CLINICAL TRIALS
Commentary
Clinical Trials 2014, Vol. 11(6) 624–625 Ó The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1740774514553483 ctj.sagepub.com
Commentary on Vickers Colin McCowan and Ian Ford
The interesting article by Vickers in this edition of the journal states that the ‘US clinical trials system is broken’ before suggesting four methodological fixes to help improve the future of trials and to ensure they continue to deliver benefits to patients. A view from Europe would agree that the well-documented problems in recruitment to clinical trials1,2 and the difficulty of increasing costs should be seen to threaten their future viability.3,4 In the United Kingdom and particularly in England, a coordinated response, to try to address some of the challenges, involved the creation of national support networks for trials.5 This initiative included the creation of topic specific networks with associated funding distributed across the country to provide expertise and coordination of recruitment to trials in as many hospitals as possible. As an example, this resulted in a sixfold increase in recruitment into stroke trials in England. The fact that one only needs to get a protocol approved by a single ethics committee for a multi-centre trial and ongoing work to standardise contracts and costs should result in further improvements in the time to first patient recruited. A further development has been the professionalising of clinical trials units by the establishment of a formal system of registration.6 Vickers’ first two methodological fixes suggest that costs can be reduced by simplifying trials through reduced eligibility criteria and using existing routinely collected data to record trial endpoints. The first of these fixes resonates well with the calls for more generalisable trials which relate more to the clinical population the intervention is intended to serve. The second fits with other initiatives to improve the conduct of clinical trials through increased use of existing electronic health records for trial feasibility, patient recruitment, within trial recording of clinical data and the extension of follow-up beyond the original trial. An ongoing European collaborative project Electronic Health Records for Clinical Research (EHR4CR) involving major pharmaceutical companies, hospitals and academia is researching approaches in these areas.7 Likewise, the newly created Farr Institutes in the United Kingdom have the use of routinely collected health records in trials as a major research theme.8
Vickers’ other two fixes are aimed at alleviating the recruitment burden. He postulates, with examples from existing trials with which he is involved, that greater use of cluster randomisation where patient consent may not be required could ease recruitment worries. Of course, cluster trials bring with them lots of complexities. Even the interesting development of cluster crossover trials that might eliminate overall heterogeneity among clusters in event rates does not eliminate likely variability due to seasonal patterns and random sources of variation (e.g. episodes of hospital acquired infections), nor does it deal with cluster by treatment interactions. Early consent is of course valuable, particularly in the cancer context, although only possible in trials of an evolving condition. One of the key messages from the article, however, is that each of these fixes is only appropriate for certain types of trials or in certain circumstances. Vickers argues that each trial and the reason for undertaking it should have a design created specifically to best suit that purpose, rather than being forced to follow the more traditional design required to prove the clinical efficacy of a new medicinal product. This may have particular resonance as while there is an obvious need for Phase IV clinical trials,9 the difficulties in their conduct and the cost of performing them would suggest that integrating some of Vickers’ proposed fixes to their design could ensure the continued medical benefits are delivered to patients through a better working clinical trial system. We do, however, need some help from regulatory authorities. Why, in a Phase IV trial of an old drug where we can inexpensively and efficiently collect hospital admissions and operations and procedures, cancer diagnoses and deaths electronically, do we need to set up a parallel complex and expensive system to have investigators report serious adverse events? Declaration of conflicting interests None declared. Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK Corresponding author: Ian Ford, Robertson Centre for Biostatistics, University of Glasgow, Boyd Orr Building, Level 11, Glasgow G12 8QQ, UK. Email: [email protected]
Downloaded from ctj.sagepub.com at The University of Iowa Libraries on June 18, 2015
McCowan and Ford
625
Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
References 1. McDonald AM, Knight RC, Campbell MK, et al. What influences recruitment to randomised controlled trials? A review of trials funded by two UK funding agencies. Trials 2006; 7: 9. 2. Treweek S, Lockhart P, Pitkethly M, et al. Methods to improve recruitment to randomised controlled trials: Cochrane systematic review and meta-analysis. BMJ Open 2013; 3: e002360. 3. Hawkes N. UK must improve its recruitment rate in clinical trials, report says. BMJ 2012; 345: e8104.
4. Collier R. Rapidly rising clinical trial costs worry researchers. CMAJ 2009; 180: 277–278. 5. Darbyshire J, Sitzia J, Cameron D, et al. Extending the clinical research network approach to all of healthcare. Ann Oncol 2011; 22(Suppl. 7): vii36–vii43. 6. United Kingdom Clinical Research Collaboration. Welcome to the UK Clinical Research Collaboration, http:// www.ukcrc.org/ (2005, accessed 18 July 2014). 7. Coorevits P, Sundgren M, Klein GO, et al. Electronic health records: new opportunities for clinical research. J Intern Med 2013; 274: 547–560. 8. Farr Institute. The Farr Institute of Health Informatics Research, http://www.farrinstitute.org/ (2013, accessed 18 July 2014). 9. Hill TP. Conducting Phase IV clinical studies: a moral imperative? Ecancermedicalscience 2012; 6: 276.
