Analyzing global recruitment strategies to improve local trial enrollment

White paper 30% faster start-up in certain therapeutic areas 50% higher patient recruitment rates with our Partner Sites Analyzing global recruitment strategies to improve local trial enrollment A global investigation into what works where for patient recruitment and retention tools and techniques Chris Frega, Senior Director, Integrated Site Services Stacy Whaley, Associate Director, Patient & Site Services Executive summary Patient recruitment and retention has continued to be one of the largest challenges in clinical development for biopharma companies, as evidenced by the startling data that 70 percent of clinical trials experience startup delays and almost half complete late (Source: CenterWatch Survey of Investigative Sites, 2007). However, experience has taught us that if we implement a very targeted site strategy, we can start up studies quicker (up to 30 percent faster in certain therapeutic areas) and we can deliver 50 percent higher patient recruitment rates with our Partner Sites. We can also drive much faster investigator contracting timelines to help streamline start-up. Recruitment challenges, combined with the increasing complexity of global clinical trials and the myriad recruitment and retention strategies available to researchers, have been driving the need for greater focus of our efforts. To put this focus into action, Quintiles has developed a two-part global investigation in more than 100 countries to confirm what works where for patient recruitment and retention tools and techniques.

Table of contents Executive summary 3 Introduction 4 Investigation rationale and methodology 4 A country examination of tools and techniques 4 The voice of the investigator 5 Key findings 5 Conclusion 10 References 11

Executive summary Patient recruitment and retention has continued to be one of the largest challenges in clinical development for biopharma companies, as evidenced by the startling data that 70 percent of clinical trials experience start-up delays and almost half complete late (Source: CenterWatch Survey of Investigative Sites, 2007). However, experience has taught us that if we implement a very targeted site strategy, we can start up studies quicker (up to 30 percent faster in certain therapeutic areas) and we can deliver 50 percent higher patient recruitment rates with our Partner Sites. We can also drive much faster investigator contracting timelines to help streamline start-up. Recruitment challenges, combined with the increasing complexity of global clinical trials and the myriad recruitment and retention strategies available to researchers, have been driving the need for greater focus of our efforts. To put this focus into action, Quintiles has developed a two-part global investigation in more than 100 countries to confirm what works where for patient recruitment and retention tools and techniques: 1. An analysis by country on which tactics are allowed from a legal/regulatory/privacy perspective and are culturally acceptable 2. An analysis of investigator preference based on previous experience Our findings concluded that: While nearly all recruitment and retention tools and techniques are acceptable in the U.S. and Canada, acceptability drops significantly in other parts of the world particularly in Eastern Europe/Middle East. However, in recent years acceptability of all tools and techniques is increasing across the board. To recruit patients, investigators from the U.S. and Canada indicate a positive response to different materials than the rest of the world. For example, within their own sites, investigators from these areas have found posters and flyers most effective, while patient education materials were mentioned most often in all other regions. Outside of their practice, advertising has been the most effective way to recruit patients, while all other regions indicated physician referrals as the top method. To retain patients at sites, investigators in all regions indicate robust patient education and contact and reminder services are the most effective tools. When reaching out to referring physicians, investigators tend to favor more traditional tools, such as letters and email templates, over newer tactics such as physician referral websites. 3 www.quintiles.com

