Bringing Patient recruitment and retention; A ...

Bringing Patient recruitment and retention; A revolution to Clinical trials – eBook Dr.Sreedhar Tirunagari, Dada Hayath Shaik, Anil Golani

Introduction: Over the last few years, clinical research departments have incurred worsening delays in conducting clinical trials. Nearly 80% of trials fail to meet milestones, thus delaying the delivery of potentially life-saving drugs to market. Operations professionals are constantly expected to improve efficiency and productivity, to deliver cost-effective studies to deadlines and within budget, while maintaining quality and ethical standards. A recent study from Cutting Edge Information* showed that average clinical trials overrun across all therapeutic areas and phases, mainly because of patient enrollment: some sites never manage to enroll a single patient; even worse, others wait a long time and eventually recruit one patient but still have to expend time, resources and supplies until the patient completes the study or withdraws. (Data from Covance Xcellerate® Knowledge base provides a breakdown of nonperforming sites per therapeutic area, with Oncology showing 60%) Selecting under-performing sites leads to delays in patient recruitment, adding an average of 10.8 months to every trial. If you multiply this by 30 trials per pharmaceutical company, the annual cumulative loss reaches a staggering 26 years per company! (Beasely, “Recruiting”. 2006) These delays affect not just study costs but subsequent sales, causing potential losses of $600,000 to $8 million per day, according to a recent CenterWatch study.** Enrollment delays cost pharmaceutical companies $8 million each day a study is delayed, according to a recent report from Cutting Edge Information. These delays are normally due to recruiting patients into the trial. According to the Center for Information and Study on Clinical Research Participation, missed enrollment deadlines extend phase I studies by 42% on average, while phase II and III studies last 31% and 30% longer, respectively. Achieving clinical trial research participant enrollment is essential to conducting a successful trial. Adequate enrollment provides a base for projected participant retention, resulting in evaluative patient data. Without sufficient patient retention from the time of study initiation to closeout, the number of remaining participants may prove to be too small a pool from which to derive conclusive proving or disproving the goal of the clinical trial sponsor. Obtaining final evaluative data is dependent on successful patient and principal investigator retention. Patients cannot be retained without an initial pool of enrolled volunteers. This initial pool of screened, then enrolled participants, depends on designing sound strategies for patient and investigator recruitment

PATIENT RECRUITMENT AND RETENTION-BOOK

In this Book, we discuss the common issues encountered in recruiting patients for Clinical trials. It is intended for anyone conducting Clinical trials, including medical students, residents, and junior and senior researchers. You will understand on sequence to be followed from developing a protocol through recruiting participants to closing the trial and analyzing the results for a Protocol .As you go through each chapter you realize the importance of Various steps involved in patient recruitment and retention for a Clinical trial. You can find various strategies, resources and tools considered at each step in the following chapters. By the end of this Book, readers will be able to develop strategies to avoid some of the common pitfalls in recruitment like Develop an effective recruitment strategy that encompasses innovative methods to reach project goals and integrate protocols · Determine patient recruitment feasibility Understand where to plan-out and implement recruitment methods that best meets the study needs · Discover approaches to recruiting special populations: minorities, specific age groups and rare diseases Recognize practical and proactive strategies for preventing drop outs or lost to follow up subjects · Incorporate patient experience management ,education plan and technology (ePRO) to improve retention Leverage social media and new channel opportunities to promote awareness, communication and enrollment Identify and understand methods to overcome common problems to getting programs off the ground · Investigate current ethical, safety and regulatory considerations

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Chapter 1: During Development of the Trial Recruitment strategies: Study protocol phase: It is at this stage of the trial that the issue of recruitment needs to be considered and addressed carefully. This section highlights the key elements in protocol development that directly affect patient recruitment in Clinical trials. Successful clinical trial patient recruitment begins at the protocol writing stage. Beyond the scientific merit of a proposed clinical trial, protocol developers should think carefully about how the field as well as potential participants might receive the trial. In developing a protocol, consider competing trials, the availability of the study population, and ways to reduce the study burden on sites and participants. How much interest do you expect to find for your trial among your colleagues, institutional leadership, and researchers across the country Evaluate the level of scientific interest in the trial from the field and from the institution by analyzing the level of interest in the protocol as it varies from a community or academic setting. Discuss your idea at the institution and using what you learnt from conferences, journals, and online communities to form an opinion about the level of scientific interest. Evaluate the level of commitment from the field and your institution with an eye towards trial feasibility With not only investigators enthusiasm about the science behind a trial, but also to consider other factors that such as the lack of staff or funding, or even a participant population that differs too greatly from the needs of the trial. Check for competing trials at the institution and nationally whether other relevant research is underway, either funded by a grant or sponsored by a pharmaceutical or biotechnology firm. Also check within the institution and with other institutions to see what trials open or planned, are related to the study topic you are considering as Competing trials are especially problematic for research on rare types of diseases. Key points to be considered during recruitment feasibility Use feasibility studies to test recruitment strategies. A feasibility study compiles quantitative and qualitative data to illuminate issues that can affect recruitment. Such studies are of particular use for larger Phase III trials. Research teams should use feasibility study findings to guide choices related to study design and site selection that aid the recruitment potential of the study. Determine the availability of the study population at the institution and country by reviewing the incidence and prevalence of data nationally and at the institutions, Find for institution’s data systems to determine the number of potentially eligible participants. Assessment of how proposed

