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Rapid Responses: Rapid Responses published:
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![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
Streamlining ethics review will save lives
- Paul P Glasziou, Sir Iain Chalmers (3 June 2009)
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Robust Research Ethics Review in Europe in need of fine tuning. Lessons from the UK
- Michael F. Bone (3 June 2009)
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UK ethics response process time
- Edward K. Geissler, Andreas A. Schnitzbauer, Philipp E. Lamby, Ingrid Mutzbauer, Carl Zuelke, and Hans J. Schlitt (8 June 2009)
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More and harmonized ethics committees (ECs) for best patients’ safety and quality of clinical research
- Roberta Minacori, and Antonio G. Spagnolo - Professor of Bioethics, Dpt. of Educational sciences, University of Macerata, (25 June 2009)
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Some additional problems encountered during a large EU funded trial.
- Curt Brugman, Theo Verheij, Gilly O’Reilly, Paul Little, Chris Butler, Samuel Coenen, Katherine Loens, Herman Goossens, on behalf of the GRACE Project Group (26 June 2009)
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Paul P Glasziou, Professor of Evidence-Based Medicine University of Oxford, Oxford, OX3 7LF, Sir Iain Chalmers
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The substantial delays in UK research ethics committee approval documented by Schnitzbauer et al [1] deserve attention, and change. While frustrating for researchers, such delays are hazardous for patients. For example, by comparing US and UK requirements for informed consent for participants in the ISIS-2 trial, Collins et al estimated that around 10 000 unnecessary deaths were attributable to whatever it was that slowed trial recruitment in the US [2]. In addition, the unpredictable delays waste research resources and may inhibit some research from ever being conducted. The options for reform discussed by Schnitzbauer seem insufficient to address this serious problem, however. We have previously suggested that ethics review in the UK needs substantial streamlining [3]. To optimize the use of ethics review time, it must be recognised that a "one size" process does not fit all studies. Too often, current review processes treat all studies, from a short survey to the "first in man" use of a new drug, in much the same way. As the risks to patients vary enormously, the processes should vary also. For example, surveys might be checked by a single support person; trials of standard agents (or additional centres – as in Schnitzbauer’s case) by a committee chair. Only in cases of doubt or substantial risk-benefit uncertainty should research proposals be referred for full committee review. The current delays frustrate researchers, waste research funds, but most important do not serve the interests of patients effectively. References 1. Schnitzbauer AA, Lamby PE, Mutzbauer I, Zuelke C, Schlitt HJ, Geissler EK, for the SiLVER05 Study Group Procedures for ethical review for clinical trials within the EU BMJ 2009;338:b1893 2. Collins R, Doll R, Peto R. Ethics of clinical trials. In:Williams CJ, ed. Introducing new treatments for cancer: practical, ethical and legal problems. Chichester: John Wiley, 1992. 3. Chalmers I, Glasziou P. Ethics review roulette: what can we learn? That ethics review has costs and one size doesn’t fit all. BMJ 2004;328:121–2. Competing interests: None declared |
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Michael F. Bone, Consulting Physician South Tyneside NHS Foundation Trust
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The criticism of research ethics review in the UK by Andreas Schnitzbauer 1 is an unjust and misleading appraisal of the current situation. The procedure has undergone substantial review over the last 5 years such that the average time for completion of the process takes only 35 days. There are clear deadlines and standard operating procedures which dictate a written response to the Chief Investigator within 10 days. There is only one ethical review required in the UK but site specific assessments may also be needed depending on the nature of the study and the interventions contemplated. It is only right and proper that there should be local consideration of research inflicted on a particular population but that duty has now been devolved to the local Research and Development Office of each Institution. There is now an electronic integrated research application system, IRAS, which makes it vastly easier for investigators to satisfy all requirements and speed the process. Clear guidance is available on the National Research Ethics Service website 2. Across Europe as a whole the time for authorisation of a clinical trial has reduced by 25% to 48 days since 2004 but time to first participant recruitment increased by 37% to 152 days indicating a common burden of bureaucracy. This was after all a complex study involving a particular vulnerable group with an unusual arrangement between academic institution and the drug manufacturer with the Institution acting as sponsor. That alone has major ramifications as attested in a recent US Court of Appeal decision in favour of Amgen against a group of research participants 3. The high level of resubmissions (2 attempts in the UK alone) across Europe and 46% of ethics committees having substantial concerns about the quality of patient information, safety and data protection as well as the indemnity arrangements (all issues that ethics committees are tasked to consider in the European Directive) points to the inadequacy of the original submission. The Tegenero case in London emphasised the marked diversity of insurance provision for clinical trials across Europe 4, 