Achieving enrollment milestones can literally be the sole determining factor in the survival of small biotech organizations with only one or a few therapies in their pipelines. For many patients, it is literally life or death⁴.

Patient enrollment, or lack thereof, is frequently cited as the primary reason for clinical trial delays. As such, there is growing fervor for the implementation of robust subject recruitment and retention initiatives in research studies. The widespread adoption of new technologies and services such as social media, electronic medical records (EMRs), and remote data capture, brings many opportunities to boost protocol participation, but also introduces many new challenges. The key takeaway for today’s study environment is that subject management, from pre-screening through study completion, must be carefully planned and closely supervised; it cannot be taken for granted to proceed on its own1. And even with technological advancements, the industry cannot underestimate the importance of interpersonal relationships³⁰.

Recruiting the modern-day patient is a difficult task
There is widespread interest in clinical trial participation with 94 percent of the public agreeing that research involvement is “very important to advance medical science” ⁵ and similar metrics support research and its funding in general⁸. When it comes to actually recruiting clinical trial participants, however, the industry is fighting an uphill struggle. A 2008 survey revealed that only 17 percent of 1,000 respondents believed clinical trials to be “very safe” and 14 percent revealed that they had no knowledge on the topic whatsoever⁸.  Seventy percent of those questioned for a recent industry white paper indicated having no awareness of the most common online clinical trial databases (e.g. ClinicalTrials.gov) ¹², further sustained by 74 percent admitting “no ‘real’ knowledge of the clinical research process” and nearly everyone stating they don’t have the tools to appropriately evaluate potential studies⁵.

With the proliferation of online communication methods, the rapid expansion of social networks, the “always-on” 24-hour news stream, and expanded access to mobile media, we are inundated with data at a pace never before seen. The typical person is exposed to the equivalent of an entire novel’s worth of information every single day⁶. It should come as no surprise that even the most targeted messages may get lost in the fold. Despite uptake of social media, its use for engaging patients is still in its infancy due to privacy concerns and lack of proper guidance from regulators. After years of debate, the FDA’s initial draft guidance issued in December 2011 for patient-initiated requests arrived with no clarity to what may be allowable regarding engagement via social media outlets¹⁴.

Still, figuring out a way to use these newer media in a targeted and acceptable way is a potential boon for clinical research. In May 2011, 179 “e-patients” – those who rely on social media and online networks for health information – revealed that they more consistently visit a doctor, are more apt to adhere to prescribed medical schedules, and are 60% more likely than the general populace to have participated in a clinical trial¹². Interestingly, this same survey showed that the vast majority – 80 percent – read information available on healthcare websites and social networks, but are not necessarily inclined to post content in response; thus a successful social media campaign cannot rely on self-reporting from potential subjects. It is up to the industry to get the word out via these alternative venues.

Where social media shines is in its ability to reach those with similar, often unique or orphan conditions or circumstances¹³. Tapping into networked communities of those with rare diseases and/or similar life situations gets directly to the populations of interest for trial recruitment. By advertising or otherwise engaging in these communities, Sponsors, CROs, and sites alike can reach a ready pool of potential subjects guaranteed to meet basic study criteria. Considering a broad definition of social media, there are dozens of focused and immediate opportunities with topical communities like PatientsLikeMe and the Fox Foundation’s Fox Trial Finder^{10, 23, 15}. On PatientsLikeMe, for example, users can enter their conditions, gender, age and location to find relevant clinical studies nearby. From the investigation side, reviewing a specific ongoing study shows the number of registered PatientsLikeMe users who may qualify based on their profiles. Registered users are able to directly interact by drilling down through other registered users’ profiles making direct contact between researcher and potential subject simple, though perhaps a bit invasive when done improperly²³. With a lack of regulatory guidance, it is left to Sponsors to work with IRBs in determining the most appropriate means to engage patients in this fashion²⁵. But if sponsors advertise or otherwise promote their trials in like communities, they have an immediate leg up in gaining the attention of the high-value “e-patients.”

