Direct-to-Patient Enrollment Strategies

Recruitment of patients for participation in clinical trials is a major source of research expense. Estimates of recruitment costs vary by study and disease state; however, data suggests that patient recruitment costs range between less than $10 to more than $1300 per completed subject.^1,2 Patient recruitment delays can compound costs by delaying the time to product approval, often decreasing the period of exclusivity post-launch. Studies, for example, have demonstrated that recruitment difficulties can account for up to 45% of study delays, and these often can last six months or more.³

As sponsors search for more time-efficient, less-expensive approaches to conduct community outreach for clinical trials, Internet-based sources have gained more attention. Of particular interest has been the emergence of health-focused, online social networks. In theory, these online social groups, formed around specific medical conditions or health interests, are comprised of people that are highly engaged in their disease, and potentially, motivated to participate in clinical trials.

While the number of marketing and research groups using online social networks has increased,^4,5 few have published data that explores the potential effectiveness and costs of working with these groups, especially in comparison to outcomes associated with other techniques. In this article, we address this gap in the literature by presenting effectiveness and cost outcomes associated with three different patient outreach approaches.

Objective and methods

The objective of this study was to compare the effectiveness and costs of three direct-to-patient outreach strategies: direct mail outreach through use of a third-party mailing list; email outreach through use of a third-party email list; and email outreach through iGuard.org, a Web-based medication monitoring service that includes a social network of members interested in sharing feedback on their medications.

This study assessed the ability of these three different outreach strategies to identify potential study participants for two clinical trials in rheumatoid arthritis and multiple sclerosis. These medical conditions were chosen because they comprise large numbers of patients suffering chronic illness with substantial potential for morbidity and mortality, and they are often the focus of many costly clinical trials.

The outreach was conducted in the United States in June, July, and August 2009. Participants from any of the three outreach methods who completed an online survey received $10 in compensation for their time. The survey was blinded and did not contain any information on actual study medication, sponsor, or investigator site. Surveys conducted through iGuard.org are covered under a blanket Institutional Review Board (IRB) assessment from Independent Review Consulting, Inc. IRB approval for the direct mail or email outreach was not seeked because the blinded nature of the questions (i.e., no clinical trial specifics included) met the criteria of 45 CFR 46.10 related to research on educational practices.

Setting and Participants. The third-party direct mail and email outreach was conducted by Automated Information Systems, Inc. (Glen Ellyn, IL), a vendor chosen among other candidates for the size of their patient databases in these therapeutic areas; their ability to send both email and direct mail communications; and their ability to prevent duplication between the electronic and paper-based methods. Automated Information System's mailing list is derived from multiple sources, including managed care organizations and patient advocacy groups. Email communications were checked for accuracy using a matching system from Experian, Inc. (Costa Mesa, CA).

The social network outreach was conducted among members of iGuard.org, a free, medication service that monitors the safety of prescription medicines, over-the-counter medicines, and health care supplements for over two million patients. iGuard.org attracts members through online search engines as well as outreach efforts with physicians, pharmacies, and health-related Web sites. iGuard.org members were randomly screened for participation in this study if their profile included an oral rheumatoid arthritis (azathioprine, hydroxychloroquine, leflunomide, methotrexate, or sulfasalazine) or multiple sclerosis (beta interferon or glatiramer acetate) medication.

Measurements. The effectiveness of each outreach strategy was measured by the proportion of those contacted who completed the online survey (i.e., the response rate) and the costs associated with generating one individual interested in the study (i.e., a function of response rate, unit costs, and clinical trial interest). The current study focused on outreach and did not follow patients through the investigator site screening process and enrollment.

The unit cost for third-party mailing was $0.86 and $0.42 for third-party email. Actual marginal costs to contact the iGuard.org members were negligible as the community and communication platform already existed. For the purposes of this analysis, however, the cost associated with iGuard.org outreach was assumed to be equivalent to the third-party email cost of $0.42 per email contact.

Analysis. Response rates and demographic characteristics were compiled for each outreach strategy. Comparison between the strategies on gender was performed using Chi-square test, and on age using one-way analysis of variance (ANOVA), with Bonferroni correction to adjust for multiple comparisons. These analyses were conducted using SAS Version 9.1 for Windows from SAS Institute Inc.

Results

The third-party vendor sent 12,500 letters and 15,000 emails to patients with rheumatoid arthritis and multiple sclerosis (total 25,000 letters and 30,000 emails); these numbers reflected the vendor's minimum requirements. Overall costs associated with these contacts totaled $21,500 for the direct mail ($0.86 per letter) and $12,600 for the email contact ($0.42 per email).