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inclusion/exclusion criteria will affect recruitment. See for overly restrictive eligibility criteria which would be a recruitment barrier.KOL opinion to broaden the study criteria without sacrificing the outcome. Study sites should consider these questions when selecting and preparing to open a Trial. And also to assess and minimize the study burden on patients by viewing the trial through a participant’s eyes. How “burdensome” is the research? Consider such questions as: “How much time away from home is required?”, “How many blood draws?”, and “What protocol costs are not covered by insurance?” Choose study sites carefully Evaluating the recruitment histories of potential sites, by site’s past performance can predict future success. Ask about each site’s capacity to recruit and carry out the trial. For example, you may need to discuss workspace, committed staffing, and lab and pharmacy needs. Ask the sites what study needs would cause difficulties at their site and determine if those can be overcome. Determine the available resources of potential sites (e.g., staffing or facilities) Look at the potential sites’ competing trials by enquiring prospective sites about existing trials that may compete with your trial for participants and resources, and how they propose to handle the situation. Prepare trial-specific materials Prepare participant-friendly informed consent document, Create trial-specific materials for participants, like brochures and fact sheets help participants understand the trial and talk about it with family and friends. Other materials like newsletters and Badges can be tangible tokens that show participants they are part of something meaningful. Always keep trial-specific materials participant friendly and balanced when describing the costs, benefits, and goals of the trial. Note: Ensure that materials are culturally appropriate.

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Chapter2: Selecting and Preparing to Open the Trial Where and which Site to be opened for clinical trial •

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Evaluate Site’s clinical trial Infrastructure and participant population. Confirm that the trial’s scientific question is relevant and of interest to the institution, Gauge the level of interest about whether the trial is important and salient to the organization’s goals and the needs of its patient population. Look at organization’s research as a whole- both basic scientific as well as clinical research. Evaluate whether the trial further works in a relevant area. Also, look at institution’s open trials and evaluate whether the proposed trial fills a gap or helps you offer patients a fuller spectrum of trials. Importantly, checking for competing trials. Verify that there are no conflicts of interest in this trial Find out about any conflicts of interest early. Ensure that the trial matches patient population, Review databases and what you know about the community, Determine whether the institution sees enough potentially eligible patients or can identify and reach sufficient numbers to meet recruiting goals in a timely way, Ask the institution has succeeded in recruiting to similar studies in the past. Assess the financial burden the trial will place on participants. Explore what expenses will be covered by the trial sponsor, private insurance or Medicare, and what the out-of-pocket costs will be to participants (e.g., travel expenses and meals). Determine the level of study burden on participants and their support systems. Ask the Site staff whether they think these burdens (e.g., blood draws, overnight stays, or unpleasant medical procedures) are within reason for study participants

Assess institution’s infrastructure and resources •

Ask questions to understand operational issues such as scheduling and resources by obtaining feedback on the trial from key staff In terms of protocol requirements, from nurses, research coordinators, pharmacy, and lab.

Ensure stakeholder commitment • •

Consider all the stake holders opinion involved in implementing the trial by addressing the recruitment, retention, and any other difficulties that may be involved in future. Ensure stake holders to make understand that clinical trials are central to the organization’s culture which shows potential participants that trials are routine, helps staff understand how their contribution furthers progress against Diseases, and thus increasing enrollment in trials.

Plan internal processes to conduct the trial

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Prepare a start –up check list that ensures all staff, materials, and required tasks are covered, Plan trial logistics, scheduling, Dedicate staff and budget to recruitment in the beginning Work with insurance companies and get ideas and suggestions from the institution’s specialists such as the billing office to help in planning ahead for how participant costs will be covered Capitalize on IT systems or appropriate software to automate trial activities such as identifying and tracking eligible participants

Write a comprehensive recruitment and retention plan Integrate recruitment and retention plans with institutional activities. By setting up a system to identify potential participants: Prepare site-specific trial promotional materials for potential participants Address diverse and underserved populations Include plans for community outreach Include plans to work with referring physicians. Set milestones, metrics, goals, back-up plans which should be included in trialspecific Evaluation Plan. Determine methods for tracking patient recruitment progress. Set patient recruitment performance thresholds (e.g., time from trial opening to first participant enrollment)

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Chapter 3: Identifying the target Clinical trial participants At this stage, it is vital to continue to be thoughtful about participants, staff, and those in the community with access to participants such as physicians and partner organizations. Use good communication skills (like being participant-friendly) and habits (like keeping referring physicians in the loop) Engaging intermediaries to aid Patient recruitment Assure that plans to reach referring physicians are being executed by Checking to Recruitment and Retention Plan and think about how well the ideas are being executed. How effectively is the team keeping referring physicians informed about the trial and its value? Assure community outreach plans are being executed. By determining how well the community outreach ideas defined in Recruitment and Retention Plan are being executed. How effectively are they working with partner organizations? Pay particular attention to whether the outreach efforts reflect the community’s diversity. Share information with Advocates who value the trial in reaching potential participants and engage them early and often during the trial. Engage patient navigators who can find ways around barriers—which can greatly help patients reducing fear and stress for participating in Clinical trial and clinical research staff who are navigating the requirements for a trial.

