OR WAIT null SECS
The current initiatives and a historical overview of the clinical trial landscape.
The United Kingdom has a long history of involvement in clinical trials and has enjoyed a position of strength within biopharmaceutical research and development. There is widespread agreement across industry and government that this position is under threat, and has been for some time. This has led to a number of initiatives within the United Kingdom aimed at streamlining regulations and facilitating performance in clinical trials. The purpose of this article is to briefly chart the history of these initiatives, and provide the reader with a summary of the landscape for Phase II and Phase III clinical trials in the United Kingdom at present.
JOHN WANG/GETTY IMAGES
Concern in the late 1990s that the United Kingdom was losing its "market share" to other countries in Europe and other regions of the world led to the formation of a joint industry and governmental advisory body, the Pharmaceutical Industry Competitiveness Task Force (PICTF) in 1999. The PICTF committee examined threats to competitiveness for clinical trials in the United Kingdom under headings such as Start-up Time, Recruitment, and Research Quality and Research Costs, and in its final report published in 2001 made many key recommendations to address the issues.1
Shortly afterward, the Association of the British Pharmaceutical Industry noted that:
In recent years, the performance of UK sites involved in these international clinical trials has declined in terms of the speed of trial site initiation, patient recruitment, and quality of data generated, while trial costs have, in general, risen faster than in comparable countries. With increasing competition from research sites in the developing world and states in Eastern Europe, it has become more difficult for pharmaceutical companies to justify the inclusion of UK sites. Unless their performance improves, the extent of UK participation in international trials will continue to decline, with possible adverse consequences for the UK pharmaceutical industry more generally, as well as the status of the UK as a center of medical and research excellence.2
Immediately after the PICTF report was published in 2001, the Ministerial Industry Strategy Group, which is described by the Department of Health as "a high-level group bringing together government and pharmaceutical industry representatives" was formed and continues to meet twice each year with the aim to drive forward the implementation of the PICTF report recommendations.
In 2003, the Academy of Medical Sciences (a non-governmental group of UK-leading medical scientists) published a report entitled "Strengthening Clinical Research"3 which also identified the decline in clinical research activity in the United Kingdom and made several recommendations focused on increasing the perceived value of clinical research within the healthcare system of the United Kingdom. These recommendations were not aimed specifically at distinct areas, such as set-up, regulation, cost, recruitment, etc., but rather at more wide-reaching strategic approaches to encouraging clinical research in the United Kingdom. These recommendations included the creation of a national, government funded body (the National Network for Clinical Research) tasked with facilitation of clinical research at every level, and incentivizing doctors within the National Health Service (NHS) to become involved in clinical research.
The 2006 publication "Government Strategy—Best Research for Best Health"4 acknowledged that industrial and academic research and development was a crucial factor in ensuring UK patients benefitted for innovative new treatments. The strategy also acknowledged the challenges facing clinical trials in the United Kingdom and set out a five-year plan to address them. As a result of this report, the National Institute of Health Research (NIHR) was established in England in April 2006 in order to carry forward the vision, mission, and goals of best research for best health, including facilitating conduct of industry-sponsored clinical trials within the NHS. As part of the implementation of these plans, and perhaps in reference to the suggestions of the Academy of Medical Sciences, a national network for clinical trials was indeed established (the NIHR Comprehensive Clinical Research Network—CCRN).
In 2009, the UK government launched the Office of Life Sciences (OLS), dedicated to improving the operating environment for the pharmaceutical, medical biotech, and medical devices sectors. In December 2009 the OLS published its Life Sciences Blueprint5 including the important statement:
The Government will reinforce the need for greater emphasis on research and clinical trials in the next NHS operating framework, building on the existing commitment to include numbers of patients in clinical research in the metrics which trusts report in their quality accounts.
This statement is very important; at present there is little incentive in the United Kingdom for doctors, patients, or managers to engage seriously in clinical trials. With this latest initiative, for the first time the key performance indicators by which the success of chief executives of NHS hospitals are judged will include the number of patients in their hospitals who participate in clinical trials. This will hopefully increase the extent of high-level managerial commitment in NHS hospitals to drive forward the adoption and success of clinical trials.
