Abstract
Background and objective
A PhD project involving designing and implementing a small-scale clinical trial at Jersey General Hospital encountered a variety of difficulties in obtaining ethics approval due to Jersey’s unique legal and constitutional position. Clarification of the necessary route of application took some 28 months. It was established that only local ethics approval is required for clinical trials taking place in the Channel Islands and that there is no need for Medicines and Healthcare products Regulatory Agency (MHRA) approval in the form of Clinical Trials Authorization (CTA), because Jersey falls outside the existing legal and regulatory framework. The experiences and findings gained from this project would prove of use to other researchers planning to conduct clinical trials in the Channel Islands.
Jersey’s position within the British Isles
This article describes the process of obtaining ethics approval for a small clinical trial, based at Jersey General Hospital, Channel Islands. Jersey is the largest of the Channel Islands and sits in the English Channel, closer to France than to England. It covers 45.5 square miles and has a population of 98,000, 1 Jersey, Guernsey and the Isle of Man are part of the British Isles. England, Scotland and Wales make up Great Britain, while the United Kingdom includes Great Britain and Northern Island. Jersey is a British Crown Dependency. Jersey is self-governing and has its own financial and legal systems. The constitutional position that Jersey enjoys today was founded on links with the English Crown that started in the Middle Ages when the Channel Islands sided with King John against the French King in 1204. Subsequent monarchs have confirmed this position by Royal Charter and there were significant constitutional changes in 1856 and 1948 when Deputies and Senators were appointed to the States Assembly. 1
Pilot study
This clinical trial was part of a PhD thesis which itself arose from a series of events starting with a chance conversation between a retired Professor of Pathology and a Jersey farmer in a French café. The recommendation by the Professor was for the farmer’s wife to travel to England for a consultation with Claire Haresnape, a registered homotoxicologist, before commencing fertility treatment in Jersey. The eventual happy outcome of a live birth led to the birth of another idea, that of a double-blind placebo-controlled trial of a complex homeopathic product purporting to promote fertility in females. A collaboration was formed with Neil MacLachlan the lead consultant at the Department of Obstetrics and Gynecology, Jersey General Hospital with a view to implementing the pilot study.
Trial design
The trial sought to recruit 90 women who had been diagnosed with infertility due to a failure to ovulate. They were to be randomized to six treatment groups and stratified for age. The outcomes to be measured included: follicular count, follicle stimulating hormone levels, estradiol (E2 or 17β-estradiol, also oestradiol) at day 2, progesterone levels at day 21, pregnancy confirmed with a pregnancy test and live birth.
Ethics application
The initial inquiry to the MHRA confirmed that: UK clinical trial legislation does not apply in the Channel Islands. The Channel Islands and the Isle of Man are self-governing dependencies of the British Crown, that is, Her Majesty Queen Elizabeth II is their Head of State but they are not part of the UK. They are subject to European Unity Directives so far as trade is concerned but the inhabitants are not citizens of the EU … For your clinical trial in sites in Jersey you will need local ethical approval and may require local regulatory approval but you do not require MHRA approval of a CTA.
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The National Research Ethics Service (NRES) Queries Line was then approached to provide guidance in this dilemma and their response was as follows: Jersey is not part of the UK and the favourable opinion from the UK REC would not formally confer ethical approval for the study in Jersey. Nor would the REC undertake any site-specific assessment of the Jersey research site as this is outside its remit. It is entirely a matter for the island authorities to determine what process is required to include a site in Jersey.
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Trial medication
The status of homeopathic and homotoxicological medicines was also an issue at this point. On 18 March, Professor Johnston, my PhD supervisor, queried the position of homeopathic and homotoxicological remedies in the European Union (EU) Directive with the MHRA.
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Dr Malcolm Barratt-Johnson, Medical Assessor at the Clinical Trials Unit and to the Licensing Division at the MHRA, confirmed that homeopathic products lie within the scope of a CTA because they have the ability or potential to treat individuals. According to European Legislation (Article 1, paragraph 2 of Directive 65/65 EEC), a preparation constitutes medicinal product where: the substance or combination of substances either prevent or treat disease in human beings or are administered to human beings with a view to making a medical diagnosis or to restore, correct or modify physiological functions in humans.
