Chris Watson

It is widely accepted that electronic clinical outcome assessments (eCOA) are the preferred means of collecting participant data. In traditionally designed, site-based studies, eCOA has proven to be an effective method for capturing high-quality data while meeting all necessary regulatory requirements. Today, the use of electronic patient-reported outcomes (ePROs) and electronic clinician-reported outcomes (eClinROs), two of the most utilized eCOAs across all studies and all therapeutic areas, are commonplace.

While many eCOAs are still taken during in-person clinic visits, the flexibility of the electronic platforms proves valuable. This allows study teams to gather participant data, including regular quality-of-life measures, more frequently and cost effectively while maintaining compliance.

Digital collection and submission of outcome assessments are a natural fit for today’s decentralized clinical trials (DCTs). One of the key advantages of DCTs is the ability to expand participant recruitment beyond the geographical limitations common in site-based clinical studies. This allows sponsors to reach a much wider range of participants, including those living in rural areas located great distances from study center hospitals. This is significant, with more than 70% of clinical trial participants living two or more hours away from a study center. This is obviously beneficial for those seeking to conduct large, global studies while finding the most inclusive group of participants possible and is particularly useful for recruiting and enrolling optimized participant groups for rare disease trials. With DCTs, eCOA is useful in monitoring and managing participants spread out over great distances, as remote assessments help to minimize the number of in-person visits.

That said, global DCTs also present specific challenges for eCOA that should be considered and addressed to ensure study success. This article will discuss learnings and insights for sponsors conducting global DCTs

 Data security is a challenge for all industries that process and store data digitally. A recent poll taken of stakeholders in the clinical trials industry showed that 32% of respondents reported that concerns about data security was their primary barrier to using more digital technologies in clinical research. For DCTs and hybrid studies to work efficiently, data needs to be captured remotely from participants and other users, increasing both the risk of data incidents and the need for effective controls to maintain data integrity.

To keep data secure, numerous regulations and laws exist around the world that spell out the various approaches that need to be taken and safeguards that need to be in place. In healthcare, where data including personal health information is particularly sensitive, strict regulations must be acknowledged and followed. These regulations vary from country to country.

This can be a challenge for global trials, as the regulations for each country in which a participant lives must be adhered to. For example, in trials where participants live exclusively in the United States, all eCOA activity—ranging from participant-entered data to assessments recorded during telehealth visits, must be compliant with patient privacy regulations such as HIPAA (Health Insurance Portability and Accountability Act). For trials that involve participants living in the European Union and United Kingdom, GDPR (The General Data Protection Regulation) is an even more strict set of regulations designed to keep all personal data (not only health-related information) of EU citizens private and secure. GDPR equivalent regulations are now in place within Asia-Pacific countries as well.

 When conducting global clinical trials, there is no such thing as one-size-fits-all eCOA. For each country represented by participants in a study, eCOA must be available in the appropriate languages and dialects. To maintain content validity, there needs to be a consistent presentation for all languages. Simply translating from one language to another is not realistic—validated eCOA has approved translations for use which have gone through rigorous equivalence testing. Thought must be given to how each language will reflect in the presentation of the eCOA instrument and how this will be impacted on screens ranging in size from smartphone screens to laptop and desktop monitors. Each language must be presented in a way that maintains the validity and intuitiveness and ease-of-use of eCOA applications. At the same time, content needs to mirror how the user actually speaks while avoiding terms or words that might be offensive in certain regions of specific countries. In any case where a translation does not exist, and where approval of the new language is not required by the scale author (e.g., questionnaires, surveys, eDiaries, etc.), it is useful to seek out translation vendors who can provide linguistic validation to ensure that the proper meaning and intent of the content is in place.

The translation process should not be underestimated; such processes can be complex. Choosing experienced vendors to manage this process on your behalf can simplify the experience for you and reduce or eliminate any potential language-specific user issues. Following is an example of a translation workflow for eCOA:

 The source content and, more importantly, the context around the intent of how the content will be used is shared with the translator, who then translates the content (preserving meaning and intent) into the desired language.

 Localized dialect experts ensure that the translation is optimized for the intended target population.

 The forward translation is reviewed and edited (as necessary) by a different translator.

 The forward version is translated back into the source language and checked to ensure that the original intent and meaning of the content are preserved.

