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Rapid Responses: Rapid Responses published:
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Over-Regulation of Clinical Trials - A UK Problem?
- Ingolf Cascorbi, Michael Orme, John R. Cockroft (17 October 2008)
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Bureaucracy: the biggest threat to UK clinical research
- Rupert McShane (18 October 2008)
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Challenge to compliance of researchers to over-regulation of clinical research
- Hazel Thornton (18 October 2008)
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Developing commensurate research ethics review
- Hugh T Davies (23 October 2008)
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Time for patients to speak out?
- Christine A Gratus (28 October 2008)
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Regulation Gone Mad
- Bonnie Sibbald (29 October 2008)
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Modern Advances?
- Peter H Sonksen (29 October 2008)
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Current form of regulation poses serious threat to trainee researchers.
- Kennedy Cruickshank, Moulinath Banerjee (31 October 2008)
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A view from a Trial Manager’s perspective.
- Sally A Warmington (31 October 2008)
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Regulation—the real threat to clinical research
- Richard IG Holt (3 November 2008)
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Clinical Research Approval Process - Time to Research What Really Works
- Iva Hauptmannova (6 November 2008)
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How much clinical research is never done through fear of the bureaucracy involved?
- Anisur Rahman (9 November 2008)
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Overregulation is an instrument with a potential for misuse
- Vasiliy V Vlassov (9 November 2008)
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Barrier to research harming doctors and patients
- DAVID G SAMUEL (10 November 2008)
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Ethics is not always simple
- Neville W Goodman (10 November 2008)
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What about GCP?
- Steve Goodacre (12 November 2008)
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Can anyone beat my delays
- Martyn Parker (14 November 2008)
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“One size fits all” approach to regulation hinders non-clinical research
- Debbie C Cooke, Julia Lawton, David Rankin, Marie Clark, Celia Emery, Stephanie Amiel and Simon Heller (19 November 2008)
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Running the gauntlet of bureaucracy in UK clinical research: a personal view
- Hedley CA Emsley (19 November 2008)
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The complexity of securing approval for a multicentre public health study
- Oluwatoyin O Ejidokun, Rebecca Close, James M Stuart, (30 January 2009)
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The Academic Researcher– Sisyphus or Prometheus
- Sriram Vaidyanathan (17 July 2009)
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Ingolf Cascorbi, Chairman of EACPT 24105 Kiel, Germany, Michael Orme, John R. Cockroft
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The European Association for Clinical Pharmacology and Therapeutics (EACPT) was very concerned to read in this journal about the reported degree of over-regulation that was experienced by some doctors in training in the United Kingdom following the request for permission to undertake a clinical trial (1). Even though the initial report was anecdotal, the article does point to a more widespread problem in approving of clinical trials. While trainees in many medical specialties undertake clinical trials as part of their training, only in clinical pharmacology and therapeutics (CPT) is the involvement in a clinical trial such a fundamental part of the learning experience for a trainee in the specialty. Since the EACPT was founded in 1993 (2), the association has worked hard to help develop CPT in Europe particularly in the developing countries in Eastern Europe. Over the years since then the United Kingdom has been seen by EACPT as one of those countries where the discipline of CPT was particularly effective and the situation in the UK has often been held up as a model for those developing countries. At its recent meeting in Stockholm the EACPT Executive Committee discussed the problem of getting permission to undertake a clinical trial and it was clear from those countries represented around the table that the problem was predominantly a United Kingdom issue. Representatives of seven countries stated that clinical trials were nearly always fully approved in their country within 60 days of the application being made and this included action by the regulatory body and any necessary approval by an ethics committee or hospital authority. This is in line with a recent paper, comparing the time from application to approval of multicenter clinical trials in European countries, in United States and Australia (3). Interestingly the time for approval in European countries following the EU clinical trials directive (4) was longer than in other European countries that were not following that directive (75 days versus 59 days). The prolonged time for approval of clinical trials may be due to over-regulation due to following the rules or to incapacity to implement the rules. The impression given in the paper by Stewart et al. (1) is that the latter reason is the cause of the delayed approval time in their case. The time for approval in the European study (3) is much shorter in both arms of the study than in the situation outlined by Stewart et al. (1). More information on this topic will be forthcoming at a European meeting in Brussels in December (5). The data presented in the letter (1) is limited in size but if the problem of over-regulation is as widespread as the authors maintain then the EACPT hopes that action will be taken urgently to correct an obvious over-regulation of clinical trials in the UK by learning the lessons from other countries in Europe so that young clinical pharmacologists can be readily recruited and trained. Only then will the discipline in the UK be restored to its former status as one which other European countries can learn from. References 1 Stewart PM, Stears A, Tomlinson JW, Brown MJ. Regulation -The real threat to clinical research. BMJ 2008;337:a1732 2 Orme M. European Association for Clinical Pharmacology and Therapeutics. Eur J Clin Pharmacol 1993;45:295-296 3 Heerspink HJL, Dobre D, Hillege HL, Grobbee DE, et al. Does the European clinical trials directive really improve clinical trial approval time? Brit J Clin Pharmacol 2008;66:546-550 4 Directive 2001/20/EC of the European parliament and of the Council. www.eortc.org/Services/Doc/clinical-EU-directive-04-April-01.pdf. 5 European Forum for Good Clinical Practice - Conference on the impact on clinical research of European legislation. Brussels December 2nd 2008 Prof Ingolf Cascorbi, Chairman
