As the biopharmaceutical industry is facing a longer, more complex, and more expensive drug development process, all stakeholders must demonstrate flexibility and the ability to innovate and find solutions to overcome challenges. Patient recruitment for clinical trials that are well managed studies, with a high level of consideration towards the subjects, a close follow up, and robust quality of data collection is one of the many challenges within the industry.
A multi-site partnership represents, in many ways, a win–win situation for the study sponsor, and also for both a clinical research organization (CRO) and the hospitals it collaborates with for early phase clinical trials. If a hospital is interested in carrying out such studies, but does not already have a dedicated Phase I unit, working closely with a clinical CRO will give them access to the necessary know-how. One model involves the CRO setting up satellite units within a number of different hospitals.
For such a partnership to work, any hospital that wishes to be included will need to be able to provide an appropriate location within its site for the satellite unit. The amount of space offered does not need to be huge – three or four rooms spread across 1600 square feet, for example, is likely to suffice in most cases. It is important, however, that the space can be separated from the hospital’s everyday standard-of-care activities.
Commonly, the investment will be made concurrently with a wider scale upgrade of a site’s infrastructure. If the necessary equipment is not already in place, it can be provided by, or leased from, the CRO. This will typically include secure cupboards, temperature controlled storage areas and devices such as a –70°C freezer and a refrigerated centrifuge, and safety monitoring equipment.
The CRO will also be able to supply staff experienced in the precise details and protocols of running Phase I trials. These would automatically be provided if the trial is being run within the center by the CRO, but if required they could be permanently based within the unit, and run trials for other sponsors. Typically, this professional clinical team would include a research physician, study nurses, and usually a site coordinator. This way, the unit can belong to the hospital, but the CRO has operational ownership of the activities that are carried out there.
The primary advantage for the CRO comes in the form of access to patients and the ability to build good relationships with clinical investigators based at the hospital. With a relatively small investment, the hospital gains the appropriate infrastructure and human resources required to run Phase I trials, experience which will also benefit investigators running Phase II and Phase III trials in the wider patient population.
Satellite Unit Versus Traditional Model
A traditional Phase I unit might involve the CRO or sponsor renting out, say, 3000 square feet of space within a large hospital, in a location where there is a good potential patient population. It might also involve a construction project, for example, a new wing of the hospital, which would be paid for and owned by the CRO. This might be in a separate location outside of the hospital but, for safety reasons, a Phase I unit will usually be positioned as close to a major hospital as possible, even if it is not within the footprint of the hospital itself.
For the CRO, this model has a downside in that its costs will be higher, and there is much less flexibility. With the satellite center model, the investment costs are lower, and it is possible to gain access to more patients for the same amount of money by setting up further units in different locations. The key deciding factor is to go where the patients are.
A major advantage for the hospital is the professional support provided by the CRO in terms of clinical pharmacology and deep knowledge about the details and procedures involved in running an early phase trial. For the CRO, the access to patients with a reasonable investment is the highlight. And for the trial sponsor, there are two important advantages: patient recruitment and a guarantee from a professional CRO that the study will be properly run and controlled, and will satisfy the regulators.
In Phase I and also Phase IIa trials, sample handling and patient management are critical. An early phase trial may be short in duration, but is very busy operations-wise on dosing days. A professional, experienced staff dedicated to the trial is important to ensure that quality standards are met in terms of clinical execution and sample handling. This is much more likely to happen with an experienced CRO team than with medical professionals whose experience of running this type of trial may be limited and where priorities may be focused on their standard of care operations.
The success of a healthy volunteer trial is based on the management of the high number of subjects; it can often involve the enrollment of up to 24 subjects in a single trial per day. Sufficient space, nurses and lab technicians are required to handle a high quantity of samples. This is especially true if multiple trials are running at the same time, a quantitydriven control mechanism will have to be in place to handle a high amount of data properly.
In contrast, with trials in patients, it is unlikely that more than one or two patients will be recruited into the study at the same time, and only very rarely will it be as many as three or four. Quality control is crucial here, with the patients being such a scarce resource. Patients are more commonly used for Phase I trials than human volunteers in oncology indications, and this population is more difficult to work with. The investigational treatments, too, often have significant biological effects, and there is a higher chance of significant side-effects occurring. A particularly close follow-up with patients, and a quality-driven control mechanism, is important for safety reasons.
Competition For Subjects
If a hospital or academic center hosts many early phase patient trials for different sponsors and CROs, then it can make access to patients more competitive, with several trials fighting to enroll the same subjects. Conversely, it is usually easier to enroll healthy volunteers because of the wider outreach into the community such a site may have.
