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The time has come for “Real-World Studies” (RWS)
Clinical eHealth 1 (2018) 28–29
Contents lists available at ScienceDirect
Clinical eHealth journal homepage: ww.keaipublishing.com/CEH
The time has come for ‘‘Real-World Studies” (RWS) Ningfang Wang a,b, Mark Heitner c, Chunxue Bai a,b,⇑ a
Zhongshan Hospital, Fudan University, Shanghai 200032, China Shanghai Respiratory Research Institute, Shanghai 200032, China c HealthSolutions, San Francisco, CA 94118, USA b
a r t i c l e
i n f o
Article history: Received 3 November 2017 Revised 2 August 2018 Available online 22 November 2018
a b s t r a c t The time has come for ‘‘real-world studies (RWS)” to assume its rightful place in clinical trials. RWS have a broader and more representative scope than randomized controlled trial (RCT) (Roy-Byrne et al., 20031). We discuss how the medical Internet of Things (IoT) (Bai, 20142) helps RWS overcome its shortcomings while satisfying real-world evidence (RWE) requirements (Sherman et al., 20143). Ó 2018 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).
Opportunity and limitation of RWS RCT tests drug or therapy effects by following the three principles of randomness, control, and replication. The detailed inclusion and exclusion enrollment criteria of RCT, which closely restricts the participants’ age, diseases and concomitant drugs, rarely anticipate the realistic circumstances of widespread use of drugs subsequent to RCT. RWS focuses on the actual use of drugs in a much larger patient population than RCT. Patients are non-randomly selected. The goal of RWS is clarifying the long term effectiveness and safety of clinical interventions. Researchers observe and document changes in drug use in RWS. They do not interfere with customary clinical treatment. The RWS database lends itself to the discovery of chronic, unanticipated or uncommon drug reactions and to the detection of new indications. In addition, RWS covers a broader range of diagnostic and prognostic studies, making it easier to translate research findings into clinical practice. The large sample size of current RWS creates problems of high cost, time-consuming data collection, and errors in registry analysis. The US FDA published ‘‘Real-World Evidence-What Is It and What Can It Tell Us?‘‘ in ‘‘The New England Journal of Medicine” to address these issues.3 The FDA notes that RWE was not equal to no intervention or randomization in the experiment design. The FDA recommended that strict scientific standards should be followed in approval of RWE. The FDA indicated that RWE provide
⇑ Corresponding author at: Zhongshan Hospital, Fudan University, Shanghai 200032, China. E-mail address: [email protected] (C. Bai).
scientific evidence on par with traditional clinical trials, in the context of data acquisition, rather than the design similar to RCT. The FDA recommended that RWE should consider two types of challenges, data acquisition and research methods. Nevertheless, it is still difficult for current RWS to obtain scientific data of the safety of patients while evaluate its effectiveness at the same time. The amount of data required for RWS studies is quite large. It is difficult to for RWS to simultaneously of drug effectiveness and drug safety.
Solutions to the difficulties of RWS In order to meet the requirements of FDA, it is a great challenge for both RWS and RWE to evaluate the safety of the tested patients in all circumstances, while simultaneously validating the study. Fortunately, the development of IoT technology has brought new opportunities of solving this problem. IoT is the expanded network of Internet enabled connected objects. This network makes it possible to exchange information and communication between smart objects.4 IoT is widely used in network integration through communication technologies such as intelligent perception, recognition and pervasive computing. With the help of three major processes (comprehensive perception, reliable transmission, and intelligent processing of information from both subjects and researchers and ten basic functions of IoT (Table 1) integrated into them, current clinical trials could evolve into Internet-assisted RWS that is more scientific, safer and more effective. Compared with the conventional RCT, there are many changes in the RWS and RWE with IoT:
https://doi.org/10.1016/j.ceh.2018.10.001 2588-9141/Ó 2018 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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N. Wang et al. / Clinical eHealth 1 (2018) 28–29 Table 1 Ten Advantages of IoT in clinical trials. Online monitoring
Monitoring patient responses and conducting clinical trials online, including individualized clinical trials Suitable for clinical trials at home; using sensors, mobile terminals, home intelligent facilities and video surveillance systems to monitor the subjects and ensure their safety Providing alarm for vital signs; three level linkages (researchers, subjects and families) to ensure safety Monitoring safety and standardizing implementation of clinical trial protocols Presetting regulations of clinical trial management, all-time management and timely disposal Providing users or subjects confidence about their data integrity A much larger clinical trial can be created, thereby serving the needs of researchers and subjects Ensuring the normal operation of the IoT clinical trial system and its automatic updates of the IoT system Helping both researchers and subjects to better solve clinical problems, especially when PI need provide decision-making advice, such as to determine the adverse reactions Supporting PI to propose solutions to the clinical emergency and to real time make strategic and tactical decision
Location tracking
Alarm linkage Command and control Program management Security & privacy Remote maintenance Online update Operator Interface
Decision making
Data centre
Mobile terminal
5G/WiFi
PI
Doctor PC
Device USB/ Bluetooth
5G/ WiFi Mobile terminal
Internet Cloud plaorm
Paents
PC
Fig. 1. Overview of the mobile phone-based Internet of Things (mIoT) platform. Physiological parameters are collected from a patient and transmitted through Bluetooth to the patient’s mobile terminal. It is further transmitted from the mobile device to the mIoT platform via WiFi or the fifth generation (5G) network. The platform software analyzes data and yields results, which are stored in the system and transmitted to the physician’s mobile terminals. Medical staff may then modify the results and provide feedback to patients. Patients, general practitioners in community hospitals, and specialists in medical centers may communicate via mobile terminals.
