Participant recruitment and retention is crucial for the success of any clinical study and indeed lack of recruitment, and loss to follow up, are the most significant factors in a study not being able to answer the question that it is designed to address.

Successful identification strategies for eligible participants ensures both timely execution of the study and avoids selection bias. It is important to actively plan for participant recruitment rather than relying on sites to recruit participants within the time frame specified without this sort of proactive guidance.

A recent analysis of more than 100 clinical trials (see references) showed that less than a third of the studies achieved their original recruitment target and half were awarded an extension. It is unclear why certain studies recruit well while others do not. Several potential limiting factors may be responsible, such as constraints on clinician time, lack of available staff, complexity of study procedures, overestimating the number of participants available for study participation and the perceived relevance of the research question to the clinicians. Barriers to participants' involvement include lack of knowledge and trust in studies and unacceptability of randomisation.

It is clear that many studies do not meet their recruitment targets. Those that do may achieve them only after extending the length of the study. In some cases, studies may have to close prematurely due to recruitment problems.

While there are several possible consequences of poor recruitment, perhaps the most crucial is the potential for a study, in particular clinical trials, to be underpowered. This increases the chance that an effective intervention will either be abandoned before its true value is established, or at the very least, delayed as further studies or meta-analyses are conducted. Similarly, while poor recruitment can be addressed by extending the length of a study, this too can create a delay in making potentially effective interventions available, as well as increasing the cost and workload of the study itself.

Participant recruitment methods
Predominately, the investigator will recruit from their patient pools or patient referrals.
An investigator may also promote the study to colleagues in their healthcare facility hospital or at associated hospitals, or to colleagues in private practice in order to gain referrals of suitable participants. When participants from primary care setting are required, sponsors/investigators may advertise studies in local media and/or hold information sessions with local community leaders.

Strong community engagement plans are essential, whether the study being planned is urban or rural community based research. To read more about community engagement strategies, see the resources and comments sections in this step.

You can also visit resources on the Global Health Network’s bioethics member area, http://www.globalhealthbioethics.org.

Research coordinators and study coordinators may also assist with participant recruitment through various means; including reviewing clinical medical records. All of these methods have proved to be effective and can help boost recruitment but there needs to be a more proactive approach to recruitment to ensure a successful study.

Strategies to improving recruitment
Depending on the type of the study, typically, the study statistician would have worked out the number of participants required to answer the research question. In multicentre studies the task of the study leader will then be to identify sites that have sufficient participants to support recruitment as well as provide adequate plans to ensure recruitment stays on track. There are a number of factors to bear in mind and if properly implemented, will help ensure the study recruits the required Participants within the specified time frame.

Site feasibility and qualification for multicentre studies and collaborations
Selecting sites for clinical studies typically starts with the pre-planning stage. The pre-planning stage involves a thorough recruitment feasibility to determine the number of participants that sites need to enrol to make up the total enrolment figures. Based on average recruitment rates on a country-by-country basis, study leaders can determine whether the study timeline and budgeted number of sites are feasible. This background knowledge should help study planners identify potential sites for the study. Ideally, each potential site should be able to recruit the minimum number of participants per site, but if not, it will then be up to whoever makes the ultimate decision on site selection as to whether or not sites can be included in the study.

Recruitment to clinical studies is rather complex and cannot be worked out by mere metrics alone. There are other factors to consider such as the site’s previous reputation, whether or not the principal investigator is well known in this field, the quality of research work done at the site, results from previous internal or external audits etc.
Failure to perform proper site feasibility means there is a potential of identifying inadequate sites that provide unrealistic estimation of recruitment rates, slow administrative procedures, unnecessary multiple study reviews and approvals, (lack of) principal investigator (PI) availability for timely site initiation visits, and lack of contract negotiation capabilities. One way of preventing these issues is by asking the “right” questions during site feasibility assessment. This should include basic feasibility questions in addition to protocol-specific questions such as site staff and PI motivation, administrative capabilities, the availability of study coordinator, regulatory procedures, competing studies, and more. One key pointer to site’s capability is their responsiveness to basic start up questions. A site that is slow or non responsive to start-up questions will probably not respond during the study. Therefore, if you’re a site involved with an external collaborator or sponsor, do ensure that you answer any correspondence in a timely manner.

Back-up strategy
With the best will in the world sometimes there are unforeseen problems that ultimately result in particular studies, or in the case of multi-centre studies, specific countries/sites unable to deliver on their recruitment promise. One method of circumventing these issues is by including back-up sites in the start-up process. These back up sites follow the same approvals and start up process as the “usual” sites until the point of site initiation. It is at this point, the study team decides whether or not to activate back-up sites.
Another method is to select more than the required sites for the study and make start-up activity competitive. This means that the first set of sites that are able to complete their start-up activities in time will be included in the study.

