Clinical research operates in a far broader and more competitive global marketplace than ever before. At the same time, regulators, prescribers and reimbursers are demanding increasingly specific and detailed evidence of treatments’ safety, efficacy and cost-effectiveness. These factors would lead any country with an established research history to expect a decreasing share of a growing global volume of research, the net effect depending on the competitiveness of all aspects of that country’s performance. There are many layers of perception and received opinion characterising the UK’s performance, with a basic view that we are not performing as well as we might in comparison to other countries (generally in terms of being slower and/or more expensive) and are losing business as a consequence.
However, much of the evidence for this is anecdotal, and where metrics do exist they are often specific to an organisation, therapeutic area or part of the process (eg, final protocol to first patient visit). Broader research could show the extent to which study teams in different organisations saw significantly differing performance, whether delays in one process were made up somewhere else, or identify the study phases, therapeutic areas etc. on which the UK should focus to maximise the value it adds.
As such, it was extremely interesting to have been invited to a one-day conference held in September to discuss initial results of a 2-year study that looked across the entire research process, encompassing both commercial and non-commercial research in all therapeutic areas. The study was conducted by researchers at Queen Mary University of London and the University of Warwick, and aimed to identify the current social, organisational and managerial challenges and impediments to clinical research in the UK. Data collection for the study had only just been completed, so these are preliminary analyses, with a final report with more detailed analysis to be published in the next 3 months; this report will also be made available to all members of ICR.
To provide some additional context and discussion of the topic, key stakeholders from the commercial and non-commercial sectors were also invited to present and participate in a panel discussion. This report is based on live posts made to the CRfocus blog (http://crfocus.wordpress.com) where you can read the full text of my live report, and coverage of similar events as they happen, often several weeks prior to publication in CRfocus.
Managing clinical research in the UK
Prof. Maxine Robertson welcomed delegates and introduced the study. The first phase of the study consisted of a systematic literature review and 57 qualitative interviews with various stakeholders. The second, quantitative phase was an online survey of UK clinical researchers and clinical trial managers. The final part of this survey asked for attitudinal data from these respondents. Over 300 respondents took part, providing detailed data on 247 clinical trials.
Dr Sarah Evans presented some of the quantitative findings of the study. Significantly, pharmaceutical studies significantly outperformed other commercial and non-commercial studies in terms of speed of set up, end of recruitment and completion of study. However, a larger proportion of pharma studies are also terminated after the recruitment stage, possibly due to tactical decisions regarding efficacy or other market considerations.
Looking at hitting recruitment targets, pharma’s 72% reaching 90% of target outperforms other studies, with other commercial studies (eg, biotech and device studies) performing worst. Similarly, pharma and non-commercial studies were more successful at completing within budget. One possible explanation for this is that small biotechs might have less experience in budget setting or project management. Study completion timelines have also been significantly better since 2007, with the improvement taking place in the recruitment stage rather than the (more frequently discussed) set-up stage. Significant predictors of success include retaining the same personnel on the project team, to maintain key experience and ways of working. The number of regulatory submissions were also highlighted, suggesting that sponsors should invest time in meeting regulatory hurdles correctly first time.
Timelines to receive approvals showed an average of 85 days for R&D, 76 days for ethics and 71 days for regulatory. These have all shown a downward trend since 1999, although regulatory and R&D approvals showed a significantly speedy blip in the 2 years BEFORE implementation of the EU Clinical Trials Directive! Non-commercial studies were slightly slower, perhaps due to more specialised personnel to handle the process in the commercial sector. Looking at research phases, late phase R&D approval took significantly longer than both early and post-marketing studies.
Another question looked at the factors influencing the choice of recruitment sites. Reputation and previous track-record were considered important, but site resource was most important; interestingly, ease of contracting was not rated particularly important.
Stakeholder perspectives
Commercial research in a global context
David Gillen, formerly UK Medical Director and currently Head of Medical for the Primary Care Business Unit at Pfizer (covering Europe, Canada, Australia and New Zealand) gave an industry perspective on UK research conducted in a globalised context. He stated that we need to have a long-term vision, but also to have a dose of realism as to what types of studies the UK is good at conducting. The UK is historically good at discovering and developing new medicines, second only to the USA; however, in the commercial sector there is no place for sentimentality, with decisions ultimately being made by people with no vested interest in the UK.
David highlighted time and consistency as the key drivers for pharma in siting studies. He presented data on query rates in a large study, showing that the UK performed particularly badly, even compared to other EU countries, particularly those in Eastern European countries, which are also generally cheaper and faster. Similarly, consistency of recruitment performance is low compared to even western European countries. Even within a sponsor organisation, competitive recruitment processes can make it difficult for the UK. This has been borne out in reality, with the UK dropping from 3rd to 9th in global clinical research rankings since 2000.
However, David thinks that the UK has made significant improvements in recent years, particularly through the NIHR, and he expects the OLS Blueprint to build further on this. This change in attitudes is starting to flow through to CEOs of NHS Trusts, and they are starting to take notice and prioritise clinical R&D in a Trust’s portfolio of activities.
David highlighted therapeutic areas where the UK should focus, because they are areas that we can deliver well, such as oncology, Alzheimer’s, paediatrics and early phase work. He closed by suggesting that the single most important thing we could deliver is a parallel process for site set-up, beyond the regulatory/ethics approval process.
CRfocus will shortly be publishing an interview with David exploring these areas in greater detail.
Non-commercial research in the UK
Professor John Gribben, R&D Director for Barts and The London School NHS Trust, started the afternoon session with a discussion of the perspective of the non-commercial research sector. He is also Professor of Experimental Cancer Medicine, so many of his examples came from oncology.