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Tracking of potentially eligible participants •

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Sites information system is an obvious starting point for identifying potential clinical trial participants. No matter which tools you use, it is important to know all the potentially eligible participants are being identified. Follow up with potentially eligible but non-consented individuals. Keep track of individuals who are potentially eligible, but have not yet consented. Assure that they are undergoing work-up to confirm eligibility, and that any outstanding questions or concerns are addressed. Identify and report on participant non-adherence indicators.

Engage participants in the Informed Consent Process •

The two-way communication flow that helps participants feel comfortable and informed when originally joining the trial should continue throughout the study. Use plain language, Participant-friendly materials, Present the trial in a culturally appropriate manner, Seek the help of translators when needed, Emphasize on the key role of the physician presenting the trial, Present the trial in a balanced manner—both pros and cons, Provide continued support as people consider their decision to participate and continue on the trial.

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Manage communication of screening results and failures. As participants, and their primary care providers, require communication about both successes and failures. Thoughtful communication can help keep open the possibility of future trial participation. Be aware of and monitor regulatory issues such as HIPAA regulations. Regulatory and IRB issues can be fluid, so it is important to keep on top of potential changes that may be occurring, both at the site and on a country level.

Consider participant financial issues •

Establish relationships with insurance companies, to facilitate coverage .Minimize insurance surprises by tracking past trial coverage and getting expert advice from Sites billing office, Insuarnce companies. Find ways to include eligible participants who have inadequate or no insurance coverage for the trial .Work with specialists (Billing officers at the Site, Third party insuarance Vendors etc) to identify alternative financing if a potential participant has no insurance.

Maintain the morale and interest of staff, participants and their families •

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Keep in touch with participants on trials (e.g., through newsletters or reminders). See which among the different ways (newsletters, email, small branded items etc) will work best for participants. Suggest support groups, participant networking, lists of local and online support resources making it easy for participants to get the support they need. Conduct satisfaction surveys with trial participants for obtaining thoughtful feedback to learn what is helping and not helpful for recruitment and retention. Acknowledge and celebrate successes while also supporting any staff who needs help. Reward staff for following the recruitment and retention plan and for spotting surprises and eliminating barriers. Regularly update staff on trial patient recruitment. Talking about accrual helps clinical trials and recruitment to be a part of the normal daily work. In addition, being open about how a trial is accruing will help you gain the insights of others in solving problems. It also helps keep team members and leadership from feeling unpleasantly surprised if accrual goes poorly.

Update participants regarding study related events and results •

Keep contact lists current and note the best way to communicate with individual participants .Monitor media regularly and have a plan in place to respond to trial-relevant media stories (to participants, to the media, and to stakeholders).Have a plan for notifying participants/families, staff, and stakeholders if the trial is put on hold or closes unexpectedly by updating participants in a timely fashion.

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Chapter 4: Managing the Trial Implementing the Trial By using a written Recruitment and Retention Plan, the team will be well-prepared to manage recruitment, retention, promotion, and evaluation activities as well as quickly spot and respond to any major change or recruiting difficulty. A. Implement strategies as determined during pre-initiation phase of plan B. Assess eligibility of individual potential participants Begin supportive relationship with participant Consider non-compliance and retention potential a) Exclude participants unlikely to comply and stay on study – unless you can provide compensatory support and follow-up (1) Known history of non-compliance (2) Socially unstable (3) Expressed difficulty with, and numerous objections to, protocol requirements (4) Cavalier attitude toward protocol (5) Verbalized a minimization of cancer risk (6) Verbalized desire for “active drug only” C.Explore participant’s objections to enrollment 1. Clarify any misconceptions 2. Offer to resolve manageable logistical problems 3. Consider multiple objections as red flag indicating possible retention/compliance problems D. Involve participant’s social network in decision-making E. Continuously evaluate strategies as planned during pre-initiation phase i. Monitor and document task completion for timeliness 1. Regulatory requirements 2. Weekly meetings 3. Meeting minutes ii. Evaluate and document strategies and outcomes 1. Track results of each strategy: number of participants enrolled in a defined time period 2. Maintain screening/enrollment log forms with attribution to specific strategy and reasons for ineligibility, or non-enrollment 3. Calculate cost of enrollment per participant 4. Survey of participants’ opinions re: strengths and weaknesses of strategies iii. Rapidly implement modified or alternative plans if recruitment is lagging 1. 2.

Communicate regularly with stakeholders and referring providers

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Regularly communicate the trial’s accrual status to key staff/stakeholders (referring physicians, community partners, and others positively engaged in Patient recruitment) and seek feedback. It is always better to talk about recruitment difficulties when they are first detected and potentially easier to solve. Monitor trial progress and accrual metrics Monitor recruitment and retention plan activities (impact of operations and logistics on trial accrual, screening data for diverse and underserved populations, promotion activities, tracking, evaluation goals, objectives, etc) and adjust when necessary. Review trial accrual indicators against expected performance. This activity is a reminder to specifically check accrual performance as outlined in the Evaluation Plan and to use the data to make accrual performance judgments. Regularly assess the trial’s costs against its budget. Implement alternative recruitment strategies when accrual milestones are not achieved Retention and adherence phase – Be proactive A. B.

