Deborah Covington

In the healthcare arena, the concept of patient-centeredness has expanded over the last 50 years, beginning as a term to describe patient engagement in self-health management and evolving to include various aspects of patient engagement in healthcare research.

 The creation of the Patient-Centered Outcomes Research Institute (PCORI) further solidified the concept of patient-centered research by its dedication to improving healthcare and outcomes by producing evidence-based data for research guided by patients, their caregivers, and healthcare providers.

	In this article, the authors discuss patient-centered research (also termed "direct-to-patient") that uses the "remote" study approach. This type of remote patient-centered study puts individuals, rather than investigative sites, at the center of the research process. Both the design and operation of remote patient-centered studies revolve around patients (see Figure 1). Remote patient recruitment, enrollment, and retention programs, data collection, and long-term follow-up evaluation offer opportunities to increase research efficiencies. At the same time, this operational approach intensifies patient-centeredness by engaging patients directly in research functions, overcoming geographic obstacles to connect stakeholders, and incorporating patient input into the research process. The remote patient-centered model offers great potential to advance both observational studies and randomized controlled clinical trials.

	Remote, patient-centered research has been conducted in observational studies for more than two decades, most commonly in the form of registries. These non-interventional studies typically follow patients with a particular disease or exposure longitudinally to examine the occurrence of associated health outcomes. For example, pregnancy registries monitor women and their offspring who were exposed to certain medications during pregnancy to observe possible adverse outcomes, such as birth defects.

	More recently, drug developers have been exploring potential applications in interventional clinical trials. Forerunners such as the REMOTE (Research on Electronic Monitoring of OAB Treatment Experience) pilot trial sponsored by Pfizer have sparked increasing applications of remote patient-centered study designs in efforts to increase access to patient populations and to improve operational efficiencies.

 Although this methodology is still in early stages of development, interest and support from regulators, sponsors, and patients likely will propel it forward in the near future.

	The purpose of this article is to examine the remote patient-centered study approach in clinical research. First, we review design and operational elements of remote patient-centered studies. Next, we address some of the challenges to conducting remote patient-centered studies. Finally, we discuss the types of studies best suited to the remote patient-centered study approach.

The remote patient-centered study approach

	Most remote patient-centered studies share three basic characteristics: patient engagement; use of a limited number of study sites coordinated by a single-study coordination center; and data collection from multiple reporters and sources (see Table 1).

	In remote patient-centered studies, awareness and recruitment activities are targeted directly to patients to engage them in the research process. Interested patients typically contact the study via a study website or contact center where they learn more about the study and how they can contribute and participate, if eligible. Eligible patients then self-enroll directly in the study without visiting a traditional study site. Once enrolled, patients provide study data and/or grant permission for their treating healthcare professionals (HCPs) to provide study data. Patients need not be treated at a particular study site by the trial's principal investigator (PI) to enroll. Any eligible patient who is interested in participating and who has access to the required technology (telephone, Internet, smartphone, etc.) can participate in a remote patient-centered study, even those who live in rural areas or who are unable to travel (e.g., elderly, disabled, infants). This approach has potential to maximize engagement and enrollment of all eligible patients. For example, one study found that 69% of subjects who had participated in a remote Internet-based clinical trial reported that they would prefer to participate in this type of trial again rather than to participate in research that used other modes of data collection.

Limited number of sites facilitated by a central study coordination center

	Because patients are not required to visit a particular site, there is often only a single site or, for global studies, a single site in each participating country, to manage regulatory submissions. Studies are managed centrally by a remote study coordination center that facilitates all research activities, including recruitment, screening, informed consent, enrollment, and data collection. A medical team, led by the PI, monitors the health and safety of study participants by reviewing all data as they are reported in real time. By relying on a single site or a limited number of sites, the remote patient-centered approach is highly cost-effective, given that cost estimates for management of an active site range from $1,500 to $2,500 per month.

	In remote patient-centered studies, it is possible to collect many types of data, both quantitative and qualitative, from a wide variety of primary sources. Unlike site-based studies, data are not collected by investigators during site visits, but rather through the central study coordination center. Remote patient-centered studies support data collection directly from multiple sources, including patients themselves, caregivers, HCPs, electronic health records (EHR), existing registries, databases, laboratories, and biospecimen repositories. Depending on the design of a study, collected data can include basic demographic information; anthropometric, biological, 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.

	Remote patient-centered studies facilitate the engagement of stakeholders throughout study design, recruitment, and operation. Key stakeholders include patients themselves, caregivers, doctors, researchers, advocacy/support groups, foundations, research consortia, government organizations, and representatives from biopharmaceutical companies with potential therapies in their pipelines. Empowering stakeholders to play an active role in the study, including participation in advisory committees and protocol development, can greatly improve overall success.

	The direct-to-participant approach of remote patient-centered studies and the ability of the remote study coordination center to facilitate global communication make these studies ideal for engaging stakeholders. Study coordinators provide ongoing around-the-clock support via email and telephone to data providers. An investigator-led medical team reviews data in real time to monitor patient safety and data quality. Sophisticated information technology platforms can be used to support these functions while integrating multiple data streams and accommodating the participation of multiple stakeholders.

Addressing research challenges using the remote patient-centered approach

	Recruitment is one of the greatest challenges faced in clinical research. A recent study found that 37% of sites under-enroll, and 11% fail to enroll a single patient.