Yet all this talk of social media is not without its complications. Pfizer’s much ballyhooed REMOTE study, designed to be entirely technology-driven with social media at the core of the recruitment strategy, was terminated prematurely in June 2012 due to lagging enrollment¹¹. Rahlyn Gossen – a former research coordinator who now runs RebarInteractive.com²⁶ which explores advancement of new means of recruiting trial patients – is firmly committed to digital methodologies, yet she remains equally critical of social media’s potential, particularly because of the long-term commitment needed to make venues like Twitter successful²². She suggests that social media today can most effectively be used to increase awareness and build rapport by creating original content and getting the word out through channels like YouTube²⁴. Gossen sees this as a developing area as effects of traditional media wane²². So social media may very well be a means to augment, rather than revolutionize, patient accrual at the current juncture.

As a less progressive but more immediately accessible technology, increasingly routine use of electronic medical records (EMRs) provides excellent opportunity to quickly and efficiently scan patient data that were entirely inaccessible or severely cumbersome to navigate in their previously disparate state. Use of EMRs has already shown promise to accelerate research recruitment^{28, 3}. As demonstrated in a 2011 general practice study in Germany, implementation of a study specific “clinical trial alert” tool allowed site research coordinators to partially automate the patient identification process such that they combed through over 16,000 potentially eligible EMRs in order to contact nearly 2,000 patients leading to over 1,500 enrolled subjects²⁹. This type of rapid, automated screening process would not be possible in the ‘paper world.’ Pre-screening EMRs for potential patients has additional added benefits of confirming the viability of a potential study as described in Case Study A (see inset).

It should be noted that the proliferation of technology on its own cannot resolve the entire recruitment challenge. Given the intimacy of healthcare information, trust is primarily achieved through credibility and respect for privacy that can only be offered from physician interactions; transparency is paramount to success^{9, 12}. Patient recruitment agency Blue Chip suggests that, when considering social media as part of the accrual strategy, it is important to ensure demographics of the study requirements and the targeted communities are well-aligned, that transparency is actively maintained with involvement of a physician, and that information is timely, accurate, and readily available for sharing within or outside the target forum¹². A 2012 meta-analysis further confirms that direct physician involvement in the design and recruitment of studies is the single most important criterion in successful enrollment¹⁶.

Similarly, though it may seem obvious, proper site selection by Sponsors and CROs can be the ultimate determining factor in successful recruitment. Retrospective analyses by Pfizer and Lilly have shown, perhaps not surprisingly, that strong site performance on a prior study is the most important factor in likelihood of recruitment success on a new study. This is even further amplified when investigator experience is taken into consideration¹⁷. And when other factors influence the start of a trial as in Case Study B (see inset), additional effort is required to ensure recruitment proceeds as planned.

Recruitment is Not the End of the Line
With intense industry focus on means to bolster study accrual, patient retention often goes without planning. It costs significant capital – financial, temporal, labor, opportunity cost – to enroll each trial subject, so keeping them on a study through completion is equally as important as the initial recruitment. There will always be the unavoidable loss of subjects – unrelated adverse events, relocation, co-morbidities – so there is good reason to make certain that, barring medical reason, subjects are encouraged to remain on study. This requires creativity, flexibility and real commitment from the Sponsor and the trial site.

One means of helping to retain the modern day study subject is via the reduction of in-office requirements. Though Pfizer’s REMOTE study as discussed previously may be considered a disappointment as relates to enrolling subjects, the entirely decentralized patient-centric approach with minimal intervention from trial investigators demonstrates maximal flexibility for the modern day study subject. Trial participants have been able to complete all their data reporting via electronic patient reported outcomes (ePRO) tools, regardless of trial site proximity, and have been able to reach study physicians 24-hours a day to discuss participation. Whether a fully virtual trial is ‘science future’ or ‘science fiction’ remains to be seen, but certainly some of the tools, including expanded collection of remote data, is a growing trend to improve study speed and subject retention and compliance²¹. Sponsors need to be creative and flexible in acquiring data, particularly for long-term or highly involved studies so as to minimize disturbance of subjects’ everyday activities with commitment to patient convenience^{20, 27}.

