The following is a conference report that was originally written in 2012 for Clinical Research focus magazine, but was left unpublished.
As a profession, we often criticise ourselves for being stuck in “silos”, whether technical, corporate or national. So, it was interesting and refreshing to represent ICR at a symposium, held in London on October 16th, 2012, that brought together nearly 50 delegates from the UK and France. The purpose of the event was to share background information and ongoing developments on a bilateral basis. While the meeting demonstrated that our two countries are facing similar challenges and responding in broadly similar ways, it was clear that there was also plenty that we could learn from each other. This report presents highlights from some of the sessions at this symposium.
Setting the scene
After being welcomed to the event by Dr Julie Maxton (Executive Director of the Royal Society) and His Excellency B. Emié, the Ambassador of France, the first part of the event gave an overview of the structures to promote and conduct clinical research in France, England, Scotland, Wales and Northern Ireland.
The French landscape
The first presentation was given by Prof. A Syrota, President and CEO of The Institut National de la Santé et de la Recherche Médicale (INSERM, www.inserm.fr). INSERM initiates around 40 studies every year, ranging from basic research, through clinical trials to public health. Around 12% of these studies are therapeutic clinical trials. These trials are run through university hospitals but also across a network of 41 Clinical Investigation Centres throughout France. In addition to 27 general centres, ten specialise in biologicals, eight in medical devices and nine in epidemiology. These centres provide a platform to support research throughout France, particularly for large late-phase and post-authorisation research. As dedicated research centres, they provide a compliant environment for the smooth set-up and conduct of both academic and commercial studies.
Prof. Syrota highlighted the Centre National de Gestion des Essais des Produits de Santé (CENGEPS, www.cengeps.fr), a set of investigator networks designed to reinforce patient recruitment to commercial clinical trials. This network was set up in 2007 as a public/private partnership and encompasses investigator networks in 21 disease areas. This suggested comparisons with the therapeutic networks set up in the UK by the NIHR, but in response to a question, Prof. Syrota clarified that the networks are less formal in structure with a smaller management overhead.
France was also the birthplace of the European Clinical Research Infrastructure Network (ECRIN, www.ecrin.org) which grew from the French national network F-CRIN (www.fcrin.org). ECRIN has hubs in all EU member states, and aims to bring together stakeholders in academic and commercial clinical trials facilitate improved competitiveness, particularly in early phase and multicentre studies.
In summary, Prof. Syrota heralded the sophisticated infrastructure and networks to support clinical research in France. However, these are underpinned by multiple financial lines and layers of administration, which leads to a fragmented system that could sometimes be co-ordinated.
Around the UK
Prof. Tom Walley next gave an overview of the history of the NIHR in England, with which many readers will be familiar. As a response to the changing parameters of their own funding reviews, universities had moved from therapeutic research to basic biomedical research, which indirectly resulted in the UK being less able to capitalise on its excellent basic research. Research was recognised as a core activity in the 2006 review of NHS R&D strategy and NIHR was founded to commission research in areas of market failure and to influence clinical practice.
While an initial priority for NIHR was to underpin practice within the NHS, he highlighted that it was important to coordinate better with groups outside the UK, to enable bigger, better studies. Tom gave the example of the IVAN study to compare Avastin with Lucentis, which was conducted with 610 UK patients. At the same time, the CATT study was making the same comparison with 1208 patients in the USA. The Persephone study on the use of Herceptin for breast cancer in the UK was very similar to the French Phare study.
Tom concluded his presentation with a mention of plans to rationalise the research networks in England. The details of this rationalisation were still being discussed, but it was likely that the 120+ networks active across England will be reduced to around 15, reducing management overhead without substantially reducing activity.
Mike Stevens, Acting Director of the Chief Scientist’s Office of Scotland, spoke next. Scotland has a system of integrated approvals for R&D and ethics, in contrast with the system in England. He said that this enables rapid approval of studies, leading to faster start-up. However, he conceded that patient recruitment to commercial studies averages only 76% of target, despite efforts to improve this.
Mike highlighted the investment of NHS Research Scotland (www.nhsresearchscotland.org.uk) in bio-repositories and health informatics. Four regional bio-repositories underpin basic research, and are based on collecting tissue using a generic, enduring consent process. In the pilot scheme, 97% of patients who were asked to donate samples in this was were happy to do so. Research into health informatics will be of more interest to CRfocus readers. The Scottish Health Informatics Programme (SHIP) aims to establish a national safe haven, firmly embedded within NHS Scotland that will provide rapid, secure access to the types of data required by clinical scientists. Due to go at the end of 2012, this will enable single electronic health records from birth to death, linkable to non-NHS data as appropriate, to underpin feasibility analyses for individual studies, inform stratification for ‘personalised medicine’ studies and facilitate epidemiological research.
