This is the Table of Contents of Clinical Research focus 20(10) issue for October 2009. Members of The Institute of Clinical Research can view the full text of each article by clicking the link and logging in with their username and password.

Global competition

Multinational Trials: A New Balance Point?

Andrew Smith

Given that multinational (often ‘massively multinational’) trials are now the default position for anything beyond the earliest phase of clinical research, it is somewhat surprising that they still polarise opinion. To some, they are the only way to complete large studies even remotely on deadline and within budget. To others they are damaging to local professionals and research infrastructure and of limited clinical relevance to a medicine’s target patient population. In this extended editorial, Andrew Smith takes a look at the evolving bigger picture of globalising clinical research and suggests how we might find a new balance point to deliver global performance combined with local relevance.

Managing Clinical Research in the UK: Survey & Conference

Andrew Smith

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). A one-day conference was 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. Andrew reports…

Feature

My Clinical Study is Over; What Happens to the Data? An Introduction to the Clinical Study Report

Emily Scott

Conducting a clinical study takes a considerable amount of planning, resource, and commitment. But, after the last subject is out, the database has been cleaned, and the planned analyses have been done, what happens to the data that were collected? For interventional studies conducted in accordance with the International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), data collected in a clinical study should be submitted to the authorities in a Clinical Study Report (CSR). Emily Scott provides an introduction to CSRs, how they should be constructed and how other study personnel should be involved.

Prof. development

Study Management for Research Nurses: ICR Research Nurse Forum

Nicky Perry MICR

The ICR Research Nurse Special Interest Group (SIG) held their second forum on June 18th at the ICR office. Sixty research nurses attended. The agenda for the day was set following the training needs analysis conducted via questionnaire, which was sent out last year. The result of this survey highlighted that nurses wanted to know more about study management, especially how to cost a clinical study.

Virtual Learning in the Real World: ICR Tainers’ Forum

Iain Searle MICR CSci, Merryn Collard RICR & Jane Nathan RICR

ICR’s Trainers’ Forum generally holds three meetings each year, designed to address topical issues and challenges for those involved in training functions across health, pharmaceutical and life science industries and services. This event was prompted by the rapid development of remote delivery methods within our sector, with a wide range of solutions being implemented across the industry. The days’ agenda had been developed by the Steering Committee, which has a mission to support the interests and further development of trainers within ICR by providing topical meetings, with expert speakers from within and beyond the pharmaceutical industry.

Trial technology

Ten Things You Need to Know About Infusion Pumps for IV Delivery in Clinical Trials

Elena Skryabina

In the latest in our series of introductions to key topics, Elena Skryabina examines the use of infusion pumps for intravenous drug delivery in clinical trials. She demonstrates the amount of control that is possible in a single Phase I unit but also the care that should be taken in larger studies, where differing pumps at different sites can impact on the precision of study drug delivery.

Book review

“Trial by Fire: Lessons from the History of Clinical Trials”

Allan Gaw, reviewed by Andrew Smith

The rationale for this excellent little book is summed up by Mark Twain, quoted in the introduction: “The past does not repeat itself, but it rhymes.” Learning about the history of clinical trials helps us to understand why the present is the way it is, and this book provides insights into ways of thinking and working that many of us would otherwise simply take as given. It is written in a clear, readable style, with interpretation as well as factual account, highlighting the aspects of each topic that have had the most significant impact on the way clinical research is done today.

Regular update

Fit For the Future: Message from the Chair

Janette Benaddi MICR CSci

Like most organisations, the Institute has experienced a difficult operating environment this year, caused by the global recession. However, the Board of Directors and Senior Management Team (SMT) took early, proactive steps at the beginning of the year to manage us through the recession. These included a thorough overhaul of our operating costs and we are starting to see the benefits of these actions. Janette thanks you, our members, for your continuing support. We have received many communications from you supporting ICR over recent months, as we have gone through the change management process. The staff are extremely encouraged by this.

It’s Not All Work, Work, Work…

Compiled by Andrew Smith

Our regular look at the lighter side of clinical research, including some ideas for blockbuster movies involving clinical research, examples of “frontier science” in literary classics (and the new Dan Brown), and “Ten things that suggest global clinical research is starting to pick up again…”.

Prothero didn’t believe in these new-fangled feasibility studies and rankings to decide where to site clinical studies...