As evidence of this, utilizing ‘in-home’ study visits is another means of boosting patient retention, particularly for studies that require lengthy or frequent procedures or data collection. For example, a study nurse may visit trial participants in their homes or offices to collect blood samples or administer IV dosing rather than requiring a subject to travel to a study site. Not only is this a significant added ease for trial subjects, but it has the effect of fostering a stronger bond between participants and the trial caregivers, thus improving long-term retention²⁰. In a case study published by Symphony Clinical Research, dropout rates across multiple Phase II/III two-year orphan drug pulmonary studies were reduced from two-thirds to just three percent with addition of homecare services. For those planning new studies, use of decentralized patient care may be a useful and cost-effective tool in certain situations to reduce participation burden and thus improve long-term retention⁷.

Interestingly, whereas recruitment is evolving to include more technology-driven concepts, retention may be enhanced through significantly less evolved methods. Research shows a direct correlation between the level of involvement of the principal investigator, the approach and attitude of the research nurse, and the level of empathy for the trial subjects¹⁹. So though these facets may be perceived as less controllable by those managing studies, employing a high level of site education and training with a concerted focus on patient-centric ideologies may be the most effective means to ensure subject retention.

Finally, in cases of long-term studies use of retention specialist organizations may significantly improve outcomes. In one example, an HIV study which had lost over 25 percent of participants after 6 months was able to re-engage nearly 90 percent of those lost subjects using concentrated outreach efforts, suggesting again that planning for retention is a necessary part of overall study planning². Case Study C (see inset) explores a solution used to maximize patient retention over a long-term study.

Applying Lessons Today
All told, the actionable lesson from this is that it is critical that Sponsors, study investigators, and clinical monitors assess the specific qualities of each protocol and site in order to customize the best approach to recruit and retain for each given circumstance; there is rarely a “one-size-fits-all” solution to successfully enrolling and maintaining trial patients. Perhaps the most important consideration for a multisite protocol is recognition that each site will have its own unique needs, and that all stakeholders need to collaborate with each sites’ investigators and coordinators to define and implement an appropriate strategy¹⁸. Investigators’ direct involvement starting at the consultative stages is key to gaining patient buy-in. And the quantitative effect of all strategies needs to be continually assessed and reconfigured as the trial proceeds. Like most parts of research, subject management is a “living” process that starts and ends with humans1, and planning is essential.

The rise of social media and increase in “crowd-sourced” engagement brings new avenues to interact with and gain attention from potential and enrolled trial subjects. But use of these and all media have to be carefully planned in order to meet the rigors of ethical and regulatory guidelines, as well as to gain the trust and acceptance of the broad population. Planning, monitoring, and reacting to subject recruitment and retention trends, are critical to ensuring trial success²⁷. In the end, recruiting and retaining research subjects are very human endeavors, and relationships matter. Planned efforts have never been more challenging, more creative, or more necessary, and are only going to continue to evolve.