Mode shift – The clinical trial center can be combined with all networked clinical trial units to improve the reach of clinical trials. All space-time-Real-time online clinical trials and management could be conducted anytime and anywhere. Full cycle – Clinical trials can be run throughout a patient’s lifetime. Lifelong clinical trial files would be established in the cloud servers for future RWS and RWE’s references. Individualization – Personalized clinical trials and management programs are created for different scenarios. Quality control – Digitalization of clinical trials can assure implementation of high standard methods. Applying IoT to clinical trials Equipment and cloud computing software such as mobile and desktop platforms, wearable devices and cloud computing software are configured to form a real-time interaction of clinical pharmacology databases, researchers and subjects (Fig. 1).5 This will enable uploading the data of the subjects or clients to clinical pharmacology databases by the sensors or IoT. Corresponding feedback
can be provided to clinical trials managers. With large-scale data storage, deep processing and mining of massive information the management of RWS will be more sophisticated, dynamic, and intelligent. The efficacy of the trial will fully satisfy the FDA requirements of RWS and RWE. The real time approach of IoT-based research will help clinical trials to become more scientific, safer and more effective RWS.
References 1. Roy-Byrne PP, Sherbourne CD, Craske MG, et al. Moving treatment research from clinical trials to the real world[J]. Psych Serv. 2003;54(3):327–332. 2. Bai Chunxue. Practical internet of things (Chinese) [M]. Beijing: People’s Health Publisher; 2014. 3. Sherman RE, Anderson SA, Dal Pan GJ, et al. Real-world evidence – what is it and what can it tell us?[J]. New England J Med. 2016;23(375):2294–2297. 4. Steele R, Clarke A. The internet of things and next-generation public health information systems[J]. Commun Netw. 2013;5:4–9. 5. Zhang J, Song Y, Bai C. MIOTIC study: a prospective, multicenter, randomized study to evaluate the long-term efficacy of mobile phone-based Internet of Things in the management of patients with stable COPD[J]. Int J COPD. 2013;8:433–438.
Contents lists available at ScienceDirect
Clinical eHealth journal homepage: ww.keaipublishing.com/CEH
The time has come for ‘‘Real-World Studies” (RWS) Ningfang Wang a,b, Mark Heitner c, Chunxue Bai a,b,⇑ a
Zhongshan Hospital, Fudan University, Shanghai 200032, China Shanghai Respiratory Research Institute, Shanghai 200032, China c HealthSolutions, San Francisco, CA 94118, USA b
a r t i c l e
i n f o
Article history: Received 3 November 2017 Revised 2 August 2018 Available online 22 November 2018
a b s t r a c t The time has come for ‘‘real-world studies (RWS)” to assume its rightful place in clinical trials. RWS have a broader and more representative scope than randomized controlled trial (RCT) (Roy-Byrne et al., 20031). We discuss how the medical Internet of Things (IoT) (Bai, 20142) helps RWS overcome its shortcomings while satisfying real-world evidence (RWE) requirements (Sherman et al., 20143). Ó 2018 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).
Opportunity and limitation of RWS RCT tests drug or therapy effects by following the three principles of randomness, control, and replication. The detailed inclusion and exclusion enrollment criteria of RCT, which closely restricts the participants’ age, diseases and concomitant drugs, rarely anticipate the realistic circumstances of widespread use of drugs subsequent to RCT. RWS focuses on the actual use of drugs in a much larger patient population than RCT. Patients are non-randomly selected. The goal of RWS is clarifying the long term effectiveness and safety of clinical interventions. Researchers observe and document changes in drug use in RWS. They do not interfere with customary clinical treatment. The RWS database lends itself to the discovery of chronic, unanticipated or uncommon drug reactions and to the detection of new indications. In addition, RWS covers a broader range of diagnostic and prognostic studies, making it easier to translate research findings into clinical practice. The large sample size of current RWS creates problems of high cost, time-consuming data collection, and errors in registry analysis. The US FDA published ‘‘Real-World Evidence-What Is It and What Can It Tell Us?‘‘ in ‘‘The New England Journal of Medicine” to address these issues.3 The FDA notes that RWE was not equal to no intervention or randomization in the experiment design. The FDA recommended that strict scientific standards should be followed in approval of RWE. The FDA indicated that RWE provide
⇑ Corresponding author at: Zhongshan Hospital, Fudan University, Shanghai 200032, China. E-mail address: [email protected] (C. Bai).
scientific evidence on par with traditional clinical trials, in the context of data acquisition, rather than the design similar to RCT. The FDA recommended that RWE should consider two types of challenges, data acquisition and research methods. Nevertheless, it is still difficult for current RWS to obtain scientific data of the safety of patients while evaluate its effectiveness at the same time. The amount of data required for RWS studies is quite large. It is difficult to for RWS to simultaneously of drug effectiveness and drug safety.