A. Maintain communication with referring physicians re: participant progress B. Establish and maintain rapport among staff during follow-up 1. Newsletter 2. All-site teleconferences 3. Buddy system among coordinators 4. Adequate staff compensation 5. Staff recognition/awards 6. Clinic non-protocol staff recognition

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C. Establish and maintain rapport and communication with participants 1. Identify and track red flags for possible attrition a) Adverse effects b) Missed appointments c) Frequent appointment time changes d) Major personal or family events e) Health deterioration f) Loss of support system g) Do not promise support that cannot be maintained 2. Adverse effects (AEs) a) Inform patients as to what to expect b) Have prepared AE management protocol 3. Maintain current contact info 4. Enlist support of participant’s social network a) Transportation Page 10 of 26


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b) Encouragement c) Agent compliance Provide compensation for expenses incurred as budget permits a) Parking b) Time lost from work c) Transportation d) Child care Ensure pleasant clinic visits a) Limit waiting room time b) Coordinate assessments (e.g., blood work, imaging, etc.) with visits c) Provide refreshments d) Flexible scheduling e) Toll-free numbers Ensure consistent staff contact person and access to PI Establish schedule for contact with participant Consider retention tools a) Calendars b) Newsletter c) Appointment reminder cards and calls d) Anniversary cards e) Certificates of appreciation and appreciation f) T-shirts, mugs, magnets g) Buddy system h) Support groups Track participant withdrawals and reasons for withdrawal

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Chapter 5: Lessons Learned in Participant Recruitment and Retention Analyze the trial’s accrual data for lessons learned Review accrual data and discern lessons learned to improve future trials. Analyze the data to see how realistic your accrual goals and actions for the trial were Report and share accrual experiences with others Prepare and submit a summary of trial-specific accrual findings and lessons learned to key stakeholders. A. B. C. D.

Review study recruitment and adherence data from all tracking documents Discuss lessons learned with team Document lessons learned Consider submitting manuscripts for publication 1. Successful strategies 2. Lessons learned

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Chapter 6: Patient recruitment Emerging Regions of the World

Formerly known as the “Third World”

BRIC: Brazil, Russia, India and China South-East Asia: Korea, Malaysia, etc. Other countries in South America Eastern Europe: Poland, Romania, Ukraine, Serbia Africa (only for a few indications)

Emerging Regions are Pooled for a Reason

Similar health-care infrastructure Similar patient pools Similar economic conditions Similar history of clinical trials Similar political and business environments Similar access to resources

Role of Emerging Regions in Meeting Recruitment Goals

Few trials Few investigators and sites (but rapidly increasing) Relatively limited availability of Western standard of care Large treatment-naïve patient pools High rate of patient compliance Patients in dire need for standard treatments “Few” regulatory hurdles (case-by-case) Business friendly environment Future markets

Common History

Most clinical trials were Government funded and supported Since at least 25 years Mostly at govt. hospitals Mostly on collaborative projects with other governments Few Regulations Private-funded research mostly started in the last 10 years, at most. Mostly multi-national corporations Mostly large multi-national CROs Indigenous CROs with limited experience

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Perceptions

Reduced Cost Per patient cost Data management Trial management Reduced Time Rapid recruitment All indications Friendly Regulatory Environment Easier approval Faster than US/EU Less restrictive than US/EU

CEE and Russia. This region has one of the highest patient-recruitment rates among emerging regions (Platonov 2003). In many CEE countries and Russia, a primary factor in this rapid patient enrollment is the centralized healthcare systems. Because of centralized healthcare patients are separated into specific disease groups and are primarily treated in major hospitals, providing access to large subject numbers. Among the fifteen CEE countries, currently ten are European Union (EU) member states. The most dominant CEE countries in clinical research include many countries that have recently joined the EU, such as the Czech Republic, Poland, Hungary, Romania, and Bulgaria. All EU member states follow the EU Clinical Trials Directive which was designed to harmonize clinical research practices for subject recruitment and improve patient protection, while aligning clinical research conducted in the EU with international standards. Many CEE countries that joined the EU more recently are at different stages of implementing the Directive. The requirements for initiating clinical trials in CEE are less well defined than in Western Europe (Motteram and Richardson 2004). For example, there may be undocumented requirements and additional regulations that must be met in parallel with the usual clinical trial approvals. Most CEE countries complete approvals within 60 to 70 days (Getz 2007), and in addition to the national Ethics Committees, there are local committees in many major medical centers. However, no two countries have the same review process or evaluation procedures for IRBs. In Bulgaria, for example, the local Ethics Committee of the respective clinical site approves clinical trials, and approval by the Ministry of Health may take an average of nine weeks. In the Czech Republic, regulatory approval by the Ministry of Health takes up to two months, and both a local Ethics Committee (in major healthcare facilities) and the Central Ethics Committee (established by Ministry of Health) approve clinical trial applications. In Russia, the Ministry of Health issues approval which usually takes up to two months. Clinical trial applications are also reviewed by