 The final version is submitted for review to all relevant parties, including sponsor and clinical team members

These steps will need to be repeated for every language—and dialect of each language—involved in the study. For large, widespread global studies, this is quite an undertaking. The right translation vendor, again, can help manage and simplify this process.

Despite the previously mentioned challenges, eCOA is an accepted interface for global data collection and is a standard feature within DCT. eCOA can be conducted in a variety of ways while maintaining the “fit-for-purpose” validation requirements set by regulators. For example, a majority of eCOA can be conducted via virtual telehealth visits that are device agnostic, do not require provisioned devices, and allow the users (participants, caregivers, home health nurse, etc.) to be anywhere while conducting the assessment. This adds flexibility to the process while meeting all eCOA license holder requirements such as user interface specifications, form factor restrictions, and process steps.

eCOA, combined with specialized telehealth platforms, can digitally recreate much of the in-person visit experience. Using the video and audio recording capabilities of a standard handheld device, for example, assessments of participant movement and vocal characteristics can be made remotely.

To realize the benefits of eCOA in global decentralized and hybrid trials, we must overcome the security, privacy and user-related challenges discussed earlier. Having helped sponsors and CROs (contract research organizations) perform hundreds of DCTs over the years, THREAD has developed some best practices for how to optimize eCOA in these studies.

Seek out systems with built-in privacy and security: 

Countries around the world present different sets of regulations regarding data security and privacy. Some are more stringent than others, so it is important to ensure that any software or platform vendors adhere to the most stringent regulations across your trial portfolio, irrespective of where any one single study is being conducted. eCOA platforms that are designed from the ground up with this in mind can help to address these differences. For example, GDPR is one of the strictest sets of restrictions regarding personal data in the world. By developing an eCOA platform that meets the strict standards of GDPR, a vendor will also meet or exceed any other sets of less-stringent regulations used in other parts of world. An example would be a vendor who utilizes advanced tokenization strategies to effectively mask all personally identifiable information (PII). Tokenization is a process by which PII is collected, only when necessary, directly from the participant and then immediately tokenized—or masked—and encrypted. In this way, all participant identification data is obscured immediately and completely.

Going digital also raises concerns around what security standards are applied to your data sets and what measures need to be taken to minimize data incidents. Choosing platforms built from the beginning with a cloud infrastructure can protect data from breaches.

Provide localized expertise and support to help global DCT eCOA run smoothly, study leaders should involve local experts and support in the regions of the world where participants are located. This helps to mitigate regional challenges like navigating country-specific regulations, different languages and dialects, and cultural norms.

Local knowledge enables sponsors—and any vendors helping them to conduct studies—to be aware of any changes in the regulatory landscape before they occur. This is essential to keeping each region involved in a global trial running smoothly.

Language translation and use of correct regional dialects are much easier to achieve if you have native speakers on the ground in those areas. These professionals—who can be employees or contractors—can help to confirm that the language has been accurately translated in a way that preserves the intent and meaning of the eCOA application while respecting any and all relevant cultural idiosyncrasies of the participant population. This is true for eCOA application content, of course, but also is necessary for all participant/user study materials including training manuals, interface user guides, process walkthroughs and more.

Region-based support is critical for participants and other users (caregivers, clinicians, etc.) who may need assistance with the applications, the devices, or other challenges associated with their eCOA responsibilities. Providing access to expert support in the native language and dialect helps to solve issues quickly and keep participants on track.

Use participant-friendly, intuitive technologies:

 Easy-to-use technologies are a must for successful eCOA in any type of study. For global studies, intuitive interfaces are critical to keeping the stream of eCOA data flowing. Comprehensive applications anticipate the most common needs of users and offer a focused user interface similar to those found in the kinds of consumer applications that the study population is already familiar and comfortable with. Intuitive interfaces reduce the need for user training and minimize the potential for human error. Structured screen presentation helps to onboard new users, guiding them through instructional screens that serve to educate them on what is required for study participation. Moving later into the study, the same kind of screen flow and support functions help guide the eCOA process itself.