Competing interests: None declared |
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Rupert McShane, Consultant in Old Age Psychiatry, Dementias and Neurodegenerative Diseases Local Research Network John Radcliffe Hospital, Oxford, OX3 9DU
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Stewart et al are absolutely right that bureacracy is the biggest threat to UK clinical research and that this is a post-code lottery. Sadly, as regulations are of ever increasing complexity, the starting position is always NO. Slow set-up times scupper the chances of delivering patients into commercial and non-commercial studies alike. It can take 6 months to negotiate all the permissions and contracts to add a site for a trial which already has MREC approval. Competing interests: None declared |
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Hazel Thornton, Honorary Visiting Fellow, Department of Health Sciences, University of Leicester "Saionara", 31 Regent Street, Rowhedge, Colchester, CO5 7EA
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We again [1] see the publication of a robust challenge [2] to the effects of the implementation of regulatory systems that delay and prevent researchers from improving the health, care and welfare of patients and the public. Viewed as `an intervention`, the regulatory burning hoops that researchers are forced to jump through have been revealed in this exposé for the exhausting, costly, unethical, morale-sapping spectacle that they are. Costly to whom? To the very people they are intended to benefit. Costly in terms of delayed acquisition of better understanding of the benefits and harms of interventions; costly in terms of the wasted time and energy of health professionals striving to improve what they find; costly in terms of non-co-ordinated silos of bureaucrats who seem to feel no urgency or shame in slowly processing a multiplicity of similar documents, thereby thwarting the very objective they are supposed to be achieving. As the authors [2] state: `Those who make and enforce the rules often seem detached from the reality of clinical research and act as though they are protecting patients from rapacious researchers`. Where are the patient/researchers involved in the research process? [3] They should be rallying with their health-professional co-researchers against this iniquitously time-consuming bureaucratic heavy-handedness. They should join to vigorously demand the streamlining and reappraisal advocated by Stewart and colleagues so that the UK might begin to regain its place as a leader in clinical research, and in order to be able to properly utilise the structures put in place to facilitate translational research. [1] Chalmers I. Regulation of therapeutic research is compromising the interests of patients. Int. J. Pharm. Med 2007; 21 (6): 3954-04 [2] Stewart PM, Stears A, Tomlinson JW, Brown MJ. Regulation – the real threat to clinical research. BMJ 2008; 337:a1732 [3] Thornton H. We all have a responsibility to contribute to research. BMJ 1997; 314:1479. Competing interests: None declared |
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Hugh T Davies, Research Ethics Advisor at National Research Ethics Service 4-8 Maple St London W1T 5HD
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For better or worse, we live in a more regulated world. Research is no exception but we will extricate ourselves more quickly from the regulatory brambles if we work together. The National Research Ethics Service shares many of Stewart et al’s concerns [1] and we have written separately to invite them to a meeting. Where NRES disagrees is how far we have got in addressing the problems. I therefore outline some of our initiatives. 1. The Integrated Research Application System (IRAS) streamlines application for all health research. It is a single electronic portal linked to different regulatory or funding bodies where information is entered only once. Feedback has been positive. The Medicines and Healthcare Products Regulatory Agency (MHRA) has been very supportive of IRAS but European constraints beyond their control have meant they could not use it initially. By early next year, however, MHRA applications will be possible through IRAS and we hope in the future IRAS can promote open, ethical research. 2. For 10 years we have funded well received training days in research ethics where reviewer and researcher study research and research ethics together. Those who learn together may better work together. 3. We run and are currently auditing an email queries line to help researchers through the intricacies of regulation(queries@nres.npsa.nhs.uk). 4. We have run a pilot study in 2008 to assess the feasibility of an expedited review process for research with “no material ethical issues”. A live pilot project will start early next year in South London. 5. We have worked with others to differentiate audit, service evaluation and research (“Defining research” at http://www.nres.npsa.nhs.uk/rec- community/guidance/#researchoraudit ) to free work of unnecessary regulation. So, “Come now and let us reason together “, we issue this invitation sincerely and hope these initiatives demonstrate our commitment to developing commensurate review. Yours Sincerely Hugh Davies MD FRCPCH Research Ethics Advisor National Research Ethics Service 4-8 Maple St London W1T 5HD 1 Stewart PM, Stears A, Tomlinson JW, Brown MJ. Regulation – the real threat to clinical research BMJ 2008;337:a1732 Competing interests: I am seconded to the National Research Ethics Service as the Research Ethics Advisor , and as such may be seen to have a conflict of interests. |
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Christine A Gratus, Consumer rrepresentative/service user 32 The Grove W5 5LH
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The problem of excessive and counter-productive regulation isn't confined to therapeutic trials. As a consumer representative/service user I have been involved in recent years in several epidemiological studies or surveys that have been delayed - and in some cases prevented - by what appear to the woman on the Clapham omnibus to be pointless and almost wilfully obstructive decisions or delays, not only by ethics committees but by PIAG and local R&D committees. Last week I had a despairing e-mail from a researcher who has waited for five months for R&D approval from his local PCT for a questionnaire study; his funding will run out before he can obtain R&D approval from other PCTs, so he had had to change his research plan. On two other studies on which I'm currently representing patient interests, both involving linkage of primary care or hospital records with cancer registry records, after ethical approval had been granted PIAG has taken in one case six months and in the second almost a year to enter them on its register of approved studies, without which the cancer registries will not release their data. Surely if the reviewers, the grant awarding body and the local research ethics committee all think that the study