 Unlike site-based studies that recruit only patients treated at particular preselected sites, remote patient-centered studies can include patients without regard to proximity to a site. Thus, recruitment activities must be targeted directly to patients in addition to other stakeholders and data reporters, such as HCPs and pharmacies. This multi-pronged recruitment approach can be complex and requires expertise to design and implement recruitment strategies. Recruitment efforts should be customized to the population of interest. For example, Internet and social media can be used to reach younger patients, whereas television, radio, and print media can be used to reach older patients. To identify and contact potential subjects, researchers also can leverage disease-specific entities, including registries, research consortia, foundations, advocacy and support groups, and patient communities. Recruitment efforts to reach healthcare providers may include medical and scientific journal advertisements and articles, medical and scientific conferences, and medical websites.

	Along with recruitment, the retention of patients in clinical research studies is an enormous challenge.

 Key obstacles to retention include reporter burden, participant privacy concerns, and lack of incentive. Remote patient-centered studies can be designed to maximize retention by engaging patients and other data reporters throughout the study, streamlining processes, minimizing reporter burden, providing ongoing support, and sharing data among stakeholders. Human data sources, whether patients, HCPs, or caregivers, are vulnerable to survey fatigue. Cumbersome questionnaires and case report forms can dampen participant enthusiasm and provoke study dropout. When designing a trial, the primary and secondary endpoints of interest should be selected carefully and the data collected should be limited to only the information necessary for analysis of these endpoints. Data collection processes can be tailored to study-specific needs and made simple and succinct. Alternative data sources such as EHRs should be considered whenever possible to minimize the burden on those reporting data. For example, electronic data capture (EDC) methods can be used to streamline the collection of data from medical records, laboratory data, and biological samples, while electronic patient-reported outcomes (ePRO) systems can streamline the collection of data directly from patients.

	Patients and HCPs are concerned with maintaining the privacy of their information. Some are wary to share online and are more comfortable providing the information over the phone. Just as in site-based studies, appropriate safeguards should be put in place to ensure that data are protected. Thoughtful pairing of technology with live contact center personnel is often required to obtain an effective balance between efficiency and patient security.

	Patient attrition also can be lessened through incentives. Where allowed, monetary incentives can facilitate retention. Remote patient-centered studies that do not require the patients to travel to a site often are less burdensome and could potentially require less incentive for participation (i.e., payment for travel to the site). Additionally, remote patient-centered studies are well suited to provide non-monetary incentives through data sharing. The direct-to-participant nature of remote patient-centered studies allows for dissemination of disease-specific communications, such as periodic newsletters and study results. These can be effective methods to improve retention of patients, who are especially motivated by information pertaining to their diseases.

	The remote patient-centered model is ideal for streamlining processes and maximizing the participation of patients identified through direct-to-patient recruitment. Centralized operation via a remote study coordination center allows the processes of screening, informed consent, and medical record release to be performed remotely. All patient interactions are done by the same team at the coordinating center at the patient's convenience and, ideally, use the patient's preferred method of communication (e.g., telephone, Internet, smartphone, etc.).

	From an analytical perspective, the self-selection of participants in remote patient-centered studies can threaten the external validity of study results, as several researchers have noted and discussed.

 Essentially, patients who voluntarily self-enroll represent a "convenience" sample of the population and may be different from the general population in terms of certain demographic or disease-related characteristics. For example, in a remote patient-centered study recruiting patients only from an online patient community (e.g., PatientsLikeMe, 

, Inspire), it is possible that patients who enroll are more Internet savvy and interested in health information than the general population. Hence, results may be less generalizable than those of studies with a random selection of participants. Combining different methods of recruitment and offering more than one mode of participation and data collection improves the generalizability of results. As Internet recruitment technology and strategies continue to evolve and the population with the facility to use this technology broadens, concerns about the generalizability of results from this type of study should subside.

	Success of the remote patient-centered approach is dependent upon a thoughtful blend of technology and human experience. Remote study coordination centers may require sophisticated information technology platforms for implementation and operational efficiency. The contact support staff tasked with managing the study must be experienced with the platform and able to guide participants through all processes of the study. Remote clinical trial designs are in their infancy, and few pharmaceutical companies and contract research organizations (CROs) currently possess the technology and experience needed to effectively manage these studies and serve as a study-coordinating center. Technology platforms that offer patient recruitment, screening, consenting, and data management functions within one efficient package are ideal for remote patient-centered studies, particularly if they include mobile device capabilities (e.g., enrollment via smartphone) and automated data management features (e.g., email reminders). Experience with these platforms and the ability to tailor them to fit study-specific needs undoubtedly will improve operational efficiencies.

	There is little official regulatory guidance on designing and conducting remote patient-centered studies. As would be expected, remote patient-centered studies that are observational or that include non-product interventions face fewer regulatory and ethical hurdles than studies that include product interventions. Policies and processes vary by country and region, so remote patient-centered studies require consultation with the appropriate regulatory bodies as early in the research process as possible. In a global study, it may be worthwhile to name a PI for each country or region included to facilitate the submission and review of regulatory and institutional review board (IRB)/ethics committee (EC) documents.

	Remote patient-centered studies that can address the intricacies involved in conducting global studies offer great advantages in accessing patients and harnessing global resources. Study coordination centers must be prepared to support participants from around the world by accommodating cultural and language differences. The positive effects of tailoring communications to the personal preferences of the participants and providing prompt, courteous, and accurate support cannot be underestimated.