A specialist academic research hub will attract expert clinicians, and therefore patients. For the early stage trials, it is important to trust the investigator to run the trial and collect the data correctly. Whereas in the late stage trials, one can have 20, 50 or even 100 sites participating in a large, multi-center study, so if there are problems with patient management or data collection at one or two sites, it is simple to remove them from the analysis. But in an early phase trial this is not possible as it is likely that only a few sites will be participating, so if there are issues with one site this will have a dramatic – if not devastating – impact on the viability of the trial overall. Running a network of professional and dedicated clinical units and associated sites goes a long way towards ensuring protocols are followed to the letter and the trial is not put at risk.
Looking towards the future, it is likely that patient trials will become more common, and play a more significant role in the early phases of drug development. As the shift continues towards personalized medicines and targeted therapies, although it will still be appropriate to do a first-in-human study in healthy volunteers if the product safety profile allows it, the results it provides will be limited to pharmacokinetics and safety. To get better indicators of likely success or failure more quickly, a population of patients rather than healthy volunteers will be important.
Pharmaceutical companies are under ever greater pressures over time and costs, and there is a concomitant need for early go–no go decisions. They need to be able to decide as early as possible whether the treatment is likely to work and be beneficial to patients and, therefore, whether it is worthwhile to continue investing in its research and development. Even in Phase I trials now there are often efforts to collect secondary data or establish exploratory objectives, such as collecting data on biomarkers and pharmacodynamics information.
Many of these biomarkers can only realistically be seen in a patient population. For example, if an antibody designed for a chronic inflammatory disease is being investigated, if the levels of the relevant inflammatory biomarkers are reduced following the first injection of the product, this provides a signal that the compound might work. Much more information will be required, of course, such as an insight into its safety profile, or the side effects that it might cause, and the duration of action remains unknown, but at least there is a signal that it is having a positive effect. Conversely, if there are no significant changes in the biomarker level, this might inform an early decision to discontinue the project.
A Multi-Site Model
With an established central research base, having a number of these supporting satellite sites across hospitals in multiple countries with specialist research focus can increase the efficiency of patient recruitment for early phase trials.
It is common that a single site is not sufficient for adequate recruitment, even in a small-scale Phase I trial, as insufficient numbers of patients or healthy volunteers may be available. Duplicate sites in different locations within the same country expands the potential patient pool, and the staff in an established site can assist and train staff, in a second facility, and offer logistical support.
Central and Eastern European countries such as Hungary, Poland and the Czech Republic typically have strong subject recruitment rates, allied to more reasonable budgets and strong investigator motivation. By choosing countries within the European Union, transparency from a centralized healthcare system, and an adherence to European guidelines should be assured. The overall business and political risk is low in these countries, compared to the complexities of the political situation in countries such as Russia and Ukraine. Indeed, some sponsors request that studies are not done in these more difficult countries, because of fears that the situation may change during the trial period, leaving the study uncompleted.
Hungary is an attractive country for a satellite site, because it has an excellent oncology network, and a well-established and efficient regulatory environment. The authorities are currently looking to reduce the 60-day study approval timeline to 45 days, and the process for gaining approval is very transparent. Both the central ethical committee, responsible for study design and patient issues, as well as the pharmaceutical authority which gives the approval and is responsible for GMP oversight, welcome open communications.
Potential satellite units will usually be identified through their strengths in particular therapeutic areas, for example oncology. However, there would obviously be the option to use the unit for studies in other indications to make the workspace more flexible and economically viable. It is crucial to establish a multi-service agreement with partner hospitals to ensure the smooth set up and running of the satellite site, setting out the establishment of the facility and the responsibilities of each party. For example, the hospital may carry out the construction and installation of infrastructure of the facility, and the CRO provides the permanent staff, essential equipment, correct procedural and quality documentation, as well as liaising with the regulators to seek the approval to operate.
Having a satellite unit allows umbrella protocols to be run, with the initial single ascending dose study in healthy volunteers being run at the CRO’s central facility, and then switching to patients for the second, multiple ascending dose part of the trial. Moving to a satellite unit in central Europe for the second part can greatly assist in the recruitment of patients, and the continuity of using the same protocols and SOPs makes for a quicker and more seamless process than having to start from scratch for the second part of the trial.
Implementing a satellite site model has the aims of expanding the available patient pool, while keeping quality up and costs down. By giving faster results at lower cost, a network of satellite units is well placed to speed up the trials process in a time when pharmaceutical companies’ R&D budgets have never been under more pressure.