Introduction There are numerous factors contributing to patient recruitment and retention delays across biopharma trials, with those in Figure 1 being just a few of the most common. Figure 1: Contributing factors to trial delays Increasing complexity of global trials Competition with other trials Changing regulatory environments Cultural differences across sites and geographies Trial budgetary/ time constraints Mitigating these challenges starts with a research-driven approach to deploy targeted recruitment and retention strategies at the local level. These approaches are not one size fits all. They are unique, defined by many factors including location, language and cultural relevance. These approaches must also be robust at study start and nimble in response to potential changes throughout the course of any given trial. In the midst of this complexity, it is critical to maintain focus on the patient as the key stakeholder in the research. One way Quintiles maintains this focus is by ensuring we use the right solutions to provide patients with clear messages, easy access and thorough education as they consider or participate in clinical trials. To reinforce our confidence in our application of tools and techniques, we embarked on a two-part global investigation in more than 100 countries to confirm what works where. Investigation rationale and methodology A country examination of tools and techniques Geography and culture play very important roles in determining which tactics are best suited for a particular study, and there are a number of nuances to consider when determining the right tool. Regulatory guidelines broadly define the level of support we can provide sites to recruit and retain patients; however, we must also consider that even if a tactic is allowed, it may not be culturally acceptable among sites and/or patients. Furthermore, the approval of tactics can vary across regulatory groups and indications within the same country; one approval does not guarantee or obviate the next. As a result, it is extremely important to have a global strategy that is designed to not only maximize recruitment for the overall study but also readily customize the recruitment/retention strategy to what is most appropriate within each specific country and site. Quintiles internally evaluated 36 patient recruitment and retention tools and techniques across the globe to help our teams determine the best methods for each study that we manage. Our analysis included traditional patient- and site-facing materials (e.g., posters, flyers, brochures, informed consent flip charts, referral tools and templates), advertising (e.g., print, radio, television), digital tools (e.g., Internet advertising, email campaigns, patient websites) and retention tools (e.g., study guides, visit schedules, appreciation items, reminder services, retention communities). Data was captured locally through a number of means including specific regulatory and medical guidance, personal experience and investigator feedback each applied as available and necessary. This investigation was completed and compiled in Q2 and Q3 2014 and compares against a previous investigation in 2012. 4 www.quintiles.com

The voice of the investigator The role of investigators cannot be understated in today s clinical development environment. We rely upon investigators to ultimately screen, enroll and retain patients in the studies that we conduct. They are the experts on what works at their particular sites or practices, so their perspectives are critical to our success. Just as individual countries differ in which approaches work for them, there can also be significant variability from site to site within a single country. It is the combination of investigator knowledge and ability to apply the techniques that are broadly acceptable in specific countries that allows us to maximize potential enrollment. For this reason, we also surveyed and received responses from more than 9,400 investigators across nearly 100 countries to understand their needs, experiences and preferences across these same tools and techniques. The online survey was conducted internally by Quintiles, and Quintiles was identified to participants as the company conducting the inquiries. Key findings A primary goal of our investigation into retention tools and techniques across various countries was to identify how acceptable commonly used practices are in each of these areas. Ideally, we are looking for techniques that are both allowed and acceptable. However, if the answer is no for either of those questions, it doesn t mean that the tool or technique is not able to be used; it just means that there are likely some hurdles to overcome that should be considered. Figure 2: Percentage of recruitment and retention tools and techniques by regional acceptability 100 80 8% 6% 12% 14% 27% 13% 9% 6% 3% 19% While nearly all recruitment and retention tools and techniques are acceptable in the U.S. and Canada, acceptability drops significantly in other parts of the world particularly in Eastern Europe and the Middle East. 60 40 92% 82% 59% 79% 94% 78% 20 0 Africa Asia Pacific Eastern Europe/ Middle East Latin America U.S./Canada Western Europe Allowed/Acceptable Not allowed AND not acceptable Not allowed OR not acceptable 5 www.quintiles.com

The analysis found that 94 percent of tools and techniques are both allowed and culturally acceptable in the U.S. and Canada. Outside of those areas, we see some significant drops, such as only 78 percent allowed and acceptable in Western Europe and only 59 percent allowed and acceptable in Eastern Europe and the Middle East with the lower percentage being mostly driven by advertising and lost-to-follow-up services (see Figure 2). We also examined which tools and tactics were deemed both allowable and acceptable by region in 2012 and compared those numbers to those that were deemed both allowable and acceptable in 2014 to show the trend of acceptance (see Figure 3). Figure 3: Comparison of acceptance of tools and techniques, 2012 2014 However, in recent years acceptability of all tools and techniques is increasing across the board. 92% 82% 74% 79% 84% 94% 78% 58% 59% 61% 42% 14% Africa (n=1) Asia Pacific (n=14) Eastern Europe/Middle East (n=27) Latin America (n=10) U.S./Canada (n=2) Western Europe (n=12) 2012 2014 The investigation found that Asia Pacific s acceptance spiked 24 percent over the two years examined, from 58 percent to 82 percent. Eastern Europe and the Middle East, while still trending the lowest for overall acceptance, in fact showed one of the most substantial gains from 2012 to 2014. It moved the needle from 42 percent acceptance to 59 percent in the two-year period. (Note that Africa, while only one country was represented in our analysis, did show a significant increase mainly due to a number of techniques having been allowed in the past but not seen as culturally acceptable.) The analysis results also show that among tools and techniques, those gaining the highest increase in acceptance from 2012 to 2104 are patient- and site-facing tools (such as branded site awareness items, informed consent videos and physician referral advertising), while advertising/outreach (direct mail and call centers) saw the least (see Figure 4). 6 www.quintiles.com