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the National Ethics Committee, which requires another month. (Kordab 2006). Currently, the European Union member states are striving to harmonize their regulatory approval procedures. After several CEE countries joined the EU, many CEE physicians proficient in English left to pursue better work opportunities in Western Europe. As a result, the number of investigators proficient in English has decreased. Furthermore, according to a 2006 European Commission survey of English proficiency among EU citizens, proficiency in CEE is reportedly lower than in Western Europe. This means that English proficiency is also lower among patients in CEE. According to the EU Directive, all patient-related materials including informed consent must be translated into the patient’s own language. In addition to the language differences of CEE countries, each has a unique culture which must be taken into consideration. CEE and Russia also have common cultural factors that affect clinical research. For example, the patient-physician relationship in the United States is such that patients are more likely to question their physician’s recommendations (only one-third of patients enrolled in U.S. clinical trials result from physician referrals (Kremidas 2007)). In contrast, in CEE and Russia, the majority of patients are motivated to participate in clinical trials solely by the influence and encouragement of their treating physicians. There is a strong relationship of trust that exists between the patient and physician in CEE and Russia, in addition to a high regard for doctors in general. According to Natalie Gershman, CEO and medical director of Geny Research, a Russian-based CRO in Moscow, this relationship significantly helps to increase subject enrollment and retention rates, and improves patient compliance (2008 interview with Language Connections). That many patients have not had the chance to benefit from the most recent advances in medical care is another factor which affects patient enrollment in CEE and Russia. Participation in clinical trials therefore provides an opportunity to receive the latest medical treatments for their disease. Latin America. Argentina, Mexico, and Brazil, which currently have the most established regulatory environments in the region, conduct the largest number of clinical trials. The majority of patient populations in these countries reside in highly populated urban centers, which greatly facilitates recruitment. In most Latin American countries, the approval times from the Ministries of Health range from 30 to 90 days. Mexico and Brazil continue to have the lengthiest approval times (Gambrill 2006), although both governments are committed to improving the situation. Approvals from the majority of Ethics Committees or IRBs typically range from 30 to 60 days (Glancszpigel 2003). Most Latin American regulatory bodies are working to shorten their approval times. Furthermore, recent government support in many countries has led to regulatory reforms and increased compliance with international clinical research standards. In most Latin America countries, clinical trial documents must be translated into Spanish, with the exception of Portuguese in Brazil. Most investigators are proficient in both Spanish and English. However, among patient populations English proficiency may be low, and differences in

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spoken Spanish exist because of influences from the dominant native and immigrant groups in each country or geographic region. The differences between countries in Latin America, as well as local regional differences within each, must be considered separately. For example, Argentine Spanish has certain linguistic distinctions from other Spanish-speaking countries such as Mexico because of cultural differences (ie. the use of voseo in Argentina versus tu in Mexico). Pronunciation and local native culture in Mexico City is different from those in Mexico’s Yucatan Peninsula. Although these are primarily spoken differences, some linguistic and cultural differences must be considered for their effect on patient recruitment and informed consent procedures. Other factors that compromise informed consent procedures and affect patient recruitment in the region are poverty and illiteracy. In order to improve patient protection, some countries have increased requirements. For example, in Mexico it is common for subjects to sign a second informed consent form that is written in simpler language and includes the signatures of two witnesses and their relationship to the patient (Fiuza 2006). Taking into account patient differences in literacy, as well as regional variations in spoken Spanish, further ensures that patients’ rights are adequately protected. The emphasis on family in Latin American culture and family decision making on medical treatment must also be considered. Like patients in CEE and Russia, patients in Latin America do not often question their physicians’ recommendations. As 80% of subjects in Latin America are offered enrollment by their physician, this greatly influences their decision to enroll in clinical trials (Fiuza 2006). In addition, economic factors play a significant role for many patient populations in Latin America, as many patients have no other treatment options available to them. India, China, and Southeast Asia. Among the Asian countries most prominent in clinical research, South Korea and Singapore currently have the most efficient and predictable systems for regulatory approval. For example, the process in South Korea is so streamlined that approval by the Korea Food and Drug Administration (KFDA) can be completed within one month. The IRB approval occurs in parallel, further facilitating the process. In Singapore, the average regulatory approval period is four weeks, followed by an additional four to six weeks for site-level IRB/Ethics Committee approval. Although both China and India have recently become primary offshoring locations because of their extensive recruitment capabilities, their regulatory approval times differ greatly. China currently has the longest approval time in the region (and possibly in any emerging country), up to nine months, because clinical trial applications must pass through six regulatory approval bodies. In India the average time for regulatory approval is 10 to 16 weeks. The approval process with local Ethics Committees at the site level occurs in parallel, facilitating the initiation of clinical trials (Varawalla 2006). Although English is considered a second language in the majority of Asian countries involved in clinical research, many of the less-educated subject populations have limited proficiency in the

