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.
Introducing the NIHR CRN
Dr Morgan is Director for Industry, National Institute for Health Research Clinical Research Network (NIHR CRN) Co-ordinating Centre. The old ‘UK CRN’ is no more. Instead, England has the NIHR CRN co-ordinating an array of Topic-Specific Networks and a Primary Care Network; Scotland has its Chief Scientist Office (CSO) Networks; Wales has Clinical Research Collaboration (CRC) Cymru and Northern Ireland has the Northern Ireland Clinical Research Network (NICRN). Funding in England and Wales against an initial three-year plan was granted in 2005-6 to develop an England-wide infrastructure embedded into the NHS. The three years ended in April 2009. So, how is the process going?
The historical backdrop to this had been an dismal reputation for unreliable delivery both in target patient numbers and adherence to schedules, variable costs across Trusts, slow set up times (especially for R&D approval), poor data quality and inadequate investigator commitment. In my personal experience, I did not typically identify too many cases of the last two items listed, but almost always the first three, especially in the five years or so up to 2005.
The end of the beginning
Are things better yet? Have the networks significantly improved industry-sponsored trials in these areas? The audience thought not. Clare did not disagree, but explained that it is still too early to judge: we must bear in mind that the three-year set-up period is only now ending.
In the three-year period, there have been 167 industry trials placed in the English CRN system. The natural duration of clinical trials is such that to date only eight of these have closed with complete follow-up. A further 29 had closed to recruitment by December 2008 and will be completing follow-up over the coming months. In addition, 52 are open to recruitment and 54 are in set-up; 24 had been suspended, a rather high proportion, but the reasons were not examined.
Numbers of industry trials adopted by the networks are rising and the rate of accrual of patients to English Network industry trials has accelerated from <200 patients per quarter in January to March 2007 to approaching 800 in October to December 2007 and to nearly 1700 in the last three months of 2008. So, it is fair to say that a reasonable number of commercial sponsors are giving the networks a try and may be achieving reasonable recruitment rates.
The CRNs have varying models for study start-up. Some use standard, accepted agreements across Trusts, while others have a person to whom responsibilities are devolved within the Trust. That seems inefficient, but if it can be shown to work, then I imagine we won’t want to ‘fix’ it. Whatever the model, the NIHR focus is on ‘unblocking the blockages’, wherever they might be.
Adoption is the formal process that industry-sponsored studies go through for a network to take them on, and the target for successful, timely initiation of adopted studies is to have the trial open to recruitment within 4 weeks of the planned opening date. This date will, of course, already have been discussed and agreed with the CRN, so an improvement from 20% (2 of 5 trials) in the first quarter of 2008 to 50% (6 of 12) in the last quarter of the year demonstrates that there is still some way to go before we will feel reassured.
However, progress is being made. Earlier approach by industry to the CRN is helping the process. Among the first 18 trials to have completed recruitment, a greater proportion of those studies adopted before the start of recruitment reached or were close to (=80%) their planned recruitment target compared with the number doing so that were already recruiting at the time of adoption. Apparently, only 37% of studies achieved the 80% recruitment figure when not being conducted through the NIHR CC.
Whilst these metrics are similar to the ABPI’s figures, the median number of non-recruiting sites across Network studies (223 sites) is 17% compared with 24% across the 822 sites in the ABPI metrics: some evidence that the networks have improved the targeting of sites.
From April 2009, the new, if unimaginatively named, Comprehensive Clinical Research Network (CCRN) became operational, dealing with the establishment phase of trials and leaving the Topic-specific Networks to deal with delivery. The CCRN has a number of key roles:
- Co-ordination of systems for coordinated approvals/NHS permissions
- Research Passport management
- Network wide research management
- Dedicated industry manager
- Clinical Research Intelligence Service
- Process simplification
It was acknowledged that speed through R&D is helped through the unmodified use of the model Clinical Trial Agreement (mCTA). If we insist on modifications, we have only ourselves to blame. There is shortly to be an ABPI-endorsed generic confidentiality agreement, which is also anticipated to speed up the process, though in my experience confidentiality has rarely caused delays. More useful is a model memorandum of understanding between Universities acting through NIHR and sponsor /CRO (see
www.ukcrn.org.uk/index/industry/collaborations/mainColumnParagraphs/05/document/MoU%20Network-company%20FINAL%20DRAFT%20V1%20_090105.doc), outlining the responsibilities of both parties as an adjunct to the clinical trial agreement.
