Attractive proposition

Establishing best practice in clinical trials in Europe is a complex issue in its own right. Plus, when set against the backdrop of the rapidly increasing globalisation of clinical trials, where much of the activity takes place beyond European boundaries, and in an environment where cost-cutting is king, the challenge takes on new proportions.

A recent study by the Biotechnology Industry Organisation and BioMedTracker, released in February 2011, further highlighted the importance of establishing best practice for clinical trials, revealing that the success rate for bringing new drugs to market in recent years is only one in ten in the US. The study, which examined all stages of drug development between 2004 and 2010, showed that rates were different for the clinical trials phases, ranging from a 66 per cent chance of success at phase I, to 55 per cent at phase III.

Governments across Europe are demanding cuts in healthcare budgets at the same time as the pharmaceutical industry is facing a future where its innovative new drugs are costing more and taking longer to reach the market than ever before.

Under these harsh conditions, it is unsurprising that the familiar debates focusing on the inefficiencies of clinical trials are finding receptive audiences, particularly when it is taken into account that it can cost up to $50,000 to enlist a single clinician to take part in a clinical trial and that once recruited, 60 per cent of these clinicians sign up one patient or less.

Industry sources believe that up to 95 per cent of the delays in completing clinical trials are caused by slow and inefficient recruitment. Western European countries are facing stiff competition from their Eastern European neighbours where large patient pools, encouraged by highly skilled medical professionals, are participating in clinical trials in record numbers and R&D, as well as manufacturing, costs are lower. Patient recruitment in Italy, Spain and France is stronger than in the UK, where numbers of patients continue to decline. However, it is still more expensive and slower in all Western European countries than in the CEE region.

Many of those involved in the pharmaceutical and biotech fields do not hesitate to level some of the blame for the decline in the European clinical trials sector at the European Clinical Trials Directive. Indeed, a recent report, 'A New Pathway for the regulation & governance of health research', from the Academy of Medical Sciences in the UK, published in January 2011, stated that 'there is evidence that UK health research activities are being seriously undermined by an overly complex regulatory and governance environment. This is evidenced by a fall in the UK's global share of patients in clinical trials and by the increased time and costs of navigating the UK's complex research approval processes'. However, there is also industry feedback suggesting that the Directive has had a beneficial impact, helping to reduce timelines to 60 days and stating that it is the UK's NHS governance framework that is stifling R&D in the UK.

It is not suggested that the problems faced in the UK, or elsewhere in Europe, can be blamed entirely on the Directive, but the report does go on to say that improvements need to 'be made at both the European and UK levels'. The authors of the report welcomed the UK Government's support and commitment to consider the bureaucracy affecting clinical research and to bring forward plans for 'radical simplification'. This is likely to find staunch support from the pharmaceutical sector, which is keen to see a change in the culture and acceptance of clinical trials in the UK, to support increased levels of patient recruitment and help the UK retain more clinical trials, reversing the steady decline seen over recent years.

Countries like Germany, France and Italy, which were, like the UK, traditionally favoured destinations for clinical trials, have also seen patient participation numbers steadily decline as sponsors look further afield, both to CEE countries and increasingly to countries including China, India and Brazil, with their attractive cost bases and large, treatment naïve patient populations, keen to participate in clinical trials.

While France may not be suffering to the same extent as the UK, with 1,087 trials taking place there in 2009 according to ClinicalTrials.gov, compared to 912 in the UK and 664 in Italy, it is, nevertheless, seeing a decline in patient recruitment share. Germany, too, despite its high quality infrastructure, expert personnel and reliable and efficient recruitment of patients, is not immune to the downturn in patient recruitment and the lure of the faster and cheaper options elsewhere.

The laborious nature of the clinical trials process, from site and investigator selection to patient recruitment, has for decades been a significant drain on sponsors' budgets and a block on their ability to deliver new therapies to market as quickly as they would like. Current market conditions exacerbate these problems for most western European countries, driving clinical trials elsewhere.