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language. Despite the prevalence of English in India, for example, English proficiency is low among many clinical trial subjects, and several other languages such as Hindi are dominant among much of the population. In China, low English proficiency among the majority of Chinese subjects is an even greater issue. In addition to Mandarin Chinese, there are several other secondary languages. The proficiency among investigators is less an issue, as both China and India have an increasing number of well-educated scientists who are proficient in English. However, in China, many investigators often record data in Mandarin, resulting in delays due to translation time. China’s rapid recruitment rates due to a large patient pool, centralized healthcare institutions, and highly successful recruitment based on physician-patient communication compensate for the lengthy approval process and translation requirements (Bailey et al. 2007). Although they have been found to be less effective, posters and fliers in waiting rooms at accredited clinical trial sites are also common (Anderson 2007). In India subject recruitment through patient education and advertising is more accepted. Despite concerns regarding India’s ethical and clinical research standards, the country’s increasing role in clinical data management outsourcing has resulted in a better overall environment for clinical research (Bailey et al. 2007), and some projected data indicates that by 2011 India will be conducting more than 15% of the total global clinical trials (Research and Markets Report 2007). In accordance with the culture in many Asian countries, it is considered less acceptable for physicians to disclose a patient’s complete diagnosis, particularly in the case of terminally ill patients. As a result, physicians often only partially disclose potential risks to study participants. Family hierarchy also plays a major role. The more-senior family members, particularly males, are generally responsible for making decisions about medical issues. In most Asian cultures, the patient-physician relationship is different from that in Western cultures. Recommended participation in clinical trials is more widely accepted than in the United States, which facilitates patient recruitment and retention rates, and improves patient compliance. In India, China, and several other countries in Southeast Asia, economic factors and access to medical care also play a pivotal role in patient recruitment.

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Chapter 7: The Role of Social Media in Clinical Trial Recruitment Social media comprise a number of online and mobile resources that provide a forum for the generation, sharing, and discussion of individualized ideas and content. Social media are commonly defined by specific applications and/or Web tools, most of which are widely accessible and free to use or available at minimal cost. These applications may be categorized by purpose, including such functions as professional networking (LinkedIn, Doximity), social networking (Facebook, Google+), recommending/filtering (Yelp, Delicious), media sharing (Flickr, YouTube), content production (blogs, Twitter), knowledge/information aggregation, and locationbased services (Foursquare), among others. (1) When integrated into health communication campaigns and activities, social media can encourage participation, conversation, and communities—all of which can help spread key messages, influence decision making, and promote behavior change. Social media also helps to reach people when, where, and how it’s convenient for them, which improves the availability of content and might influence satisfaction and trust in the health messages delivered. Social media is also a key tool in building awareness and credibility Advantages Raising awareness at no cost – Unlike expensive television, radio or print campaigns, geo-social networking is often entirely free of cost and typically requires minimal routine maintenance. If someone checks-in at your site, it’s essentially a free endorsement from a trusted source. Information spreads instantaneously – Like all social media networks, geo-social check-ins have the potential to reach out to hundreds or even thousands of individuals. Users who check-in often have the option of syncing their accounts with other social media such as Twitter or Face book Feeds, so the information is being spread very quickly across multiple social media applications. Detailed demographic data – Users that check-in are tracked and analyzed by demographics such as age and gender. Foursquare specifically, even provides social reach statistics i.e., how many people have sent their check-in to Facebook or Twitter feeds. Principles of Effective Social Media Writing Creating Content It’s easy to get wrapped up in the technology when talking about social media, but flashy tools alone won’t make a campaign effective—good content does. Social media content should be

o o o o

Relevant, useful, and interesting Easy to understand and share Friendly, conversational, and engaging Action-oriented

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Social media is most effective when the content relates to a particular interest or desire of a specific group of people. Because your target audience can receive multiple messages from multiple sources every day, try to make your messages relevant, useful, and interesting so your audience will interact and be engaged. Relevant Relevant social media content makes people think “This matters to me.” Relevant information can be based on

o o o o

Time Geography Audience Interests

Useful When people can use social media information to see their lives in new ways, change behavior, or learn something they didn’t know before, it’s useful. Make information useful by suggesting practical steps or citing convincing statistics or report findings.

Interesting To capture a reader’s attention, create content that piques curiosity. Interesting social media content is more likely to be shared. Of course, content should always be professional and relevant to a health topic.

Social media can now be viewed as a valuable communication channel that should be considered when developing clinical research recruitment strategies. This was reinforced in a recent survey from Industry Standard Research, where respondents from biopharmaceutical companies overwhelmingly reported that the internet and social media had the biggest positive effect on patient recruitment and had the capability to demonstrate higher value than traditional promotional channels.