is important and methodologically sound, it is unethical to hold the research up in this manner? Delays aren't the only issue. There is an almost obsessive pursuit of patient confidentiality- often by 'patient representatives' - that can be in no-one's interests, particularly those of patients themselves. Allowing experienced researchers to access anonymised medical records has very little potential for harm, but the default position - and one that the public has been conditioned into adopting - appears to be that any attempt to do so is a wicked infringement of personal rights. One study with which I'm involved is exploring the relationship between a primary care diagnosis of iron deficiency anaemia and subsequent diagnosis of bowel cancer. Since non-response would introduce invalidating levels of bias, this valuable study, which has the potential to help early diagnosis of a disease much more likely to be successfully treated in its early stages, is only possible by analysis of routinely held records. How it can be argued that delaying such studies is in the public interest is beyond me. Public pressure may be able to help. Those of us engaged in public/patient representation need to make our views known and encourage others to do so. Competing interests: None declared |
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Bonnie Sibbald, Chair, National Health Services Research Network (HSRN) University of Manchester M13 9PL
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Stewart et al present excellent examples of regulation gone mad in relation to clinical trials in human subjects. But the situation is even more ludicrous in relation to health services research where the study ‘subjects’ are very often health care practitioners or organisations, and the methods of investigation are as innocuous as interviews or postal questionnaires. Investigators undertaking health services research are subjected to the same regulatory systems as investigators undertaking clinical trials of treatments where there is genuine uncertainty about the risks to patients. We have examples such as a health services researcher required to have occupational health checks to undertake telephone interviews, and another where an ethics committee objected to qualitative case studies in a handful of patients on the grounds that the sample would not be statistically representative of the population. The former illustrates the system’s inability to tailor regulatory procedures to the risks actually posed by the research. The latter illustrates the system’s inability to judge the quality (and hence the ethics) of research which does not fit the conventional biomedical model. The costs of dealing with this misguided bureaucracy are enormous as they absorb months of researcher and administrator time. Urgent action is needed to make regulatory systems fit for purpose. Competing interests: None declared |
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Peter H Sonksen, Emeritus and Visiting Professor Home: SO32 1HP
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My heart bleeds for modern clinical scientists! Since I became a Consultant/Senior Lecturer in 1971 the collaboration between the NHS and Universities has deteriorated and become strangled by bureaucracy and has led to a progressive decline in efficiency with no tangible benefits. When I see the efforts that have to go into getting formal approval for even a simple research protocol (or protocol amendment) all I can do is think is "Bring back the good old days!" Maybe I was lucky but I know of no patient who was harmed by joining any of my research projects but very many who benefitted. Competing interests: None declared |
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Kennedy Cruickshank, Professor of Cardiovascular Medicine University of Manchester, 46 Grafton Street, Manchester, M13 9NT, Moulinath Banerjee
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To Paul Stewart and colleagues’ timely paper on ‘Regulation as the real threat to clinical research’ (1), may we add two examples which also illustrate threats to training of the next generation of high quality researchers? As part of his doctoral project, having obtained standard ethics permission on the long central form, MB wished to do a single challenge with a standard dose of sub-lingual glyceryl trinitrate and of a salbutamol inhaler spray. These drugs are in use thousands of times a day across the country, let alone the world. To be allowed to do this, we discovered we had to submit first to our University Faculty’s ‘officer in charge’ of such interventions, and he required this also to go to the MHRA. When MB investigated, it required the same lengthy form Stewart et al referred to. After a month’s delay, we were told what we proposed was a clinical trial and therefore was subject to their £750 processing fee (not budgeted for in the PhD fellowship). After several phone calls and re- sending it to higher authorities within MHRA, some 3 months after submission, it was eventually agreed that this was not a clinical trial but still needed a processing fee for approval. In the time available the intervention was simply not done, so the experiment was lost. A second example was of the local bureaucracy. Here the ethics form, NHS R&D office in the hospital Trust and our Wellcome Research Facility all required variations on the same approval theme. One of our overseas clinical students doing his PhD managed two of the hurdles, and then found that one office required his Criminal Records Bureau clearance to be backdated. In order to get his visa for the UK, he had already sent his previous clearance to the British Embassy in the relevant country; that took eight months before his visa was approved. The local authorities here initially required CRB cover for the 8-month gap while the visa was being approved. As he was now in the UK, this would take another six months to achieve. Eventually common sense won and local CRB and previous national security clearance was adequate. Together with several other delays, blocks to ethical permission for parts of the protocol which were then approved with no changes or resubmission, merely attendance at their meeting, it took nearly a year for his PhD field work to commence. Stewart and colleagues’ suggestion for a preferably simplified, single central form and a much simpler and transparent MHRA process are absolutely essential if we are to encourage any research in the current generation of trainees. References: 1 Stewart PM, Stears A, Tomlinson JW, Brown MJ. Regulation -The real threat to clinical research. BMJ 2008;337:a1732 Competing interests: None declared |
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Sally A Warmington, Senior Trials Manager Birmingham University B15 2TT