Situations ideally suited to the remote patient-centered study approach

	Situations ideally suited to the remote patient-centered study approach involve patient populations that are difficult to reach using traditional site-based studies and/or that require data from multiple sources (see Figure 2). The remote patient-centered approach is particularly valuable when studying rare diseases or rare exposures, where it is critical to maximize enrollment of all eligible patients. This approach is also useful when it is important to facilitate participation of patients who may have difficulty traveling to a study site or who do not reside in close proximity to a site.

	The remote patient-centered approach is also useful when it is critical to collect data from multiple sources, including treating HCPs, specialists, patients, and caregivers. The study coordination center can facilitate the collection of data directly from the patient and his/her primary healthcare provider, specialists, and caregivers to allow the collection of data from the most applicable source of that particular data. For example, in a pregnancy registry, prenatal data can be collected from the pregnant woman's obstetric healthcare provider and the neonatal data can be collected from the infant's pediatrician.

	With the industry's ongoing emphasis on efficiency, effectiveness, and timeliness, remote patient-centered studies are gaining more prominence and appear to be on the path to becoming an important part of clinical research going forward. Although they offer such advantages as maximizing enrollment and reducing study timelines and costs, those benefits are countered by potential regulatory, operational, and analytical challenges.

 DrPH, is Executive Director, Registries & Observational Studies, PPD, email: 

 PharmD, MPH, is Senior Epidemiologist, Real World Outcomes, PPD, email: 

	1. D.L. Covington, K.M. Veley, H.B. O'Donnell, "Evolution of the Patient Centered Concept in the Published Literature," Value in Health, 17(3):A164 (2014).

	2. PCORI Patient-Centered Outcomes Research Institute, "About Us," 

	3. D.L. Covington, L.F. McKain, "Post-approval Methods for Monitoring Safety of Drug Exposures in Pregnancy," Applied Clinical Trials, 20, 46-50 (2011).

	4. Pfizer Inc., "Pfizer Conducts First 'Virtual' Clinical Trial Allowing Patients to Participate Regardless of Geography," Press release, June 7, 2011, 

http://press.pfizer.com/press-release/pfizer-conducts-first-virtual-clinical-trial-allowing-patients-participate-regardless-

	5. S. Brophy, C.L. Burrouws, C. Brooks, et al, "Internet-based Randomized Controlled Trials for the Evaluation of Complementary and Alternative Medicines: Probiotics in Spondyloarthropathy," BMC Musculoskelt Disord, 9:4 (2008).

	6. J. Comstock, "The Year for Mobile-enabled Clinical Trials: 2013-2030?" 

http://mobihealthnews.com/19158/the-year-for-mobile-enabled-clinical-trials-2013-or-2030/

	7. K. Langel, "Virtual Clinical Trials-'They're Here to Stay,'" E-Clinical Health, March 18, 2013, 

http://eclinicalhealth.com/virtual-clinical-trials-theyre-here-to-stay/

	8. E. Mathieu, A Barratt, S.M. Carter, G. Jamtvedt, "Internet Trials: Participant Experiences and Perspectives," BMC Med Res Methodol, 12:162 (2012).

	9. G. Li, B. Harper, L. Sirabella, "Activating Investigative Sites in a Staggered Process; Challenges and Solutions. In: Parexel Biopharmaceutical R&D Statistical Sourcebook 2011/2012. Waltham, MA; Parexel International Corp. (2011).

	10. Tufts Center for the Study of Drug Development, "New Research from Tufts (CSDD) characterizes Effectiveness ad Variability of Patient Recruitment and Retention Practices," News, January 15, 2013, 

http://csdd.tufts.edu/news/complete_story/pr_ir_jan-feb_2013

	11. R. King, "Embracing Electronic PRO," Applied Clinical Trials, March 2009, 

http://www.pharmtech.com/pharmtech/Viewpoint/Embracing-Electronic-PRO/ArticleStandard/Article/detail/587071

	12. E. Cascade, P. Marr, M. Winslow, et al., "Conducting Research on the Internet: Medical Record Data Integration with Patient-reported Outcomes," J Med Internet Res, 14(5) (2012), 

	13. N. Taylor, "Pfizer Director Defends Virtual Trial After Recruitment Struggle," 

http://www.outsourcing-pharma.com/Clinical-Development/Pfizer-director-defends-virtual-trial-after-recruitment-struggle

	14. M. Donahue and L. Henderson, "Pfizer's REMOTE Virtual Experience," Applied Clinical Trials Online, January 12, 2012, 

http://www.appliedclinicaltrialsonline.com/appliedclinicaltrials/article/articleDetail.jsp?id=755171

Articles

In the healthcare arena, the concept of patient-centeredness has expanded over the last 50 years, beginning as a term to describe patient engagement in self-health management and evolving to include various aspects of patient engagement in healthcare research.1

The Remote Patient-Centered Approach in Clinical Research

 In the healthcare arena, the concept of patient-centeredness has expanded over the last 50 years, beginning as a term to describe patient engagement in self-health management and evolving to include various aspects of patient engagement in healthcare research.