In the last 10 years, therefore, there has been a number of government and industry initiatives in the United Kingdom focused on increasing the attractiveness of the United Kingdom as a location for clinical trials. The next questions are: what have these initiatives delivered to date, and what is the current landscape for set-up and delivery of clinical trials in the United Kingdom? In exploring the answer to these questions, the authors will focus on multi-center clinical trials conducted in secondary care within NHS hospitals. The landscape for clinical trials in primary care is largely the same, although there are some subtle differences which are beyond the scope of this article.
Importantly, in the United Kingdom all set-up processes can now be conducted in parallel, which in theory means that all approvals can be gained within approximately 35 days of the first submission.
Since the United Kingdom implemented the EU Directive on Clinical Trials on May 1, 2004, the regulatory agency in the United Kingdom (Medicines and Healthcare Regulatory Agency—MHRA) reviews and approves clinical trials according to the same regulations as every other EU member state. However, in reviewing valid applications within 30 days of receipt it is one of the fastest regulatory agencies in Europe. The applicant should receive a letter communicating the outcome of the review within 35 days of submission. If approval is not immediately granted and further information is requested by the MHRA this must be provided within 14 days and the MHRA must provide the final decision within 60 days of the original application. Timelines can be extended in certain circumstances (e.g., applications involving gene therapy) to 90 days. Applications for studies recruiting only healthy volunteers are generally considered within 14 days, which again compares very favorably with other countries in Europe and is indeed shorter than most countries in the world.
Between July 2008 and July 2009, a total of 674 applications were received by the MHRA for studies involving patient populations, which were reviewed in an average of 27 days (Figure 1). In the same time period there were 253 applications for healthy volunteer studies that were reviewed in an average of 13 days.
Figure 1. The interval review time in days in the UK for patient and healthy volunteer studies.
With respect to timelines, therefore, the United Kingdom retains a position of parity at least with other regions in the world for regulatory approval of Phase II/III studies, and retains a position of strength regarding timelines for approval of Phase I studies.
With respect to fees for regulatory submissions to the MHRA, these are comparatively modest, as shown in Table 1. Additionally, the level of information required is comparable to that in other regions, and is generally similar to an FDA IND submission.
Table 1. Current fee structure and documentations for submission of clinical trials to the MHRA.
Consistent with the EU Directive on Clinical Trials, there is a now a single opinion for ethical review in the United Kingdom. This means that the sponsor or investigator applies to a main Research Ethics Committee (REC) that reviews the ethical aspects of the protocol and other documents to be used in the study—Patient Information Sheet/Informed Consent (PISIC), questionnaires, advertisements, etc. The EU Directive stipulates timelines for REC review, and the final decision of the REC must be provided within 60 days of the initial application. In reality, however, the decision of the REC is usually received much sooner than 60 days—approximately 21 days is the norm for the initial response (which typically includes a requirement for modifications to some aspect of trial documentation—usually the Patient Information Sheet/Informed Consent form) and confirms that the committee delegates authority to the chairman to issue final approval if these concerns are adequately met. The sponsor can usually address these issues by letter within approximately a week, and final approval is typically granted within 35 to 40 days of the initial application. It should also be noted that there are a number of fully regulated, independent ethics committees which are typically accessed by commercial clinical pharmacology units and whose timelines are considerably shorter than mainstream NHS RECs.
There are approximately 100 NHS RECs in the United Kingdom, and the REC to whom the application is sent is chosen by the sponsor/investigator. Meeting dates, submission deadlines, and contact details for all RECs are published on the National Research Ethics Service (NRES) website (http://www.nres.npsa.nhs.uk/). When the preferred meeting of the nominated REC is already full, it is possible for the study to be reviewed by any of the appropriate RECs wherever their geographic location in the United Kingdom.
