David Blackman

Knowledge transfer in clinical drug development has followed a well-worn path from the mature research environments of North America and Europe to the developing regions of Eastern Europe, Asia and Latin America. Digital research technologies could well turn the tables, giving emerging nations an advantage in pioneering digital-based, operational models for 21st century clinical trials.  

	Digital research platforms-including the current integration of wearable mobile health (mHealth) devices with smartphones to facilitate data collection-promise improvements in both data quality and cost efficiency. Their adoption has been slowed by the need to integrate these fast-evolving technologies within existing research infrastructure and practice. Environments free of legacy systems have the advantage of building comprehensive, “right-by-design” digital and mHealth models spanning all trial operations. Such approaches will be best able to optimize the benefits of digital platforms to improve data accuracy and reduce reliance on costly clinic-based operations. At the same time, digital platforms will facilitate clinical trials in underserved populations where lack of infrastructure has made traditional research models unfeasible.

	While there are wide variations in maturity of industry, infrastructure and clinical capabilities, many believe the cumulative “blank-slate” opportunity is greatest in Africa, which accounts for about 15% of the world’s population but hosts only an estimated 0.9% of global clinical trials.

 Inadequate medical and research infrastructure has made clinical trials cost-prohibitive. Africa’s research landscape is maturing, however, due to economic growth and the rise of non-communicable diseases more characteristic of developed regions. 

	Africa’s population is expected to reach 2.4 billion by 2050.

 By 2020, non-communicable diseases, including cancer, diabetes, hypertension and cardiovascular disease will account for 65% of mortality.

 As demand for therapies to treat these conditions grows, Africa’s economies are growing as well. GDP is projected to rise to $3.3 trillion in 2020. And, according to a 2015 McKinsey report, Africa’s $20.8 billion pharmaceutical market could reach $60 billion by 2020.

	Africa’s research capabilities are now primed to enable digital trials designed for this special environment. An increasing number of major clinical trials are being supported by collaborations like The World Health Organization’s Special Programme for Research and Training in Tropical Diseases (TDR) and the European and Developing Countries Clinical Trials Partnership (EDCTP) are setting the stage. A 2007 EDCTP report identified qualified Phase II/III clinical sites in 19 sub-Saharan countries with capability to conduct trials in tuberculosis (TB), malaria and HIV.

 Infrastructure now can sustain studies like Wyeth’s 2009 river blindness trial in Ghana, Liberia and Democratic Republic of Congo,

 and the TDR cosponsored TB trial involving 1,800 patients across five countries, published in 2014.

	Digital research platforms have the potential to create a fully capable digital environment in Africa, especially when they incorporate wearable devices and telemedicine approaches that are designed to simplify the participation in a trial for patients and connect them to the best global scientific research regardless of their location. For instance, medical grade wearable sensors integrated with smartphones now enable accurate, continuous real-world data collection, independent of sparsely located clinical sites. Smartphones are widely used in African healthcare settings. Some 21 million new mobile subscribers were tallied in the first quarter of 2015 alone.

	Using today’s available technologies, the following discussion proposes an operational framework to support African-based digital studies across trial operations-from site initiation and patient enrollment through study conduct, data collection and site closeout. 

	In Africa, digital research platforms will have three fundamental requirements: cost-effective digital technologies to support operations across clients, service providers and investigative sites; reliable electrical power and Internet connectivity; and regulatory acceptance of and study compliance with digital technologies and approaches.

	Figure 1 below outlines a framework of digital capabilities currently used to conduct studies across three operational spheres: activities conducted by the client; activities conducted in collaboration with technology and service providers, primarily contract research organizations (CRO); and activities conducted by investigative sites. These technologies enable pre-trial intelligence (study feasibility and identification/recruitment of investigator sites); training for site personnel; study management; document management; drug supply management; and data management.

	Using these digital technologies, three operations centers would be sufficient to conduct all trial activities: 

-such as a project office at a university teaching hospital-would be responsible for study coordination.

-either central or remotely located-would conduct subsets of activities for multiple patients. These include central laboratories, imaging facilities and primary health clinics supporting treatment and follow-up.

 would conduct small subsets of tasks for a small set of patients. For example, community health workers administering surveys or collecting data during visits to patients’ homes. 

	Figure 2 below details the necessary infrastructure requirements for participating study centers, which includes access to electrical power, network Internet connectivity, physical security to protect study materials and data, and the ability to control access to essential data.

	Access to power and Internet communications typically are barriers to conducting trials in Africa. The digital platform suggested here would increase the feasibility of African-based trials since lower levels of access are sufficient for different

 operational centers. Only the central study office would require continuous power and connectivity. Field offices and operations would need daily access but could fully meet study responsibilities with intermittent power and Internet access, as illustrated in Figure 3 at right.  