In this article, the authors discuss patient-centered research (also termed “direct-to-patient”) that uses the “remote” study approach. This type of remote patient-centered study puts individuals, rather than investigative sites, at the center of the research process. Both the design and operation of remote patient-centered studies revolve around patients (see Figure 1). Remote patient recruitment, enrollment and retention programs, data collection, and long-term follow-up evaluation offer opportunities to increase research efficiencies. At the same time, this operational approach intensifies patient-centeredness by engaging patients directly in research functions, overcoming geographic obstacles to connect stakeholders, and incorporating patient input into the research process. The remote patient-centered model offers great potential to advance both observational studies and randomized controlled clinical trials.

Remote, patient-centered research has been conducted in observational studies for more than two decades, most commonly in the form of registries. These non-interventional studies typically follow patients with a particular disease or exposure longitudinally to examine the occurrence of associated health outcomes. For example, pregnancy registries monitor women and their offspring who were exposed to certain medications during pregnancy to observe possible adverse outcomes, such as birth defects.

More recently, drug developers have been exploring potential applications in interventional clinical trials. Forerunners such as the REMOTE (Research on Electronic Monitoring of OAB Treatment Experience) pilot trial sponsored by Pfizer have sparked increasing applications of remote patient-centered study designs in efforts to increase access to patient populations and to improve operational efficiencies.

The purpose of this article is to examine the remote patient-centered study approach in clinical research. First, we review design and operational elements of remote patient-centered studies. Next, we address some of the challenges to conducting remote patient-centered studies. Finally, we discuss the types of studies best suited to the remote patient-centered study approach.

Most remote patient-centered studies share three basic characteristics: patient engagement; use of a limited number of study sites coordinated by a single-study coordination center; and data collection from multiple reporters and sources (see Table 1). 

Table 1. Remote patient-centered research: Design and operational elements

In remote patient-centered studies, awareness and recruitment activities are targeted directly to patients to engage them in the research process. Interested patients typically contact the study via a study website or contact center where they learn more about the study and how they can contribute and participate, if eligible. Eligible patients then self-enroll directly in the study without visiting a traditional study site. Once enrolled, patients provide study data and/or grant permission for their treating healthcare providers (HCPs) to provide study data. Patients need not be treated at a particular study site by the study’s principal investigator (PI) to enroll. Any eligible patient who is interested in participating and who has access to the required technology (telephone, Internet, smartphone, etc.) can participate in a remote patient-centered study, even those who live in rural areas or who are unable to travel (e.g., elderly, disabled, infants). This approach has potential to maximize engagement and enrollment of all eligible patients. For example, one study found that 69% of subjects who had participated in a remote Internet-based clinical trial reported that they would prefer to participate in this type of trial again rather than to participate in research that used other modes of data collection.

Limited number of study sites facilitated by a central study coordination center

Because patients are not required to visit a particular study site, there is often only a single site or, for global studies, a single site in each participating country, to manage regulatory submissions. Studies are managed centrally by a remote study coordination center that facilitates all research activities, including recruitment, screening, informed consent, enrollment, and data collection. A medical team, led by the PI, monitors the health and safety of study participants by reviewing all data as they are reported in real time. By relying on a single site or a limited number of sites, the remote patient-centered approach is highly cost-effective, given that cost estimates for management of an active site range from $1,500 to $2,500 per month.

In remote patient-centered studies, it is possible to collect many types of data, both quantitative and qualitative, from a wide variety of primary sources. Unlike site-based studies, data are not collected by investigators during site visits, but rather through the central study coordination center. Remote patient-centered studies support data collection directly from multiple sources, including patients themselves, caregivers, healthcare providers, electronic health records (EHR), existing registries, databases, laboratories, and biospecimen repositories. Depending on the design of a study, collected data can include basic demographic information; anthropometric, biological, 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.

Figure 1. Remote patient-centered studies revolve around the patient

Remote patient-centered studies facilitate the engagement of stakeholders throughout study design, recruitment, and operation. Key stakeholders include patients themselves, caregivers, doctors, researchers, advocacy/support groups, foundations, research consortia, government organizations, and representatives from biopharmaceutical companies with potential therapies in their pipelines. Empowering stakeholders to play an active role in the study, including participation in advisory committees and protocol development, can greatly improve overall success. 

The direct-to-participant approach of remote patient-centered studies and the ability of the remote study coordination center to facilitate global communication make these studies ideal for engaging stakeholders. Study coordinators provide ongoing around-the-clock support via email and telephone to data providers. An investigator-led medical team reviews data in real time to monitor patient safety and data quality. Sophisticated information technology platforms can be used to support these functions while integrating multiple data streams and accommodating the participation of multiple stakeholders. 

Recruitment is one of the greatest challenges faced inclinical research. A recent study found that 37% of sites under-enroll, and 11% fail to enroll a single patient.

 Unlike site-based studies that recruit only patients treated at particular preselected sites, remote patient-centered studies can include patients without regard to proximity to a study site. Thus, recruitment activities must be targeted directly to patients in addition to other stakeholders and data reporters, such as HCPs and pharmacies. This multi-pronged recruitment approach can be complex and requires expertise to design and implement recruitment strategies. Recruitment efforts should be customized to the population of interest. For example, Internet and social media can be used to reach younger patients, whereas television, radio, and print media can be used to reach older patients. To identify and contact potential subjects, researchers also can leverage disease-specific entities, including registries, research consortia, foundations, advocacy and support groups, and patient communities. Recruitment efforts to reach healthcare providers may include medical and scientific journal advertisements and articles, medical and scientific conferences, and medical websites.

Along with recruitment, the retention of patients in clinical research studies is an enormous challenge.