 Another advantage of electronic assessment applications is their ability to house a wealth of easily accessible support content. Users can access content like videos, diagrams, or text on a variety of topics, such as:

Answers to frequently encountered questions

Education on their condition and symptoms

When and how to schedule a telehealth visit

Handheld devices, such as smartphones and tablets, are particularly useful at providing bite-sized content. This utility is a perfect fit for providing clinical trial participants and other users of eCOA applications, quick, image-heavy resources to support them over the course of a study. This helps them to address potential issues before they become problems and can help reduce the need for clinical team outreach, saving time and cost.

Articles

Guidance on the unique challenges presented by electronic outcomes.

Perspectives and Guidance for Effective eCOA in Global DCTs

	A review  of over 10,000 clinical study protocols by 

 found strong evidence of increasing study complexity (significantly greater numbers of unique procedures, as well as increased procedural frequency, longer trial durations, more data collected in the Case Report Form (CRF), and increased site ‘work burden’). This is likely due to the desire to capture direct evidence from patients, in conjunction with the growing specialism and demand for Phase IIIb and IV clinical studies.

	This emerging new trend changes the overall balance of study data to a dataset that is increasingly patient self-reported, often lengthy, as it includes large volumes of participants, and one which carries an enhanced risk of response or completion issues, and potential data entry-related errors. It is in this arena that mobile eCOA comes into its own right.

Electronic data collection has been used with increasing frequency in Clinical Outcome Assessments (COA) over the past 10 years, including outcomes attained directly from the patient (Patient Reported Outcomes or PRO). The proliferation of mobile technology on a global scale has provided a new means of access to patients and created an ideal platform for the capture of ePRO assessments to replace the outdated, traditional pencil and paper-based data collection methods.

	Incorporating mobile eCOA into clinical studies has a myriad of benefits. Native apps facilitate the collection of objective data from medical devices (e.g. spirometers and glucometers) and wearable technology such as activity trackers alongside patient diaries. Data from these devices can be transmitted directly into an app via Bluetooth, removing the requirement for 

. Furthermore, date and time stamps for each data point can be captured from patient source through to EDC database, and fraud can be eliminated by introducing two-factor authentication.

	Mobile technologies can also play a role in enhancing clinical data cybersecurity and protecting confidentiality in ePRO. Firstly, unique PINs are created by users to ensure control over who is entering the data within the mobile device. Not only is this reducing the risk of fraudulent data entry, but the restricted access also prevents others from seeing the record, and therefore, it enhances data confidentiality. One of the most fundamental methods of data protection is data encryption. With mobile data capture, both the transmission of information and the offline storage of resting data can be readily secured via this methodology. Furthermore, any ‘sensitive’ data such as Personally Identifiable Information (PII), or indeed the actual content of the completed questionnaire/diary (Protected Health Information or PHI) are encrypted to ensure data protection.  
	 

	Mobile eCOA has another practical advantage, which is providing more efficient patient engagement. A patient who has missed diary completions can be reminded of the importance of taking part in the study, and should this not improve future ePRO compliance rates, sites can follow up immediately. Site staff can discuss any difficulties or misunderstandings with patients and provide additional timely education and support to enable continuation in the study before they are lost.

	Since 1980, in global terms, the over-60 demographic has more than doubled, rising from a figure of less than 400 million to over 800 million. By 2050 the figure is expected to exceed two billion.

	It has been suggested that the prevalence of particular medical conditions among the elderly could hinder their ability to complete surveys using these mobile technologies. However, mobile devices are now very familiar technologies to most people and are not viewed as ‘study specific’ hardware additions. Therefore they can be integrated into elderly patients’ lives more seamlessly. The sophistication of the technology is such that age (or impairment) is not a barrier to the successful capturing of data.

	Professor Nicholas Bellamy of the University of Queensland, an authority in validated clinical assessments who has developed and globalized the WOMAC and AUSCAN Indices for the evaluation of patients with Osteoarthritis, comments that "[although] it might be assumed that cognitive and dexterity problems in elderly patients would preclude their use of mobile ePRO,” elderly populations are “using technology regularly,” particularly mobile phones. “So long as the interface is designed appropriately and is user friendly,” Bellamy suggests, “then it should be implementable across a broad range of age groups, including the elderly.” The use of mobile technology allows assessments to be tailored to specific devices and the individual requirements of each patient. For example, larger fonts and buttons on tablets may be used to aid the visually impaired.