Regarding working with industry, Mike reminded us that delays are not only caused by the sites and networks: last-minute changes to study protocols and other industry requirements also introduce delays. He highlighted formal collaboration as a method to increase mutual understanding and to work together more smoothly. Both PPD and Quintiles have recently signed collaborative agreements to work in Scotland.
Prof. Keith Lloyd of the Welsh National Institute for Social Care and Health Research (NISCHR, www.wales.nhs.uk/sites3/home.cfm?orgid=952) based his presentation on his group’s efforts to win research grants, as health and social care represents over 40% of the Welsh government budget. To do this, he highlighted the importance of streamlining research processes and pointed to a study turnaround of 40 days for permissions and start-up.
Prof. Bernie Hannigan of the Public Health Agency in Northern Ireland (www.publichealth.hscni.net/directorate-public-health/hsc-research-and-development) gave an overview of the situation in Northern Ireland, where much of the research is concentrated around two universities and a single medical school. She showed a series of ‘kite diagrams’ representing the distribution of research funding, demonstrating a shift towards therapeutic evaluations. She highlighted strength in respiratory/COPD research and also in new areas of research related to home-based care and stratified medicine. Bernie also highlighted an academic research partnership between Northern Ireland, the Republic of Ireland and the USA, based on US NIH peer review.
Picking up on one of the themes of the morning, she also mention their involvement in the European Connected Health Alliance (www.echalliance.com). One of the delegates welcomed these multiple projects around electronic health records, but raised the issue of interoperability, so that the datasets can actually be related. Tom Walley confirmed that there is a project to address this being funded by the Department of Health. Mike Stevens and Keith Lloyd confirmed that the Scottish and Welsh projects are discussing how to make their systems interoperable.
Regulation, governance & ethics
The second session of the day looked at issues around regulation and oversight of clinical research, generally taking a more international view.
Fergus Sweeney, Head of Patient Protection at the European Medicines Agency, gave some an update on some of the metrics collected by the EMA. At present, roughly 38% of pivotal trial data for EMA submissions has been generated within the EU, compared with 30% from the US. Given the general distribution of market share for clinical research, it might be a little surprising that US data does not dominate. However, it is perhaps less surprising that the proportion of data coming from the ‘Rest of World’ is increasing. Digging more deeply into the data, it is clear that while the number of industry clinical trials being conducted in the EU is decreasing slightly, the total number of EU patients taking part in those studies is decreasing more dramatically, suggesting that the number of sites per study and/or patients per site within the EU is declining. This is one of the driving forces behind the proposed Clinical Trials Regulation, which was published in draft form over the summer.
Fergus went on to speak about the move towards a risk-based approach that is going on in many aspects of clinical trials. He suggested that much of the resistance to change is to do with industry’s perception of regulators’ requirements rather than the reality. He clarified that the quality of data should be “sufficient to support the decision-making process”. The previous EMA and FDA guidelines around risk-proportionality have been discussed in CRfocus, but Fergus also mentioned draft guidance from the OECD and EMA guidance that was expected to be published shortly, relating to the context of GCP inspection findings and how to assess whether they a finding would be more or less likely to impact on the overall risk/benefit decision on a medicine.
Finally, Fergus spoke about data transparency, which is currently a hot topic. He told us that guidance on the publication of summarised trial results had been published and would be implemented in 2013. He confirmed the intention of the EMA for clinical study reports to be made public once an MAA is approved. This story has moved on since this presentation, and will be reported in more detail in a future issue of CRfocus.
Jacques Demotes spoke next, giving additional details around the ECRIN project, which he coordinates. In particular, he highlighted that the project is attempting to address some of the barriers to international cooperation related to gaining access to expertise and patients, particularly for academic studies, throughout Europe. This is despite issues around national-level funding leading to fragmentation.
The ECRIN Integrated Activity (ECRINIA, www.ecrin.org/index.php?id=141) project is the next step in ECRIN’s development, funded by the EU under the FP7 programme. This is designed to build a consistent organisation for clinical research in Europe, with ECRIN developing generic tools and providing generic services to multinational studies, and supporting the construction of pan-European disease-oriented networks. There will be 16 networks in specific disease areas, to be set-up by 2015.