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As a Trial Manager, I thought I was inured to matters bureaucratic, having spent years as a local government officer, medical auditor and research administrator. However, the experience of trying to gain ethical committee and PIAG approval for a Cancer Research UK funded study has left even this old hand seriously concerned for the future of research in this country. In a nutshell, the time expended on gaining regulatory approvals for this particular study - from initial application to final approval, was a year. This is for a feasibility study which aims to link data from three routinely collected NHS datasets – no medicines or medical devices which might put patients at risk involved! The funding for this feasibility study was for only six months. The obstacles encountered by Prof. Stewart and colleagues when conducting randomised clinical trials involving medicines are also hampering epidemiological studies. As other non-NHS contract holding University researchers will recognise, there are also considerable additional time delays in gaining honorary contracts and the necessary clearances before setting foot in an NHS establishment for research purposes. A simplified Case Study for this study is as follows: In March 2007, we heard that we had received funding for this project, a submission to the Oxfordshire REC C was made on 20 August 2007 and in September 2007 REC approval was received. In November 2007 an application was made to PIAG. Eventually, in February 2008 we received email notification that PIAG approval was granted. However, we could not proceed with the study until the study was placed on the PIAG register, and this did not happen until August 2008. This is no ‘isolated incident’ - I have a couple of other studies to manage contiguously, and have found time spent on the application processes completely disproportionate to the time available in which to actually conduct the studies. The problems have been raised with NRES and PIAG, but to no avail. On a positive note, I was heartened by the enthusiasm and drive of the group at the NHS Connecting for Health Research Capability Programme meeting on 29 October, so will battle on, looking forward to implementation of the Research Capability Programme. Competing interests: None declared |
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Richard IG Holt, Professor in Diabetes and Endocrinology University of Southampton
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I read with increasing anger and relief the letter by Stewart and colleagues; anger because I could only agree with their sentiments and relief to find that I was not the only one blighted by regulation and that the issue is being raised nationally. My own experiences include a 6-month delay following an ethics amendment in which we requested approval to take 10 blood samples from healthy subjects. Bearing in mind the whole study took one morning to complete, this seemed disproportionate. My last three grants have taken more than a year from award to full approval leading to the embarrassing situation of the first year's annual report in which our achievements are listed as "ethics and R&D approval obtained". As well as the delays we too have been subject to inconsistent decisions, e.g. one ethics committee agreed to our subjects self-administering GH for 28 days at home while another declined allowing subjects to give even a single injection at home where this was more convenient for the subject. It is becoming increasingly difficult to attract fellows and students who have become increasingly disheartened as their first experience of research turns to one of impenetrable administrative hurdles. I wholehearted support Stewart and colleagues attempts to improve the situation. Competing interests: None declared |
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Iva Hauptmannova, Research Governance Manager HA1 3UJ
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I always read with interest the regulations and bureaucracy debate, which occurs regularly on the pages of various journals. I have a vested interest, I have worked in the field of research governance and have in the past 5 years tried to understand the regulatory processes, assist researchers with their applications from funding to trial closures. Navigating mine and others way through changes, acronyms, guidances, applications, legal requirements, various departments from HR to medical physics, and back again with frustration. It has been my job, and daily routine, and I have much admiration for those who persist in attempting to conduct research in this environment, burried under mountains of paperwork. Clinical researchers especially. Clinical research, which provides evidence base for clinical practice is required to produce sound and rigorously tested information. It has been accepted over long period of time that scientific rigour as well as some form of ethical review is required to ensure patient safety, and only sound and tested results can be translated into practice. It therefore seems a contradiction of terms that the approval system surrounding clinical research is subject to such ad hoc changes and review, which have little basis in rigorous assessment, but are more reactive to incidents within the clinical research environment often implemented with very little practical thought with very heavy management technique. The result is inevitably a system, which provides excessive burden on anyone attempting to set up clinical research, accompanied by not only frustration, but large economic burden of administrative processes. The cost of frustration translates into loosing valuable individuals who want to conduct research, the financial cost will be passed on in the final marketing result. The new UK strategy introduced as part of Best Research for Best Health is taking steps in the right direction on streamlining - introducing Honorary Research Passports, IRAS, Coordinated System for Gaining NHS Permissions (CSP), which will be introduced in November of this year and should standardise the R&D approval process as well as reduce set up times for multicentre studies. But reading Stewart's et. al article makes one think that perhaps we need more. Approval systems supported by evidence that they provide patient protection, economic value and support those interested and capable of providing great new ideas. Perhaps it is time that research and modelling was undertaken to provide the evidence base required of our research colleagues so we can deliver sound ethic-legal review system, which does not over burden clinical researchers, but provides valuable patient serving research approval process. A UK based initiative, which would provide an example and step towards creating a global review processes, which ensure faster translation of new ideas into clinical practice in a way, which does not compromise patient safety, and also does not discourage researchers. Following that we may in few years time read the praises to what has been achieved. Final note of correction to Stewart et. al's article TeGenero disaster happened at Parexel, private unit renting space at Northwick Park Hospital, which responded to the after care of the disaster. Further details of the initiatives mentioned CSP etc. can be found on http://www.ukcrn.org.uk/index/clinical.html Competing interests: The view represented within this response are personal views, not necessarily representing the emloying organisation. |