	While not losing sight of the challenges that still need to be overcome to address political instability, corruption and the absence of reliable shipping and storage facilities for clinical trial supplies in some regions, Africa is evolving. The regulatory environment is maturing through standards and practices specifically pertaining to Africa with, for example, ethical guidelines developed by the Swiss Tropical and Public Health Institute (Swiss TPH)

 and a regional trial registry created by the Pan African Clinical Trials Registry (PACTR).

	Historically, sponsors have conducted African trials in compliance with the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA) and other global standards. Regulations are emerging to guide the implementation of digital approaches, but regulators are hard-pressed to stay current with fast-moving digital and mHealth technologies. FDA issued guidances in 2014 and 2015 presenting regulatory views on the use of mHealth devices in clinical trials.

 Other pertinent guidelines include: FDA guidance on use of electronic source (eSource) data (2013)

; standards for eSource data standards of the Clinical Data Interchange Standards Consortium (CDISC)

; and EMA’s reflection paper on eSource data and EDC tools (2010).

	This proposed operational framework for digital-based clinical trials in Africa is intended as a starting point toward three important goals: expanding drug development research in underserved African populations; laying the technology groundwork for developing and building scientific expertise; and piloting “right-by-design” digital research approaches in a blank-slate environment free of legacy infrastructures that slow adoption of disruptive methodologies. The technologies described in this article are available now. Their utility and benefits have been demonstrated, and they currently are used in clinical trials to improve data collection, data management, safety monitoring and informed consent. Africa offers a compelling opportunity to pilot digital and mHealth research platforms to revolutionize clinical trial operations worldwide.

	1. M. Bairu and R. Chin (eds.), “Global Clinical Trials Playbook: Capacity and Capability Building,” Elsevier, Academic Press, London, 2012. 

	2. Population Reference Bureau, “World Population Data Sheet 2014,” 

http://www.prb.org/Publications/Datasheets/2014/2014-world-population-data-sheet/data-sheet.aspx

	3. World Health Organization, “Non Communicable Disease Prevention and Control Overview, Regional Office for Africa,” 

http://www.afro.who.int/en/clusters-a-programmes/dpc/non-communicable-diseases-managementndm/overview.html 

	4. T. Holt, M. Lahrichi, J. Mina and  J.S. DaSilva, “Insights into Pharmaceuticals and Medical Products. Africa: A Continent of Opportunity for Pharma and Patients,” McKinsey and Company, 2015

	5. S. Agwale, “Identification of Credible Clinical Trials Sites in Africa,” Second DCC/ENNP Joint Meeting, Douala, May 9, 2007, 

http://www.edctp.org/fileadmin/documents/NOE_-_Simon_Agwale.pdf  

	6. World Health Organization, “New Drug Being Tested in Africa for River Blindness,” News Release, July 2009,  

http://www.who.int/mediacentre/news/releases/2009/river_blindness	_20090701/en/ 

	7. World Health Organization, “Boost for Research Capacity in West Africa Tropical Disease Research,” News Release, October 2014, 

http://www.who.int/tdr/news/2014/research-capacity-west-africa/en/ 

	8. Ericsson Mobility Report, June 2015,  

http://www.ericsson.com/res/docs/2015/ericsson-mobility-report-june-2015.pdf 

	9. Training and Resources in Research Ethics Evaluation (TRREE), 

	10. The Pan African Clinical Trials Registry (PACTR), 

	11. U.S. Food and Drug Administration, “Draft Guidance for Industry: Intent to Exempt Certain Class II and Class I reserved Medical Devices from Premarket Notification Requirements,” August 2014, 

http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-meddev-gen/documents/document/ucm407292.pdf 

	12. U.S. Food and Drug Administration, “Guidance for Industry: Mobile Medical Applications,” February 2015, 

http://www.fda.gov/downloads/MedicalDevices/.../UCM263366.pdf  

	13. U.S. Food and Drug Administration, “Guidance for Industry: Electronic Source Data in Clinical Investigations,” September 2013,  

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatory	information/guidances/ucm328691.pdf 

	14. Clinical Data Interchange Standards Consortium (CDISC), “Electronic Source Data Interchange (eSDI) Group: Leveraging the CDISC Standards to Facilitate the Use of Electronic Source Data within Clinical Trials,” November 2006,  

http://www.cdisc.org/system/files/all/reference_material_category/application	/pdf/esdi.pdf

	15. European Medicines Agency, “Reflection Paper on Expectations for Electronic Source Data and Data Transcribed to Electronic Data Collection Tools in Clinical Trials,” June 2010, 

http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and	_procedural_guideline/2010/08/WC500095754.pdf 

Articles

A proposed operational framework to support digital- and mHealth-based clinical trials in Africa.

