Patients required

Lara Haynes, Rich Baptista and Faiz Kermani from Chiltern International show how contract research organisations can help solve the recruitment dilemma of clinical trials

Clinical trials are a vital step in bringing new drugs to market. While pharmaceutical companies have been successful in designing complex clinical trials, ensuring that enough patients participate in these studies continues to be an issue.

The process of finding, screening, and recruiting clinical trial patients is an ongoing challenge for even the wealthiest pharmaceutical companies. As a result, many trials are plagued by delays. For example, in the UK, less than half of clinical trials are completed within the planned timescale.¹

Pharmaceutical companies are increasingly turning to contract research organisations (CROs) to help them run their clinical trials. It has been estimated that project sponsors are now using CROs on more than 60% of their clinical projects.²

A few CROs, such as Chiltern International, have good geographical coverage, broad therapeutic coverage and years of experience in managing complex trials. They can provide companies with valuable input to the trial process. In particular, these organisations can run specific patient recruitment campaigns in order to accelerate enrolment.

targeted messages

Successful enrolment is dependent on the ability to produce a broad range of targeted patient messages, through radio, and print ads; direct mail campaigns; free public service announcements; clinical educational presentations; internet and website programmes; and community outreach initiatives. When properly implemented, these campaigns allow clinical trial planners to model various resource investment scenarios, estimate specific costs, and forecast timetables.

Companies are realising that there is the potential to improve clinical cycle times by speeding up the rate of patient recruitment. However, the nature of the trial will affect the recruitment period and so the degree of improvement that can be made will differ from trial to trial. Companies have to weigh up a number of factors when considering patient recruitment.

Clinical trials vary in size depending on the stage of the development process, therefore different recruitment strategies are employed. For example, a Phase I first into man study may require only six subjects whereas a Phase III trial can involve thousands of patients. Understanding the frequency at which the patients are seen by clinicians is also very important as it ensures that a realistic assessment of the recruitment rate is made for a particular study.

safety and tolerability

Before a drug can be investigated in patients, the drug needs to be tested in healthy volunteers. These type of early phase studies look at the safety and tolerability of the investigational drug product rather than the efficacy.

Chiltern's Clinical Research Unit (CCRU) has a database of 7,000 volunteers. The database has evolved over the years primarily through word of mouth, although this ultimate form of publicity has been supplemented by advertising in newspapers, on the radio, on the web and in communal areas such as community centres and GP surgeries.

Database records are updated on a six monthly basis by sending an update questionnaire to the volunteers. This ensures that the database is up to date with people ready and willing to volunteer for studies.

For any particular study, the dedicated recruitment department would plan to mail all the suitable candidates on the volunteer database to inform them of the impending start of the study and ask them to reply as to whether or not they would be available to be screened for it. The volunteers who respond positively will then be placed on hold in the database until approval from the Ethics Committee is received.

Once received, the volunteers would then be mailed again with detailed study information, as approved by the Ethics Committee.

screening invitation

All the volunteers who are still available and interested in the trial would then be contacted for a telephone screen and if successful, would then be invited in for a screening appointment. Identifying volunteers in advance, means that lag time from Ethics Committee approval to first subject first dose will be reduced.

Obviously the methods of recruitment outlined above are for early phase work. The methods of recruiting patients for larger international, multicentre studies are very different, as these studies can either be GP- or hospital-based.

When conducting patient studies, it is important to be as proactive as possible to identify sites that will be good at recruiting. Some of the issues that must be considered in order to run a successful study are recruitment plans, which can include the source of patients, the number of patients to be assessed for suitability; the number of patients to discuss participation; recruitment staff; recruitment schedule; recruitment rate, and signing off by each site prior to initiation

Much of the effort in tracking patient recruitment by the centres will fall to the Clinical Research Associate (CRA) at the CRO. A number of strategies can be employed to improve the chances of successfully recruiting patients. A typical approach employed by Chiltern involves the following:

• Recruitment Plans – Each centre is required to complete and sign a recruitment plan, which states from where they will find patients for the proposed study and in what timelines this will be achieved. The advantage of this approach is that it gives the CRO something in writing and thus makes the centre more accountable to the CRO. It also acts as a motivating factor for a centre to think actively about recruitment strategies from early on in the study i.e. where their patients will be sourced from and what it will take to do this.

• Trial Commitment Fee – Each centre is requested to provide a list of potential patients that are not only eligible for the study but have also agreed in principle to take part in a study. This list will tie in with the numbers agreed in the recruitment plan.

In Chiltern's case, as long as this list is provided prior to the initiation visit, a trial commitment fee will be paid. The actual amount is dependent upon which country the site is located in. This recognises the time and commitment an investigator site has put in to produce a realistic list.

It is also important to have contingency plans in place should the sites not manage to recruit the desired number of patients. Some of the contingency plans that Chiltern has in place include Select more sites with ethics approval – typically 20%; Consider reserve countries; Set targets within recruitment phase; Assess inclusion/exclusion criteria;Learn from successful centres

Even with these strategies being adopted, it is important to maintain a high profile at the centre, so that investigators do not forget about the study and forget to recruit patients. To achieve this, the following additional approaches can be used:

• Screening logs faxed to the CRO weekly for assessment by the CRA;

• Monthly newsletters with minor incentives for recruitment e.g. the first centre to recruit five patients gets a bottle of champagne;

• Weekly contact with the relevant site staff;

• Motivational visits by the CRAs

The recruitment process is crucial to getting the clinical trial off to a good start and, as described above, is dependent on many factors. CROs can provide sponsors with special expertise in this area by devising targeted recruitment programmes. Customising the recruitment programme to suit different types of studies will ensure a successful start to the study.

However, it is also important for the CRO to be flexible and responsive to the study's changing requirements to ensure that the decisions made are in the best interest of the sponsor regarding the product's development.