Solutions to the difficulties of RWS In order to meet the requirements of FDA, it is a great challenge for both RWS and RWE to evaluate the safety of the tested patients in all circumstances, while simultaneously validating the study. Fortunately, the development of IoT technology has brought new opportunities of solving this problem. IoT is the expanded network of Internet enabled connected objects. This network makes it possible to exchange information and communication between smart objects.4 IoT is widely used in network integration through communication technologies such as intelligent perception, recognition and pervasive computing. With the help of three major processes (comprehensive perception, reliable transmission, and intelligent processing of information from both subjects and researchers and ten basic functions of IoT (Table 1) integrated into them, current clinical trials could evolve into Internet-assisted RWS that is more scientific, safer and more effective. Compared with the conventional RCT, there are many changes in the RWS and RWE with IoT:
https://doi.org/10.1016/j.ceh.2018.10.001 2588-9141/Ó 2018 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
29
N. Wang et al. / Clinical eHealth 1 (2018) 28–29 Table 1 Ten Advantages of IoT in clinical trials. Online monitoring
Monitoring patient responses and conducting clinical trials online, including individualized clinical trials Suitable for clinical trials at home; using sensors, mobile terminals, home intelligent facilities and video surveillance systems to monitor the subjects and ensure their safety Providing alarm for vital signs; three level linkages (researchers, subjects and families) to ensure safety Monitoring safety and standardizing implementation of clinical trial protocols Presetting regulations of clinical trial management, all-time management and timely disposal Providing users or subjects confidence about their data integrity A much larger clinical trial can be created, thereby serving the needs of researchers and subjects Ensuring the normal operation of the IoT clinical trial system and its automatic updates of the IoT system Helping both researchers and subjects to better solve clinical problems, especially when PI need provide decision-making advice, such as to determine the adverse reactions Supporting PI to propose solutions to the clinical emergency and to real time make strategic and tactical decision
Location tracking
Alarm linkage Command and control Program management Security & privacy Remote maintenance Online update Operator Interface
Decision making
Data centre
Mobile terminal
5G/WiFi
PI
Doctor PC
Device USB/ Bluetooth
5G/ WiFi Mobile terminal
Internet Cloud plaorm
Paents
PC
Fig. 1. Overview of the mobile phone-based Internet of Things (mIoT) platform. Physiological parameters are collected from a patient and transmitted through Bluetooth to the patient’s mobile terminal. It is further transmitted from the mobile device to the mIoT platform via WiFi or the fifth generation (5G) network. The platform software analyzes data and yields results, which are stored in the system and transmitted to the physician’s mobile terminals. Medical staff may then modify the results and provide feedback to patients. Patients, general practitioners in community hospitals, and specialists in medical centers may communicate via mobile terminals.
Mode shift – The clinical trial center can be combined with all networked clinical trial units to improve the reach of clinical trials. All space-time-Real-time online clinical trials and management could be conducted anytime and anywhere. Full cycle – Clinical trials can be run throughout a patient’s lifetime. Lifelong clinical trial files would be established in the cloud servers for future RWS and RWE’s references. Individualization – Personalized clinical trials and management programs are created for different scenarios. Quality control – Digitalization of clinical trials can assure implementation of high standard methods. Applying IoT to clinical trials Equipment and cloud computing software such as mobile and desktop platforms, wearable devices and cloud computing software are configured to form a real-time interaction of clinical pharmacology databases, researchers and subjects (Fig. 1).5 This will enable uploading the data of the subjects or clients to clinical pharmacology databases by the sensors or IoT. Corresponding feedback
can be provided to clinical trials managers. With large-scale data storage, deep processing and mining of massive information the management of RWS will be more sophisticated, dynamic, and intelligent. The efficacy of the trial will fully satisfy the FDA requirements of RWS and RWE. The real time approach of IoT-based research will help clinical trials to become more scientific, safer and more effective RWS.
References 1. Roy-Byrne PP, Sherbourne CD, Craske MG, et al. Moving treatment research from clinical trials to the real world[J]. Psych Serv. 2003;54(3):327–332. 2. Bai Chunxue. Practical internet of things (Chinese) [M]. Beijing: People’s Health Publisher; 2014. 3. Sherman RE, Anderson SA, Dal Pan GJ, et al. Real-world evidence – what is it and what can it tell us?[J]. New England J Med. 2016;23(375):2294–2297. 4. Steele R, Clarke A. The internet of things and next-generation public health information systems[J]. Commun Netw. 2013;5:4–9. 5. Zhang J, Song Y, Bai C. MIOTIC study: a prospective, multicenter, randomized study to evaluate the long-term efficacy of mobile phone-based Internet of Things in the management of patients with stable COPD[J]. Int J COPD. 2013;8:433–438.