white paper Beyond Patient-Reported Outcomes: Designing and Conducting Patient-Centered Studies

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1 white paper Designing and Conducting Patient-Centered Studies ppdi.com June 2013

2 Deborah Covington, Dr.PH Kristin Veley, PharmD, MPH Paige Churchill Margaret Richards, PHD MPH CPHQ INTRODUCTION The concept of patient-centeredness first gained momentum in the early 1990s, and publications on the topic have increased exponentially in the past 10 years (Figure 1). This explosion in interest has been fueled by: (1) patients taking a more active role in their health and well-being; (2) wide-spread availability of health information and related tools on the Internet; (3) development of health technologies, such as telemedicine and mobile applications for tracking health-related behaviors; and (4) a government focus on improving the quality of health delivery and outcomes, including the creation of the Patient-Centered Outcomes Research Institute (PCORI) and documents on patient-reported outcomes issued separately by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). 1-3 The term patient-centered is used frequently in two separate but related contexts: medical care and research. In medical care, the term patient-centered describes the engagement of patients in the management of their own health and healthcare and the consideration of patient preferences and values when making medical decisions. It also refers to the inclusion of patients, caregivers, and patient advocates on advisory panels that review research priorities. In research, patient-centered refers to the measurement of patient-reported outcomes, such as symptom severity and quality of life, and the direct enrollment of patients into clinical studies. This paper is focused on patient-centered (or directto-patient) research that puts individuals, rather than investigative sites, at the core of the study. First, we examine the process for designing and conducting patient-centered studies and discuss the associated opportunities and challenges. Then, we review the evolution of patient-centered clinical studies, discuss future directions, and consider which types of research are best suited to this approach. Figure 1: Number of PubMed-indexed publications with patient-centered in the title or abstract. Search conducted using on April 3, *Projected based on data from 1/1/13 to 3/31/13 2

3 DESIGNING AND CONDUCTING PATIENT- CENTERED STUDIES In theory, all aspects of a patient-centered study s design and operation revolve around the patient. By prioritizing and actively engaging patients, the patientcentered approach effectively brings the study to the patient (Figure 2). Most patient-centered studies share three key elements: Open-enrollment: eligible patients can self-enroll in the study without involving a physician or other healthcare provider; Few study sites: patients are not required to visit the study site, so there is often only a single site (or a single site in each country that is participating in a study); Study coordinating center: the study is managed centrally by a group of associates who screen/enroll patients by phone or online and facilitate data collection, often from multiple sources. Patient-centered studies offer advantages over site-based studies but present unique challenges. This section describes the process of designing and conducting patient-centered studies, highlighting key departures from the site-based approach and discussing associated opportunities and challenges. Defining the Patient Population Unlike site-based studies that recruit only patients treated at particular preselected sites, patient-centered studies typically include patients without regard to proximity to a study site. Any patient with access to the required technology (telephone, Internet, smart phone, etc.) can participate, even those who live in rural areas or who are unable to travel (e.g., elderly, disabled, infants). This approach is particularly valuable when studying rare diseases (defined as conditions affecting fewer than 200,000 individuals in the US 4 or no more than 1 per 2000 people in Europe 5 ). It is also valuable when examining product safety, efficacy, or effectiveness in particular subgroups (e.g., pregnant women, children, certain racial/ethnic groups). The challenge to this approach is that patients are selfselected, so results may not be generalizable to the entire population. Figure 2: Patient-centered research revolves around the patient. 3

