particularly because of the placebo effect.Conclusions: The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. An outline for best practice was produced in the form of the Applying Surgical Placebo in Randomised Evaluations (ASPIRE) guidelines for those considering the use of a placebo control in a surgical randomised controlled trial.Limitations: Although the workshop participants involved international members, the majority of participants were from the UK. Therefore, although every attempt was made to make the recommendations applicable to all health systems, the guidelines may, unconsciously, be particularly applicable to clinical practice in the UK NHS.Future work: Future work should evaluate the use of the ASPIRE guidelines in making decisions about the use of a placebo-controlled surgical trial. In addition, further work is required on the appropriate nomenclature to adopt in this space.

KW - GASTROESOPHAGEAL-REFLUX DISEASE

KW - OBSTRUCTIVE SLEEP-APNEA

KW - LASER PHOTO-COAGULATION

KW - MAMMARY-ARTERY LIGATION

KW - BLIND CONTROLLED-TRIAL

KW - SHAM-CONTROLLED TRIAL

KW - RANDOMIZED-TRIAL

KW - ENDOSCOPIC SPHINCTEROTOMY

KW - KNEE OSTEOARTHRITIS

KW - GASTRIC BUBBLE

U2 - 10.3310/hta25530

DO - 10.3310/hta25530

M3 - Article

SN - 1366-5278

VL - 25

JO - Health Technology Assessment

JF - Health Technology Assessment

IS - 53

ER -

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

Abstract

Bibliographical note

Keywords

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