Are clinical trials units essential for a successful trial?BMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h2823 (Published 27 May 2015) Cite this as: BMJ 2015;350:h2823
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We prefer a CTU, set within an academic centre, above a single trial manager functioning in a ‘standalone context’ for the following reasons:
An academic CTU that acts as a centre-point for those in the academic centre interested in developing and conducting clinical studies, enables the involvement of all relevant multidisciplinary expertise in a clinical study. Being easy accessible and liaising closely with the clinician-investigators, an academic CTU ensures that the clinician-investigators are adequately supported during the design, conduct, analysis, and report of the study and the link with the medical community and patient population is preserved.
Having a quality system in place, compliance of the CTU’s services with the Good Clinical Practice guidelines (ICH-GCP) (1) and other applicable (inter)national guidelines and legislation is assured. This safeguards the quality, safety and ethical conduct of clinical studies.
Additionally, an academic CTU offers the ability to train research personnel as well as to develop/explore new methodologies associated with clinical studies.
Moreover, academic CTU support has the advantage that long-term continuity of staff is ensured and multidisciplinary knowledge and expertise are maintained and continuously improved, in contrast to a single project manager working under standalone conditions. Especially in the investigator-initiated research environment, the project manager often is a young, unexperienced investigator, who does this job within the context of obtaining an academic degree (PhD). Once the research project (and thesis) is finished, this person leaves and, thereby, built research capacity is lost and invested resources are inefficiently used.
Rather than more guidelines and standards, we advocate the development of practical tools and templates, compliant with applicable legislation and standardised guidelines (e.g. ICH-GCP, CONSORT, SPIRIT guidelines (1-3)), for study protocols, Case Report Forms, statistical analysis plans,and risk analyses. This will support the design and conduct of clinical studies according to best practices and, thereby, help to protect the rights, safety, and well-being, of the study participants and to ensure data and research integrity.
1. See http://www.ich.org/home.html
2. Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Devereaux PJ, Elbourne D, Egger M, Altman DG. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c869. See also http://www.consort-statement.org
3. Chan AW, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, Dickersin K, Hróbjartsson A, Schulz KF, Parulekar WR, Krleza-Jeric K, Laupacis A, Moher D. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ 2013;346:e7586; see also: www.spirit-statement.org
Competing interests: RJdH is director and CAMJdB and MPM are senior staff members of the Clinical Research Unit (CRU) of the Academic Medical Centre (AMC), University of Amsterdam, Amsterdam, The Netherlands.
We agree that clinical trials units (CTUs) provide essential academic functions, which should be incorporated into routine practice. As part of this, CTUs might have a pivotal role in data handing. Hidden or lost clinical trial data is symptomatic of wasted resources and raises ethical concerns (1). A number of institutions including the British Medical Journal and the Alltrials initiative have sought to maximise reporting and transparency of trial data through dedicated campaigns (2, 3). CTUs offer capacity to hold large volumes of data in secure repositories. By doing so, they may help to prevent loss of data and promote data sharing after study completion. Not only would this ensure transparency, it would also promote reporting of all planned outcomes regardless of results.
We suggest that data sharing becomes a requirement of all clinical trials performed in the UK and that this data should be held by CTUs, meaning that CTUs are essential. This would be best achieved by provision of anonymised, open access, patient-level data via online sources. Sharing of the CRASH 1 and CRASH-2 trial data has proven that this is feasible previously (4). This strategy would speed individual patient meta-analysis and other re-analyses.
(1) Chapman SJ. Shelton B. Mahmood H. Harrison EM. Bhangu A. Discontinuation and non-publication of surgical randomised controlled trials: observational study. BMJ 2014;349:g6870
(2) British Medical Journal Open Data Campaign. Available at: http://www.bmj.com/open-data [Accessed: 1st June 2015].
(3) AllTrials Initiative. Available at: http://www.alltrials.net. [Accessed 1st June 2015].
(4) FreeBird. Bank of Injury and Emergency Research Data. Available at: https://ctu-app.lshtm.ac.uk/freebird [Accessed 1st June 2015].
Stephen J Chapman (1), Ewen M Harrison (2), Aneel Bhangu* (3)
(1) Academic Foundation Trainee, University of Leeds, UK
(2) Senior Lecturer in General Surgery, University of Edinburgh, UK
(3) Clinical Lecturer in Colorectal Surgery, University of Birmingham, UK
* Correspondance: firstname.lastname@example.org
Competing interests: No competing interests
Increasing infrastructure and capacity
In order to advance surgical practice we require a strategy that will foster and disseminate high quality surgical research in order to dispel existing attitudes that tolerate high levels of anecdotal evidence, retrospective series and single institution cohort studies to guide patient care. Multicentre studies are more likely to change clinical practice by demonstrating generalisability across a range of cultures and health service structures. Surgeons are increasingly working collaboratively through CTUs to support such high-impact multicentre studies. The Research Division of the Royal College of Surgeons of England has appointed 14 national surgical specialty leads to work with six independently appointed surgical trials centres to strengthen the culture of trials research in UK clinical practice. Their remit is to develop multicentre clinical research including randomised trials and observational studies.
