Clinical Trials: The future is hub-shaped
pharmafile | July 2, 2007 | Feature | Research and Development |Â Â clinical trials, designÂ
The global clinical trials market continues to grow and is currently worth an estimated $10 billion; so much so that clinical trials represent the single largest cost centre in drug development, with patient recruitment being a key element.
Change has been slow in coming and, at present, the old way of undertaking clinical trials through the individual investigator – usually a GP or specialist who fits their clinical trial work around their patients – still constitutes more than 90% of the way late-phase primary care clinical trials are run. However, this outdated method finally looks set to be replaced with a new model which is gathering momentum in the market.
This new way of working has considerable benefits; not least its potential to position the UK, once again, as a major and competitive player in the clinical trials market. Last year, the new model was utilised in three global phase III studies, all of which were based in the UK and involved the recruitment of thousands of patients – in contrast to the original plans whereby the UK had been scheduled to recruit only a few hundred patients.
Recruitment and retention
Recruitment and retention is a major bottleneck of drug development. Despite this, the industry has traditionally placed this vital element of the process with single investigators who, on average, are able to recruit just five patients each because they can usually only do so opportunistically as and when a suitable patient comes before them.
However, the reality is that many of these investigators never actually enrol a single patient and a significant percentage only recruit one or two, something which is particularly galling when it costs thousands of pounds to sign up each individual investigator. Furthermore, it is very difficult for the pharmaceutical company to put pressure on these investigators because they are also its customers in their day-to-day patient work.
This way of working has grown up over time, but has a number of serious defects: it requires a large quantity of health professionals to recruit the necessary number of patients, and it presumes that these health professionals have the time and inclination to educate the patients to ensure they fully understand the process and the importance of remaining on the trial. It also doesn't deal with the attributes of today's patients who have evolved from simply being willing collaborators with their doctors to becoming informed individuals who take a much more proactive approach to their health.
And although there is a belief that trialling a new medicine with GPs seeds the marketplace for the introduction of the drug when it comes to market, in the UK only two per cent of doctors undertake clinical trials – in other words, not very many. Furthermore, these doctors go from one trial to another, and by the time the medicine is launched one to two years later, there is little interest in it. In fact, research has shown that there is no greater uptake by doctors who have been involved in a trial than by those who have not.
Is it feasible?
The new model takes into account all the concerns of the old model and places the recruitment and retention of patients with a professional organisation that is focused on running clinical trials.
These professional organisations carry out a very comprehensive feasibility assessment which sets out the number of patients, their profile, how they will be recruited and the timeframe. As a consequence, these studies enable organisations to deliver within the agreed timeframe an area which needs to be addressed because presently across the industry, more than 70% of all clinical trials run late.
Using the new model, patient retention rates are substantially improved as it treats the patient also as a customer. Furthermore, the hub sites provide a pleasant environment with comfortable seating, television screens and refreshments available.
For the patient, one of the benefits reported from the new model is that he or she is provided with the opportunity to talk to the investigating doctor about general health concerns as they go through their procedures. Patients also rarely have to wait to be seen because the centre is dedicated to running clinical trials and doesn't have the emergencies and stresses of a normal surgery where the appointment for a clinical trial patient of an independent investigator has to be squeezed into the normal working day
.And for the new product, which has a finite patent life, getting it to market quickly can make or lose a company millions of pounds; for example, Lipitor is presently selling at around $1 billion a month, so a couple of months lost at the end of the patent life, when maximum sales are usually being achieved, can involve huge sums of money.
A sense of scale
Another of the key benefits of the new model is scalability. This system is capable of recruiting and managing thousands of patients through its network of hub sites and has evolved to meet the increasing demands of the regulatory authorities for bigger, longer and more complex trials. A phase III trial can now involve as many as 40,000 patients, and to run a trial of this size using the traditional method could potentially require as many as 8,000 individual doctors or investigators. By contrast, a large hub site, as used with the new model, can easily accommodate 1,000 patients.
As well as the scale and on-site expertise, the new model also connects the recruitment process. In addition to screening and running the trials, the hub site is responsible for the marketing campaigns which are used to recruit the patients, and this joined-up method is proving to be far more successful than the traditional method. Other benefits include faster recruitment, the collection of higher quality data and the use of more sophisticated medical procedures.
The new model doesn't just have cost-saving implications from a speed perspective, it also has them from a setup and ongoing monitoring perspective in fact, the new model can be a more cost-effective option by as much as a factor of 10. Using the new model, a pharmaceutical company or CRO negotiates one contract across all its centres covering hundreds, if not thousands, of patients. This is far more cost-effective than the traditional method, which requires the pharma company or CRO to set up individual investigators who may then only recruit a handful of patients or, in some cases, none at all. Using the new method, monitoring costs are also substantially reduced as the monitors only have to visit relatively few sites, rather than a large number of individual investigators as they would under the old system.