 Key obstacles to retention include reporter burden, participant privacy concerns, and lack of incentive. Remote patient-centered studies can be designed to maximize retention by engaging patients and other data reporters throughout the study, streamlining processes, minimizing reporter burden, providing ongoing support, and sharing data among stakeholders. Human data sources, whether patients, HCPs, or caregivers, are vulnerable to survey fatigue. Cumbersome questionnaires and case report forms can dampen participant enthusiasm and provoke study dropout. When designing a study, the primary and secondary endpoints of interest should be selected carefully and the data collected during the study should be limited to only the information necessary for analysis of these endpoints. Data collection processes can be tailored to study-specific needs and made simple and succinct. Alternative data sources such as EHRs should be considered whenever possible to minimize the burden on those reporting data. For example, electronic data capture (EDC) methods can be utilized to streamline the collection of data from medical records, laboratory data, and biological samples, while electronic patient-reported outcomes (ePRO) systems can streamline the collection of data directly from patients.

Patients and healthcare providers are concerned with maintaining the privacy of their information. Some are wary to share online and are more comfortable providing the information over the phone. Just as in site-based studies, appropriate safeguards should be put in place to ensure that data are protected. Thoughtful pairing of technology with live contact center personnel is often required to obtain an effective balance between efficiency and patient security. 

Patient attrition also can be lessened through incentives. Where allowed, monetary incentives can facilitate retention. Remote patient-centered studies that do not require the patients to travel to a study site often are less burdensome and could potentially require less incentive for participation (i.e., payment for travel to the study site). Additionally, remote patient-centered studies are well suited to provide non-monetary incentives through data sharing. The direct-to-participant nature of remote patient-centered studies allows for dissemination of disease-specific communications, such as periodic newsletters and study results. These can be effective methods to improve retention of patients, who are especially motivated by information pertaining to their diseases. 

The remote patient-centered model is ideal for streamlining processes and maximizing the participation of patients identified through direct-to-patient recruitment. Centralized operation via a remote study coordination center allows the processes of screening, informed consent and medical record release to be performed remotely. All patient interactions are done by the same team at the coordinating center at the patient’s convenience and, ideally, use the patient’s preferred method of communication (e.g., telephone, Internet, smartphone, etc.). 

From an analytical perspective, the self-selection of participants in remote patient-centered studies can threaten the external validity of study results, as several researchers have noted and discussed.

 Essentially, patients who voluntarily self-enroll represent a “convenience” sample of the population and may be different from the general population in terms of certain demographic or disease-related characteristics. For example, in a remote patient-centered study recruiting patients only from an online patient community (e.g., PatientsLikeMe, MediGuard.org, Inspire), it is possible that patients who enroll are more Internet savvy and interested in health information than the general population. Hence, results may be less generalizable than those of studies with a random selection of participants. Combining different methods of recruitment and offering more than one mode of participation and data collection improves the generalizability of results. As Internet recruitment technology and strategies continue to evolve and the population with the facility to use this technology broadens, concerns about the generalizability of results from this type of study should subside. 

Success of the remote patient-centered approach is dependent upon a thoughtful blend of technology and human experience. Remote study coordination centers may require sophisticated information technology platforms for implementation and operational efficiency. The contact support staff tasked with managing the study must be experienced with the platform and able to guide participants through all processes of the study. Remote clinical trial designs are in their infancy, and few pharmaceutical companies and contract research organizations (CROs) currently possess the technology and experience needed to effectively manage these studies and serve as a study-coordinating center. Technology platforms that offer patient recruitment, screening, consenting, and data management functions within one efficient package are ideal for remote patient-centered studies, particularly if they include mobile device capabilities (e.g., enrollment via smartphone) and automated data management features (e.g., email reminders). Experience with these platforms and the ability to tailor them to fit study-specific needs undoubtedly will improve operational efficiencies.

There is little official regulatory guidance on designing and conducting remote patient-centered studies. As would be expected, remote patient-centered studies that are observational or that include non-product interventions face fewer regulatory and ethical hurdles than studies that include product interventions. Policies and processes vary by country and region, so remote patient-centered studies require consultation with the appropriate regulatory bodies as early in the research process as possible. In a global study, it may be worthwhile to name a PI for each country or region included in the study to facilitate the submission and review of regulatory and institutional review board (IRB)/ethics committee (EC) documents. 

Remote patient-centered studies that can address the intricacies involved in conducting global studies offer great advantages in accessing patients and harnessing global resources. Study coordination centers must be prepared to support participants from around the world by accommodating cultural and language differences. The positive effects of tailoring communications to the personal preferences of the participants and providing prompt, courteous, and accurate support cannot be underestimated. 

Situations ideally suited to the remote patient-centered study approach 

Situations ideally suited to the remote patient-centered study approach involve patient populations that are difficult to reach using traditional site-based studies and/or that require data from multiple sources (Figure 2). The remote patient-centered approach is particularly valuable when studying rare diseases or rare exposures, where it is critical to maximize enrollment of all eligible patients. This approach is also useful when it is important to facilitate participation of patients who may have difficulty traveling to a study site or who do not reside in close proximity to a site. The remote patient-centered approach is also useful when it is critical to collect data from multiple sources, including treating HCPs, specialists, patients and caregivers. The study coordination center can facilitate the collection of data directly from the patient and his/her primary healthcare provider, specialists, and caregivers to allow the collection of data from the most applicable source of that particular data. For example, in a pregnancy registry, prenatal data can be collected from the pregnant woman’s obstetric healthcare provider and the neonatal data can be collected from the infant’s pediatrician.