For more clinical research humour visit http://www.icr-global.org/crfocus/clinical-research-jokes/

This is the Table of Contents of Clinical Research focus 20(09) issue for September 2009. Members of The Institute of Clinical Research can view the full text of each article by clicking the link and logging in with their username and password. Due to its special significance, the cover story is accessible to all, free of charge, during September 2009

Feature

Still Relevant After All These Years? Should ICH GCP be Reviewed & Revised? – FREE ACCESS DURING SEPTEMBER

Compiled by Andrew Smith

ICH guideline E6 (ICH-GCP) is, along with the Declaration of Helsinki, arguably the most important document in clinical research. Since its adoption in 1996 (in Europe; 1997 in the USA and Japan), ICH GCP has been the ‘bible’ for CRAs, auditors and other clinical research professionals worldwide. However, the world of clinical research has moved on quite some way in the past 13 years. Following a remark made by a speaker at this year’s ICR Annual Conference, we wondered whether ICH E6 should be reviewed and potentially revised. We undertook a qualitative survey, asking all CSci and FICR members what elements of the guideline should be updated and/or what should be added that did not exist in 1996. We present some of the most interesting and provocative comments.

People

A Leader of CRO Innovation & Growth: An Interview

Rob Davie PhD MICR

Dr Robert Davie is Vice President and General Manager, Europe, for Clinical Development at Covance. In this interview with Andrew Smith, he talks about the current period of innovation in outsourcing arrangements, the challenges of long-term global partnerships between CROs and pharmaceutical companies, learning lessons from other industries, differences between ‘old’ and ‘new’ Europe and the ‘flattening’ of the world of developing medicines.

Where Have All the Career CRAs Gone? An Interview

Stewart Hulse

Stewart Hulse is Director of Recruitment Services for Novella Clinical. In this brief interview with Max Golby, he discusses what has happened to the once-great well of monitoring expertise, and what has led new CRAs to chase the ladder of promotion as fast as employers will allow. He calls for better rewards for long-term CRAs to retain that expertise and points out that going freelance too early can actually be a career-limiting move.

National updates

Changes Across the Pond: Barack Obama, Stem Cells, Incentives & Pre-emption

Angus E Donald LLM HonFICR

In the latest in a series of letters from his new home in the USA, long-time ICR member Angus Donald reports on some of the significant changes around clinical research and healthcare in general that are taking shape in the first few months of the presidency of Barack Obama. The past few months have seen considerable changes in the landscape of pharmaceutical development in the US and indications suggest that these radical changes, both in administrative policy and litigation, will continue during the current administration. Angus discusses the changes in funding for basic medical research, including human embryonic stem cells, financial incentives for innovation, an expanded budget for the FDA, and closing loopholes on ‘exclusion payments’ on generics. He also goes into detail on the issue of pre-emption, and discusses the implications of the recent US Supreme Court ruling on Wyeth v Levine.

Net Benefits of Working with Networks? The ICR Scottish Forum

Graeme Scott HonFICR CSci

The ICR Scottish Forum is now in its ninth year and it is clear from attendance figures that it continues to offer what ICR members want. A healthy 70 or so of us attended the forum’s February meeting to listen to Dr Clare Morgan, Dr Matthew Cooper and Dr Roma Armstrong tell us about the progress and performance of the Research Networks both North and South of the border. There was the usual opportunity for awkward questions and healthy debate. Graeme Scott presents this report, which is equally relevant for those of us working outside Scotland.

Prof. development

Trials & Tribulations of Monitoring: A Week in the Life of a CRA

Polan Chetty & the ICR CRA Special Interest Group

When Polan Chetty and her colleagues in the ICR CRA Special Interest Group started writing this article, they tried to describe a typical week in the life of a Clinical Research Associate. However, any CRA will tell you that there is no such thing as a typical week. If you are hoping for a straight 9 to 5 job, you are not going to find it here. While the few days described are fictional, they are entirely realistic…

Viewpoint

OLS Blueprint: PICTf 3.0?