Surgical CTUs can speed innovation
CTU involvement comprises more than just providing isolated access to specific individuals with appropriate skillsets, such as statisticians or methodologists. They deliver a support framework for the longer duration aiding a level of staff development not possible outside of a trials unit. Whilst we expect surgeons to have documented evidence of their ability to perform operations, a CTU with UKCRC registration has equivalent formal evidence of quality and capability, including study design and management to show that they can safely and properly deliver trials. The surgical trials units are also actively engaged in training surgeons in clinical research skills, thereby fostering and strengthening a culture of high quality evaluation of innovation and evidence-based clinical practice. They utilise these networks to speed delivery of trials and surgical innovation, as shown the ROSSINI(1), DREAMS(2), ROCSS(3) and ROMIO(4) trials, all of which have recruited ahead of schedule.
Future of CTUs
Surgical CTUs need to expand over the coming years to accommodate a greater volume of studies, engaging more researchers and patients, whilst maintaining high standards. They are developing ‘open door’ policies, linking surgeons with existing research teams and methodological support. Training more trials managers should support this, with surgeons being embedded within CTUs and in many cases providing clinical leadership to the units.
Birmingham Surgical Trials Consortium: Mr Aneel Bhangu, Dr Laura Magill, Mr Thomas Pinkney, Dr Dmitri Nepogodiev, Mr Simon Bach, Professor Jon Deeks, Professor Pamela Kearns, Professor Dion Morton
Bristol Surgical Trials Centre: Professor Jane Blazeby, Dr Chris Rogers
Surgical Intervention Trials Unit, Oxford: Professor David Beard, Professor Freddie Hamdy
North West Surgical Trials Centre: Professor Nigel Bundred, Professor Paula Ghaneh, Professor John Neoptolemos
National Facial and Oral Research Centre: Professor Peter Sasieni, Professor Iain Hutchison
1. Pinkney TD, Calvert M, Bartlett DC, Gheorghe A, Redman V, Dowswell G, Hawkins W, Mak T, Youssef H, Richardson C, Hornby S, Magill L, Haslop R, Wilson S, Morton D; West Midlands Research Collaborative; ROSSINI Trial Investigators. Impact of wound edge protection devices on surgical site infection after laparotomy: multicentre randomised controlled trial (ROSSINI Trial) BMJ. 2013 Jul 31;347.
2. The DREAMS Trial, http://public.ukcrn.org.uk/search/StudyDetail.aspx?StudyID=10426
3. The ROCSS Trial http://public.ukcrn.org.uk/search/StudyDetail.aspx?StudyID=13461
4. Avery KN, Metcalfe C, Berrisford R, Barham CP, Donovan JL, Elliott J, Falk SJ, Goldin R, Hanna G, Hollowood AA, Krysztopik R, Noble S, Sanders G, Streets CG, Titcomb DR, Wheatley T, Blazeby JM. The feasibility of a randomized controlled trial of esophagectomy for esophageal cancer--the ROMIO (Randomized Oesophagectomy: Minimally Invasive or Open) study: protocol for a randomized controlled trial. Trials. 2014 Jun 2;15:200
Competing interests: DM is the Director of Surgical Research at the RCS and a director of the Birmingham Surgical Trials Consortium
Of course a Clinical Trials Unit (CTU) is not essential for a successful trial, but it is increasingly difficult to run a multi-centre trial without the support of a multi-disciplinary team experienced in designing and running clinical trials. The question should not be is a CTU essential, but does involvement of a CTU increase the chance of success and is it a cost-efficient way to invest in clinical trials.
Ian Chetter lists several barriers to success of clinical trials and suggests that a CTU is unlikely to have much influence on these barriers. We disagree.
Time-constraints: We wanted to recruit patients for a trial during a routine GP consultation, but were told that we would need to add 20 minutes to a primary care consultation in order for a nurse to recruit and obtain informed consent. With the help of the CTU we discussed the design with individual practices and successfully ran a trial in which patients were recruited without substantially increasing the time of the consultation.
Doctor-patient relationship: By organising patient (and doctor) involvement in the design and management of trials we can help ascertain what the issues are and often find that the relationship is strengthened.