Both of these options carry some element of risks as some sites may be disappointed if they are not selected for the study. However, with proper planning and clear communication it could prove to be a very valuable tool as competitive start-up activity will naturally filter sites that are sluggish in responding to administrative aspects of the study. Also, if additional sites are required during the study, they can immediately be initiated with little or no delays.
As an incentive to sites, sponsors may elect to pay for the time spent in start-up activities if sites are not used for the study.
Either of these strategies will no doubt add to the cost of running the study but the time savings gained will more than pay for this additional cost. Again, study planners will need to decide whether or not this is an expense they can afford, and ultimately the decision will be dependent on the phase of the study, the complexity of the study and how important the study is to the sponsor.

National initiatives
Individual countries are beginning to see the benefits of clinical studies to their local economy and healthcare programmes, and have started to put in place measures to improve participants’ involvement in research.
In March 2011, the UK government announced an initiative to increase participant participation in clinical research in the performance of National Health Service (NHS) providers, in initiating and delivering clinical research (including commercial studies). The National Institute of Health Research (NIHR) now have a transparency process so that providers of NHS services publish the outcomes of studies against a 70 day benchmark to which to achieve, First Participant In (FPI). NHS providers are now required to publish this information for commercial clinical studies in an accessible part of their website. If the 70 day benchmark has not been met, the NHS organisation must provide reasons for the failure to achieve this timeline.

In Australia a similar initiative was put together by the Australian authorities to aid participation in clinical studies, known as the clinical study action group. Their remit, among others, is to improve recruitment into clinical studies. Some of the recommendations put forward include:

- Making the current registries such as the Australian New Zealand Clinical Studies Register (ANZCTR ), clinicalstudies.gov and the International Clinical Studies Registry Platform more consumer-friendly so that they include information on all current clinical studies in Australia to aid participants’ search for studies.
- Linking the study registry to existing participant databases of consumer advocacy groups and existing clinical study networks.
- The ability to list all clinical studies being conducted in Australia and be accessible to the general public, investigators, academic institutions, hospitals and industry bodies through an easily searchable database.
- The ability for members of the public to register their interest for studies in a particular therapeutic area, thereby allowing sites to quickly identify potential subjects.
- An investigator database where potential investigators could register their interest in studies or seek information about clinical study outcomes.

Focusing on the recruiter
The design and conduct of studies can affect clinicians’ willingness to invite participants to participate in a study. For example, the availability of research nurse support, the timing of recruitment relative to difficult stages of the participant’s illness, and fear that recruitment could have an adverse effect on the clinician-participant relationship can all affect recruiter’s motivation.

Recruiters inevitably influence potential participants and it is important to ensure that recruiters are truly committed to the study, comfortable approaching potential participants and are at ease discussing and presenting the study treatments whilst avoiding terminology that may be misinterpreted.
Another way of increasing participation is to hold regular recruiter training sessions for all recruiting staff to provide an opportunity for recruiters to air their views of the study and their perceptions of how participants regard it. At this meeting good and not so good practices can be explored and issues addressed. Also recruitment tips and advice can be shared with less successful recruiters.

Other activities to maintain recruiters’ engagement throughout the study include circulating newsletters on progress and the outcome of DSMB meetings, especially if they are positive.

Participant recruitment strategies
Participant databases exist in some locations and for some diseases. In searching participants’ databases, one method of optimising recruitment (where possible) is by using opt-out procedures. This is a process where potential participants have to contact the study team if they did not wish to be approached about the study. This approach remains controversial, as ethics committees generally require that research participants provide express approval for research participation, including being contacted about the study by researchers.

The use of telephone or SMS reminders for non-respondents and providing financial incentives for participants can both be used and are accepted as a legitimate recruitment tool, but they may be considered a form of coercion depending on the context. Often, covering study costs may be considered the most ethical approach.
Another important strategy in improving participant recruitment is through linked integration systems. In many hospitals there could be thousands of clinical studies taking place but very few systems integrated into regular participant care. The treating physicians are therefore often not aware about the possibility of a clinical study, or their heavy work load limits their capacity to identify studies that are relevant for the participant.

As electronic participant records have become more readily available, basic information entered in a Hospital’s Information System (HIS) like diagnosis, gender and age may be sufficient for an automated screening tool.A query of the each clinical study database can then be generated based on the inclusion and exclusion criteria of each study and available HIS items. If there are new potential study subjects, an email notification is generated to the responsible study nurse or physician. To address privacy issues, the email generated can be such that participant’s identifiers are not included.

Language barrier and cultural awareness
In most clinical studies, many sponsors rely increasingly on English as a global language whereas local physicians work with participants in their native languages.
Cultural values and behaviours present benefits and challenges for those sponsoring multinational clinical studies.
In Latin America, Japan and India, the majority of participants are offered enrolment by their doctors. This difference is important when preparing recruitment plans and materials. Sponsors may consider publishing some key training materials in local languages.
However, if materials are to be published in English only, sponsors may benefit from providing materials to participants in advance, so that participants have a chance to prepare comments and questions for the meeting. Graphics and diagrams may also be used to bridge language barriers, although care should be taken to consider the cultural appropriateness of images.