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Professor Johnston queried this decision with the local research ethics committee who in turn escalated it to one of the NRES regional managers for guidance. Maria Robinson, SRES Manager, South West, gave the following response: This is an interesting scenario, Although outside the UK and technically outside our remit for ethical review, this study being a CTIMP falls under the EU regs and therefore must be reviewed by a UKECA recognized REC and receive authorization from the MHRA. This being the case, we would need to review this project.
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Clarification from NRES
In December 2009, David Neal, Deputy Director (policy), NRES, was asked for his opinion. He agreed that this was an unprecedented situation and apologized that it had not been clarified sooner. His email of 10 December 2010 is shown below: I explained that we had sought advice from the Department of Health about whether a mainland REC could review the trial on a voluntary basis. We have now been advised as a matter of policy that it should not do so. The background is as follows: The European Clinical Trials Directive applies to the Crown Dependencies, which for purposes of European law are considered to be part of the UK Member State, although not part of the UK in domestic law. The States of Jersey were therefore required to transpose the Directive into States law by 1 May 2004; they have not so far done so. The Medicines for Human Use (Clinical Trials) Regulations 2004 do not apply to Jersey, and under present arrangements the United Kingdom Ethics Committee Authority is not able to recognise ethics committees to review trials taking place in Jersey, though we understand that the Crown Dependencies have been offered the option of UKECA recognition for their ethics committees. In these circumstances, it is not considered appropriate for a mainland REC to review and give an opinion or otherwise advise on a trial taking place solely in Jersey. Responsibility for the trial lies with the authorities in Jersey. If it were proposed to start the trial at a mainland site, an application could then be reviewed by a UKECA recognised REC and an opinion given in relation to that site.
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Local application
This clarification of the situation allowed the project to proceed with a local application to Jersey in September 2009, 10 and Claire Haresnape and Dr Art Tucker, my second PhD supervisor, attended the ethics committee meeting on 9 March 2010. Written confirmation that the committee were ‘minded to grant a favourable ethical opinion subject to receipt of an amended patient information leaflet’ was received on 24 March 2010. 11
The changes were made to the patient information leaflet and the favourable ethics opinion was confirmed by letter on 24 May 2010. 12 The process of clarifying who had the authority and jurisdiction to grant a favourable ethics opinion took 28 months. To a degree, this had a detrimental impact on the project as a whole as two batches of trial medication were manufactured and expired during this time.
Discussion
Findings
A combination of circumstances and criteria led to a PhD project being planned at Jersey General Hospital. During the planning stage of this project, it was found that clinical trials taking place in the Channel Islands only need to obtain local ethics committee approval. There is no need for MHRA approval in the form of CTA because Jersey falls outside the existing legal and regulatory framework. This study has also confirmed the need for CTA for homeopathic medicines.
Strengths and weaknesses
The delays caused by the initial lack of clarification were not foreseen and they had an impact on the planned and projected timescales and financial cost of the PhD project. Future researchers can utilize the findings of this report to avoid similar delays and costs as there is now a clear route to follow.
It is recognized that this information has relatively limited application because it only applies to researchers planning studies in the Channel Islands or other British Crown, or studies involving homeopathic medicines.
Implications
Jersey does not require regulation by the MHRA, which means that it is a relatively unregulated research environment. This could make it potentially vulnerable to unscrupulous investigators who could use Jersey as a site for trials that would not mean the standards set down by the MHRA.
The MHRA represents a well-resourced and established pathway for making sure that the design and conduct of clinical trials for medicines and medical devices provide acceptable levels of protection for participants. 13
There are also benefits to being part of the NRES structure including help with optimizing research ethics reviews and so improving the research environment. Hosting clinical trials could potentially represent a new revenue stream for Jersey’s economy. At the current time, all the responsibility for the trial subject’s rights, safety and well-being rests with the local ethics committee. Perhaps the time is ripe for review of the legal and regulatory framework for clinical research in the Channel Islands.