Lack of equipoise: Where there is lack of equipoise, a trial must be designed carefully to ensure that it addresses a relevant clinical question about which there is equipoise and does so without compromising individual clinicians who may not have equipoise. Designs in which patients are randomised to see different specialists (rather than requiring the specialist to randomise patients to different treatments), for instance, are becoming more common. CTUs can play a role in surveying clinicians and patients to find out where there is equipoise.
Patient information and consent: Most CTUs have considerable experience in working with patient representatives and running focus groups to improve consent procedures and to ensure that the patient information is clear and balanced.
A key benefit of working with a CTU is that the large team should enable an individual trial to continue smoothly should the trial manager leave suddenly.
One of the biggest challenges to clinical trials today is the increasing bureaucracy caused by ever more stringent regulation and risk-averse research offices. The number of clinical trial applications fell by 25% from 2007 to 2011 and the cost per patient recruited in NIHR funded trials has increased sharply. Maybe it is too much to ask of CTUs to reverse this worrying trend.
Competing interests: PS is the director of a CTU, BA is the operations manager of a CTU
In response to Ian Chetter, we would like to point out that Clinical Trials Research is team science and requires high quality collaboration from a wide variety of experts, not just trial management. Over the last decade the increasing complexity in the regulatory environment and complexity of trial questions as we move for example to personalised medicine or more international collaboration requires a multidisciplinary team response.
Many of these multidisciplinary experts (statistician, data managers, qualitative researchers, clinicians) are found in Clinical Trials Units and the team interaction contributes to the overall quality and robustness of trial findings. The Mazari trial, which did not use a CTU and is noted as successful, suffers from a number of methodological weaknesses; they did not utilise independent randomisation (sealed envelopes were used), do not appear to use intention to treat analysis in the exercise groups, which may have biased the findings in favour of exercise, and they undertook baseline statistical testing. Many CTUs incorporate qualitative research within their trials and this has been shown to successfully address patient barriers to participation (Donovan). Most CTUs actively engage, train and coordinate patient representation at every stage of the trial process.
Collaboration with a CTU provides security and stability in trial management as opposed to reliance on a single trial manager. The CTU environment is ideally suited to training trial managers, providing professional and career development. It also ensures that they have direct and immediate access to a wide range of expertise required to successfully execute a trial including quality assurance, programmers, statisticians and regulatory advice. The UKCRC Registration System for CTUs ensures that CTUs have the required expert multidisciplinary team, robust quality assurance and data management systems, and appropriate regulatory systems and can provide security and stability for trials in unforeseen circumstances. This robustness and assurance is not in place for standalone trials and can lead to poor quality which is both unethical and a waste of money. Clearly you do have to pay an adequate amount to ensure quality. Commercial trials may not use CTUs but this is arguably due to their business needs rather than costs as they do utilise commercial contract research organisations, which are likely to be more expensive.
Finally rather than being divorced from clinical communities UKCRC Registered CTUs are required to demonstrate that they have senior clinical input at a strategic level and around 50% of them have Clinical Directors of the Unit.
Donovan et al. Improving design and conduct of randomised trials by embedding them in qualitative research: ProtecT (prostate testing for cancer and treatment) study. BMJ. 2002 Oct 5; 325(7367): 766–770.
Competing interests: I am the Director of the UKCRC Registered CTU Network and Director of the Leeds Clinical Trials Research Unit
NIHR supports 24 UKCRC registered CTUs to conduct trials funded by NIHR. We do this because we believe that involvement of CTUs has raised the quality of trials substantially, and contributes to our policy of increasing value in research (1). Prof Chetter is correct that CTUs are not essential to the successful conduct of trials – but the functions of a CTU (as described by Mr Gohel) are.
Some trial teams have all of these functions, without a formal title of a CTU and we are happy to receive applications from them. But failing to consider and demonstrate the likelihood of good trial management in an application will certainly result in its rejection. It is particularly true that many smaller trials (often phase I or II) can be managed perfectly well by an experienced team without the full engagement of a CTU. CTUs are not uniform: some provide all the essential functions, and some fewer. Nor are they a panacea: trials are always difficult and challenging, but essential for all the reasons that Mr Gohel and Prof Chetter list. NIHR is committed to supporting trials that have the potential to improve clinical practice: we see CTUs as important partners in many of these.
1. Ioannidis J, Greenland S, Hlatky M, Khoury M, McLeod M, Moher D, Schulz K, Tibshirani R. Increasing value and reducing waste in research design, conduct, and analysis. The Lancet 2014;383: 166 – 175
Competing interests: I am responsible for funding CTUs on behalf of NIHR