Religion may also affect enrolment: for example, a study requiring a complete sexual history from women in a predominantly catholic country could be off-putting for participants. Also, some protocols may not readily accept abstinence as a method of contraception and may need to be addressed via a local amendment.
Another important socio-cultural issue concerning unmarried female subjects in India is that they feel offended if they are asked to perform pregnancy tests, which is a common requirement in almost all protocols.

In some countries, a culture of compliance dictates that participants follow doctors’ orders explicitly. This tradition presents a benefit to sponsors in that enrolment is quick and retention is high, but of course requires careful consideration to ensure that the enrolment is ethical and the participants do not feel that they have no choice but to take part in the study.

Participants who are from farming backgrounds tend to join family members to help during harvest. This means that participant inflow to hospitals tends to be limited during these periods, thereby leading to slower recruitment. Indians for instance celebrate many festivals and cultural programs, and each community has their own set of cultural functions. These programs sometimes compel participants to miss scheduled follow-up visits if the event falls during those days.

Conclusion
It is inevitable that slow recruitment or the inability to recruit participants within the study time frame will ultimately result in delays in completing the study; and consequently, a delay to the overall sponsor developmental plans.
No doubt, there is also the additional cost required to implement contingency plans to bring the study back on track; thereby depleting funds allocated for further development plans.

It is therefore recommended that as much planning is put in place at the onset as is currently being done in ensuring that the scientific basis for the study is right. It is also prudent (depending on the phase, type and complexity of the study) that adequate contingency plans and funds are set aside and can be utilised sooner rather than later to ensure that the study is on track; as the overall knock on effect of slow recruitment means that potential drugs that could benefit participants are delayed.

Further reading, and a template participant retention plan, are available here: http://globalhealthtrials.tghn.org/articles/participant-retention-plan/

References
o Dugas Martin, Lange Matthias, Berdel Wolfgang and Muller-Tidow Carsten “Workflow to improve Participant recruitment for clinical trials within hospital information systems - a case study” Trials 2008, 9:2
https://trialsjournal.biomedcentral.com/track/pdf/10.1186/1745-6215-9-2?site=trialsjournal.biomedcentral.com

o Treweek Shaun, Lockhart Pauline, Pitkethly Marie, Cook Jonathan, Kjeldstrom Monica, Johansen Marit, Taskila Taina, Sullivan Frank, Wilson sue, Jackson Catherine, Jones Ritu and Mitchell Elizabeth “Methods to improve recruitment to randomised controlled trials: Cochrane systematic review and meta-analysis” British Medical Journal 2013, 3
http://bmjopen.bmj.com/content/3/2/e002360.full

o Mills Nicola, Clark Mike, Young Bridget, Murray Gordon, Williamson Paula, Donovan Jenny, Bhopal Raj and Blazeby Jane on behalf of the working group “Tips to consider when optimising recruitment of Participants to clinical trials” HTMR Recruitment working group July 2013
http://methodologyhubs.mrc.ac.uk/files/5114/3403/2146/Recruitment_July2013V2.pdf

o McDonald Alison, Treweek S, Shakur Haleema, Free Caroline, Knight Rosemary, Speed Chris and Marion Cambell “Using a business model approach and marketing techniques for recruitment to clinical trials” Trials 2011 12:74
https://www.ncbi.nlm.nih.gov/pubmed/21396088

o National Institute for Health Research “Performance in initiating and delivering clinical research - information submission guidelines Q3 2013/14 Draft09/12/13 NIHR Central Commissioning facility
https://www.nihr.ac.uk/research-and-impact/nhs-research-performance/performance-in-initiating-and-delivering-research/ 

o Cohen Jaime “Identifying and Reducing Site Initiation Delays in Multinational Clinical Studies” GOR 2006 8:4
http://bbkworldwide.us/newsroom/_articles/GlobalOutsourcingReview_SiteInitiation.pdf

o Commonwealth of Australia “Clinically competitive: Boosting the business of clinical trials in Australia - Clinical Trials Act ion Group Report” 2011
https://industry.gov.au/industry/IndustrySectors/PharmaceuticalsandHealthTechnologies/ClinicalTrialsActionGroup/Documents/Clinical_Trials_Action_Group_Report.pdf

o Sahoo Umakanta, Sanghavi Vimal and Kermani Faiz “Subject Recruitment: An Indian Perspective Increasing cultural awareness is key to helping the country meet recruitment challenges” Applied Clinical Trials 2006
http://www.appliedclinicaltrialsonline.com/subject-recruitment-indian-perspective

o Stober Mary “Multinational Clinical Trials: Breaking Language and Cultural Barriers” Applied Clinical Trials 2003 http://www.appliedclinicaltrialsonline.com/multinational-clinical-trials-breaking-language-and-cultural-barriers