Africa a Ripe Proving Ground for Digital Health

The rapid consumer adoption of wearable devices for the collection of health data is laying the foundation for the next revolution in clinical trial operations. The integration of wearable health monitors with smartphones offers capabilities to collect continuous, accurate health data in real time. This emerging digital research platform has the potential to increased data accuracy and timeliness, improve operational efficiencies, and achieve greater patient engagement in the clinical trial process.

	In the burgeoning consumer market, more than 97,000 mHealth apps were available to consumers by 2013.

 Health and wellness devices like the FitBit wristband and the Misfit Wearables clothing tag conveniently track physical activity based on smartphone and GPS technology. Apple is developing a biometric headphone system to monitor vital signs while the wearer listens to music.

	Broad consumer use of such devices is building familiarity and will facilitate the implementation of similar medical grade devices in clinical studies. Anticipating this future, major technology companies are entering the clinical research space. Google recently developed a health-tracking wristband for use in clinical trials capable of measuring pulse, heart rhythm, skin temperature, light exposure, and noise levels.

 The new Apple ResearchKit offers a software platform that allows researchers to create apps to manage data collected via wearable devices and smartphones.

	Medical grade monitoring devices now support patient care in most therapeutic areas including gerontology and chronic disease. Devices are available that monitor respiration, oxygen saturation, ECG, blood pressure, skin and core temperature, and galvanic skin response. Other devices transmit patient measurements directly to caregivers using

 Bluetooth technology. A number of technologies are available to monitor drug adherence. For example, ingestible monitors are available that collect data on medication ingestion, dose timing and physiologic responses, then transmit measurements to the patient’s smartphone. In our experience, we are seeing more and more biopharma and technology companies partnering to launch mHealth apps that monitor conditions ranging from diabetes to heart attacks.

	In clinical trial applications, electronic patient-reported outcome (ePRO) companies are integrating wearable devices to advance data collection by adding objective data points to subjective PROs. For example, one company offers ePRO software for mobile devices with apps on Android, Windows 8, and iOS. Another company offers dedicated mobile devices for use in clinical trials, including site-based devices and “bring-your-own-device” options that allow patients to use their own smartphone apps.

mHealth in Clinical Trials: Benefits and challenges

	Clinical trial models based on the integration of wearable devices and smartphones are in their infancy, but early applications demonstrate compelling benefits, including:

		Real-world, continuous measurement of health status as subjects follow their daily routines; opportunities to build richer patient health profiles

		Accurate measurements to improve patient-reported outcomes (PRO); deliver time-marked data to compare and verify PROs

		Improvement in subject retention by delivering prompts, encouraging compliance, sharing information; more convenience to encourage research participation

		Reduced costs by decreasing the need for expensive clinic visits

	An increasing number of trials use mobile devices or applications in therapeutic areas ranging from asthma and cancer to schizophrenia and diabetes. Results from the comparative Mobile Diabetes Intervention Study of 163 patients found that adding a mobile patient coaching application, together with feedback on personalized analysis of blood glucose data and lifestyle behaviors via smartphones, substantially lowered glycated hemoglobin levels for more than a year.

 The long-term Healthy eHeart Study will combine use of social media, smartphones and wearable mHealth devices with clinic visits to develop more accurate predictions of heart disease, while creating personalized tools to forecast patients’ risk and disease progression.

	According to a 2015 SCORR/Applied Clinical Trials survey of CROs and other service providers, mHealth’s greatest benefits will come from improving data accuracy and patient experience.

 A growing body of research is evaluating mHealth capabilities to improve subject retention and reduce site management costs. With dropout rates as high as 30%

 and site management costs as high as $2,500 per month,

data collection based on integrated wearable devices and smartphones could reduce site dependence and deliver significant cost reductions.

	Drug developers identify five major challenges in the adoption of mHealth technologies in clinical trials:

		Adoption costs and demonstration of return on investment

		Implementing mHealth technology on a global scale

	Evolving regulation will help drive adoption of mHealth-based research models. In this fast-moving environment, however, regulators are hard-pressed to keep guidance current and industry informed regarding the accepted use of these new technologies in the setting of regulatory submissions and product registration. The U.S. Food and Drug Administration has issued two sets of guidance (in 2014 and 2015, respectively) presenting regulatory views on use of mHealth technologies in clinical trials.

These evolving guidelines, together with regulatory consultation, can help sponsors determine regulatory acceptance of a given mHealth application in a specific trial setting.