Recent developments in the UK REC service have focused on ease of use and clarity of the review process. Detailed information regarding requirements for ethics committee submission and documentation (including advice on acceptable construction of the PISIC for example) is published on the National Research Ethics Service website. All letters conveying an opinion from a REC now contain a clear listing of the title, date, and version number of all reviewed documents. In addition, a list of the committee members is also provided alongside a statement confirming that the REC operates to relevant UK SOPs and regulations.
The submission to the ethics committee is not complex, and can be performed by sponsor, CRO, or chief investigator (the chief investigator is required to sign the application whoever makes the submission). Encouragingly, ethics committees are now open to contact from either investigator or the sponsor/CRO and both parties are invited to attend the review meeting. Sponsors and investigators should attend the REC whenever possible in order that clarifications can be provided where necessary to the committee directly during the meeting.
At present, there are no fees levied by NHS research ethics committees. Therefore, the ethical approval process in the United Kingdom is now clear and cost effective with timelines that are competitive, adhered to, and regulated.
Until 2009, NHS hospital sites were obliged to receive local approval from both their local ethics committee and their research and development department. However, in 2009 this system was streamlined to introduce a single local approval process. In multicenter trials, each investigator site applies for "site specific approval" from their research and development department (in the case of NHS sites) or their local ethics committee (in the case of independent clinical research sites). This process runs in parallel with the regulatory and main REC applications.
Site-specific approval is not a second ethical review, but acts as a check on the local suitability of the trial documentation, investigator qualifications, and site suitability. This approval is issued by research and development departments for NHS research sites and confirms that the supporting facilities in the hospital (e.g., laboratories, pharmacy, etc.) are aware of the study and willing to participate. In addition, this local approval at NHS sites is released once contracts are agreed, which is a further check to ensure that the management of the hospital site accept the fee structure proposed.
In order to apply for site-specific approval, a site-specific information form is completed, signed either electronically or by hand by all relevant parties, and all the required localized documents submitted (e.g., PISIC on local headed paper).
Local approval by NHS R&D departments is currently the only aspect of clinical trial set-up in the United Kingdom with timelines, which are unregulated and somewhat variable. Whilst the documentation itself is clear, the collection of approval signatures on the submission document and finalization of the contract, for example, can hamper the approval timelines and are often outside the control of the investigator themselves. Approval signatures on the submission document may include, for example, the hospital data protection manager, the head of research and development, the heads of biochemistry and hematology laboratories, the head of radiology, and the head of pharmacy where the support of these services is required. There is often no incentive for these busy individuals to review the protocol and budget in a timely fashion and apply their signatures to the form. For this reason, local knowledge is helpful regarding which UK sites tend to have speedy local approval processes, and which do not. Additionally, the familiarity of the investigator and sponsor representatives with the local approval process, and their willingness to drive this process remain critical.
Integrated Research Application System (IRAS). In the past, sponsors and investigators had to complete many separate forms when applying to regulatory and governance bodies, and there was a large degree of duplication of information between forms completed. The IRAS website, however, allows both regulatory (MHRA), ethics committee, and all related applications to be completed simultaneously. This application involves creation of one data set, from which forms required for various approval functions can be created. In addition, the forms can be shared electronically with others to allow, for example, review by sites when the sponsor/CRO is collating and submitting the ethics committee application. Where additional forms are required (e.g., gene therapy trials, for those involving radiation), these can be created from within the system.
The full list of organizations, each with their own submission form, supported by the IRAS system include:
The IRAS website can be freely accessed (https://www.myresearchproject.org.uk/) and also contains a detailed online training module and support documents.
The NIH CRN. The National Institute of Health Research Clinical Research Network is now fully operational in England, and links into similar networks within Scotland, Wales, and Northern Ireland. The aims of the NIH CRN include:6
In order for clinical trials to benefit fully from the support of the CRN, the study must be "adopted" by the CRN. Application for adoption is very straightforward, and provides the sponsor with important feasibility information within 10 days of the application. If this stage is positive, a more intensive review occurs, providing the sponsor with detailed information about the sites that are interested in participating, and their potential for recruitment. Importantly as well, site budgets are created and reviewed at this early stage.