Standardisation of Costing
In May 2008, NIHR launched a costing template for industry-sponsored trials (seewww.crncc.nihr.ac.uk). A guide ‘Costing Industry Sponsored Studies Through NIHR Networks (Pharma/biotech contract research in secondary care)’ is also available on the website. It provides staff hourly rates and notes a single standard overhead rate of 70%... but before you get apoplectic, these apply only on the DIRECT COSTS, meaning what it costs the NHS. For example, the hourly rate for a senior consultant is declared in the document as £68.75. Adding 70% overheads to this still brings the gross charge per hour to something considerably lower than the BMA rate of £174.50 (as per the BMA Fees Guidance schedule 1 April 2008). Dr Morgan noted that there are additional elements: a 20% addition to DIRECT costs for ‘capacity building’ and a multiplier for geographical variation, a sort of London weighting. The template contains recommended prices for investigations, pharmacy, R&D and other set up costs.
The template is also the subject of discussion with Scottish parties: Charles Weller (Dundee) and Douglas Young (Edinburgh). A Scottish testing of the template is perhaps imminent.
The template is in Excel spreadsheet format and I found that I needed to adjust my security settings to avoid a warning message at download due to the macros within. Not an issue for a freelance like me, but perhaps a source of irritation for some of those in pharma and large CROs. The template is for industry users to populate and send to the Network CC to check. Dr Morgan warned that problems typically occur when the template has been inadequately completed in the first place. NIHR have had success with the template. In one example given by Dr Morgan, 17 of 18 Trusts accepted without change the costing for a study done using the template. One Sponsor (who are you?) is using the template for costing all its English studies. A new version (V1.3) was implemented in March.
There are four key steps:
- Sponsor company to populate Industry Costing Template
- Network CC to review that costs are within expected range
- Costs presented to Local RN by CCRN
- Negotiation of site-specific costs with company facilitated by LRN
Feedback is desired and can be given via
crncc.costingfeedback@nirh.ac.uk.
“Central sign-off”
As anyone having anything to do with, or waiting for, trial set-up in the UK knows, R&D approval is the biggest of the problems facing us. We are generally agreed: ethics review now works well, but R&D still has a way to go. The Coordinated System for gaining NHS Permission (CSP) might be just what we need. CSP offers a single point of access to the Integrated Research Application System (IRAS) for all NHS sites. For industry trials, it is available only to those that have been adopted in to the NIHR portfolio. For non-industry trials, it is routinely available. Similar systems in each of the other three ‘home nations’ are being developed to be compatible. It may be here that NIHR has found a big enough carrot to entice us to seek adoption. The system was launched in November 2008, so we have yet to see what performance is like, but the ABPI statistics to beat are: 82 days median time from R&D notification to sign off and a whopping 187 days median time from first R&D submission to first patient visit.
There are those among us that have made good earnings from sorting out the start-up problems in the UK. I hope we all agree, though, that one key way to stem the flood of clinical trials away from the UK is to provide easier, faster start-up. CSP through adoption to the networks might just work, and it’s free! Standard R&D fees are still payable in the same way as if dealing with R&D directly. It was noted that some companies have been charged in the past but that should not happen now.
So which Trusts and Investigators are in a Network and which are not? Well, it doesn’t work that way: all are ‘in’! There are, however, significant numbers of investigators who have opted not to participate. For example, they consider that they have a set-up that already works well for them and they don’t want to take advantage of research staff provided by the Network. Of existing industry trials that have been associated with networks, 50% have been phase III and 30% have been phase IIa. Early phase work is increasing.
While NIHR CC gains experience, recruitment target-setting seems to be done much as traditionally done by CRAs. There’s nothing new as yet, but experience will improve this. NIHR already has some ability to know when an investigator is offering “a good 5” patients for recruitment rather than “an over-optimistic 20”. Where NIHR has an advantage over industry is being at the centre, and as more trials channel through the Networks and more reach completion, so prediction of recruitment rates will be refined. I am 50; I’d like to think that I will still be working when we see the benefits.
