Accepted Article
A novel randomised controlled trial design in prostate cancer 1
Eleni Anastasiadisa, Hashim Uddin Ahmedb,c, Clare Reltond, Mark Embertonb,c
a
Clinical Effectiveness Unit (CEU), Royal College of Surgeons of England and
London School of Hygiene and Tropical Medicine, London, UK b
Division of Surgery and Interventional Science, University College London, UK
c
Department of Urology, University College London Hospitals NHS Foundation Trust,
London, UK d
School of Health & Related Research (Public Health section), University of
Sheffield, Sheffield, UK
Address for Correspondence:
Eleni Anastasiadis
The Clinical Effectiveness Unit
The Royal College of Surgeons of England
35-43 Lincoln's Inn Fields
London
WC2A 3PE
Email: [email protected] Tel: 020 7869 6600
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bju.12735
This article is protected by copyright. All rights reserved.
Accepted Article
Email addresses for Authors:
Hashim Uddin Ahmed - [email protected] Clare Relton - [email protected] Mark Emberton - [email protected]
Words: 1000
Abstract
Objectives: To discuss the challenges in recruitment to head-to-head randomised controlled trials (RCTs) in prostate cancer, and to introduce a novel alternative design - the cohort-embedded multiple randomised control trial (cmRCT). Methods: Commentary. Results and conclusions: The cmRCT design may offer an efficient method for recruitment to prostate cancer trials and for ascertaining long-term outcomes.
Introduction Randomised controlled trials (RCTs) on surgical interventions often pose significant methodological challenges(1). The problems have been extensively reviewed by the proponents of
the IDEAL approach to the evaluation of
novel surgical
procedures(1,2). Problems include:
1) Professional resistance due to lack of clinical equipoise (i.e. surgeon’s belief that the treatments being offered may not be in the patient’s best interest)(1,2);
This article is protected by copyright. All rights reserved.
Accepted Article
2) Lack of ability to blind patients and surgeon to treatment allocation(1,2); 3) Technical improvements in the intervention during the course of a trial(1,2); 4) Patients not wanting their treatments to be decided by chance alone(1,2).
Similar concerns were found in a Health Technology Assessment (HTA) study assessing barriers to recruitment for the Prostate Testing for Cancer and Treatment (ProtecT) study(3). With one or two notable exceptions(3,4), trials evaluating prostate cancer treatments in early disease have failed to accrue despite incorporating lessons learned from pilot studies(3). These problems tend to be underestimated, as the number of men approached for recruitment is never truly disclosed. Where there have been successes(3,4), large amounts of funding was required, e.g. GBP35million in the ProtecT study.
An alternative trial method Relton et al described an alternative method to the standard RCT, in an attempt to overcome some of these issues whilst retaining the robust need for reducing bias in comparative effectiveness research. They proposed the “cohort multiple randomised control trial (cmRCT)” (Box 1)(5). The cmRCT design entails the creation of an observational cohort of patients who consent to be followed-up over time. A proportion of those eligible for a trial intervention are selected randomly and offered the novel intervention, the rest form the “control” arm and receive usual care. Some of these controls could be randomised at a later date to participate in the intervention arm of a second RCT – i.e. multiple RCTs can be embedded in this cohort. The
controls would be eligible to participate in other traditional RCTs provided that they continue to receive standard treatment.
The cmRCT is being used in (non-surgical) trials in the United Kingdom and Canada, and, more recently, within breast and rectal cancer in the Netherlands. Funders for
This article is protected by copyright. All rights reserved.
Accepted Article
these trials include major institutions such as the National Institute for Health Research (NIHR) Health Technology Assessment Programme (HTA) in the U.K (7) and the Canadian Institute for Health Research (CIHR).
Is the cmRCT design the way forward for prostate cancer trials in the U.K? Figure 1 illustrates how the cmRCT design might work. Men would be approached and consented to: 1) join the cohort and have questionnaires sent to them for the first few years, to collect information on functional and quality of life (active follow-up); 2) be followed-up in the long-term via electronic data on healthcare utilisation and vital status (passive follow-up); and 3) be contacted should they become eligible for a trial of a new treatment (only the eligible patients who are randomised to the intervention under trial would be contacted). After the initial limited period of “active” follow-up, the status of the patient could be defined and updated electronically, at little expense, from currently existing electronic data sources that routinely collect data. For example, GP electronic records could be used to ascertain whether patients have been started on androgen suppression therapy (indicating a change from nonmetastatic to metastatic disease), and treatments can be tracked through cancer registry and hospital admissions data. This method may thus be more cost efficient than the traditional RCT. One of the problems of any RCT is that patients may refuse to receive an intervention to which they are randomly allocated to(5). An intention to treat analysis is usually undertaken to overcome this, but dilutes the treatment effects. There are a further two methods that can mitigate this: 1) the “complier average causal effect (CACE)” analysis, which compares the outcome of “compliers” in the intervention group to the estimated “compliers” in the control group. This method may result in loss of power, but can provide an unbiased estimate of treatment effect (in contrast to per protocol or on treatment analysis)(5,6); and 2) patients can be shown a list of possible interventions at the start of the cohort consent process, asking them which
This article is protected by copyright. All rights reserved.