4 Choosing Endpoints With patient-centered studies, reporter burden is a significant issue that should not be overlooked. Human data sources, whether patients, healthcare providers, or caregivers, are unlikely to devote the time necessary to complete detailed questionnaires or case report forms, so endpoints using data from these sources should be carefully selected. Additional data needs, particularly medical history and lab results, may be best met using electronic health records (EHR). Regulatory and Ethical Approval There is little official guidance on designing and conducting patient-centered studies to the standards of regulatory agencies. As would be expected, patientcentered studies that are observational or that include non-drug interventions face fewer regulatory and ethical hurdles than studies that include drug interventions. Although it is possible to design patientcentered, randomized clinical trials that are acceptable to regulatory agencies and institutional review boards/ ethics committees (IRB/EC), policies and processes vary by country/region and consultation with the appropriate bodies as early as possible is recommended. In a global study, it may be worthwhile to name a principal investigator (PI) for each country/region included in the study to facilitate the submission and review of regulatory and IRB/EC documents. Study Coordination Patient-centered studies are typically coordinated by a single site and virtual study coordinating center under the direction of a single PI or a limited number of PIs, as determined by the volume of patients and/or regulatory submissions. The study coordinating center facilitates all research activities, including recruitment, screening, informed consent, enrollment, and data collection. Study associates provide ongoing, often around-the-clock, support via and telephone to patients and healthcare providers reporting data. A medical team, led by the PI, reviews data in real-time, monitoring the health and safety of study participants without waiting for paper files to be transcribed or for clinical research monitors to travel to study sites. Technology platforms that offer patient recruitment, screening, consenting, and data management functions within one efficient package are ideal for patientcentered studies, particularly if they include mobile device capabilities (e.g., enrollment via smartphone) and automated data management features (e.g., reminders). Retro-fitting technologies employed in site-based studies for use in patient-centered studies provide, at best, a mediocre solution. By limiting the number of sites and investigators, patient-centered studies often cost less than their sitebased counterparts. However, few companies currently possess the technology and experience needed to effectively manage these unique studies and serve as a study coordinating center. Patient Recruitment By definition, recruitment activities for patient-centered research are targeted toward patients. Through an open-enrollment model, eligible patients can selfenroll in a study without involving a physician or other healthcare provider. Recruitment materials typically provide basic study information and refer interested patients to the study coordinating center or web site. Printed materials may be distributed through doctors offices, direct mail, patient advocacy organizations, or support groups. Large studies often utilize media outlets including newspapers, television, and radio. Today, these traditional approaches are augmented, and sometimes supplanted, by online and social media efforts. By maximizing enrollment of eligible patients, patient-centered studies may reduce overall study timelines and decrease costs. However, not all patients may feel comfortable sharing confidential medical information online or enrolling without consulting their healthcare provider beforehand. Screening, Informed Consent, and Medical Records Release The processes of screening, informed consent, and medical record release are performed by the same team of associates at the study coordinating center. All interactions are at the patient s convenience and, ideally, 4

5 use the patient s preferred method of communication (e.g., telephone, internet, smart phone). Typically, a patient interested in participating in a study answers a few simple screening questions online. If the patient is deemed eligible and wishes to participate, he/she can contact the study coordinating center immediately or have a study associate call him/her at a convenient time. The study associate then further assesses the patient s eligibility and guides him/her through an electronic informed consent process as well as the forms necessary to authorize the release of any needed medical records. As with site-based studies, patient privacy is a high priority and appropriate safeguards are in place to ensure that data are protected. Data Collection In patient-centered studies it is possible to collect many types of data, both quantitative and qualitative, from a wide variety of primary sources. Rather than depending on a single source for data reporting, patient-centered studies can collect data directly from multiple sources, including patients themselves, caregivers, healthcare providers, EHR, existing registries, databases, laboratories, and biospecimen repositories. One novel approach uses home health agencies to make clinical assessments, which is particularly valuable for studies involving patients who cannot easily travel to a study site, such as newborns, the elderly, and the disabled. Depending on the design of the study, collected data can include basic demographic information; anthropometric and laboratory measurements; medical, family, occupational, and behavioral histories; disease status and natural history; drug treatment information; quality-of-life, disease-related disability, and treatment satisfaction information. The process should be as simple and succinct as possible, utilizing electronic data capture (EDC) methods when appropriate to streamline the collection of data from medical records, laboratory data, and biological samples. With reporter burden and data management in mind, data should be collected directly from the primary source, and obtaining the same information from multiple sources should be avoided. Cumbersome data collection processes and/or lengthy questionnaires can overburden reporters, which can negatively impact participation. In addition, collecting the same data from multiple sources can yield conflicting data, which can require an arduous and time-consuming adjudication process to resolve. Retention In patient-centered studies, retention can be facilitated by engaging participants, minimizing reporter burden, and providing ongoing support. Simple, clear processes are critical for retaining both patients and healthcare providers. Empowering patients to play an active role in the study reduces loss to follow-up, and sharing reporting responsibilities between patients and healthcare providers increases the likelihood of sustained participation. In addition, the positive effects of tailoring communications to the personal preferences of the participants and providing prompt, courteous, and accurate support cannot be underestimated. EVOLUTION OF PATIENT- CENTERED RESEARCH Patient-centered research has been conducted for over 20 years, most commonly in the form of registries. These observational studies typically follow patients with a particular disease or exposure longitudinally for the occurrence of associated health outcomes. For example, pregnancy registries which enroll expectant women exposed to particular medications and monitor these women and their offspring for adverse outcomes, such as miscarriages, infant mortality, and major birth defects. 6 The Xolair Pregnancy Registry is one such example. 7 5