Figure 4: Percent change of tools both allowable and culturally acceptable, 2012-2014 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% Poster Flyer Study/educational brochures Physician-to-patient letters and cards Informed consent flipchart (print) Informed consent video Site support tools Branded site awareness items Physician referral tools Physician referral advertising Pre-identification website or online pre-screening log Patient website with questionnaire Centralized call center Direct mail campaigns Email campaigns Pharmacy outreach Print advertising Radio advertising TV advertising Internet advertising Outdoor advertising Study guide Patient ID/emergency card Appointment/visit reminder card Patient disease education Appreciation/milestone items Figure 5 reveals the disparity in which different tools are allowable and/or acceptable in Eastern Europe and the Middle East. Each bar on this chart represents a specific tool or tactic within the category shown. From this, we see that advertising as outreach is the lowest across all of the various types. Figure 5: Percentage allowable and acceptable by tool or tactic in Eastern Europe/Middle East Advertising/ outreach Retention tools Patientfacing Sitefacing Lost-tofollow-up services 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% When asked which types of tools have been effective within their own clinics or institutions, 59 percent of investigators from the U.S. and Canada named posters or flyers. However, in most other regions, patient education materials are considered most effective. In both Asia Pacific and Latin America, investigators preferred study brochures (41 percent and 32 percent, respectively), and EMEA investigators named the informed consent form tool as most effective (36 percent). Interestingly, all regions named social media, such as Facebook, among the least effective tools, and email also received low marks across the board even within the U.S. and Canada, where we often presume these tactics to have the most impact. This indicates that while new tools may be building momentum, traditional tools still have the stronghold on recruitment effectiveness for now (see Figure 6). To recruit patients within their own sites, investigators from the U.S. and Canada indicate they have found posters or flyers most effective, while patient education materials were mentioned most often in all other regions. 7 www.quintiles.com

Figure 6: Most effective patient recruitment tools within investigator practice 60 59% 50 40 30 23% 24% 20% 20 10 0 48% Letter/postcard mailing 12% 14% 18% Email sent to patients 29% 34% 19% 28% 41% 34% 32% 51% 17% 12% 15% 42% Poster or flyer Study brochure Posting on clinic website 11% 8% 4% 24% Social media (e.g., Facebook) 36% 35% 24% 30% Informed consent form tool 19% 19% 15% 9% Recruitment tools not needed 3% 4% 6% 1% Recruitment tools not allowed Asia Pacific EMEA Latin America U.S./Canada When asked which methods have been most effective when recruiting patients from outside of their own practices on previous studies, 57 percent of investigators in the U.S. and Canada indicated advertising. This runs in contrast to every other region studied, where investigators indicated referrals from other physicians, and coincides closely to the percentage of investigators who feel they have adequate patients at their own sites and do not require external recruitment. Only 28 percent of investigators in the U.S. and Canada felt they had enough patients at their sites, compared with 33 percent to 42 percent in other regions (see Figure 7). Patient advocacy groups scored low in all regions, particularly EMEA (11 percent), and, with the exception of the U.S. and Canada, advertising was ranked low as well. Figure 7: Most effective patient recruitment tool external to investigator practice 70 65% Investigators in the U.S. and Canada indicated that advertising has been the most effective way to recruit patients outside of their practices, while all other regions indicated physician referrals are the top method. 60 50 40 30 20 10 22% 19% 18% 11% 24% 15% 20% 57% 54% 52% 51% 42% 35% 33% 28% 0 Patient advocacy group Advertising Referrals from our physicians Asia Pacific EMEA Latin America U.S./Canada I have adequate patient numbers at my site 8 www.quintiles.com