Kenneth A Getz of Applied Clinical Trials, stated: "The vast majority, more than 90 per cent, of trials must delay enrolment for an average of six weeks. And in any given multi-centre study the same pattern is observed: 20 per cent of sites deliver the majority of patients. Half of the sites either under-enrol or fail to enrol a single patient."

The cost impact of this problem in the pharmaceutical market is significant, with even a single day's delay estimated to cost in the region of $1m in lost revenue. The ability to reach a go/no-go decision as quickly as possible is critical to the success of future drug development and R&D investment. In order for this to happen, recruitment to clinical trials needs to change.

It is beyond doubt that the decades-long practice of relying on individual clinicians to recruit patients on to clinical trials opportunistically is stifling new drug development, but what will take its place is less conclusive. With later-phase trials often now looking for upwards of 15,000 patients, the new 'best practice' must deliver significant volumes of patients reliably, quickly and cost effectively. It must also deliver patients to trials from EU countries, despite inefficiencies and cost implications, to ensure that the demands of the regulatory authorities are met.

There are two companies in Europe that have developed a model that is becoming increasingly attractive for recruiting to, and running, clinical trials to help make Western European sites more competitive and successful. One of them, UK-based Synexus, has been increasing the number of trials it is involved in across its Western European sites for several years. Now, this commercial clinical trials site model, which has been in existence for nearly 20 years, is gaining recognition and acceptance among sponsors as it matures into a respected and credible alternative to the problematic old ways.

The other leader in this sphere is CCBR-Synarc, based in Denmark. Both companies were founded by doctors in the 1990s. Synexus has 26 sites in Europe, South Africa and India, with plans to acquire several in the US during 2011, while CCBR-Synarc has 12 owned sites across Europe, China, India and Brazil.

The success of the new, but proven, model for clinical trials hinges on owned sites that specialise in conducting clinical trials. These companies' prime focus is to deliver timely and cost effective clinical trials and they are already showing great results, whether they are recruiting study subjects in the UK, Poland, South Africa or Brazil. It is this recruitment reliability that appeals to sponsors.

Each research site has its own permanent team of clinical experts as well as state-of-the-art diagnostic equipment and access to a substantial local patient database. Sponsors reap multiple benefits, not least the rigorous application of uniform standard operating procedures (SOPs) alongside a significant reduction in monitoring costs.

In addition, there is the benefit of getting information from experts with local knowledge of each country or region, drawn from the local clinical trials team. This includes an understanding of local regulatory and governance issues relating to studies, which can help avoid lengthy delays in getting trials initiated. It also extends to the detailed workings of the local healthcare system and nature of the patient population, meaning that access to the patient pool is more straightforward and delivers improved results, including better profiling and more efficient planning. Individual sites often recruit hundreds of patients, in contrast to the fewer than 10 recruited by single investigators under the old model.

Commercial clinical research sites offer a way forward for more efficient and effective clinical trials and a route to establishing best practice for an industry that continues to struggle with old methods that are failing to deliver.

The globalisation of clinical trials has been driven by the need to recruit more patients, more quickly while restricting costs. Some fear that the impact of such rapid expansion risks a decline in patient safety and the reliability of data from distant sites where regulatory frameworks are little understood. Working with organisations dedicated to clinical research and with an expanding global footprint removes the majority of these risks, with each site governed by a single set of SOPs, run by permanently employed, highly trained staff reporting to a single project team.

Reliability
Sponsors who work with such sites are reporting trials that start on time, that recruit according to plan and deliver consistently good quality data. It is no longer sustainable to recruit four or five patients per site when a study needs several thousand patients to get underway.

There are signs that the industry is ready to embrace new alternatives that support a short recruitment period and help to deliver minimal time to market, with scaleable outreach and infrastructure, lower dropout rates and high quality data.

If Europe is to compete with emerging markets like China, which experienced a 73 per cent growth in clinical trials between 2007 and 2009 and is predicted to become the third largest pharma market by 2020, it will have to move swiftly to adopt new models of patient recruitment that stop the running of clinical trials being a drain on precious resources and a barrier to faster innovation.

The Author
Ian Smith is founder and medical director at Synexus in the UK.

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