Downloaded from ctj.sagepub.com at The University of Iowa Libraries on June 18, 2015
Commentary
Clinical Trials 2014, Vol. 11(6) 624–625 Ó The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1740774514553483 ctj.sagepub.com
Commentary on Vickers Colin McCowan and Ian Ford
The interesting article by Vickers in this edition of the journal states that the ‘US clinical trials system is broken’ before suggesting four methodological fixes to help improve the future of trials and to ensure they continue to deliver benefits to patients. A view from Europe would agree that the well-documented problems in recruitment to clinical trials1,2 and the difficulty of increasing costs should be seen to threaten their future viability.3,4 In the United Kingdom and particularly in England, a coordinated response, to try to address some of the challenges, involved the creation of national support networks for trials.5 This initiative included the creation of topic specific networks with associated funding distributed across the country to provide expertise and coordination of recruitment to trials in as many hospitals as possible. As an example, this resulted in a sixfold increase in recruitment into stroke trials in England. The fact that one only needs to get a protocol approved by a single ethics committee for a multi-centre trial and ongoing work to standardise contracts and costs should result in further improvements in the time to first patient recruited. A further development has been the professionalising of clinical trials units by the establishment of a formal system of registration.6 Vickers’ first two methodological fixes suggest that costs can be reduced by simplifying trials through reduced eligibility criteria and using existing routinely collected data to record trial endpoints. The first of these fixes resonates well with the calls for more generalisable trials which relate more to the clinical population the intervention is intended to serve. The second fits with other initiatives to improve the conduct of clinical trials through increased use of existing electronic health records for trial feasibility, patient recruitment, within trial recording of clinical data and the extension of follow-up beyond the original trial. An ongoing European collaborative project Electronic Health Records for Clinical Research (EHR4CR) involving major pharmaceutical companies, hospitals and academia is researching approaches in these areas.7 Likewise, the newly created Farr Institutes in the United Kingdom have the use of routinely collected health records in trials as a major research theme.8
Vickers’ other two fixes are aimed at alleviating the recruitment burden. He postulates, with examples from existing trials with which he is involved, that greater use of cluster randomisation where patient consent may not be required could ease recruitment worries. Of course, cluster trials bring with them lots of complexities. Even the interesting development of cluster crossover trials that might eliminate overall heterogeneity among clusters in event rates does not eliminate likely variability due to seasonal patterns and random sources of variation (e.g. episodes of hospital acquired infections), nor does it deal with cluster by treatment interactions. Early consent is of course valuable, particularly in the cancer context, although only possible in trials of an evolving condition. One of the key messages from the article, however, is that each of these fixes is only appropriate for certain types of trials or in certain circumstances. Vickers argues that each trial and the reason for undertaking it should have a design created specifically to best suit that purpose, rather than being forced to follow the more traditional design required to prove the clinical efficacy of a new medicinal product. This may have particular resonance as while there is an obvious need for Phase IV clinical trials,9 the difficulties in their conduct and the cost of performing them would suggest that integrating some of Vickers’ proposed fixes to their design could ensure the continued medical benefits are delivered to patients through a better working clinical trial system. We do, however, need some help from regulatory authorities. Why, in a Phase IV trial of an old drug where we can inexpensively and efficiently collect hospital admissions and operations and procedures, cancer diagnoses and deaths electronically, do we need to set up a parallel complex and expensive system to have investigators report serious adverse events? Declaration of conflicting interests None declared. Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK Corresponding author: Ian Ford, Robertson Centre for Biostatistics, University of Glasgow, Boyd Orr Building, Level 11, Glasgow G12 8QQ, UK. Email: [email protected]
Downloaded from ctj.sagepub.com at The University of Iowa Libraries on June 18, 2015
McCowan and Ford
625
Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
References 1. McDonald AM, Knight RC, Campbell MK, et al. What influences recruitment to randomised controlled trials? A review of trials funded by two UK funding agencies. Trials 2006; 7: 9. 2. Treweek S, Lockhart P, Pitkethly M, et al. Methods to improve recruitment to randomised controlled trials: Cochrane systematic review and meta-analysis. BMJ Open 2013; 3: e002360. 3. Hawkes N. UK must improve its recruitment rate in clinical trials, report says. BMJ 2012; 345: e8104.
4. Collier R. Rapidly rising clinical trial costs worry researchers. CMAJ 2009; 180: 277–278. 5. Darbyshire J, Sitzia J, Cameron D, et al. Extending the clinical research network approach to all of healthcare. Ann Oncol 2011; 22(Suppl. 7): vii36–vii43. 6. United Kingdom Clinical Research Collaboration. Welcome to the UK Clinical Research Collaboration, http:// www.ukcrc.org/ (2005, accessed 18 July 2014). 7. Coorevits P, Sundgren M, Klein GO, et al. Electronic health records: new opportunities for clinical research. J Intern Med 2013; 274: 547–560. 8. Farr Institute. The Farr Institute of Health Informatics Research, http://www.farrinstitute.org/ (2013, accessed 18 July 2014). 9. Hill TP. Conducting Phase IV clinical studies: a moral imperative? Ecancermedicalscience 2012; 6: 276.
Downloaded from ctj.sagepub.com at The University of Iowa Libraries on June 18, 2015