6 In the last decade or so, the opportunities for patientcentered research have expanded with the growing implementation of EHR. EHR databases can be used to identify patients who are eligible for a study, and, with appropriate consent, individual EHR can serve as a valuable data source. One recently published study of older patients with back pain used EHR data in addition to a series of surveys to compare pain, functional outcomes, diagnostic testing, and treatment utilization in patients with and without early imaging. Surveys assessed patients pain, disability, and quality of life, while EHR data were used to determine when, if ever, the patients underwent imaging studies. 8 Most recently, the unprecedented global expansion of communications technologies including the internet, smart phones, and mobile applications has created numerous opportunities to enable and streamline patient-centered research. Today, recruitment can be done online via targeted advertising and social media; reminders can be automatically sent via or text messaging; and data collection can occur at the patient s convenience with only a few clicks or taps. Recognizing the advantages of technology-based, patientcentered research, Pfizer created the REMOTE study, the first prospective virtual clinical trial conducted entirely via the internet and telephone. This pilot project, designed in consultation with FDA and launched in 2011, was a randomized, phase IV comparison of tolterodine tartrate versus placebo in women with overactive bladder. It attempted to replicate the results of a previously completed, site-based study. 9,10 Although REMOTE was unable to enroll a sufficient number of patients, 11 it successfully pioneered a number of processes critical to virtual clinical research, including patient consent using video/multimedia technology and shipment of blinded study drug directly to the patients. 9,10 Pfizer intends to apply their learnings to future trials 11 with other pharmaceutical and biotechnology companies expected to follow suit. Today, the best applications of patient-centered research involve areas or issues that are difficult to evaluate using traditional, site-based clinical studies and/or require data from multiple sources (Figure 3). Figure 3: Situations ideally suited to patient-centered research 6

7 CONCLUSIONS While the patient-centered approach has been used for more than two decades, in recent years it has begun to attract more attention. In part, this surge in interest is due to the increasingly active role many patients are playing in the management of their own health and well-being. Technological innovations are also opening new avenues for patient-centered research. Internet, social media, and mobile applications are facilitating expanded patient recruitment, while advanced EDC systems and linkage with EHR are easing the burden of data collection. Now, with the REMOTE study, patient-centered research has expanded to include prospective, interventional, clinical trials. Although this methodology is still in the early stages of development, interest and support from regulators, sponsors, and patients will likely propel it forward in the near future. Patient-centered studies offer opportunities by maximizing patient enrollment and reducing site costs, but pose regulatory, operational, and analytic challenges. Researchers opting to employ patient-centered studies must weigh the challenges versus the opportunities in the design phase. With the increasing demand for real-world evidence to guide public health and clinical decision-making, the patient-centered approach will be an integral part of future research endeavors. 7

8 REFERENCES 1 Patient-Centered Outcomes Research Institute. About Us. Accessed April 3, US Food and Drug Administration. Guidance for industry. Patient-reported outcome measures: use in medical product development to support labeling claims. December European Medicines Agency. Reflection paper on the regulatory guidance for the use of health-related quality of life (HRQL) measures in the evaluation of medicinal products. January National Institutes of Health. Office of Rare Diseases Research. Rare diseases and related terms. Accessed April 3, Orphanet. About rare diseases. net/consor/cgi-bin/education_aboutrarediseases. php?lng=en#. Accessed April 3, Covington DL, McKain LF. Post-approval methods for monitoring safety of drug exposures in pregnancy. Applied Clinical Trials. 2011;20: EXPECT: the Xolair Pregnancy Registry. Accessed April 18, Jarvik JG, Comstock BA, Bresnahan BW, et al. Study protocol: the back pain outcomes using longitudinal data (BOLD) registry. BMC Musculoskelet Disord. 2012; 13:64. 9 Pfizer. Press release: Pfizer Conducts First Virtual Clinical Trial Allowing Patients to Participate Regardless of Geography. June 7, com/news/press_releases/pfizer_press_release_archive. jsp?guid= en&source=2011&page=9. 10 Donahue M and Henderson L. Pfizer s REMOTE virtual experience. Applied Clinical Trials Online. January 12, appliedclinicaltrials/article/articledetail. jsp?id= Silverman E. Pfizer ends social media bid for trial recruitment. Pharmalot. June 19, pharmalive.com/pfizer-ends-social-media-bid-trialrecruitment. 8

9 For more information, please visit us at or call us at Pharmaceutical Product Development, LLC. All rights reserved.