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Anisur Rahman, Professor of Rheumatology University College London
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I applaud Paul Stewart and colleagues for their thoughtful analysis of the problems associated with the regulation involved in carrying out research involving patients. Their examples are by no means atypical. Even far simpler research protocols requring nothing more invasive than questionnaires or taking blood/urine samples also require extensive person -hours devoted to regulatory paperwork. The authors point out that new research fellows may spend almost 12 months obtaining regulatory approval for any clinical research project and this is also my experience. It is impossible to know how many worthwhile research projects are never done, simply because the investment of time and effort necessary to obtain regulatory approval deters scientists or clinicians from even starting. This applies particularly to unfunded projects designed to carry out a preliminary test of an idea or to collect information from patients in a clinic or GP surgery. The requirement to obtain statistical analysis, external peer review and sometimes proof of some kind of funding as well as completing a multi-page application form is a clear deterrent to starting this type of project. Some might argue that those small projects are of little worth anyway but I disagree - and in any case, does that make them unethical? One could also argue that if you think the research is important enough you should be prepared to put in the hours required to jump through the regulatory hoops. But do we know how many researchers declined to collaborate in studies or shelved promising ideas after calculating that the time required to put in those hours could not be justified in the face of competing commitments? Personally, I have done both. Competing interests: None declared |
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Vasiliy V Vlassov, Moscow Medical Academy, professor Moscow Medical Academy, Trubetskaya 8, Moscow, 101000
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Bureaucratic/ethical control damaging research is not only a problem in UK or EU countries. The instrument of prevention of harm to participants of research may be hijacked by industry. In Russia for years, right from the moment the ethical control of applications for clinical trials was introduced in the federal Law on Drugs, art. 37 says that only the developer of the drug can initiate the trial. So far as I know, Russia is the only country in the world where State or Academic or non-industrial organizations are barred from initiating clinical research. This tool is systematically used to block any independent drug research in the academy. Another tool invented for the defence of patients recently hijacked by industry – the demand to have participants of clinical research insured for possible harm. Although some clinical studies are connected with minuscule risks from experimental procedures (like risk from interview or donation of the urine sample), ethics committees demand the full scale insurance, which makes the study impossible without generous external support. This anecdotal situation supports the total system of production of very low quality clinical research in Russia, limited to case series and convenience sample cohort studies. It is difficult to prove, but it seems that such regulation may be only an outcome of a corrupted legal system. After the Russian president D. Medvedev declared war on corruption, the new amendments to Law on Drugs were prepared by the Ministry of Health, again, limiting the right of initiation of trials to industry. Competing interests: None declared |
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DAVID G SAMUEL, F1 Surgery Prince Charles Hospital, Merthyr Tydfil. CF47 9TD
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As a Foundation 1 doctor I am keen to take part in research and audit. I am currently undertaking a rotation in Breast and general surgery. I have a particular interest in Oncology, palliative care and Breast Cancer. I therefore decided to approach members of my multi- disciplinary team in order to carry out a simple “questionnaire” based study on the experiences of partners of Breast Cancer, focusing on the quality of support and advice offered to partners. Having submitted a substantial R+D application form along with draft copies of questionnaires, patient information sheets, consent forms etc….. I was then informed that the application would have to be considered by the regional ethics board. A further 3 weeks down the line and a letter through the post informs me that I must now apply for full ethical approval. I therefore enter the online ethics website to submit a form. Apparently once the form is completed applicants have to “lock” their submission before printing and submitting the form. I could not for the life of me find any button offering to lock my form! All this has taken me the best part of my 4 month rotation. I am no closer to starting my study and in 3 weeks time I transfer to the department of medicine. The study was non-invasive. The study was confidential. The study was a simple one-off questionnaire sent to patients and partners who, if they wished to participate would return the completed questionnaire in a pre-paid envelope. The main aim of the study was to identify areas of weakness in the current Breast cancer rapid access clinic and to improve services for patients and their partners. The whole experience has underlined to me how prohibitive, laborious and beurocratic attempting to conduct research has become. I am unsure how I would cope if I ever propose a study that is invasive or involves using medications. The proposal itself would take me the best part of my core training years! In an era where juniors are encouraged to engage in research and audit, and at a time where new breakthroughs are needed to tackle bacterial resistance, emerging illnesses and more complex co-morbidities surely the long winded pathway to conducting research is harming doctors and more importantly, patients. Competing interests: None declared |
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Neville W Goodman, Retired Anaesthetist Bristol, BS9 3LW, UK
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I agree with the overall tenor of Stewart and co-authors' article, but I am wary of their idea that there can be a "national and consistent ethical review process". Most projects are ethically simple, with plenty of precedents to guide decisions. When I was chair of an ethics committee, we had few discussions about real and contentious ethical issues; the main problem was translating information sheets from garbled medicalese into a language that participants could understand. But the nature of ethics is that there are no absolutes: there is no computer program that can decide whether a study is or is not ethical. While it is reasonable to ask that any one group of people should be consistent in their ethical decisions, it is not reasonable to ask that all groups of people would always agree with those decisions. Competing interests: None declared |