References
^1. Dyas, J. V., Apekey, T., Tilling, M. & Siriwardena, A. N. Strategies for improving patient recruitment to focus groups in primary care; a case study reflective paper using an analytical framework. BMC Medical Research Methodology. 9, 65-73 (22 Sep 2009).
^2. Sitapati, A. M., Limneos, J., Bonet-Vazquez, M., Mar-Tang, M., Qin, H. & Matthews, W. C. Retention: Building a Patient-Centered Medical Home in HIV Primary Care through PUFF (Patients Unable to Follup-up Found). Journal of Health Care Poor Underserved. 23 (3 Suppl), 81-95 (Aug 2012).
^3. Lichter, A. S., Fehrenbacher, L. & Hortobagyi, G. N. Minimizing Research Delays: Identifying Successful Strategies to Keep a Clinical Trial Moving Forward. Journal of Oncology Practice. 3(6), 306-307 (Nov 2007).
^4. von Eschenbach, A. & Hall, R. FDA Approvals Are a Matter of Life and Death (Editorial). (17 Jun 2012).
^5. Http://ciscrp.org/professional/aware.html, visited on 22 Aug 2012.
^6. Sheridan, B. Is Cue the Cure for Information Overload? Bloomberg Businessweek. (19 Jun 2012). Http://www.businessweek.com/articles/2012-06-19/is-cue-the-cure-for-information-overload, visited on 24 Aug 2012.
^7. Case Study: Improved Patient Retention Orphan Drug Studies (White Paper). Symphony Clinical Research. (2003).
^8. Http://ciscrp.org/professional/facts_pat.html, visited on 23 Aug 2012.
^9. Http://ciscrp.org/professional/facts.html, visited on 24 Aug 2012.
^10. Pogorelc, D. Match.coms of clinical trials make it easier to connect patients, researchers. MedCity Media. (19 Jun 2012). Http://medcitynews.com/2012/06/the-match-coms-of-clinical-trials-make-it-easier-to-connect-patients-researchers/, visited on 22 Aug 2012.
^11. Silverman, E. Pfizer Ends Social Media Bid for Trial Recruitment. Pharmalot. (19 Jun 2012). Http://www.pharmalot.com/2012/06/pfizer-ends-social-media-bid-for-trial-recruitment/, visited on 27 Aug 2012.
^12. Engaging E-Patients in Clinical Trials through Social Media (White Paper). Blue Chip Patient Recruitment. (May 2011).
^13. Meyer, E. Social media a godsend for those with rare diseases. (12 Jun 2012).
^14. FDA Draft Guidance For Industry: Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices. Dec 2011.
^15. Https://foxtrialfinder.michaeljfox.org, visited on 23 Aug 2012.
^16. Ngune, I., Jiwa, M., Dadich, A., Lotriet, J. & Sriram, D. Effective recruitment strategies in primary care research: a systematic review. Quality in Primary Care. 20(2), 115-123 (2012).
^17. Getz, K. Predicting Successful Site Recruitment. Applied Clinical Trials. (01 Nov 2011).
^18. Chlan, L., Guttormson, J., Tracy, M. F. & Bremer, K. L. Strategies for Overcoming Site and Recruitment Challenges in Research Studies Based in Intensive Care Units. American Journal of Critical Care. 18(5), 410-417 (Sep 2009).
^19. Good, M. & Schuler, L. Subject Retention in a controlled clinical trial. Journal of Advanced Nursing. 26 (2), 351-355 (Aug 1997).
^20. Donahue, M. Bringing Trials to the Patient at Home. Applied Clinical Trials. (12 Jan 2012).
^21. Donahue, M. & Henderson, L. Pfizer's REMOTE Virtual Experience. Applied Clinical Trials. (12 Jan 2012).
22. Online Ads for Clinical Sites. ClinPage. (19 Aug 2011). Http://www.clinpage.com/article/online_ads_for_clinical_sites/, visited on 22 Aug 2012.
^23. Http://www.patientslikeme.com, visited on 22 Aug 2012.
^24. Gossen, R. 3 Problems Social Media Can Solve for Research Sites. RebarInteractive. (11 Mar 2011). Http://rebarinteractive.com/3-problems-social-media-can-solve-for-research-sites/, visited on 22 Aug 2012.
^25. Gossen, R. A Social Media Question IRBs Must Ask. RebarInternational. (10 May 2012). Http://rebarinteractive.com/social-media-patient-recruitment-irb/, visited on 22 Aug 2012.
^26. Http://rebarinteractive.com, visited on 22 Aug 2012.
²⁷. Falcon, R., Bridge, D. A., Currier, J., Squires, K., Hagins, D., Schaible, D., Ryan, R. & Mrus, J. Recruitment and Retention of Diverse Populations in Antiretroviral Clinical Trials: Practical Applications from Gender, Race, And Clinical Experience Study. Journal of Women's Health. 20 (7), (2011).
^28. Baum, S. Penn Medicine to expand use of EMR software to find clinical trial candidates. MedCity Media. (31 Oct 2011). Http://medcitynews.com/2011/10/penn-medicine-to-expand-pilot-using-emr-app-for-clinical-trial-candidates/, visited on 23 Aug 2012.
^29. Heinemann, S., Thuring, S., Wedeken, S., Schafer, T., Scheidt-Nave, C. & Mirko Ketterer4, W. H. A clinical trial alert tool to recruit large patient samples and assess selection bias in general practice research. BMC Medical Research Methodology. 11(16), (15 Feb 2011).
^30. Penckofer, S., Byrn, M., Mumby, P. & Ferrans, C. E. Improving Subject Recruitment, Retention, and Participation in Research through Peplau's Theory of Interpersonal Relations. Nursing Science Quarterly. 24 (2), (Apr 2011).
^31. Philipson, T. J. & Sun, E. Cost of Caution: The Impact on Patients of Delayed Drug Approvals (White Paper). Manhattan Institute for Policy Research. (Jun 2010).