Accepted Article
they would agree to use if offered to them – this process may identify non-compliers
and can reduce the dilution effect(5).
How acceptable is the cmRCT design? We conducted a small focus group with six men volunteering through a local Prostate Cancer Support Group in London, to gauge the attitudes of patients to the cmRCT. The men were aged between 60-80 years, and had varying stages of prostate cancer. All gave written consent, and the process received ethics exemption by the Chairman of the Bloomsbury NHS Research Ethics Committee. In the focus group, an overview of the concept of randomisation and design aspects of head-to-head RCTs were given. The cmRCT design was explained to the group (Figure 1). Men were asked to comment freely.
The consensus was that the “basic idea was good” - they could retain choice over their treatment and clinician. The group felt that they would agree to being approached in the future if a new intervention became available in a clinical trial, but the consent process should be clear on this at the outset.
The idea of the trial becoming passive after the first few years was also well received: “ . . . Passive follow up is particularly attractive . . .”
Linkage to electronic data in order to ascertain long-term outcomes was acceptable to the group, provided confidentiality was safeguarded and that there was a research benefit.
This is a small, preliminary piece of research in a self-selecting group of men (which is not representative of all men with prostate cancer), but is the first step in assessing
This article is protected by copyright. All rights reserved.
Accepted Article
how patients may react if approached to participate in a cmRCT. Further research in this area is required.
Conclusions With multi-institutional collaboration, large cohorts of men can be followed-up within the cmRCT design, and may provide an efficient method for recruitment to trials and ascertaining long-term outcomes.
Competing Interests EA and CR declare no competing interests. ME and HUA receive funding from USHIFU, GSK and Advanced Medical Diagnostics for clinical trials. ME and HUA are paid consultants to Steba Biotech. ME is a paid medical consultant to USHIFU. ME and HUA have previously received medical consultancy fees from GE Healthcare/ Oncura. None of the funding sources had any role in the data acquisition, analyses and production of this manuscript.
Acknowledgements We would like to thank the men participating in the focus group for their time and help. We would like to acknowledge Mary Turner, Cancer Support Specialist, and Maggie's London (a cancer support centre situated in the grounds of Charing Cross Hospital), for all their assistance in recruiting and hosting patients for the patient focus group.
This article is protected by copyright. All rights reserved.
Accepted Article
References
1.
Ergina PL, Cook JA, Blazeby JM, et al. Challenges in evaluating surgical innovation. Lancet. 2009 Sep 26;374(9695):1097–104.
2.
McCulloch P, Altman DG, Campbell WB, et al. No surgical innovation without evaluation:
the
IDEAL
recommendations.
Lancet.
2009
Sep
26;374(9695):1105–12.
3.
Donovan J, Hamdy F, Neal D, et al. Prostate Testing for Cancer and Treatment
(ProtecT)
feasibility
study.
Health
technology
assessment
(Winchester, England). 2003 Jan;7(14):1–88.
4.
Wilt TJ. SPCG-4: a needed START to PIVOTal data to promote and protect evidence-based prostate cancer care. Journal of the National Cancer Institute. 2008 Aug 20;100(16):1123–5.
5.
Relton C, Torgerson D, O’Cathain A, Nicholl J. Rethinking pragmatic randomised controlled trials: introducing the “cohort multiple randomised controlled trial” design. BMJ (Clinical research ed.). 2010 Jan;340:c1066.
6.
Hewitt CE, Torgerson DJ, Miles JN V. Is there another way to take account of noncompliance in randomized controlled trials? CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne. 2006 Aug 15;175(4):347.
7.
Torgerson D. Randomised trial of a multifaceted podiatry intervention for fall prevention in patients over 70 years of age - ISRCTN68240461 [Internet]. ISRCTN - International Standard Randomised Controlled Trials Number. 2012. Available from: http://www.controlled-trials.com/ISRCTN68240461
This article is protected by copyright. All rights reserved.
Accepted Article
Box 1: Advantages and disadvantages of cmRCT methodology
This article is protected by copyright. All rights reserved.
Accepted Article
Figure 1: The cmRCT method proposed
This article is protected by copyright. All rights reserved.