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Steve Goodacre, Professor of Emergency Medicine University of Sheffield, Regent Court, 30 Regent Street, Sheffield, S1 4DA
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Stewart and colleagues have not mentioned Good Clinical Practice (GCP) training in their discussion of research bureaucracy. GCP was introduced with the harmonisation of clinical trials regulation. Although the regulations are relatively non-prescriptive, research offices are increasingly interpreting them in a bureaucratic manner and expecting all staff involved in a trial to show evidence of GCP training. In the most extreme cases this has involved insistence that clinicians with only marginal involvement in the trial (such as nurses recording routine observations that are then transcribed onto the Case Report Form) undergo formal GCP training and certification. This often incurs a direct financial cost and always takes up valuable staff time on a process that is rarely educationally rewarding. As is often the case, the patient representative on a trial I am involved with got to the heart of the matter with the comment “Good clinical practice, shouldn’t they already know all that?” Exactly. GCP training simply reiterates basic principles of clinical practice: respect for patient autonomy, recognition of the importance of valid scientific data, understanding of monitoring and the need report adverse events. Anyone who doesn’t understand and follow these principles should not only be excluded from involvement in clinical trials, they should not be caring for patients. Registration with the General Medical Council or an equivalent professional regulatory body should be sufficient evidence that the clinician understands GCP. If there are doubts about whether clinical staff understand or are following these principles then this should be addressed by their employers and the appropriate professional regulatory body. GCP training for clinical trials just creates another artificial barrier between research and clinical practice. Competing interests: I am Principal Researcher on a number of NIHR-funded projects |
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Martyn Parker, orthopaedic research fellow Orthopaedic Department, Peterborough District Hospital, Peterborough, PE3 6DA
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I read with sympathy the problems of Dr Stewart and colleagues and their application for research approval. I can easily trump their delay of one year with my study. For this randomised trial of general versus regional anaesthesia for hip fracture surgery, we were first asked to have MHRA approval. This was applied for in November 2004 and in October 2005 they replied stating that MHRA approval was not necessary for this particular study. Ethical approval was sought in October 2005 and granted in February 2007. The R&D application was made in February 2007 and approved in June 2007. The study commenced in June 2007. Total time for regulatory approval two years eight months, can anybody beat that? Competing interests: None declared |
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Debbie C Cooke, Research Fellow Epidemiology & Public Health, UCL-Gower Street Campus, 1-19 Torrington Place, London, SE23 2AH, Julia Lawton, David Rankin, Marie Clark, Celia Emery, Stephanie Amiel and Simon Heller
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Paul Stewart and colleagues describe the increasing regulatory burden that accompanies and threatens clinical research in the UK[1]. As the regulatory process for undertaking clinical research has become overly bureaucratic, so many of the same processes are applied indiscriminately and inappropriately to non-clinical research. We have been commissioned by the NIHR to conduct a programme of research related to the development of the Dose Adjustment for Normal Eating (DAFNE) structured education programme for people with type 1 diabetes. One strand of this research is a multi-centre, longitudinal questionnaire and interview study with adults with type 1 diabetes and their health care professionals. As such, this research does not focus on a vulnerable patient group and does not involve delivering a treatment or intervention. Whilst the process of gaining ethical approval was relatively quick and straightforward, obtaining R&D approval at the 10 Trusts hosting the study and honorary contracts/letters of access has proved a huge obstacle to the progress of this research. Final ethical approval for this part of the programme grant was granted in May 2008 yet it will have taken a further six months to obtain R&D approval and honorary contracts/letters of access in all the participating Trusts. The same scrutiny and rigour that would be applied to a risk assessment of clinical research has been applied to this questionnaire and interview study and the researchers involved in data collection. We would argue that this ‘one size fits all’ approach is unnecessary, time-consuming, inefficient and expensive for non -clinical researchers, research funders and the NHS. The two Research Fellows employed on this study, to collect the data, obtained Research Passports in advance of applying for R&D approval in order to avoid unnecessary duplication of Criminal Record Bureau (CRB) and occupational health checks. According to the UK Clinical Research Collaborative, during the period from September 2007-2008, there would be communication with stakeholders to ensure roll-out of the Research Passport scheme[2]. Yet only five of the 10 Trusts hosting our study would accept Research Passports and two of those only did so with persuasion. Two of the Trusts insisted on repeating CRB checks when NIHR guidelines state that the requirement for a repeat check can be set aside if one has been carried out within the previous three years. The documents and forms required for R&D approval and in particular, for our honorary contracts varied widely from trust to trust. Two Trusts required collaborative agreements between the study sponsor and themselves although no money was changing hands. This entailed complex negotiations between solicitors. One Trust initially insisted upon GCP training for any of the health care professionals handing out information sheets although that was the extent of their involvement in the research that is, they were not taking consent, administering questionnaires or conducting interviews. Another Trust seemed unable to communicate between its R&D, HR and Occupational Health departments leading to considerable delays in issuing honorary contracts. Their Occupational Health department had incorrectly stated that additional health checks were required for two of the researchers who were having no direct patient contact. Unfortunately, our experience with gaining regulatory approvals for the questionnaire and interview study was mirrored when we sought approval for the development