He started with money: the old Culyer model for research funding will be removed completely by 2010 after several years of transition, to be replaced by the new activity-based funding model. Many Trusts have dealt with this transition by stalling research activity, leading to a need for pump-priming funding. This has come to some extent from CLRN funding, but alternative funding strategies have also needed to be considered.
John stated the need for Trusts to consider R&D as a vital part of their mission: we need to demonstrate its value, in terms of patient care, grants, publications etc. along with recouping costs of patient care and obtaining access to patient referrals, drugs, imaging approaches etc. that could not otherwise be used. Partnership with NIHR is essential to this, also enabling access to separate funding streams.
Looking at impediments to non-commercial clinical trials, these include:
- The quality of the initial idea
- Capability to manufacture and test drugs to GMP level
- Funding and sponsorship
- Ethical approval
- Monitoring and pharmacovigilance (with which the non-commercial sector is only just getting to grips)
The significance of these points varies between single centre and multicentre studies.
The remainder of John’s talk discussed the network of 19 Experimental Cancer Medicine Centres, which was launched in 2006. Their aim is to bring together laboratory and clinical research to speed up development in early phase. This contrasts with the NCRN, which handles oncology trials of all phases. At John’s Trust, these two bodies are brought together in a single governance structure, to enable cross-referral of patients and to provide a single point of contact for advice, ethics applications etc.
Implications for stakeholder groups
Prof. Jacky Swan returned to the survey data that opened the conference, to discuss some of the implications for different stakeholder groups.
Looking at knowledge and skills, the survey highlighted a shortage of experienced trial managers and monitors and these personnel prove difficult to recruit and retain. However, these are the people who know how to make the systems work in practice. Smaller commercial and non-commercial organisations also lack resources to employ and train specialists in non-science areas such as legal/regulatory, project management, business and finance. Different types of organisation face different skills gaps, and geography and an organisation’s status also play significant roles in attracting staff. The ABPI have described this skills gap as a “tipping point”.
Jacky then presented a chart of perceived impediments in setting up clinical trials. This showed that cost, time and R&D approval were considered major impediments, above contract negotiation and patient recruitment. However, the non-commercial sector viewed funding and team expertise more severely than other stakeholders, while biotechs/device companies saw engaging clinical sites and recruiting patients as more important than their pharma and academic colleagues.
As retaining an experienced team is seen as vital to project success, Jacky looked at the motivations and incentives for individuals. While many diverse motivations exist, the lack of a formal career path was highlighted by research nurses.
Different stakeholders have differing perceptions regarding studies, and these play out in differing strategic imperatives. These include the profit imperative for commercial organisations and affordability of medicines from a wider health service perspective. Similarly, expertise and prestige are increasingly needed to justify funding in the non-commercial and academic sectors. Some research models are more likely to get funding (eg, rare conditions) but these are often more difficult to manage.
Concluding with a look at research governance, Jacky discussed the mixed effect of the EU Directive. This brings a higher level of bureaucracy and cost, but this is more standardised and clearer to adhere to. Government has made much of “bureaucracy busting”, and many have high expectations, but so far this has had mixed impact, so Jacky warned of a potential backlash if these expectations are not met. Earlier in the day, we had discussed the “one size fits all” model for regulatory, ethics and R&D approvals, but Jacky commented that this presents greater challenges for non-standard or innovative trials. A suggested 2010 review of the EU Clinical Trials Directive saw concerns expressed by many that this could lead to increased uncertainty and possible even tighter, more counterproductive controls.
Panel discussion
The day’s speakers were joined for a final panel discussion by Dr David Collier of QMUL, Janette Benaddi of ICR and John Hladkiwskyj of the CCRA. It is only possible to report some of these discussions here.
David Collier likened the future of clinical research in the UK to the manufacturing industries of decades ago, where we have been unable to compete on unit cost, but have become much smarter in terms of designing and marketing products. John Gribben agreed with this, and suggested that the UK being seen as smarter is the main reason that pharma has not yet left the UK in the face of rising development costs and declining revenues.
Janette Benaddi welcomed the results of the study as reaffirming the UK’s position, what we do well and also the problems that we face. We are doing much to address these, and the results are beginning to be seen. Addressing the need for a coordinated approach to change, she commented that meetings are often one-sided, dominated by participants from either the commercial or non-commercial sector.
John Hladkiwskyj also commended the results, and added that we need to more actively promote research sites to CROs and sponsor, providing a more welcoming attitude. Maxine suggested that this might also be due to the shortage of personnel and motivation. John Gribben highlighted that research nurses face the lack of career path most acutely.
Another delegate discussed the perceived problems and delays with R&D departments and questioned whether they received adequate funding. John Gribben said that they are generally expected to be self-financing with no funding from the wider Trust and suggested that this cut-off perhaps stems from practices some time ago when R&D funds were routinely siphoned off to underpin other Trust finances.
Conclusion
Even the preliminary results of this survey provide some valuable insights, and it is clear that the main virtues and impediments to conducting clinical research in the UK vary between types of sponsor organisation, phase and therapeutic area. The more sophisticated analysis due in the coming months will doubtless highlight more areas where reforms and initiatives should be targeted. The broad consensus is that, while the UK is not doing as well as it was say 15 years ago, the initiatives put in place are starting to improve conditions. These improvements lead to the spotlight falling on other aspects of the process, and so on. There is necessarily a lag time for this to have a measureable impact in terms of individual studies and, ultimately, on the volume of clinical trials being conducted in the UK, but the meeting ended with the feeling of a corner having been turned, albeit bringing the next set of challenges into clearer view.