A novel randomised controlled trial design in prostate cancer 1
Eleni Anastasiadisa, Hashim Uddin Ahmedb,c, Clare Reltond, Mark Embertonb,c
a
Clinical Effectiveness Unit (CEU), Royal College of Surgeons of England and
London School of Hygiene and Tropical Medicine, London, UK b
Division of Surgery and Interventional Science, University College London, UK
c
Department of Urology, University College London Hospitals NHS Foundation Trust,
London, UK d
School of Health & Related Research (Public Health section), University of
Sheffield, Sheffield, UK
Address for Correspondence:
Eleni Anastasiadis
The Clinical Effectiveness Unit
The Royal College of Surgeons of England
35-43 Lincoln's Inn Fields
London
WC2A 3PE
Email: [email protected] Tel: 020 7869 6600
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bju.12735
This article is protected by copyright. All rights reserved.
Accepted Article
Email addresses for Authors:
Hashim Uddin Ahmed - [email protected] Clare Relton - [email protected] Mark Emberton - [email protected]
Words: 1000
Abstract
Objectives: To discuss the challenges in recruitment to head-to-head randomised controlled trials (RCTs) in prostate cancer, and to introduce a novel alternative design - the cohort-embedded multiple randomised control trial (cmRCT). Methods: Commentary. Results and conclusions: The cmRCT design may offer an efficient method for recruitment to prostate cancer trials and for ascertaining long-term outcomes.
Introduction Randomised controlled trials (RCTs) on surgical interventions often pose significant methodological challenges(1). The problems have been extensively reviewed by the proponents of
the IDEAL approach to the evaluation of
novel surgical
procedures(1,2). Problems include:
1) Professional resistance due to lack of clinical equipoise (i.e. surgeon’s belief that the treatments being offered may not be in the patient’s best interest)(1,2);
This article is protected by copyright. All rights reserved.
Accepted Article
2) Lack of ability to blind patients and surgeon to treatment allocation(1,2); 3) Technical improvements in the intervention during the course of a trial(1,2); 4) Patients not wanting their treatments to be decided by chance alone(1,2).
Similar concerns were found in a Health Technology Assessment (HTA) study assessing barriers to recruitment for the Prostate Testing for Cancer and Treatment (ProtecT) study(3). With one or two notable exceptions(3,4), trials evaluating prostate cancer treatments in early disease have failed to accrue despite incorporating lessons learned from pilot studies(3). These problems tend to be underestimated, as the number of men approached for recruitment is never truly disclosed. Where there have been successes(3,4), large amounts of funding was required, e.g. GBP35million in the ProtecT study.
An alternative trial method Relton et al described an alternative method to the standard RCT, in an attempt to overcome some of these issues whilst retaining the robust need for reducing bias in comparative effectiveness research. They proposed the “cohort multiple randomised control trial (cmRCT)” (Box 1)(5). The cmRCT design entails the creation of an observational cohort of patients who consent to be followed-up over time. A proportion of those eligible for a trial intervention are selected randomly and offered the novel intervention, the rest form the “control” arm and receive usual care. Some of these controls could be randomised at a later date to participate in the intervention arm of a second RCT – i.e. multiple RCTs can be embedded in this cohort. The
controls would be eligible to participate in other traditional RCTs provided that they continue to receive standard treatment.
The cmRCT is being used in (non-surgical) trials in the United Kingdom and Canada, and, more recently, within breast and rectal cancer in the Netherlands. Funders for
This article is protected by copyright. All rights reserved.
Accepted Article
these trials include major institutions such as the National Institute for Health Research (NIHR) Health Technology Assessment Programme (HTA) in the U.K (7) and the Canadian Institute for Health Research (CIHR).
Is the cmRCT design the way forward for prostate cancer trials in the U.K? Figure 1 illustrates how the cmRCT design might work. Men would be approached and consented to: 1) join the cohort and have questionnaires sent to them for the first few years, to collect information on functional and quality of life (active follow-up); 2) be followed-up in the long-term via electronic data on healthcare utilisation and vital status (passive follow-up); and 3) be contacted should they become eligible for a trial of a new treatment (only the eligible patients who are randomised to the intervention under trial would be contacted). After the initial limited period of “active” follow-up, the status of the patient could be defined and updated electronically, at little expense, from currently existing electronic data sources that routinely collect data. For example, GP electronic records could be used to ascertain whether patients have been started on androgen suppression therapy (indicating a change from nonmetastatic to metastatic disease), and treatments can be tracked through cancer registry and hospital admissions data. This method may thus be more cost efficient than the traditional RCT. One of the problems of any RCT is that patients may refuse to receive an intervention to which they are randomly allocated to(5). An intention to treat analysis is usually undertaken to overcome this, but dilutes the treatment effects. There are a further two methods that can mitigate this: 1) the “complier average causal effect (CACE)” analysis, which compares the outcome of “compliers” in the intervention group to the estimated “compliers” in the control group. This method may result in loss of power, but can provide an unbiased estimate of treatment effect (in contrast to per protocol or on treatment analysis)(5,6); and 2) patients can be shown a list of possible interventions at the start of the cohort consent process, asking them which
This article is protected by copyright. All rights reserved.