5, with the need for specific consideration in each member state. Differences in ethical review procedures are well illustrated by comparison of arrangements in two nations with more mature review structures. Ethics committees in the UK are not expected nor constituted to carry out scientific analysis of a research proposal; although having the right to call for a separate critique, nor do they offer a legal opinion. Whilst in France the Comités de Protection des Personnes (CPP) are constituted as a legal obligation to authorise clinical research although specifically considering scientific and ethical justification do not primarily do so. In many member states the ethics committees have a role in oversight and scrutiny of a clinical trial whereas in the UK much of this role rests with the Competent Authority, namely the Medicines and Healthcare products Agency, MHRA. Performance and intensity of scrutiny is also markedly different varying between the 60 cases considered at a monthly meeting in Vienna to the more usual 7-8 in the UK. Thus this case illustrates how well the Directive has facilitated the development of proper ethical scrutiny and protected research participants yet respecting the diverse societies and cultures which are even greater following the augmentation of the European Union to 27 member states. Let us not forget that there was no regulatory requirement for ethical scrutiny of Phase 1 human volunteer trials in the UK before 2004. Thus there are marked differences that preclude complete harmonisation of ethical review across Europe. That responses should be timely is axiomatic but frequently time delays are due to the investigators responses themselves. The principles of ethical research practise should be universal and interpretation common although emphasis may vary with culture and historic context. In the UK, we have achieved greater consistency of REC performance over the last 10 years with improved training, shared ethical debate, consideration of sham submissions and a robust appeal system. The European Forum for Good Clinical Practice has recognised a need to similarly promulgate consistency in ethical decision making and thus organises a series of Complex Case Based Training Workshops across Europe open to all research stakeholders which hopefully will go some way to facilitate that harmonisation. References 1. Analysis: Europe gets nul points for harmony in Trials. Schnitzbauer A A, Lamby PE, Mutzbauer I, Zuelke C, Schlitt HJ and Geissler EK BMJ 2009; 338:b1893 30May 2. National Research Ethics Service website: www.nres.npsa.nhs.uk 3. Compact versus Contract-Industry Sponsors Obligations to their Research Subjects. Mello MM, Joffe S, N ENGL J Med 2007 356 2737-43 4. Compensation for Injured Research Subjects. R Steinbrook. N ENGL J Med 2006; 354; 1871-1873. 5. Compensation Arrangements across Europe. Genevieve Decoster. Association of Research Ethics Committees and Society of Pharmaceutical Medicine - Joint Conference: Research Ethics in a Material World; Birmingham 2007 Competing interests: Past Chair; Association of Research Ethics Committees: AREC, Secretary to the Board; European Forum of Good Clinical Practice, Partner; European Initiative for the Network of Research Ethics Committees: EUREC |
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Edward K. Geissler, Professor University Hospital Regensburg, University of Regensburg, Regensburg, Germany 93053, Andreas A. Schnitzbauer, Philipp E. Lamby, Ingrid Mutzbauer, Carl Zuelke, and Hans J. Schlitt
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Following our recent publication, we have become aware of a calculation error in Table 1. Our article indicates that the national UK ethics committee had our application in their hands for 168 days (as shown in Table 1), but rather it was 119 days. The mistake stems from miscalculating the time when the submissions were directly with the national committee, considering that two official replies were necessary and significant time was required for responding to the criticisms. Unfortunately, the 168 day figure reported in the article included a portion of the interim time we needed to respond to criticisms, and thus was not entirely correct. Therefore, the national ethics "in hand" time in the UK should be reported as 119 days in Table 1 , which consequentially changes the total time in the UK to a median of 197 days (range, 143-217). The same amount should be quoted in Table 2 under "separate national and local approval" as 197 days (range, 143-217). Nonetheless, the related message in the article about significantly longer ethics approval times in the UK does not change in the case of our clinical trial. When taking into account the time needed to get local ethics committee approval (median 78 days), and to respond to national ethics committee requests (154 days), which included the need to make a full protocol amendment, it took nine months to obtain approval on a study that was already being conducted within the EU. As a caveat to this topic, it is notable that the redundancy of the national and local opinion has recently been recognised by the authorities in the UK, so policy no longer requires local ethics review. This is a recent improvement in the UK system that came into effect after acceptance of our manuscript. It is also notable that at the time of our application it was actually feasible to submit to local ethics in the UK once the national committee received a complete application; this was incorrectly stated in the article. However, the experience of our CRO at the time indicated that it was more practical to get national approval first, then local approval. In the end, with an equal or greater effort being put forward in the UK, versus the other EU countries, the entire process of successfully navigating through the UK ethics review took three-quarters of one year, which is substantially longer than our experience with any other EU country. We do realise, however, that recent improvements in the UK system since our application may have speeded up the process on average. New practical experiences in this respect will be interesting to compare within the EU. Competing interests: None declared |