Figure 2. Situations ideally suited to the remote patient-centered study approach

With the industry’s ongoing emphasis on efficiency, effectiveness, and timeliness, remote patient-centered studies are gaining more prominence and appear to be on the path to becoming an important part of clinical research going forward. Although they offer such advantages as maximizing enrollment and reducing study timelines and costs, those benefits are countered by potential regulatory, operational, and analytical challenges.

Deborah Covington, DrPH, is Executive Director, Registries & Observational Studies, PPD LLC; Kristin Veley, PharmD, MPH, is Senior Epidemiologist, Evidence-Based Medicine, PPD LLC 

D.L. Covington, K.M. Veley, H.B. O’Donnell, “Evolution of the Patient Centered Concept in the Published Literature,” 

PCORI Patient-Centered Outcomes Research Institute, “About Us,” 

D.L. Covington, L.F. McKain, “Post-approval Methods for Monitoring Safety of Drug Exposures in Pregnancy,” 

Pfizer Inc., “Pfizer Conducts First ‘Virtual’ Clinical Trial Allowing Patients to Participate Regardless of Geography,” Press release, June 7, 2011, 

S. Brophy, C.L. Burrouws, C. Brooks, et al, “Internet-based Randomized Controlled Trials for the Evaluation of Complementary and Alternative Medicines: Probiotics in Spondyloarthropathy,” 

J. Comstock, “The Year for Mobile-enabled Clinical Trials: 2013-2030?” 

K. Langel, “Virtual Clinical Trials—‘They’re Here to Stay,’” 

E. Mathieu, A Barratt, S.M. Carter, G. Jamtvedt, “Internet Trials: Participant Experiences and Perspectives,” 

G. Li, B. Harper, L. Sirabella, “Activating Investigative Sites in a Staggered Process; Challenges and Solutions. In: 

Parexel Biopharmaceutical R&D Statistical Sourcebook 2011/2012

. Waltham, MA; Parexel International Corp. (2011).   

Tufts Center for the Study of Drug Development, “New Research from Tufts (CSDD) characterizes Effectiveness ad Variability of Patient Recruitment and Retention Practices,” News, January 15, 2013, 

R. King, “Embracing Electronic PRO,” 

E. Cascade, P. Marr, M. Winslow, et al, “Conducting Research on the Internet: Medical Record Data Integration with Patient-reported Outcomes,” 

N. Taylor, “Pfizer Director Defends Virtual Trial After Recruitment Struggle,” 

M. Donahue and L. Henderson, “Pfizer’s REMOTE Virtual Experience,” 

In this article, the authors discuss patient-centered research (also termed "direct-to-patient") that uses the "remote" study approach.

The Remote Patient-Centered Study Approach in Clinical Research

Scientifically rigorous efforts to monitor the potential negative effects of biopharmaceutical products are an important component of post-approval product safety. Such monitoring is critical. While the consequences of birth defects for children, their families, and society are potentially serious, the uncertainty and fear surrounding these risks can lead physicians and patients to withhold therapeutic interventions that are necessary to treat severe chronic conditions, and can also lead to unnecessary pregnancy terminations.  

During the development process, regulatory agencies require all medicinal products to undergo pre-clinical testing to determine reproductive effects, but the results of these studies are not necessarily predictive of the human experience. Clinical trials exclude pregnant women; thus, little is known about the human teratogenic effect of a product at the time it first enters marketing. Once a drug is on the market, a spontaneous safety reporting system is in place to monitor all adverse drug reactions, including both normal and abnormal outcomes of pregnancy drug exposures. Healthcare providers and patients report adverse drug reactions to the manufacturer of the drug, and the manufacturer is required by law to report these events to regulatory agencies. This spontaneous reporting system is useful for identifying severe and unusual events. However, it is inadequate for monitoring the range of reproductive events that pregnant women exposed to the drug may experience.

As a result, both the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have, with increasing frequency, required that application holders make post-marketing commitments to conduct studies of the effects of products when used during pregnancy, especially for biopharmaceutical products that have a high likelihood of use in women of child-bearing potential. Both the FDA and the EMA published guidance on monitoring exposures to medicinal products during pregnancy.

  The FDA guidance document focuses on establishing prospective pregnancy exposure registries, while the EMA guidance reviews various study design options that may be used to monitor the safety of product exposures in pregnancy. These guidance documents are useful tools, yet selecting the design that is most appropriate for a particular product or patient population remains challenging. 

Typical strategies used to assess the teratogenic potential of various products include prospective pregnancy exposure registries, longitudinal database studies, and case-control studies. The purpose of this article is to describe these three approaches, to evaluate their strengths and weaknesses, and to examine the utility of these approaches in monitoring product safety in pregnancy. 

A pregnancy registry is a prospective, observational study with an active data collection system spanning the time from exposure through a follow-up period. Pregnant women are enrolled as soon after the exposure as possible and followed throughout their pregnancy. At enrollment, the registry captures data on the exposure, as well as demographic and background information. At outcome, the registry captures data on additional exposures during pregnancy, risk factors, and details regarding the pregnancy outcome, including the presence or absence of birth defects and other perinatal complications. If a live birth occurs, the infant may be followed over a period of time and monitored for the detection of birth defects and other functional or developmental deficits. 

