According to the ICH E6 (1996, p. 13), in order to be included in a particular clinical trial investigator should demonstrate that his/her site has recruitment potential, i.e. that a sufficient number of appropriate patients/cases have been observed at this site that could have been and can be potentially included as subjects into the trial. Unfortunately, as concluded by Louis Lasagna in 1970, narrow inclusion criteria of the most clinical trials usually preclude up to 90% of patients from participation in such trials and that this is oftern overlooked by investigators at the stage of feasibility assessments (Jäger, I., Rey, S., Kleist, P., 2006, p.7). Slower recruitment leads to: greater R&D costs due to needed time extensions (again, decrease in planned profits due to delayed marketing authorization), weaker statistical power due to smaller sample size, or even failure of studies (McDonald, A.M. et al., 2006).
I can assume that this common mistake could lead to the fact that my site has enrolled only 5 of 25 subjects over the period of 6 months (half of the overall estimated recruitment period). Apart from the Lasagna’s Law (as this phenomenon is commonly called), there could be also such site-specific reasons for slower recruitment as:
- Insufficient staff recourses or inexperienced staff,
- Excessive workload or competing/conflicting studies,
- Delays in IRB/LEC review and approval.
If there have been no external reasons that impeded recruitment (i.e., logistics issues with study supplies/resources/funds), this means that either the study-specific reasons specified above or some protocol-specific reasons influenced my site’s ability to adhere to the planned recruitment plan.
As specified by Cutler S, Redmond C. (1995 cited in Goberville, M., 2007), often difficult and/or lengthy protocols with numerous interventions and tricky study procedures schedules lead to staff’s and subjects’ tiredness and lack of enthusiasm over time. Besides, there can be such reasons as poorly designed/ incomprehensive documents for patients (ICFs, ads, information sheets) that lead to lower consent rates.
Taking into account the specified above possible reasons of unsatisfactory recruitment, the following methods/strategies to improve recruitment can be used:
- Site’s performance improvement including (Goberville, M., 2007; Flory, J. & Emmanuel, E., 2004):
- dedicated team members to communicate with patients, i.e. they will not only describe a study but interact with patients/ask-answer questions / check comprehension;
- education of study staff in order to improve interaction with potential subjects;
- adherence to GCP and other ethical and scientific standards;
- development of study-specific recruitment methods taking into account population and disease specifics;
- explaining to potential subjects the degree of personal information protection, differences between treatment and research for better understanding and confidence in investigators’ actions.
- Changes of study-related documents:
- modification of too narrow inclusion criteria / interventions / schedule;
- modification of consent form to make it shorter / more comprehensive.
As a PI, I would concentrate on improvement of my study team performance first, as it often happens that workload is underestimated / staff is too busy / unwilling or insufficiently educated to communicate with potential subjects effectively. If no internal methods work within a month, I would probably ask the Sponsor to review some study-related documents.
- Flory, J. & Emmanuel, E. (2004) ‘Interventions to Improve Research Participants’ Understanding in Informed Consent for Research – A Systematic Review’, Journal of the American Medical Association, 292(13), pp.1593-1601 [Online]. Available from: http://jama.ama-assn.org.ezproxy.liv.ac.uk/cgi/content/full/292/13/1593 (Accessed: 30 October 2010).
- Jäger, I., Rey, S., Kleist, P. (2006) ‘The A – Z of Pharmaceutical Medicine’, PFC Pharma Focus, p. 7 [Online]. Available from: http://www.pfc.ch/upload/docs/Detailprogramme/The%20A-Z%20of%20Pharm%20Med1.pdf (Accessed: 30 October 2010).
- Goberville, M. (2007) Clinical Trial Recruitment: Role of ICH GCP and Recruitment Strategies Training of Clinical Sites Staff in Successful Patient Recruitment Rates [Online] Available from: http://biopharmarena.com/home/2007/06/21/clinical-trial-recruitment-role-of-ich-gcp-and-recruitment-strategies-training-of-clinical-sites-staff-in-successful-patient-recruitment-rates/ (Accessed: 30 October 2010).
- McDonald, A.M. et al (2006) ‘What influences recruitment to randomised controlled trials? A review of trials funded by two UK funding agencies’, Trials, 7:9 [Online]. Available from: http://dx.doi.org.ezproxy.liv.ac.uk/10.1186/1745-6215-7-9 (Accessed: 29 October 2010).
- The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (1996) Guideline for Good Clinical Practice E6(R1) [Online]. Available from: http://www.ich.org/LOB/media/MEDIA482.pdf (Accessed: 30 October 2010).