Andrew Smith

The counter-balance to increasing constraints on NHS spending on pharmaceuticals comes in the form of various initiatives to make more of a contribution in terms of investment by the UK government in education and training, infrastructure and organisational processes. The latest of these is the Office of Life Sciences (OLS) Blueprint, which was published over the summer. The Blueprint sets out 12 key action points, expanded to 10 pages of specific policy measures, complete with timelines and budgets, of which the policy that will be of most interest to us is the “package of measures to improve the UK environment for clinical trials”. The Blueprint has been widely welcomed by industry and commentators alike. Andrew offers “two cheers” but also sounds a note of scepticism…

Regular updates

It’s All About You: Our Members! Message from the Chair

Janette Benaddi MICR Csci

This month, as many of us return from our summer vacations, Janette Benaddi shares more information on the demographics of the entire ICR membership. If you have had the opportunity to attend our Annual Conference you will have experienced at first hand the diversity of our members and will have perhaps been astounded by the different fields our members work in. As an Institute for professionals it is important we try our best to cater for all our members whether minority or majority. You may think that with such diversity in roles and affiliations this might be difficult. However, what is interesting to one group of members will often be interesting to others. We have recently adjusted the membership prices to more closely reflect the costs to serve our members and help to bring us more in line with other professional bodies. We are looking at new ways of serving the specialist groups and are constantly striving to improve our service offerings.

It’s Not All Work, Work, Work…

Compiled by Andrew Smith

Our regular look at the lighter side of clinical research, including some unlikely holiday destinations for clinical research professionals, some possible side effects we might not need to be quite so worried about, and “Ten news stories that weren’t covered by the world’s clinical research media”.

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. Maxine Robertson highlighted four key questions to frame the debate:
* What might affect positive change in the system?
* How might we achieve a coordinated approach to affecting systemic change?
* Are there any short term fixes?
* Which stakeholder within the system is best placed to drive particular changes and how might these stakeholders go about this?

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 rather one-sided.

One delegate commented that the survey results put into formal numbers things that had been known anecdotally for several years. He called for even more sophisticated analysis to pinpoint areas for future improvement. He also called for more involvement of patients. John Gribben agreed with this, but commented that in his experience lay members of ethics committees have been some of the most difficult to deal with.

John Hladkiwsyj 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. One delegate stated that she had just appointed a lead research nurse to develop the role, and called for more experienced research nurses to have hybrid roles between research other senior nurse clinician positions.

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. This cut-off perhaps stems from practices some time ago when R&D funds were routinely siphoned off to underpin other Trust finances.

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 trials 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 a significant role 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-commecial 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 öne 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.

Jacky closed with discussion of the suggested 2010 review of the EU Clinical Trials Directive and concerns expressed by many that this could lead to increased uncertainty and possible even tighter, more counterproductive controls.

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 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.

To develop experimental medicine, we need to engage further with the public in the imprortance of clinical trials, work to increase visibility within the EM community, and stress the importance of research in the everyday work of the Trust.

John discussed the balance of activities between discovery and exploration in the medical schools and application and delivery in the Trusts.

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, and 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.

John stressed the need to challenge and change the perception from industry sponsors that UK trial units are “too expensive”, “too obstructive” and “don’t deliver on promised targets” through active collaboration.

David Gillen of Pfizer 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 in other countries by people with no vested interest in the UK. In a global context where R&D productivity is falling dramatically, and around 60% of clinical development expenditure is in phase III and beyond, industry is under pressure to conduct research as efficiently as possible, wherever this can be done.

David highlighted time and consistency as the key drivers for pharma in siting studies. David 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, Alzheimers, 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.

In response to a question, David discussed the Pfizer policy of focussing on certain countries that are performing well (eg, Spain) to receive Pfizer resource, while others that do not perform so well (eg, the UK) are handled via CROs. This could be seen as a downward spiral, with the additional difficulties of dealing with multiple subcontracted suppliers continuing to degrade performance.

I’m reporting from a conference to present and discuss the findings of a 2-year research project on managing clinical research in the UK, conducted by Queen Mary University of London and the University of Warwick. Prof. Maxine Robertson introduced the study, which looked at academic and industry perspectives to the current social, organisational and managerial challenges and impediments to clinical research in the UK.

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 respondants. Over 300 respondants took part, providing detailed data on 247 clinical trials.

The study has only just been completed, so these are preliminary analyses, with a final report due to be published in the next 3 months.