Pregnancy exposure registries offer a unique means for collecting data on pregnancy exposures early in the lifecycle of a product, at a time when interest in the product and its safety is keen and other means of safety monitoring are limited. When animal or clinical studies indicate possible risk, a registry may be useful for providing active surveillance. Pregnancy exposure registries are particularly useful for detecting major teratogenic effects, but have limited ability to detect increases in the risk of specific defects or small increases in the overall risk of defects. They have power-limiting sample size constraints due both to the infrequency of pregnancy drug exposures and the impracticality of enrolling numbers large enough to detect these differences. They may also be useful in assessing other adverse events, such as prematurity, maternal complications, or developmental deficits, although the observational nature of these studies typically limits data collection to details that are recorded in the course of usual care rather than formal standardized assessments. Pregnancy exposure registries tend to be hypothesis-generating tools rather than hypothesis-testing tools. They are used to identify potential safety signals for further study.

Pregnancy registries offer important advantages. Their active data collection system and prospective orientation offer advantages over the passive, retrospective methods of other post-marketing surveillance techniques.

  Furthermore, because the exposure clearly occurs before the outcome, this design avoids the recall bias that studies with a retrospective design may introduce, and enables the registry to promptly capture critical data directly from the source.

  The pregnant woman can provide detailed data on exposure both to the drug of interest and other drugs, as well as to risk factors associated with the outcome, in order to delineate potential influences during critical phases of fetal development. Her physicians—the prescriber and/or her obstetrician—can easily verify this information, and the obstetrician or pediatrician can provide or verify pregnancy outcome data; thus the data on all critical data points are rich and detailed. The collection of data throughout the pregnancy and during infancy contributes to the accuracy and detail of the registry data. A final advantage of pregnancy registries is that they are well suited to studying newly marketed products with low market penetration, which are commonly not well represented in automated databases. Signal detection in a pregnancy registry can be more robust than in spontaneous reporting systems, which are the default source of event reporting at initial marketing.

Table 1. A quick summary of the methods of monitoring pregnancy drug exposures.			

One disadvantage of pregnancy registries is their voluntary nature. This design may lead to selection bias—women who choose to participate may be different from those who do not. For example, women who choose to participate may be motivated to participate because they are more educated and knowledgeable about the dangers of drug exposure in pregnancy, or because they may be at high risk for a poor pregnancy outcome. Losses to follow-up can also introduce bias if, for example, women who have a good outcome lose interest in participating and fail to provide follow-up data.  

Identifying an adequate comparator group may be one of the most challenging aspects of designing a pregnancy registry. There are two commonly used sources of comparator data: an actively enrolled group of pregnant women with the disease of interest who were not exposed to the drug of interest, and background rates from external surveillance sources or published literature. There are limitations to both approaches. It may be more logistically challenging and more costly to use internal comparators rather than external comparators. In addition, while use of prospectively enrolled internal comparators may appear to be a scientifically superior approach, registry participants are not randomized, and therefore the unexposed population may differ significantly from the exposed women. Relying on background rates may be the least desirable approach from a scientific standpoint but may be the only feasible option. A recent survey of pregnancy registries found that background rates, such as the Metropolitan Atlanta Congenital Birth Defects Program,

A multi-product design can simplify identification of a comparator because one product can be compared to another. Comparison with a population that is exposed to a different drug rather than completely unexposed can create obvious methodological problems. However, the two comparator populations are recruited and managed in the same way, and typically both have the disease of interest; thus, they are more comparable with one another than either is with published rates. When choosing a comparator, it may be necessary to strike a balance between scientific rigor, feasibility, and practicality. Using more than one comparator can improve the validity of the registry, and indeed, almost three-fourths of pregnancy registries use more than one comparator group.

Registries are typically more costly than database studies, primarily because registries have a prospective design, requiring set-up, regulatory and ethics approval, and follow-up. Enrollment rates are often unpredictable, and eligible patients are not always concentrated at specific sites, so recruitment must be sought from the population at large.

				 Consequently, the enrollment period for pregnancy registries is often lengthy, running for seven to 12 years, accruing in that time an average of 400 to 700 pregnancies exposed during the critical period of organogenesis in the first trimester. Sample size is limited; even when registries continue to enroll for a number of years, the sample size is generally sufficient to rule out only a major teratogenic effect, not specific defects.

The information collected by pregnancy registries has been used in product labeling and also used to support changes in the pregnancy risk categorization used in labeling. As an example, Acyclovir was initially designated as a category C drug (indicating that animal studies suggest risk but human data are lacking). After the Acyclovir pregnancy registry determined that birth defect rates in 749 pregnancies exposed in the first trimester were similar to those of the general population, the risk category was changed to B (indicating that animal studies suggest risk but human data are reassuring).

  The FDA has proposed a major overhaul to the pregnancy labeling system. Pregnancy registries promise to play an even greater role in the proposed new labeling system, which is aimed at better describing the benefits and risks of drug use for the mother and fetus, and emphasizes the importance of human data, including data collected in pregnancy registries. 

Pregnancy registries are well suited to multinational monitoring of the reproductive safety effects of pregnancy exposures in pharmaceutical products. Differences in countries' regulatory and ethics committee approval requirements vary, which can prove challenging to any global study. However, once country-specific approval has been obtained, a multinational pregnancy registry can capture consistent data by using the same methodology in each country. 