National Cancer Research Network (NCRN) Update
Dr Matthew Cooper, Principle Fellow at the NCRN, reminded us that the NCRN is an English network. Scottish cancer research is not a part of the NCRN (and nor are Welsh or Northern Irish cancer research), but there is close co-operation. Matt has responsibility for industry trials and a general overview of the whole portfolio of trials. The NCRN Co-ordinating Centre is in Leeds, and is also responsible for co-ordinating the National Cancer Research Institute’s (NCRI) Clinical Studies Groups and Accredited Trials Units Committee, both of which have UK-wide coverage, so there is a sense in which cancer trials are managed across the whole of the UK. Note that the ABPI is represented on NCRI.
The success of NCRN is at least partly due to its fit onto existing research networks, of which there are 33 in England (Scotland and Wales each have three and NI one). Adoption by the Networks is a ‘badge of credibility’ for industry trials to achieve and the Networks open up a wider variety of sites than might otherwise be easily accessible. However, it is clear that some investigators are more engaged than others. Since its inception in 2001, NCRN/NCRI have been responsible for more than 635 trials, of which over 200 are current. More than 250,000 patients have been enrolled and the number per annum is still increasing. Whilst only 60 of these trials have been industry sponsored, a further 30% of trials within the academic portfolio have some form of industry support. Funding from adopted industry-sponsored trials currently forms a mere 7% of the research funds managed by the NCRN Coordinating Centre.
More recently, the NCRN has been trying to work through complete development programmes rather than have piecemeal involvement. In the past two years, the focus has been specifically towards increasing the number of randomised controlled trials (RCTs). Experimental Cancer Medicine Centres is a joint initiative between the NCRI and the Departments of Health in England, Scotland, Wales and Northern Ireland to drive the development of biomarkers and new anti-cancer treatments. Launched in October 2006, the network comprises 19 centres of scientific and clinical excellence and aims to speed up development of translational research by evaluating new drugs and individualising patient treatment. Of 28,000 patients enrolled in the most recent full year, 11,500 were into RCTs. That is 14% of English cancer patients in trials and 5.4% into RCTs. The proportion entering trials is thought to be higher than in any other country and at 5.4%, the number in RCT compares favourably with the US. Including accrual from the other home nations, the total for the UK reached 33,000 in the last year. The biggest growth by far over recent years, however, is in the number of patients entering trials looking at prevention, pain relief and other aspects where the patient’s cancer is not speifically being treated. That swelled the figure entering NCRN co-ordinated trials to 73,000 for 2008 compared to 53,000 in 2007 and <30,000 in 2005.
About 50% of incident cancers in the UK are breast, colorectal, haematological or lung. These patients form more than two-thirds of patients entering trials in the UK. However, over the past five years, the largest increase in patient numbers by far has been in breast disease, which already accounted for the largest numbers of trial subjects. Lung numbers have fallen and a number of ‘smaller’ cancers show increased numbers in trials. Last year, RCTs in prostate cancer accounted for more patients than lung RCTs, for example.
Current priorities remain the desire to increase recruitment to RCTs, but also to increase recruitment to studies in rare tumour types and in sub-types of common cancers, such as ‘triple negative’ breast cancer. There is also an emphasis on some surgical studies and in studies that are labelled ‘non-disease’, such as palliation, pain control etc. One particularly interesting initiative at present is the development of an Intelligence Network to link all NHS electronic data. This has the potential to provide data for clinical trials through routinely-acquired clinical data and so replace or reduce trial follow-up. This could be hugely important for the future as the NCRN’s successful accrual rates has meant that patient follow-up has become a considerable staff burden.
NCRN adoption process
Industry trials go through an adoption process, which entails formal consideration through a process developed by the Industry Road Map Group. Once adopted to the portfolio, industry trials have a high priority. The adoption process considers key criteria:
Is the study well designed and relevant to NHS patients?
- Genuinely testable hypothesis?
- Statistically valid design?
- Undergone appropriate review?
Does the network infrastructure have current capacity to deliver data reliably and on time?
- Conflicting studies?
- Sufficient numbers of subjects?
- Sufficient investigator interest?
The process works thus:
- Protocol and submission form submitted to NCRN Coordinating Centre.
- Screened by Coordinating Centre (Level 1 feasibility); company informed within 48h if considered unsuitable for the network.