of a research database, as part of the same NIHR programme grant. IRAS has only recently recognised this as a distinct type of research and produced a dedicated form for this purpose but without any useful associated guidance to ease the application through. There is clearly a lack of guidance both for those implementing the regulatory processes and those who are expected to follow them. Where guidance is available, there is a lack of communication about adhering to procedures. We welcome and await with interest the arrival of the NIHR CSP (Coordinated System for gaining NHS Permission), designed to “standardise and streamline; reducing approval times and cutting bureaucracy”. Accessed through IRAS but currently limited to studies eligible for the NIHR Clinical Research Network Portfolio, this appears to be coordinated by UKCRN and supported by CLRNs, in conjunction with the Investigators. Although this may not be a universal or a hassle-free process, the pre- release Operating Guidance document is 90 pages long, the prospect of a single point, coordinated system for multicentre approvals should be welcomed as a positive development. However, with the declared distinction of local as well as national checks, we can only hope that lines of communication are improved at all levels. As other rapid responses to Paul Stewart’s article have commented, this increasingly over -regulated environment has the potential to limit our ability to develop and improve patient services based upon research findings. 1. Stewart PM, Stears A, Tomlinson JW, Brown MJ. Regulation – the real threat to clinical research. BMJ 2008; 337: 1085-1087. 2. UK Clinical Research Collaboration. The research passport: A streamlined approach to issuing NHS honorary research contracts. World wide web: http://www.ukcrc.org/PDF/RESEARCH_PASSPORT_LEAFLET_4_HEIe_latest.pdf (accessed 17 November 2008). Competing interests: None declared |
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Hedley CA Emsley, Consultant Neurologist Royal Preston Hospital, UK
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Whilst the bureaucratic perils facing the contemporary UK clinical researcher may not be as mortal as the military gauntlets of the past, they nonetheless threaten survival, at least metaphorically. In a lecture at the Royal College of Physicians of Edinburgh in 2003, Professor Charles Warlow expressed concern that increasing regulation and legislation threaten public health through the likely demise of clinical research in the UK, except that conducted by industry (1). Five years on, my personal experiences as a clinical lecturer would suggest the situation may be getting worse. This subject has been energetically opened up for debate by the article by Stewart et al (2) and the associated rapid responses: I would like to add my own experiences to the discussion. My own aptitude and enthusiasm for a clinical academic pathway was affirmed by an intercalated BSc during my medical degree, followed later by a clinical research fellow post leading to a PhD. I secured a conventional (pre-Walport) clinical lecturer post in 2003, and have relished the variety of work typical of such a post, a blend of clinical service and training, establishing a research portfolio, and teaching commitments. So, armed with at least some measure of aptitude and considerable determination to steer a successful clinical academic course, what possible obstacles could there be? You have a reasonable research proposal, but before applying for external funding to support the project, internal approval by the Higher Education Institute (HEI) is needed (this is now becoming de rigeur in the UK). Whilst this may improve the chances of success, inherent in this is an assessment of the proposal’s compatibility with institutional research strategy and, ultimately, its likelihood of contributing positively to the UK Research Assessment Exercise, currently the key determinant of research funding income to HEIs from the higher education funding bodies. This is by no means a criticism of the HEIs per se, but rather of a system which may be operating in a manner which inadvertently restricts the diversity of clinical research projects. Quite soon one needs to grapple with the detailed financial aspects of the grant application, and at this stage one encounters the concept of full economic costing (FEC). FEC is a development of the Transparent Approach to Costing (TRAC), or ‘Transparency Review’, and has been applied to all research council grant submissions since 2005. Whilst TRAC aims to improve accountability for public funding and FEC is here to stay, a personal observation (having prepared grant applications before and after the introduction of FEC) is that FEC appears to have increased the complexity and duration of preparing a grant application. Sponsorship arrangements pose another challenge. Within the Department of Health Research Governance Framework for Health and Social Care, any research taking place in an NHS context in England must have a sponsor that assumes responsibility for confirming proper arrangements to initiate, manage and monitor, and finance the study. The second edition of this framework (2005) needed to take account of a range of new or updated legislation and/or regulations, including The Health and Social Care Act 2003, The Human Tissue Act 2004, The Mental Capacity Act 2005 and The Medicines for Human Use (Clinical Trials) Regulations 2004. Obtaining any necessary honorary research contracts, also required within the research governance framework, can also be surprisingly time consuming. Whilst the proper conduct of research must be paramount, there is undoubtedly an increased burden upon the researcher as a result of such changes. And that brings us to the ethical approval process. The Central Office for Research Ethics Committees was introduced on 1 March 2004, metamorphosing into the National Research Ethics Service (NRES) since 1 April 2007, with NRES now being part of the National Patient Safety Agency, the name change said to symbolise the change to a more responsive and robust research ethics review process. Maintaining familiarity with this ever changing system is in itself a challenge. A frequent criticism of the ethics committee meeting is the apparent excessive preoccupation with issues such as wording or font size of participant information leaflets at the expense of core ethical issues such as those relating to consent or safety of a particular intervention. New legislation doesn’t only pose difficulties for the researcher – for example, in my own encounters with research ethics committees I have come across a lack of familiarity with the implications for a study of the Mental Capacity Act. Another recent innovation is the UK Clinical Research Network (UKCRN), launched as part of the current government’s research and development strategy ‘Best Research for Best Health’, published in 2006. Inclusion of a research study within the UKCRN portfolio is to become the only route for access to NHS Service Support Costs in England. The UKCRN has laudable aims – to develop and strengthen