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Roberta Minacori, Researcher Institute of Bioethics. Catholic University of Sacred Heart 00168 Rome, and Antonio G. Spagnolo - Professor of Bioethics, Dpt. of Educational sciences, University of Macerata,
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The European directive for good practice in the conduct of clinical trials has not reached – as underlined by A. A. Schnitzbauer et al. (1) - the objective to harmonize procedures for evaluation and judgment on multicentre trials. The harmonization of the procedures should serve to two purposes: to maximize patients’ safety and the quality of the clinical research, and to reduce the times of evaluation and approval of clinical trials in all the European Countries for a fast recruitment of patients. In the study of A.A. Schnitzbauer et al. the median of time taken to get ethics committee approval of Germany (43 days with 14 ECs) and Italy (61 days with 7 ECs) has been respectively less than Finland (47 days with 1 EC) and France (123 days with 1 EC). Other Countries as Netherlands, Spain, Belgium, also involving a smaller number of ECs (2 or 3 ECs) have taken much time (91, 75, 119 days) to get ethics approval. The time, longer or shorter, to obtain judgment on the protocol doesn't seem related to the number of ECs, but it could be influenced by organizational procedures followed by ECs and their ability to interact and to communicate quickly with sponsor and investigator. So, it is seems to us an undue conclusion that the evaluation of an only ethics committee in each country it can make to reach those goals. Besides, if the judgment on the protocol is performing by only one national (or lead) ethics committee: 1) a fault in the evaluation by that EC could create great risks for patients, because of an eventual lack of the trial could be recognized with delay and it would not be modified or interrupted on time; 2) the evaluation by only one EC cannot include specific factors as the investigator, the site and the patients suitability, 3) probably only one EC would not be able to appraise, in a due time, hundreds of monthly applications for protocols, amendments, monitoring, adverse events. In Italy the time taken to get EC approval is well defined by law (2) but few ECs respect such directives. References (1) Schnitzbauer AA, Lamby PE, Mutzbauer I, Zuelke C, Schlitt H, Geissler EK. Europe gets nul points for harmony in trials. BMJ 2009; 338:b1893 (30 May). (2) Legislative Decree no. 211 of 24 June 2003. Transposition of Directive 2001/20/EC relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for clinical use, art. 7, Italian Official Gazette no. 184 of 9/8/2003, Ordinary Supplement no. 130) Competing interests: None declared |
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Curt Brugman, Project Manager Clinical Research University Medical Center Utrecht, 3508 Utrecht, The Netherlands, Theo Verheij, Gilly O’Reilly, Paul Little, Chris Butler, Samuel Coenen, Katherine Loens, Herman Goossens, on behalf of the GRACE Project Group
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We agree with Schnitzbauer et al. that ‘Europe gets null points for harmony in trials’.1 We had similar experiences when setting up a randomised clinical trial assessing the effects of amoxicillin in primary care patients with acute lower respiratory tract infection (LRTI) within a larger EU funded project called GRACE (Genomics to combat Resistance against Antibiotics in Community-acquired LRTI in Europe, www.grace- lrti.org). We would like to mention three additional problems we were confronted with, that were mainly caused by different interpretation of Good Clinical Practice rules in the 13 participating countries. First, our trial was refused ethical approval in one of the 13 countries without the possibility for rebuttal or discussion. As a consequence we lost a research network that performed extremely well during an earlier, related observational study.2 For international studies, some form of communication and consultation should be possible around ethics approvals both between ethical committees and investigators and also between the ethical committees of the different countries involved. It is not logical that one country has a totally different final assessment compared to authorities in 12 other EU countries. Second, the competent authorities from the participating countries insisted on different rules for labelling medication bottles, causing us considerable logistic problems and delays. Finally, we experienced that introducing new study sites was far too cumbersome from the regulatory point of view. Each time we included new general practices to participate in the trial, we had to seek formal approval from all national regulatory authorities. A quick and simple procedure to obtain approval from the single lead national ethics committee would mean considerable streamlining. Even more efficient would be a single, central EU body to handle these matters for the whole of the EU. References 1. Schnitzbauer AA, Lamby PE, Mutzbauer I, Zuelke C, Schlitt HJ, Geissler EK, et al. Procedures for ethical review for clinical trials within the EU. BMJ 2009;338:b1893. 2. Butler CC, Hood K, Verheij T, Little P, Melbye H, Nuttall J, et al. Acute cough in primary care: 13-country prospective study of impact of variation in clinical presentation on antibiotic prescribing and recovery. BMJ Under review;338:b2242. Competing interests: None declared |
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