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Chapter 8: Use site-management organizations In the past several years, site-management organizations have begun to use patient-recruitment campaigns to accelerate enrollment. The ability of site-management organizations to leverage a centralized process already in place enhances their efforts to continually publicize their site and constantly search for patients. "Site-management organizations, especially those that are therapeutically organized and centrally managed, are an excellent resource to clinical research," Mr. Sturgis says. "Site-management organizations have the staff to handle centralized recruitment for their sites. Since site-management organizations exist for the purpose of research, they understand that increased patient flow and recruitment assistance will help their business." With pharmaceutical companies moving into new therapeutic areas, the ability to get on good terms with an experienced clinical site-management organization could mean the difference between a successful six-month Phase II trial and a long, difficult two-year Phase II trial that fails to meet its desired endpoints. "They play a very critical role," Mr. Bogan told R&D Directions. "Most big pharmaceutical companies use contract research organizations; others may use patient-recruitment specialists. There is a host of specialists out there, and those specialists play a very valuable role. In our studies, we found that in certain areas, contract research organizations have evolved to a more advanced stage than some of the pharma sponsors." Experts caution that site-management organizations can be costly and should be used only when sponsors do not have access to the specific area. Companies should develop long-term relationships with site-management organizations. If the right connection is made, the role of a site-management organization in patient recruitment and enrollment can be magnified. "Sitemanagement organizations can help a sponsor find the right sites," Mr. Tyson says. "If sponsors are entering a new therapeutic area and they do not have a lot of connections, the management organization can instantly set up those sponsors and get them going." Site-management organizations can be useful when time is short, the marketplace is unknown, or the therapeutic area is relatively new either to the organization or to the leader of the study. Site management organizations can get feasibility questionnaires distributed and answered much faster.

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Appendix

Factors considered for Successful Patient Recruitment Protocol Design Protocol consistency • Study duration and visit schedules • Nature, number, cost and complexity of study procedures • Number, complexity and restrictiveness of eligibility criteria • Ethical and regulatory considerations and approvals for all participating countries • Sample size requirements and timelines • Realistic enrollment goals • Study value to sites and site execution difficulties • Standard(s) of care and current therapeutic options • Drug supply and availability • Safety profile of compound • Data collection requirements and procedures • Investigator, study coordinator and subject feedback on study design to incorporate and balance scientific and practical aspects

Investigative Site Selection • Sources of potential investigators • Site interest, enthusiasm and buyin to study design and rationale • Site experience (clinical research and therapeutic area) • Site staffing, resources, workload and time commitments • Site personnel skills and abilities • Staff turnover rates • Functional responsibilities of site personnel • Access to subject population with the required eligibility criteria • Subject diversity requirements • Technical facilities and equipment • Computer savvy and accessibility • Subject-friendly facilities and customer service approach of staff • Reasonable and fair study budgets • Ethical review committee policies and procedures • Institutional legal procedures • Site training and standard operating procedures • GCP compliance and inspection (audit) history • Past enrollment performance metrics • Flexibility of clinic hours • Role of key opinion leaders • Country allocation requirements and procedures • Site source document and data collection procedures • Site security and storage facilities • Site selection decision making process • Role and accountability of CRA in managing site and subject enrollment

Subject Recruitment Disease prevalence and incidence • Real effect of eligibility criteria on subject availability • Competing studies • Subject motivations and barriers • Sources of influence on study participation decision making • Language and cultural issues • Subject diversity requirements • Healthcare system and referral / treatment approaches • Subject and family / caregiver compliance • Sources of potential subjects • Recruitment, subject education and retention tactics and strategies • Recruitment / retention budget • Materials development and approval process and timeline • Privacy regulations and protections • Subject compensation

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Patient Recruitment & Retention Planning Tips WHO…is the target audience? WHAT…would motivate them to participate in this trial? WHAT…are the barriers to study participation and how will these be addressed: o Protocol-related barriers o Investigator (site)-related barriers o Subject-related barriers o Other barriers WHAT…is the competitive landscape? HOW…many competing trials are there that may impact enrollment? WHAT…are the regulatory and scientific issues that may impact perceptions about the product and ultimately influence a subject’s willingness to participate in the study? WHAT…are the characteristics of an ideal site from a subject recruiting standpoint HOW… many subjects do I need and in WHAT timeframe? WHERE… will they come from? WHO / WHAT…is a potential source for study participants? WHAT…will be done to identify and attract subjects into the study? HOW…will the potential participants learn about the study opportunity? WHAT...tools and methods will be used: o To raise awareness about the study? o To enhance or supplement the informed consent process? o To ease the burden of study participation (from the subject, family member, caregiver perspective) o To ensure sites and subjects understand and comply with all the study procedures and drug dosing requirements? WHAT…approvals are needed for the strategies? HOW…long will it take for the materials to be developed, approved and produced? WHEN… will the strategies be implemented? WHO…will implement the plan? (WHAT…resources are needed to implement the plan)? WHEN...should you consider the services of a specialized patient recruitment and retention service provider (PRSP)? WHAT…will it cost? WHAT…questions will the subjects have and how best to respond to these questions? WHO…at the site is best equipped to address the subject concerns and • HOW…should they be trained in subject communication skills?