Accepted Article
they would agree to use if offered to them – this process may identify non-compliers
and can reduce the dilution effect(5).
How acceptable is the cmRCT design? We conducted a small focus group with six men volunteering through a local Prostate Cancer Support Group in London, to gauge the attitudes of patients to the cmRCT. The men were aged between 60-80 years, and had varying stages of prostate cancer. All gave written consent, and the process received ethics exemption by the Chairman of the Bloomsbury NHS Research Ethics Committee. In the focus group, an overview of the concept of randomisation and design aspects of head-to-head RCTs were given. The cmRCT design was explained to the group (Figure 1). Men were asked to comment freely.
The consensus was that the “basic idea was good” - they could retain choice over their treatment and clinician. The group felt that they would agree to being approached in the future if a new intervention became available in a clinical trial, but the consent process should be clear on this at the outset.
The idea of the trial becoming passive after the first few years was also well received: “ . . . Passive follow up is particularly attractive . . .”
Linkage to electronic data in order to ascertain long-term outcomes was acceptable to the group, provided confidentiality was safeguarded and that there was a research benefit.
This is a small, preliminary piece of research in a self-selecting group of men (which is not representative of all men with prostate cancer), but is the first step in assessing
This article is protected by copyright. All rights reserved.
Accepted Article
how patients may react if approached to participate in a cmRCT. Further research in this area is required.
Conclusions With multi-institutional collaboration, large cohorts of men can be followed-up within the cmRCT design, and may provide an efficient method for recruitment to trials and ascertaining long-term outcomes.
Competing Interests EA and CR declare no competing interests. ME and HUA receive funding from USHIFU, GSK and Advanced Medical Diagnostics for clinical trials. ME and HUA are paid consultants to Steba Biotech. ME is a paid medical consultant to USHIFU. ME and HUA have previously received medical consultancy fees from GE Healthcare/ Oncura. None of the funding sources had any role in the data acquisition, analyses and production of this manuscript.
Acknowledgements We would like to thank the men participating in the focus group for their time and help. We would like to acknowledge Mary Turner, Cancer Support Specialist, and Maggie's London (a cancer support centre situated in the grounds of Charing Cross Hospital), for all their assistance in recruiting and hosting patients for the patient focus group.
This article is protected by copyright. All rights reserved.
Accepted Article
References
1.
Ergina PL, Cook JA, Blazeby JM, et al. Challenges in evaluating surgical innovation. Lancet. 2009 Sep 26;374(9695):1097–104.
2.
McCulloch P, Altman DG, Campbell WB, et al. No surgical innovation without evaluation:
the
IDEAL
recommendations.
Lancet.
2009
Sep
26;374(9695):1105–12.
3.
Donovan J, Hamdy F, Neal D, et al. Prostate Testing for Cancer and Treatment
(ProtecT)
feasibility
study.
Health
technology
assessment
(Winchester, England). 2003 Jan;7(14):1–88.
4.
Wilt TJ. SPCG-4: a needed START to PIVOTal data to promote and protect evidence-based prostate cancer care. Journal of the National Cancer Institute. 2008 Aug 20;100(16):1123–5.
5.
Relton C, Torgerson D, O’Cathain A, Nicholl J. Rethinking pragmatic randomised controlled trials: introducing the “cohort multiple randomised controlled trial” design. BMJ (Clinical research ed.). 2010 Jan;340:c1066.
6.
Hewitt CE, Torgerson DJ, Miles JN V. Is there another way to take account of noncompliance in randomized controlled trials? CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne. 2006 Aug 15;175(4):347.
7.
Torgerson D. Randomised trial of a multifaceted podiatry intervention for fall prevention in patients over 70 years of age - ISRCTN68240461 [Internet]. ISRCTN - International Standard Randomised Controlled Trials Number. 2012. Available from: http://www.controlled-trials.com/ISRCTN68240461
This article is protected by copyright. All rights reserved.
Accepted Article
Box 1: Advantages and disadvantages of cmRCT methodology
This article is protected by copyright. All rights reserved.
Accepted Article
Figure 1: The cmRCT method proposed
This article is protected by copyright. All rights reserved.