The researchers argue that research into new healthcare interventions should be considered as a networked, recursively-related innovation process rather than the traditional linear view of Discovery, Development and Implementation. Looking more closely at clinical trials, the challenges can be categorised as issues of Governance, Motivation, Skills and Strategy.

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 scenario for this is that small biotechs might have less experience in budget setting or project management. These completion timelines have also been significantly better since 2007. This improvement appears to be taking place in the recruitment stage rather than the set up stage.

Sarah then listed some predictors of success; these significantly retaining project team, to maintain key experience and ways of working. Ease of contract negotiation and the number of regulatory submissions were also highlighted.

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! For example, R&D approval is now around 78 days, but was as low as 66 days in April 2004. In each sector, non-commercial studies were slightly slower, perhaps due to more specialised personnel to handle the process in the commercial sector. This was also reflected by pharma respondants reporting greater ease of completing different aspects of the process. Looking at research phases, late phase R&D took significantly longer than average, compared with 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. The most significant aspect influencing a site’s ability to recruit was considered to be the inclusion criteria for the study, although experience and recruitment strategies were also important.

The UK pharmaceutical industry is one of the most significant industries to make money for ‘UK plc’ and re-invest it back into UK-based R&D, within their own organisations, in universities and throughout the NHS. As many have said, the UK ‘punches above its weight’ in our sector. Despite this, we often feel unloved, in terms of both media and public opinion and increasing constraints on revenue (eg, prescribing decisions being led by NICE guidance while reimbursement rates have been cut under the successor to the PPRS). However, the counter-balance to this top-line constraint has come in the form of various initiatives to make more of a contribution in terms of investment in education and training, infrastructure and organisational processes. As a globalised industry has far less binding ties to doing its R&D in the UK than it did 30 years ago, this policy makes a great deal of sense. Over the past decade or so, these initiatives have come under the banners of PICTf, UKCRC and, now, the Office of Life Sciences (OLS) Blueprint, which was published over the summer.

The Blueprint set out 12 key action points, which have been agreed across government, industry, the higher education sector and the NHS. This expands to 10 pages of specific policy measures, complete with timelines and budgets. The Blueprint has been widely welcomed by industry and commentators alike, and certainly, every policy measure should have a positive effect.

The measure that has received the most coverage is the Innovation Pass, ring-fenced funding for time-limited use across the NHS without appraisal by NICE (although NICE will define the criteria for medicines that can take this short-cut). This will be piloted in 2010/11 with a budget of £25m. While initially portrayed by the media as bypassing NICE, this could be a valuable experiment in ‘live appraisal’ mirroring the ‘live licensing’ model proposed by PricewaterhouseCoopers in their Pharma 2020 reports.

The policy that will be of most interest to us in the clinical research sector is the “package of measures to improve the UK environment for clinical trials”. This includes ensuring the UK “fully exploits its potential to be a world leader in heath informatics” (ie, making electronic patient records finally happen!), underlining the duty for SHAs to promote R&D, adding metrics on patient in clinical trials to Trusts’ Quality Accounts, and creating a national framework for local management of research (ie, transforming NHS R&D departments). Significantly, the last three points are essentially reworking areas covered by PICTf nearly a decade ago…

The questions that need to be asked about all these measures, though, are “Will they be implemented as planned?”, “Will they result in improvements in the productivity of UK R&D and uptake of resulting products?” and “Are they sufficiently different from previous initiatives to justify the top-line reduction in reimbursement for medicines?” The many intelligent and powerful people close to this project evidently think so. Far be it from me to disagree, but the fact that this is the third major initiative in less than a decade suggests that its predecessors did not maintain momentum in their improvements (or, more cynically, that pharma are getting increasingly itchy feet in the light of increasing competitiveness overseas).

To sound another small note of scepticism, the UK is less than 12 months from a general election, with a change of government far more possible than at any time since 1997. Although many measures in the Blueprint can be implemented almost immediately, many will take time to demonstrate success, and none will be immune from reversal under a new government.

So, I would like to raise two cheers for the OLS Blueprint: it talks a good game and will certainly have some success, but will it be enough to steady ship of UK competitiveness or just the latest in a series of defences against an insuperable drift to merely “punching our weight”? We will see…

For more clinical research humour visit http://www.icr-global.org/crfocus/clinical-research-jokes/

Cartoon for September's issue of CRfocus