Patient retention has posed as much, if not more, of a challenge across biopharma as recruitment, which is why our survey also specifically examined retention preferences of investigators. The results showed that contact and reminder services and patient education were rated far superior in terms of effectively retaining patients than travel and meal vouchers and appreciation items (see Figure 8). Figure 8: Most effective patient retention tools by region 80 70 69% 71% 73% 59% 60 50 40 30 20 10 0 Contact/reminder services 31% 26% 27% 50% 65% 59% 72% 71% 46% 39% 49% Appreciation items Patient education Travel and meal vouchers 61% To retain patients at sites, investigators indicate robust patient education and contact and reminder services are more effective tools in all regions than vouchers and appreciation items. 4% 5% 4% 3% Not allowed Asia Pacific EMEA Latin America U.S./Canada Respondents reported that in all regions the most effective tools for reaching out to other investigators are physician-to-physician letter templates and physician-to-physician email templates. U.S. and Canadian investigators, at 49 percent, had strong preference for physician-to-physician letter templates; 39 percent of Asia Pacific investigators noted the same preference; and Latin America and EMEA preferred physicianto-physician email templates (44 percent and 33 percent, respectively). Websites again ranked among the least effective tools, with only 10 percent of investigators in EMEA and Latin America selecting them; however, it should be noted that in many regions, some of these tools may not have been utilized and evaluated (see Figure 9). Figure 9: Most effective tools for reaching out to referring physicians When reaching out to referring physicians, investigators report that traditional tools, such as letters and email templates, are more effective than non-traditional tools, such as websites. 50 49% 44% 40 39% 33% 36% 33% 33% 35% 33% 30 28% 28% 29% 27% 20 20% 18% 22% 23% 10 12% 10% 10% 10% 12% 14% 11% 10% 8% 9% 9% 0 Physician-to-physician letter template Physician-to-physician email template Brochure PowerPoint slides for medical meetings (e.g., lunch and learns) Website Referral tools are not needed Physician referrals are not common practice Asia Pacific EMEA Latin America U.S./Canada 9 www.quintiles.com

Conclusion We know that patient recruitment and retention strategies are not one-size-fits-all, and the insights we have discussed in this white paper can lead us to several conclusions about how, when and where to apply these tools and tactics to give a trial the best chance for success. In regard to patient recruitment and retention tools and tactics, the U.S. and Canada behave differently from other countries; this is likely due to the fact that most tools and tactics are not only culturally acceptable but also allowed by regulatory authorities. In the large majority of our analysis, the U.S. and Canada deviated from other countries we examined. We saw this in this region s acceptance of tools and tactics, choice of recruitment tools both within and outside investigators practices and preferred retention tools. We should be mindful that a U.S.-centric approach to recruitment may not always be appropriate and/or optimal. The importance of a locally tailored strategy cannot be underestimated. This broad investigation into cultural acceptability and investigator preferences reinforces what we have long known: a tool or tactic that flourishes in one region may be ineffective in another. Advertising, which has high investigator support in the U.S. and Canada, has much less support in more emerging areas of research like Eastern Europe and the Middle East, where patients are seeking two-way communication from physicians. We must tailor our recruitment and retention strategies through the lens of regional preference and acceptability in order to ensure we are communicating with patients in the best ways possible to give our trials the best chances for success. Tech-based tools, like websites, are on the rise, but traditional tools still dominate. Although we are seeing increasing acceptance of all recruitment and retention tools examined, traditional tools are still the most effective way to reach and retain patients in nearly every region. Our tendency may be to leverage websites and social media for their seeming efficiency at reaching high volumes of patients quickly, but some patients across the globe may not yet fully embrace these tools. With this data, we have a true global cultural awareness that enables us to develop an even more targeted recruitment strategy for each study we manage. Patient recruitment and retention is a key part of the Quintiles Right Start offering that leverages our extensive experience, tools and processes to optimize study start-up. By strategically applying the right patient recruitment and retention techniques, we can help improve trial execution success and ensure that patients know about their available options for participating in clinical trials as part of their care. 10 www.quintiles.com