NHS infrastructure to support the delivery of clinical research in the UK. But it has added an additional bureaucratic layer for the researcher, who is now required to negotiate the application and approval process for study adoption – a process which is not always as straightforward as it may appear. Criteria for adoption of any study by a particular network can be restrictive, and even when a study is funded, the source of funding – for example via industry – can adversely influence the duration & complexity of the adoption process. Ultimately the UKCRN is likely to deliver significant benefits for clinical research, but there is perhaps a danger that non- portfolio studies, or even those where significant delay in adoption occurs, may lose out. The MMC debacle also unfolded during my time as a clinical lecturer. Of course, the various ramifications of MMC have been discussed at length elsewhere. But for MMC to have any impact on ongoing research projects was a little unexpected. Essentially, owing to the degree of uncertainty at the time of the Medical Training Application Service (MTAS) problems, an incumbent research fellow felt obliged to leave her post in order to secure a GP training place, for fear of facing substantial difficulties associated with deferred entry. A joint UK Clinical Research Collaboration (UKCRC)-MMC sub-committee produced the Walport report, which made recommendations for initiatives such as Academic Clinical Fellowships (ACFs) and Clinical Lectureships (CLs), appointed through selected Academic Programmes. The report also recommended that there should be various entry points into such academic programmes – although it has to be said that precisely how conventional free-standing research posts relate to either academic programmes or run-through (or uncoupled) clinical training programmes still seems uncertain. Far from being disillusioned and thinking that clinical research is simply too difficult, my enthusiasm for a clinical academic pathway remains undimmed. Having completed my clinical lecturer post, I am excited by the prospect of having academic time in my new NHS consultant post, at a NHS trust with clear academic aspirations. Undoubtedly some of the recent developments – particularly the UKCRN – will have a positive impact, but surely the ever proliferating clinical research bureaucracy in the UK must be a cause for concern? (1) Warlow C. Over-regulation of clinical research: a threat to public health. Clin Med. 2005 Jan-Feb;5(1):33-8. (2) Stewart PM, Stears A, Tomlinson JW, Brown MJ. Regulation--the real threat to clinical research. BMJ. 2008 Oct 16;337:a1732. Competing interests: Dr Emsley accepted sponsorship from the pharmaceutical industry to support research and teaching activities. |
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Oluwatoyin O Ejidokun, Consultant in Communicable Disease Control/ lead study medical consultant Health Protection Agency Southwest, The Wheelhouse,Bond's Mill,Stonehouse,Gloucestershire, GL10 3RF, Rebecca Close, James M Stuart,
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Stewart et al[1] and Sibbald [2] describe experiences similar to ours in obtaining approval for a multicentre study across three English regions. Our research involved collecting a few additional variables to data already routinely collected for the enhanced surveillance for meningococcal disease. We secured ethical approval for the study within a month of submitting our application to the National Research Ethics committee. However, the bureaucracy of the system of securing individual R & D approval from 51 NHS Trusts was enormous. It required us to complete different forms for each Trust with varying requirements in terms of supporting documentation and varying delays because of the time scale for the seating of the various committees to approve the study application. The whole process was very time consuming both in administrator and researcher time. Nine months after the initial request to Trusts, approval had still not been obtained from 18% (9/51) leading to their exclusion from the study and a corresponding reduction in the size of the study population. These hurdles undoubtedly compromised the success of the study. Standardising the requirements for securing NHS Trust R & D approval for multicentre studies would improve the experience for aspiring public health researchers and increase the likelihood of valid research outcomes. Oluwatoyin Ejidokun, consultant in communicable disease control/ lead
study medical consultant, Health Protection Agency Southwest, The
Wheelhouse, Bond's Mill, Stonehouse, Gloucestershire GL10 3RF
Rebecca Close, lead study scientist, Health Protection Agency Southwest James M Stuart, visiting chair, Department of Social Medicine, University of Bristol. Competing interests: None declared |
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Sriram Vaidyanathan, Clinical Research Fellow, Otolaryngology Asthma and Allergy
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I completely empathize with the authors’ point of view. Every researcher has charted the mind-numbing but inevitable waters of getting approval from a multitude of organizations whose ultimate purported goal is to protect humanity. The principles that bind these guardian organizations were established after humanity faced its darkest facets in the Nuremberg trials, and have driven the governance framework of research across the globe ever since. The Declaration of Helsinki (World Medical Association, 1964) states: It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the human subject. Interestingly, in the tomes and tomes of guidance on human participant protection, nothing is mentioned about the health and dignity of the researcher. High quality research is a condicio sine qua non of healthcare excellence, but the academic researcher is a fast dying breed. Regulatory and Ethical approval forms have metamorphosed from the succinct to the humungous to the frankly ridiculous. Additional questions and layers of questions, to be answered in ‘a language easily understood by a layperson’ have emerged and everything needs a version number and a date. The average time (no RCTs on this one) it takes for ‘pan-approval’ has increased from few weeks some years ago to many months now, particularly since the implementation of the European Clinical Trials Directive. Taking the proverbial ‘year’ out for research from your training programme is just not an option anymore. Somewhere in the gluttony of modern economics and the mess of the unified application service, the academic lies forgotten and forlorn. Imagine my consternation then a few weeks ago, as I lay my eyes on a rejected ethics application for lack of formatting the tick boxes in the participant consent form! When did the Ethics committee turn rogue? In the present promethean climate, I find that the tone of the review boards unfortunately has changed from supportive to inquisitorial. Surely, the principles of ethics apply to the researcher as well? Competing interests: None declared |
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