The response to direct mail outreach was 3.6% (905 of 25,000) as measured by participation in the online survey. Nearly all individuals responded within two weeks to the mail survey. Overall, 78% of individuals responding were interested in participating in the clinical trial, resulting in a cost per interested individual of $30.45.

The third-party email outreach yielded a lower response rate than the direct mail, 0.5% (157 of 30,000). Most responses for email outreach occurred within 24 hours. The proportion interested in a trial, however, was 80%, very similar to the interest expressed by individuals contacted through direct mail. The resulting cost per interested individual for the direct email outreach was $100.32.

During the June, July, and August 2009 time frame, iGuard.org surveyed 3657 members treated with a medication for rheumatoid arthritis (n=3057) or multiple sclerosis (n=600). Of these 482 responded, yielding a response rate of 13.2%. Similar to email outreach, most responses to iGuard.org outreach occurred within 24 hours. Of the individuals surveyed, 75% expressed interest in a clinical study, resulting in a cost per interested individual of $4.25 per response (assuming a cost per contact similar to charges for the third-party email outreach).

The response rates and costs associated with each of the three outreach strategies are shown in Table 1, and demonstrate that the social network-based email strategy was substantially more effective and cheaper than either third-party direct mail or email. Contrary to industry assumptions, third-party email was substantially more expensive than direct, paper-based mailings, primarily driven by the lower response rate. Interestingly, clinical trial interest among patients motivated to respond to the survey was similar across all three outreach methods.

Table 1. The social-network based recruitment strategy was substantially more effective and cheaper than third-party direct mail or email.

Some differences were observed on gender and age between the three-outreach methods. iGuard.org had a higher proportion of women respondents (84.9%) compared to other methods, however, women were generally more likely to respond in all groups (76% to 80%, see Table 2). Surprisingly, direct mail appeared to attract slightly younger respondents compared to both email approaches.

Table 2. Women were more likely to respond to an invitation to participate than their male counterparts, regardless of outreach method.

Patterns of response rates, proportion of individuals interested in a clinical trial, and costs per interested individual were similar for each of the three strategies when evaluated separately for rheumatoid arthritis and multiple sclerosis, with social network outreach through iGuard.org yielding a substantially greater response rate and lower cost per response (see Table 3). Across all outreach strategies, patients with rheumatoid arthritis were less likely to respond than those with multiple sclerosis: third-party direct mail (1.4% vs. 5.8%), third-party email (0.3% vs. 0.7%), and social network outreach (11.2% vs. 19.5%).

Table 3. iGuard.org returned the highest percentage of interested candidates among both Rheumatoid Arthritis and Multiple Sclerosis sufferers.

Once an individual responded, however, interest in clinical trial participation was very similar across all outreach methods: 70% to 73% for rheumatoid arthritis, and 79% to 85% for multiple sclerosis. With respect to costs, the social network-based approach was substantially cheaper than both the third-party direct mail and third-party email outreach for rheumatoid arthritis ($4.82 vs. $86.28 and $195.65 per interested individual, respectively) and multiple sclerosis ($2.69 vs. $18.72 and $66.77 per interested individual, respectively). In these disease specific analyses, third-party email remained the most expensive option driven by the significantly lower response rate.

Discussion

Our data suggest that patient outreach using the online social network, iGuard.org, is more effective and substantially cheaper than either third-party email or direct mail. This result is driven primarily by a substantially-higher response rate for the social network outreach: over four times higher than third-party mail and over 25 times higher than third-party email. Similar patterns were seen for responses in individual disease states, with the iGuard.org email yielding over 35 times as many responses among rheumatoid arthritis patients as the third-party email, and more than 25 times the responses among multiple sclerosis patients as the third-party email.

Although the proportion of individuals interested in the study was similar across methods, the outreach strategies differed substantially in their cost per interested individual. In this case, the social network outreach through iGuard.org ($4.25 per respondent) was seven times cheaper than third-party direct mail ($30.45 per respondent) and nearly 25 times cheaper than third-party email ($100.32 per respondent). These results persisted when evaluated by disease state, where the iGuard.org outreach was nearly seven (multiple sclerosis) to 18 times (rheumatoid arthritis) cheaper than the second best option, third-party direct mail, and faster as well (24 hours vs. two weeks to capture the majority of responses).