The NIH CRN is committed to working with sites to ensure that set-up is streamlined, recruitment is to target, and quality is high. The opportunity for sponsors to work with a single, government funded organization to address feasibility and deliver their studies across NHS sites is truly valuable and can only be positive, a view backed by recent publications.7
The magnitude of the impact of the NIHR CRN is, however, questionable at present. Figure 2 summarizes the recruitment performance of all NIHR CRN studies to the end of 2009. Only a small number of studies fall in the bottom right quadrant of the figure, which indicates the worst of all outcomes (i.e., failing to recruit to target despite an extended recruitment period). There are, however, a number of studies that lie on the line to indicate poor recruitment when recruitment closed on time. Additionally, studies in the bottom left quadrant indicate under-recruitment, however with the explanation that the recruitment period was shorter than planned.
Figure 2. A visual summary of the recruitment performance of all NIHR CRN studies to the end of 2009.
Model agreements. Model clinical trial agreements now exist which provide a contract template for clinical trials performed within NHS hospitals. These include agreements both for direct sponsor-site agreements, and where a CRO is also involved. The existence of these model contract agreements ensures that sponsors and sites no longer need extended contract review periods, since the contract template itself is the same between sites and even between studies.
Budget forecasting. The NIH CRN also makes available a standard budget template (the industry costing template), which provides a transparent process for sponsors to accurately predict and propose detailed site budgets to UK NHS sites inclusive of institutional overheads and other additional costs. This simple spreadsheet saves considerable time; costs at each NHS hospital site can be forecast in this manner. The costs for common procedures (x-rays, blood tests, etc.) are included in the template, as is the per hour cost of the investigator, research nurse, and administrator. The template also includes a market forces multiplication factor (ranging from 1.0 to 1.25) which adjusts the created budgets for the additional costs expected at those sites which are in high demand and have additional price expectations (such as hospitals located within Inner London).
Over the last 10 to 15 years there have been a number of key reports detailing recommendations aimed at facilitating the conduct of clinical trials in the United Kingdom. In response to these recommendations, there have been a number of important developments that are now changing the landscape of clinical trials in the United Kingdom in terms of set-up and delivery. It will be interesting to note whether these developments are sufficient to reverse the decline in share of the global clinical trial market that the United Kingdom has experienced.
Kerry Dyson,* PhD, is Head of UK Operations, Suite 11, Sabrina House, Longden Coleham, Shrewsbury, SY3 7BF, United Kingdom, e-mail: email@example.com, and Davide Garrisi is Head of Project Management Unit, both at CROM Group.
*To whom all correspondence should be addressed.
1. Department of Health, Pharmaceutical Industry Competitiveness Task Force: Final Report, (March 28, 2001), http://www.dh.gov.uk/ab/Archive/PICTF/index.htm.
2. The Association of the British Pharmaceutical Industry (ABPI), Model Clinical Trials Guidance, Guidance for R&D Managers in NHS Trusts and Clinical Research Departments in the Pharmaceutical Industry (2003).
3. Academy of Medical Sciences, Strengthening Clinical Research, A report from the Academy of Medical Sciences (Academy of Medical Sciences, London, 2003), www.acmedsci.ac.uk/p_scr.pdf.
4. Department of Health, Best Research for Best Health: A New National Health Research Strategy, (January 25, 2006), http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_4127127.
5. HM Government, Life Sciences Blueprint. A Statement from the Office for Life Sciences, (2009), http://www.bis.gov.uk/assets/biscore/corporate/docs/l/life-sciences-blueprint.pdf.
6. National Institute for Health Research, website, http://www.ukcrn.org.uk/index/networks/comprehensive.html.
7. S. M. Ng and A. M. Weindling, "The Impact of Networks on Clinical Trials in the United Kingdom," Trials, (10) 100 (2009).