	Generally, successful application of mobile eCOA in clinical research lies in careful evaluation of the target population to identify the optimum solution prior to the solution design phase, and it should consider the locality and the prevalence of technology in each geographical location, general characteristics of the patients to determine the modality and specification of provisioned devices and the optimum communication strategy (SMS, e-mail, in-app messaging), as well as data capture requirements of the protocol (e.g. criteria and frequency of assessments, device specification required to ensure psychometric equivalence of validated assessments, use of monitoring devices and the minimum data transfer proprieties).

	The increasing prevalence of digital technology means that it is no longer necessary to conduct trials by pushing specific technological solutions on to trial participants; instead, the best solution can be applied to suit the patients and their needs.

	Knowing how and when to introduce mobile eCOA into a study design is crucial. Different approaches can be taken by clinical trial sponsors depending on the objective behind the data collection. Possible scenarios that should be considered include site vs patient data capture (Clinical Reported Outcome (ClinRO) vs PRO, as mobile eCOA can help obtain high quality self-reported patient submission data through implementing diaries to collect momentary assessments at pre-defined time points between visits, as well as enabling the inclusion of validated instruments. Mobile eCOA can also expand options for real-time oversight by medical device integration alongside a daily diary to supplement subjective data from patients with objective data direct from Bluetooth-paired devices, which can be used by patients at home. Finally, the use of patients’ own devices through the BYOD (Bring Your Own Device) approach in Phase IV event driven studies can provide a cost-effective way to incorporate mobile eCOA and collect event-driven data recorded by patients at home in order to obtain Health Economics evidence and to keep the patients engaged in the study over extended periods of time.

	Mobile PRO has introduced a multitude of benefits into clinical trials - from patients to sites and sponsors. As well as creating a truly scalable platform to support patients during clinical trials, it has simplified the process of capturing their data, and significantly reduced the risk of it being inaccurate or incomplete.

	Using this mobile strategy, sponsors and sites can implement study communication plans that dovetail with the everyday life of patients, resulting in better data quality, better medication adherence, and, ultimately, better health outcomes.

	Mobile strategies bring near-endless possibilities to engage with patient, be it through the use of games consoles, internet TVs, or other as-yet-unknown technology. In terms of the knowledge, the capability is already there. However, for this dream to become an everyday reality the healthcare needs to escalate the adoption of existing mobile PRO so that it becomes the accepted approach to self-reported clinical data.

	Chris Watson is Product Manager for Exco InTouch

Mobile strategies bring near-endless possibilities to engage with patients in clinical trials.

Mobile, the Future of Patient Reported Outcomes

	Nowhere has the advance of technology left its footprint more visibly than in the field of healthcare and clinical research. The very future of the industry relies on ever-more intelligent solutions to increase the cost-effectiveness of clinical trials through ensuring on-time and highly accurate recording of patient outcomes.

	There is a clear market trend to design solutions fully compatible with a multitude of home monitoring devices which are capable of being integrated into eDiaries, via Bluetooth® or Near Field Communication. The growing use of ePRO data collection, combined with Bluetooth® technology being built into many devices, is fast enabling the integration of medical device readings into regular ePRO collection by patients, both in clinical trials and in healthcare settings. With the wearables market predicted to be $12B by 2018, of which 60% will be health tracking

, device integration now goes far beyond just medical devices and is fast evolving to utilize and integrate consumer technology, ranging from activity trackers (e.g. the Fitbit, or the Microsoft Band), to weighing scales and thermometers as tools to collect secondary outcomes data. While Class I or above medical devices are recommended for primary endpoints, especially in Phase IIIa studies, a broad range of medical and consumer technologies are finding application in secondary endpoints across all phases due to the valuable insight they provide into physiological data and patient well-being.

	Device integration has multiple benefits. This includes time and cost saving in large projects as well as ease of use for patients where real-time data review reduces the need for a visit to their HCPs or clinical sites. In addition, device integration resolves the problem of patients reporting incorrect information on their well-being, which can often be an issue in real world evidence collection. Healthcare providers and sponsors can now have access to real time result reporting whilst patients are able to complete assessments using devices that are an integrated part of their lifestyle, via a simple interface.