These findings are consistent with the existing literature about variation in subject recruitment based on both approach and disease state. Data acquired in association with the Lung Health Study, for example, showed great variation in recruitment rates from various sources, ranging from 1.5% from direct mail to 46% from media sources.⁶ An unexpected finding of our study was that third-party email performed worse than third-party direct mail. Specifically, the third-party email response rate was 0.5% vs. 3.6% for direct mail, and costs per interested individual totaled $100 for email vs. $30 per respondent for direct mail.

Importantly, our data extends existing knowledge about the use and relative cost-effectiveness of social networks for patient outreach. Although little has been published to date about the use of social networks in general and online social networks specifically for clinical trial outreach, our data appears to be consistent with the findings of one study conducted in nine community-based organizations. In this study, researchers successfully recruited participants for HIV testing through accessing peer (not online) networks at rates that exceeded other methods by five-fold.⁷ Furthermore, our findings about relative costs suggest that online social networks may not only increase response rate but may do so faster and at a lower cost than other approaches.

Limitations

Our data should be viewed in the context of some limitations. First, only two disease states were studied and it is possible that relative effectiveness and costs of these strategies could vary for different patient groups. The fact that our data showed similar relative response rates and costs when analyzed by specific disease states, however, suggests that the relative benefits of outreach through online social networks may hold in other disease states.

Another limitation of our data is that we studied relative differences in outreach strategies based on responses to an online survey, not through actual clinical trial enrollment. While it is possible that the relative response and cost differences between strategies erode when actual participation in clinical trials is measured, the iGuard.org experience with clinical trial recruitment in areas such as depression and gastroesophageal reflux suggests that the proportion of patients expressing interest that are ultimately enrolled in the study is somewhat consistent across outreach strategies.

It is also possible that the quality of the third-party email list may have contributed to our findings. However, as this email list was checked against Experian, Inc., which most third-party vendors use for such validation, it is unclear whether a different result would have be obtained working with another third-party email vendor. There were also differences observed in gender and age among respondents to the three outreach methods. However, it is unclear whether these differences would be relevant in the context of recruitment for clinical trials.

Finally, it is possible that unique characteristics of the iGuard.org social network account for its relatively high response rates and low costs. As of August 2010, iGuard.org had over 2.3 million members and is much larger than other online medically oriented social networks.⁸ While this may limit generalizations about the use of medically oriented social networks to recruit patients, the size of iGuard.org's membership allows its demographics to more closely approximate those of individuals seeking health information online when compared to smaller social network organizations. The outcomes associated with outreach through nonmedical social networks are unknown.

Conclusions

The data suggests that patient outreach through an online social network has the potential to be more effective and less expensive than either third-party email or direct mail in the recruitment of subjects for clinical trials. Further studies are needed to quantify the benefit of collaboration with the growing number of social network sites for actual clinical trial enrollment when compared to traditional approaches to patient outreach.

Elisa Cascade* is the Vice President, email: elisa.cascade@iGuard.org, and Hugo Stephenson, MD, is the President of iGuard.org, 66 Witherspoon Street, #262, Princeton, NJ 08542. Murtuza Bharmal, PhD, is Director, and Christopher H. Cabell, MD, is Senior Vice President, at Quintiles, Durham, NC.

*To whom all correspondence should be addressed.

References

1. L. Gren, K. Broski, J. Childs et al., "Recruitment Methods Employed in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial," Clinical Trials, 6 (1) 52-59 (2009).

2. S. Roy, S. Patel, K.H. Sheehan, J. Janavs, D. Sheehan, "Efficacy of Print Advertising for a Bipolar Disorder Study," Psychopharmacology Bulletin, 41 (1) 136-141 (2008).

3. D.L. Anderson, A Guide To Patient Recruitment (CenterWatch, Boston, MA, 2001).

4. D. Borfitz, "Social Networking Sites Have Myriad Trial-Related Uses," Cambridge Healthtech Institute, March 2009, http://www.ecliniqua.com/2009/03/02/social-networking-recruitment-sites.html~.

5. S. Kliff, "Pharma's Facebook," Newsweek.com, March 10, 2009, http://www.newsweek.com/id/187882/page/1.

6. W.M. Bjornson-Benson, T.B. Stibolt, B.A. Manske et al., Monitoring Recruitment Effectiveness and Cost in a Clinical Trial, Controlled Clinical Trials, 14 52S-67S (1993).

7. L.W. Kimbrough, H.E. Fisher, K.T. Jones et al., "Accessing Social Networks with High Rates of Undiagnosed HIV Infection: The Social Networks Demonstration Project," American Journal of Public Health, 99 (6) 1093-1099 (2009).

8. M. Allison, "Can Web 2.0 Reboot Clinical Trials?" Nature Biotechnoly, 27 (10) 895-902 (2009).