“A to Z” resources for Patient Recruitment A • “Ask me about research” I • Indian Health Service R • Radio advertising buttons and • Internet listing, • Referring physicians and badges Clinicaltrials.gov., healthcare • Advertisements (all types of CenterWatch, etc. practitioners media) • Interviews with health • Religious organizations • Advocacy groups reporters • Respiratory Therapists • Airport advertisements J • Journals, scientific • Restaurants and placemats • Allied Health Professionals publications on • Restrooms • Ambulatory care centers results of earlier phase trials S • Sandwich boards • Awareness programs, to with the • Scheduling flexibility inform the public investigational drug • School nurses of alternatives for treatment K • Key opinion leaders, to • Senior centers B • Brand-name for clinical give credibility • Service organizations

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trial, to create recognition and association to the trial • Brochures • Bus advertisements • Blimp ads • Broadcast on local TV public affairs shows • Billboards • Bulletin boards C • Call centers, to support media campaigns • Canvass college campuses; • Chamber of commerce • Chart reviews • Church organizations • Coffee shops • Community centers • Concert venues D • Database searches • Dear subject and dear doctor referral letter templates • Dinners for area physicians • Direct mail • Durable medical equipment (DME) stores E • Educational Materials, for both subjects and site personnel • Educational seminars • E-mail alerts and reminders • Emergency Medical Personnel • Emergency rooms • Employee health clinics • Employer “Brown Bag” Lunches at area employers • Endorsement by the local community

to study • Kiosks (hospitals, colleges, etc.) • Kits with recruitment materials L • Laboratories • Laminated pocket cards with inclusion/ exclusion criteria and study flowchart • Leaflets • Letters to potential subjects to investigate interest in study participation • Libraries M • Magazine ads • Malls • Marketing research, to identify regions with high incidence of disease and prescribing patterns • Mass media campaigns • Mass transit advertisements • Massage therapy clinics • Media spots • Medical society mailings • Men’s health clinics • Minority outreach programs • Movie theater ads • Multilingual materials and site personnel N • Newscast – study can be featured during the evening news’ health segment. • Newsletters, both investigator and subject on status of study • Newspaper advertising • Nursing homes O • Occupational Health

(Rotary, Lion’s Club, etc.) • Shopping centers • Social Workers • Spas and salons • Special interest groups • Speech therapists • Sporting events • Staff educational seminars • Student newspaper and radio advertisements • Subway advertising • Support groups T • Taxi advertisements (receipts, panel ads) • Technicians (e.g., EEG, ECG) • Telephone “on-hold” messages describing ongoing studies at research center • Training advertising • Transportation program, for study volunteers • TV advertising U • Urgent care clinics • Universities/University dorms • Unlimited coffee, tea, and milk for subjects in waiting room. • Update investigators on any exciting new data with regards to the compound being studied V • Vans for clinic/hospital/elderly transportation • Vendor, specializing in

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• Exam table paper with study advertisement • Exhibits and booths at events and conferences F • Fax alerts and reminders • Festivals • Fitness facilities • Flyers • Free health clinics • Free screenings G • Gay and lesbian organizations • Give always (pens, post-it notes) with study brand and call center/site # • Google advertising • Grand rounds presentations • Grocery Stores • Gyms H • Health fairs screenings, as a part of community outreach and education • Home health services (bring research to the subjects!) • Hospital Employee Paycheck Notices • Hospital ICD-9 and CPT code searches • Hospital lobbies and clinics

Nurses • Occupational Therapists • On-line advertising • Outreach programs, providing support for subjects with specific disease indications P • Pain management clinics • Payment for subject inconvenience as a method of compensation • Pediatricians offices • Pharmacies • Physical therapists • Post cards • Posters • Presentations and education seminars • Press Releases • Primary care physician offices • Public health centers • Public Service Announcements • Public transportation advertisements Q • Quick-reference criteria pocket cards, which list the inclusion and exclusion criteria of the study, can be made available to the investigator and/or study coordinator to identify potential candidates.

subject recruitment practices • Videos (educational) • Visiting nurse services W • Walk in a fundraiser walk such as Memory walk for Alzheimer’s or a Breast Cancer walk and wear tee-shirts advertising your research office • Websites (study-specific) and web advertising • Weekly pager notifications • Welcome kits, for subjects in waiting rooms • Women’s health clinics • Word of mouth X • Xerox faxed announcements to sites • X-ray clinics Y • Yahoo advertising • Yellow book ads • YMCAs • Youth organizations Z • Zip code checks for disease prevalence • Zoo advertisement (buy ads on zoo materials: maps, tickets, etc.)

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Retention Strategies Study Participation Barriers Logistical

Educational •

Emotional

Physical

Influencers

Possible Solutions Flexible/convenient appointment times See subject immediately on arrival Appoint reminder cards Appointment reminder e-mails Stipend for transportation/parking Assist with transportation coordination Provide daycare support for working subjects Home health visits Provide coordinator contact information/pager for 24 hour availability Subject newsletters – information about disease/study progress Provide summary of lab results to demonstrate progress Plan to use primary language of the target population Use of minority spokespersons or community leaders Employ research staff who speak the language of target population Stress the contribution he/she is making to medicine and research Spend extra time with subject each visit Written or telephone contacts between visits Pre-paid calling cards Birthday/holiday cards Small gifts/recognition items Subjects appreciate practical items for everyday use in particular Ensure subject sees the physician at each visit Provide summaries of lab reports or other health status information Provide alternate treatments or medical management Provide additional information about the study drug and safety Profile Provide health status updates to primary care (or other) physician Have PI contact primary care physician Invite family/caregiver to appointments Have PI contact family member/caregiver Provide general information about clinical trials and benefits of participation

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