	Device integration brings with it regulatory challenges so it is essential to define the use of the endpoint data and understand the regions in which it will be used. Regulatory authorities recognize different classes of medical devices based on their design complexity, their characteristics when in use, and their potential for harm to the patient if misused. For example, in the EU blood pressure monitors are considered to be Class I devices, whereas devices such as Vitalograph spirometers and blood glucose monitors would fall under Class II category. It is important to note the use of devices for the collection of primary endpoints in Phase IIIa studies requires the devices themselves to be fully validated and checked, and it must be ensured that they guarantee acceptable measuring tolerances which can be reproduced. In the EU, this means that as a minimum the device must be registered as a Class I measuring device and in the US, for a device to meet regulatory guidelines, it must have 510(K) registration awarded by the FDA.

	Device integration has proved its worth as a user-friendly asset for improving the accuracy, reliability and quality of patient data and reported outcomes. Allied to this is clear market trend to design solutions fully compatible with a multitude of wearable and home monitoring devices, which will report highly accurate recordings of outcomes. As a consequence, demand for device integration will be rising fast. I firmly believe that by the end of 2015 device integration will have gone some way to revolutionizing not the way data is reported, but health outcomes themselves. Watch this space.

	1.     Kvedar, J. C., (2014), “Will 2015 be mHealth’s Coming Out Party?”, The cHealth Blog 

http://chealthblog.connectedhealth.org/2014/09/08/will-2015-be-mhealths-coming-out-party/

Nowhere has the advance of technology left its footprint more visibly than in the field of healthcare and clinical research.

Advancing Clinical Research Through Device Integration

I’ve notice of late quite of lot of confusion over the approval requirements that apply when using mobile devices in clinical trials. It’s understandable, as for many the use of mobile technology in clinical trials is a new step.

The advances in technology, not just mobile phones but also medical devices and the advent of lifestyle devices and wearable technologies, have created enormous opportunity for clinical studies to collect data from patients. But with this has come an aura of complexity as the clinical community try to apply the appropriate regulatory guidance. Combine that with recent regulations, such as the 

 released last year by the FDA and it can be easy to misinterpret the focus for each piece of guidance. 

 The important consideration for those wishing to use mobile devices in clinical trials is to clarify the scope for each piece of guidance. For example both the Mobile Medical Applications guidance and 510(k) clearance for medical devices have commercial focus and only apply for marketed products.

Use of mobile devices within clinical trials should be included as part of the submission to the Ethical Review Board (ERB) or Institutional Review Board (IRB). The level of approval required is dependent on the role of the device within the trial, but can broadly be segmented into 2 categories

1) Conduit to transmit data to the eCRF 

This could include a medical device transmitting results to an app, or an app transmitting data (collected manually or via Bluetooth) to the eCRF (electronic Case Report Form). The key is the app simply transmits data without manipulating it in any way.

In this case the provider must simply comply with the FDA eSource Data Directive by conducting validation to show the data is not transformed, i.e. prove that nothing has changed from device to database.

2) More complex device, transforming data, or making decisions

In our experience developing mobile platforms for use in clinical trials there are cases where the mobile device transforms data in some way. For example in adaptive trials an app might recommend a change in dosing following entry of data that meets pre-defined criteria.

In such cases a greater level of validation is required and it is advisable to conduct a regulatory review prior to commencing the study, though this can be achieved as part of the overall ERB/IRB review. 

We’ve been incorporating mobile phones into clinical research for almost a decade. Over this time the advances in capabilities have provided a raft of possibilities for enhancing clinical research. The key to unlocking these possibilities is the ability to apply the right technology, and the right level of interaction to each trial. 

Through this approach we see pharmaceutical industry beginning to extend the support mobile offers during clinical research into the post marketing, real-world healthcare arena, going ‘beyond the pill’. Of course the regulations like Mobile Medical Apps and 510(k) are applicable for such commercial applications, and as such a forward thinking approach using the appropriate processes and associated documentation can ease burden of market submissions, using the data gathered through the clinical research to support the commercial application. 

I've notice of late quite of lot of confusion over the approval requirements that apply when using mobile devices in clinical trials.

Chris Watson

Articles

Perspectives and Guidance for Effective eCOA in Global DCTs

Mobile, the Future of Patient Reported Outcomes

Advancing Clinical Research Through Device Integration

Navigating Regulatory Requirements for Mobile Devices in Clinical Trials