Large computerized databases show great promise for monitoring the effects of drug exposure in pregnancy. Computerized database studies are derived from existing databases, such as insurance claims databases (e.g., United Health), health maintenance organization (HMO) databases (e.g., Kaiser Permanente), or national databases (e.g., Danish Medical Birth Registry). These studies require availability of data on drug exposure, prenatal and obstetric outcome, and infant outcome. Such data are not always within the same database, and often multiple databases, such as a prescription database, an obstetric database, and a pediatric database, must be linked. Linkage may be difficult. Furthermore, the databases may not contain all of the necessary data. Additional chart reviews or supplemental questionnaires may be required to obtain sufficient detail to characterize the safety of drug exposure in pregnancy. 

Database studies offer a number of advantages over registries. For example, sample size is usually not a constraint, because the populations are very large. Database studies can also provide results more quickly than a registry, and they are typically less costly. Comparator groups are more easily identified and usually may be found within the same database. The comparator may be women who have the same underlying disease but were not exposed to the drug of interest; they may be unexposed or exposed to another drug. 

One of the main disadvantages of a database study is the difficulty pinpointing the time of exposure. Assessing drug safety during pregnancy requires establishing a temporal association between the exposure and the formation of the birth defect or other outcome of interest. In a database study, exposure is usually presumed from the date the prescription was filled, which does not necessarily indicate when the drug was taken. A woman may fill the prescription and decide not to take the drug. Conversely, a woman could be misclassified as not exposed if she takes the drug after obtaining it either with an old prescription not captured in the database or from a friend's prescription. Databases often lack much-needed detail on the birth outcome, necessitating use of chart reviews or questionnaires to supplement data with detail on outcomes or risk factors, potentially increasing costs and prolonging the study. Finally, database studies may not be well suited for newly marketed drugs with low market penetration, which are usually better studied with a pregnancy registry design. 

Another strategy to monitor safety of drug exposure in pregnancy is a case-control study. Case-control studies have a retrospective design, beginning with the outcome of interest. The cases are infants who have a particular birth defect or other outcome of interest, and controls are carefully selected from infants who do not have the outcome of interest but share other characteristics with the cases. The two groups are then compared with regard to exposure to the drug of interest, with controls for risk factors. While the typical approach focuses on a specific birth defect, multiple case-control studies conducted in parallel can broaden the focus.

Case-control studies are particularly well suited to studying rare events such as birth defects. This approach offers substantial statistical power to identify teratogens among relatively rare exposures.

  However, case-control studies are limited in their ability to identify a pattern of minor and major malformations characteristic of prenatal exposure to drugs with teratogenic potential.

  Furthermore, case-control studies are retrospective, assessing drug exposure and other risk factors after the fact. Case-control studies that rely on maternal interview for exposure data can introduce recall bias, because a mother of an affected infant may be able to recall medication use in early pregnancy more readily than a mother of an unaffected infant. Medical records may be used to verify or obtain data for case-control studies, but may lack detailed data on the exposure, such as timing, dose, and duration. It may be difficult to select an appropriate comparator group that is comparable to the cases in terms of the potential for exposure to the drug of interest during the time period of risk under consideration. In general, case-control studies may be less efficient and timely than database studies or pregnancy registries.

				 Finally, rates of birth defects in the exposed and unexposed populations cannot be determined in case-control studies. 

Case-control and database studies may also be conducted multinationally. However, it may be challenging to identify data sources across countries that use the same methods and data collection strategies to assure consistency of data. 

All studies designed to monitor the impact of drug exposures in pregnancy require regulatory and/or ethics committee approval. Studies that solicit data directly from patients and their health care providers, such as pregnancy registries and case-control studies, require patient consent. Database studies, however, do not typically require patient consent, because patient identifying information is typically stripped from the analysis data set provided to researchers. 

In conclusion, pregnancy registries, database studies, and case-control studies are all viable methods for monitoring product safety in pregnancy. There are definite advantages and disadvantages to the three types of studies. The choice between a registry, database, and case-control design will depend on the drug of interest and the primary objectives of the study. It is important to carefully weigh the strengths and weaknesses of each type of design in relation to the drug, the objectives, and other imperatives, such as the timing of study conduct, outcomes of interest, and available resources.  

While all three approaches are useful for monitoring drug safety in pregnancy, no single methodology is sufficient to assess completely the potential negative effects of drugs during pregnancy; it may be necessary to adopt multiple strategies. In some situations, when resources are available, it may be beneficial to conduct both a pregnancy registry and a longitudinal database study in parallel. This strategy may be useful if investigators suspect that infrequent exposure will constrain a pregnancy registry. The database study can document the exposure frequency and place pregnancy registry enrollment metrics into perspective for sponsors or regulatory agencies. Additionally, it may be necessary to use a database study or a case-control study to explore a signal identified in a registry. All three types of studies are valuable tools for monitoring the safety of biopharmaceutical product exposure during pregnancy.  

 DrPH, is Global Head of Observational Studies and Pregnancy Registries, e-mail: 

 MD, is Medical Director, Pharmacovigilance, at PPD, Inc., 929 North Front St., Wilmington, NC.

*To whom all correspondence should be addressed. 

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 European Medicines Agency (EMA), Guideline on the Exposure to Medicinal Products During Pregnancy: Need for Post-Authorization Data, (Committee for Medicinal Products for Human Use, 2005). 

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