INSETS:
• CASE STUDY A - Electronic medical records (EMRs) to pre-screen for specific protocol requirements are a useful tool to pre-select study subjects and assess protocol viability even prior to initiating a trial.

A scientific roundtable was convened to finalize protocol development for an untried novel therapeutic approach. Many study design elements were assessed including prohibited medications, diagnostic requirements for enrollment, number and frequency of various study assessments and specific inclusion / exclusion criteria. There was general consensus among the research experts that the agreed elements, taken individually, would have minimal impact on the ‘enrollability’ of the study. To confirm this, the CRO enlisted three investigative sites to review their EMRs based on eight specific criteria proposed for the protocol. The results were self-evident: at best, only three percent of patients with the target disease may initially qualify for screening. The protocol was essentially not viable in its then-current form. This inexpensive and quick appraisal demonstrates the power of EMRs and value in quantifying enrollment potential before investing significant human and financial capital. Without these results, this trial would have failed as planned, and the protocol amendments required mid-study would have significantly delayed the timelines and degraded investigator and subject motivation.

• CASE STUDY B – Implementing multifaceted motivation and recruitment campaigns saved a Phase II respiratory study from significant delays.

Initiation of a Phase II respiratory study had to be halted due to manufacturing issues just one day before screening was scheduled to commence. The Sponsor and CRO immediately recognized the importance to proactively manage expectations for all stakeholders in order that the delay not become crippling. A mutual agreement was negotiated to ensure that the fully trained CRO team remained intact and, working through the clinical monitors, there was immediate, transparent, and continuous communication to the sites about what was going on. The management team used the delay to develop and gain IRB approval for print and radio marketing tools placed locally near trial sites. The Sponsor conducted direct outreach to each principal investigator and the CRAs conducted routine check-ins with the study coordinators to keep motivation high. Sites were provided with pre-printed postcards with information about the study that were sent by the hundreds to potential study subjects.

Just prior to reopening the study, refresher phone initiations were conducted with all sites. In recognition of additional prescreening efforts, sites were each paid an additional non-refundable retention bonus when they screened their first subjects. The significant efforts paid off when the trial started twelve weeks behind schedule and subjects were literally lined up to be consented. The expected recruitment period was condensed from twelve weeks to just eight days and the trial overenrolled. The transparent communication and additional emphasis on recruitment efforts helped build site rapport, maintain interest and trust, and create an environment of excitement at a time when circumstances may have otherwise had the exact opposite effect.  

• CASE STUDY C – Use of automated forecasts and visit tracking aids study retention efforts.

For a large multisite vaccine study, the CRO and Sponsor employed an electronic tracking system whereby, once a subject’s initial screening visit was entered, a full forecast of subsequent visits was generated. This allowed sites to print calendars of upcoming activities for use in their clinics and to be included in patient charts. The system also generated automated email and SMS text message reminders to study coordinators and patients in advance of scheduled visits, and as notifications for when projected visits had not been registered. To implement such a system, direct-to-patient communications needed prior approval from ethics committees and participation was described and approved via the informed consent process. Though not used in this case, careful planning may allow additional automation via integrations with randomization and/or EDC applications for added notification capabilities. Patients and site coordinators agreed that this approach added significant value in aiding a busy time management process.

Author BIO:
Nicholas Spittal, MBA, PMP, Director, Strategic Clinical Development at Chiltern International, has been directing multi-national clinical research studies for more than ten years in difficult-to-enroll populations, including the then-largest programs in three different ophthalmic indications. Chiltern International is a global full service contract clinical research organization offering consultation and drug development services to the biopharmaceutical industry. Mr. Spittal may be reached at nicholas.spittal@chiltern.com.