Pilot Study: Evaluating feasibility of a wearable device in data collection 

	The ultimate goal of this transformative technology is to exceed standards for data quality and study efficiencies delivered by the current “gold standard” operational models. The application of wearable devices in clinical trials is beginning with feasibility evaluations to determine how mHealth technologies can be deployed effectively.

	PPD participated in a collaborative, early-stage feasibility study of a wearable device-plus-smartphone application. Its goal was to evaluate the usability of the interface in data collection; training requirements for appropriate use of the mHealth technologies; and the impact of the model on data quality and patient engagement.

	The feasibility study was conducted as a second, mHealth-enabled arm of a large observational study. In this arm, a subset of patients used two wearable monitors: one measured blood pressure, while the second measured patient activity. Smartphones equipped with Bluetooth-enabled links transmitted and tracked the data from the wearable devices to an investigator portal. Patients received medications, the wearable device-plus-smartphone technologies, and training to use the devices and smartphones correctly.

	The goal was to test as many hypotheses surrounding the uses and types of wearable technologies as possible. For example, some patients received smartphones provided by the research team with the study mobile app installed; others downloaded the study mobile app to their own smartphones. Patients were instructed to wear the activity monitor at all times and to take their blood pressure from the wearable device at scheduled times. This allowed for the analysis of data consistency, reliability and compliance from patients on data that is transmitted constantly and automatically-without any action by the patient-with data that needed patient interaction at scheduled times. Measurements were aggregated for use in feasibility and operational future studies.

	The volume of health data generated by mHealth devices will be transformative across the entire health care spectrum, from wellness and prevention to treatment and research. During the next five years, mHealth technologies will mature to enable advanced research models, including cloud-based health databases of continuously uploaded patient data and Internet-based trials conducted remotely. This future envisions “mTrials” that use wearable devices, smartphone and tablet apps, and patient-physician interactions via telemedicine to collect accurate data in real time. The immediate challenge is to integrate mHealth technologies into global research processes, and to learn how best to apply and interpret the data tsunami they are about to deliver.

, is Senior Vice President of Biostatistics, Programming, Medical Writing and Innovation, PPD; 

	1. PriceWaterhouseCooper, “Emerging mHealth: Paths for Growth,” Global Research Study 2012, 

https://www.pwc.com/gx/en/healthcare/mhealth/assets/pwc-emerging-mhealth-full.pdf 

	2. J.E. Andrews and J.B. Moore, “Mobile Technology in Human Research,” 

Journal of Clinical Research Best Practices

	3. M. Campbell, “Apple Patents Sensor-packed Health Monitoring Headphones with ‘Head Gesture’ Control,” AppleInsider.com, February 18, 2014, 

http://appleinsider.com/articles/14/02/18/apple-patents-sensor-packed-health-monitoring-headphones-with-head-gesture-control

	4. S. McKee, “Google’s Wristband Tracker to be Fit for Clinical Research,” 

http://www.pharmatimes.com/article/15-06-23/Google_s_wristband_tracker_to_be_fit_for_clinical_research.aspx

	5. Apple ResearchKit, “Now Everybody Can Do Their Part to Advance Medical Research,” 

	6. C.C. Quinn, M.D. Shardell, M.L. Terrin et al, “Cluster-randomized Trial of a Mobile Phone Personalized Behavioral Intervention for Blood Glucose Control,” 

	7. Health eHeart Study, “What Makes This Study Different?” 

https://www.health-eheartstudy.org/study 

, “Mobile Health in Clinical Trials Survey Report,” 2015, 

http://www.scorrmarketing.com/resources/mobile-health-in-clinical-trials/

	9. National Academy of Sciences, “The Prevention and Treatment of Missing Data in Clinical Trials,” Washington, D.C. National Academies Press, 2010. 

http://www.nap.edu/openbook.php?record_id=12955&page=14 

	10. M.J. Lamberti, C. Brothers, D. Manak, K. Getz, “Benchmarking the Study Initiation Process,” T

herapeutic Innovation & Regulatory Science

	11. U.S. Food and Drug Administration, “Draft Guidance for Industry: Intent to Exempt Certain Class II and Class I reserved Medical Devices from Premarket Notification Requirements,” August 2014 

http://www.fda.gov/downloads/MedicalDevices/.../UCM263366.pdf

Pilot study evaluates the feasibility of using wearable devices in clinical data collection, including the training requirements for appropriate use of the mHealth technologies and the impact of the model on data quality and patient engagement.

David Blackman

Articles

Africa a Ripe Proving Ground for Digital Health

The Growing Availability of Wearable Devices: A Perspective on Current Applications in Clinical Trials