Elaine Godfrey of the MHRA went on to discuss trends around studies in the UK. In particular, she highlighted a decrease in the number of phase 1 studies being conducted in the UK, an area where the country has traditionally been strong. While this could be related to an overall decline in the number of studies being conducted in Europe, an initial review suggests that this might also be due to the trend to ‘roll-up’ studies into a single protocol, which might encompass multiple stages of phase 1 study and perhaps initial phase 2a studies. Elaine told us that an internal survey is currently underway to determine the extent of this ‘rolling-up’. (We hope to publish an article on this in a future issue of CRfocus.)
Elaine also discussed the Voluntary Harmonised Procedure for coordinated regulatory approval of multi-centre clinical trials across Europe. This was developed by the Clinical Trial Facilitation Group, which comprises the heads of regulatory agencies in each member state. VHP has been discussed extensively in CRfocus over the past 2 years, and its pilot has been considered by many to have been a success. As a result, a similar model for coordinated approval is now included in the proposed text of the new EU Clinical Trials Regulation.
Bringing this session to a close, Didier Caizergues, Director of Regulatory Affairs at Généthon shared his views on developing an Advanced Therapy Medicinal Product (ATMP). This product area has had its own regulatory structure since 2008, when Regulation EC/1394/2007 came into force. However, much of the disharmony that has been addressed in the regulation and oversight of conventional medicinal products has some way to go for ATMPs. In particular, Didier pointed out that the standard dossier format is not compatible with some genetically modified products, such as those involving modification of patient cells. Similarly, and perhaps unsurprisingly, the different specialist bodies reviewing ATMPs in different member states each have their own information requirements. In addition to having to process all these different dossier formats, the reviewing bodies do not coordinate their questions, leading to similar questions being returned from many organisations… which, in turn, need to be answered in different formats. As someone who has watched the development of VHP with great interest, this is precisely the kind of coordinated activity that Didier was calling for. However, given the relatively small number and high diversity of ATMPs currently in development, it might be much more difficult to put such a system in place for ATMPs.
Challenges for pharma
In the final segment of the programme covered by this report, senior representatives from British and French pharma companies discussed some of the national and international challenges facing them and shared their approaches to them.
Malcolm Skingle, Director of Academic Liaison at GSK, started by looking at the consolidation of the pharmaceutical industry since the 1980s, concluding that no company can do it all. As a result, his role within GSK is to facilitate partnerships. These can pair pharma companies with academia, biotech companies or even other pharma companies. Malcolm highlighted GSK’s focus on biopharmaceuticals and on rare diseases, but more interestingly he mentioned more diverse partnerships, such as with the Formula 1 racing team McLaren! This has contributed to GSK’s thinking on areas such as rapid prototyping and pass/fail testing.
Patrick Tricoli is Head of Scouting & Partnering at Sanofi. He characterised the past decade as being full of “much science and much information, but little patient benefit.” He picked up the theme of open data from earlier in the day and spoke of open innovation, which enables partners to share pre-competitive knowledge. As was the case with eHealth records, the key to making open innovation viable is the interoperability of organisations’ knowledge systems. Patrick called on us to rethink the traditional linear model of drug development, moving to a more cyclic model, linking patient outcomes back into subsequent research. He also highlighted the potential for scientific synergies with vaccine researchers, other types of biotech companies and even animal health companies. Patrick suggested that these could be coordinated in integrated R&D hubs.
There is insufficient space to report on all the presentations from this interesting symposium. In addition to the speakers above, Prof. Robert Lechler and Prof. Betrand Fontaine spoke about the potential for academic healthcare institutions to generate more value from their translational medicine activities, while Mike Capaldi and Francois Ballet spoke about how bio-clusters can bring academia and industry together more effectively.
Other breakout sessions included discussions about methodology and management of orphan diseases, biotherapies in auto-immune diseases and therapeutic innovation for Alzheimer’s disease.
Overall, while demonstrating that our two countries are facing similar challenges and responding in broadly similar ways by facilitating closer links between industry, academia and healthcare services, it was clear that there is much that we can learn from each other.
I am grateful to the French Embassy to the United Kingdom for the invitation to report on this event. For further information about Franco-British events relating to science and technology, please visit www.ambascience.co.uk.