- If Coordinating Centre deems it suitable, then protocol and submission form forwarded to Adoption Panel.
- In parallel, protocol forwarded to key experts/stakeholders (the relevant Clinical Studies Group plus or minus consumer advisers and/or network managers) for Level 2 feasibility.
- Adoption Panel teleconference (within 4 weeks).
Level 1 feasibility focuses on whether the UK has the relevant population and whether the protocol treatment regimens fit with the standard UK approach to treatment of the tumour in question. The more detailed Level 2 assessment is about identifying potential sites and examining issues surrounding resource and facilities.
As well as the 60 industry studies adopted to date, a further 32 are still under consideration. Only five have failed to be adopted following Level 2 feasibility, but 65 failed Level 1 feasibility. A particular problem is many trials is that chemotherapy specified by the protocol, especially those emanating from the US, does not fit with standard UK treatment protocols. The number of breast cancer studies that have been adopted dwarfs the number of any other cancer, with lung, melanoma and head and neck cancers following.
NCRN/industry cooperation
Problems of cooperation between NCRN and industry to date are typically in the following areas:
- ? Industry communicating with sites, but failing to communicate with network managers and the coordinating centre
- ? Lack of clarity over site selection and target accrual
- ? Staffing, capacity and R& D delays, especially prior to new working arrangements
- ? Lack of DGH involvement
- ? Prevalence of academic snobbery towards industry trials
“There is nothing new in Heaven and Earth”, as they say, but with time we may all be able to do the old things a little bit better.
Progress of the Scottish Networks
Roma Armstrong, Research Manager at the Chief Scientist Office of the Scottish Government, began with a confession: the Chief Scientist Office (CSO) was caught “on the hop” when the English Network system was announced three years ago. A lack of joined-up government meant that the CSO had no money earmarked for any Scottish network system. Since then almost £66 million has been spent: £18 million directly on support of individuals, projects, initiatives and facilities and £48 million supporting the cost of research in the NHS. It was not clear how much of this was new money.
Networks include Cancer and Primary Care since 2003 (built on existing arrangements), Diabetes, Medicines for Children, Stroke (all since 2006) and Mental Health and Dementia (both since 2007). In addition, and taking as much in finance as the others put together, is the Generic network, covering trials management, imaging, pharmacy, research nurses and statistics. There is NO adoption process in Scotland like there is in England. Increased funding has been agreed for a further three years from April 2009.
Roma spent some time discussing the success of the well-established Diabetic network and aspects of the Medicines for Children network and the Stroke network. Theseare used as models for newer networks, some of which are struggling to get off the ground and to recruit the right staff.
Of the studies on the networks to date, about 80% are RCTs and about half are industry-sponsored. Oncology was considered separately, as the three Scottish cancer networks (West, South-East and North-East) are strongly linked with the NCRN. Between them, the oncology network trials have recruited >2150 patients in 2007-08, with half these coming from the West. They have been recruiting successfully to commercial trials without any adoption process since 2003. Success of these cancer networks, as with their English counterparts, has led to problems with the burden of long-term follow-up.
With the additional money, it is hoped to increase recruitment to trials above the 13.9% achieved in 2005-6, support research in rarer tumour types, promote equity of access to trials in the rural areas, increase translational research and increase numbers in to RCTs in line with the NCRN target of 7.5%.
Future strategy
Scotland’s research strategy at present is to create a collaboration between four health boards and four universities (Aberdeen, Dundee, Edinburgh and Glasgow) to establish a world-leading platform of research infrastructure to attract external investment and stimulate economic development. This Scottish Academic Health Sciences Collaboration also envisages that the evidence-based culture in the NHS will be strengthened as a result. National Research Scotland (NRS) previously permitted single approval across Scotland for academic research, and extended this to cover industry trials in April 2009. As well as an increase in translational research, there is to be further emphasis on the linkage to patients’ NHS data for research benefit.
The CSO expects to publish a new strategy in the coming months at
www.sehd.scot.nhs.uk/cso/index.htm.
It may be three years since the inception of the networks, but it was clear that we are only now approaching the time when they should be evaluated. I think it would be worthwhile to have Clare, Matt and Roma come and tell us how the next 12 months has gone in the summer of 2010.