And whereas the traditional method would tender out local recruitment to its national partners, the new model can provide patients on a local basis and, for the first time, on a central level, enabling global recruitment to be undertaken from one point of contact. This way of working allows economies of scale to be enjoyed and brings considerable benefits in terms of speed and efficiency.
Quality assurance
The accuracy and quality of the initial data also both have a major impact on time and monitoring costs. Under the traditional method, individual investigators fit their clinical research activities into their working day, which often leads to missing or inaccurate data collection; however, the new model uses investigators who are solely focused on the task in hand, and because of this, a professional, full-time investigator carries out tens, or even hundreds, of patient examinations in the same trial and, as a result, becomes very familiar with the trial and its format. The new model also utilises data entry managers who check each line of data has been entered correctly, and this quality assurance activity dramatically reduces the length of time spent dealing with missing or inaccurate data.
The kind of data recorded can also now be more complex because the hub sites used with the new model are purpose-built facilities with access to key equipment, such as DEXA and ultrasound scanners. In addition, arrangements for even more sophisticated examinations – for example, CT or MRS scans – can be put in place in advance through local hospitals. This is an important step forward as increasing numbers of clinical trials now require a series of sophisticated medical tests which are beyond the scope of the average GP.
But there's another, less obvious bonus. Just recently, the UK arm of a global clinical trial into the prevention of prostate cancer involved undertaking more than 44,000 PSA tests and 2,000 prostate biopsies. In this trial, which utilised the new model, more than 400 men were found to have undiagnosed prostate cancer. Currently, there is no screening programme for prostate cancer in the UK and, consequently, being on a trial which used the new model could have, quite literally, saved the lives of these men.
Global hubs
A region which is increasingly being explored for its potential for clinical trials is the developing world, with the key advantages being the availability of treatment-naive patients coupled with lower costs. With conditions such as diabetes, patients in Europe or the US who are on an effective and well-tolerated medicine are unlikely to enrol in a study which demands a washout period, an untried new treatment, or being put on the placebo arm. This approach is also unlikely to find favour with an ethics committee.
Finding these patients in countries where there is a relatively undeveloped healthcare system is not such a problem. However, it is important that patients who do become involved in the clinical trial are well aware of what they are undertaking, and its important to develop procedures to deal with illiterate people, those who speak a local dialect, or who generally are not aware of the concepts of clinical trials.
Pharma is just beginning to use hub sites on a global basis and to recognise the huge benefits this new professional model brings, and this is being further driven by the pressure on R&D to deliver new drugs on time and at a reasonable cost. For example, the rapid expansion of Synexus has been propelled by a couple of major pharmas which are leading the way and have encouraged the company to expand and provide them with the advantages that hub sites deliver.
The hub model was developed to find patients for late-phase primary care studies in chronic disease and in disease prevention studies. But now, because of the development of patient proprietary databases by the hub sites, pharma and CROs are increasingly using this model for quite small trials as they can recruit so effectively and the huge costs of set-up and monitoring are greatly reduced. A number of major disease areas are particularly suitable for this approach.
Experience shows that hub sites are most effective when they are involved in the process as early as possible. They contain a great deal of knowledge about patient enrolment and what will be required, and they can accurately predict what will be necessary to attract a particular number of patients through their experience and their comprehensive feasibility studies. Much time can be saved if they are able to start planning and putting in place their marketing recruitment plans while the ethics are being sorted out, so they are ready to roll out once everything is agreed.
Disease prevention – a growing market
Today, many new medicines are not curative, but instead are designed to prevent diseases from occurring in the first instance and, as a consequence, disease prevention trials have become a growing market for the clinical trials industry. Usually patients with incipient diseases are asymptomatic and therefore not likely to present to a doctor, so the only way of accessing these patients is by targeting them directly.
As the new model interacts directly with the patient, it has been able to successfully recruit asymptomatic patients for disease prevention trials thereby supporting this growing market. Areas in which the new model has been used for the recruitment of prevention studies include cancer, cardiac disease lipid-lowering, impaired glucose intolerance, and diabetes.
The new model is gathering increased momentum within the pharma industry and the accelerated pace of acceptance is an indication of just how long pharma has sought an alternative way of working.
The late-stage clinical trials landscape is changing radically, and the old cottage industry method of using individual investigators simply cannot fulfil the requirements of the pharma industry today. Synexus and other companies which run similar models are increasingly being asked to handle larger numbers of patients across many countries, with the aim of reducing costs, providing a professional service and, last but not least, delivering on time.
Dr Ian Smith is founder and medical director of Synexus. For more information telephone 01257 230723, e-mail synexus@synexus.com or visit www.synexus.com
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