Estelle Haenel

Patients participating in clinical research face a whole range of challenges. For those living with multiple chronic conditions, the obstacles are greater. While digitalization has been progressively facilitating increased access to clinical trials by helping alleviate logistical burdens, less is known about how well these digital tools address the specific needs of clinical trial patients with multiple chronic conditions. To what extent are these patients ready for hybrid and remote trials?

A qualitative study investigating the experiences and expectations of 1,133 clinical trial patients with multiple chronic conditions was conducted using digital solutions. Between November 2020 and January 2021, respondents from several patient associations across North America and the EU volunteered to respond to a survey. As the pandemic significantly impacted clinical trial continuity and catalyzed their digitalization, the study also explored patient readiness for remote clinical trials. Direct feedback from patients, a third of whom live with chronic conditions in more than one therapeutic area—which creates an additional obstacle to clinical trial access, complements and nuances these findings.

How digital technology in clinical trials responds to the needs of patients with multiple chronic conditions

Clinical trials have been using digital technologies as solutions to increase data quality, while helping patients face logistical challenges. Among the most prevalent digital solutions are electronic Clinical Outcome Assessment (eCOA), used for both structured visits as well as in unstructured operational models. These can be instances where electronic Patient Reported Outcomes (ePROs) are completed between clinic visits, during telehealth virtual visits or at-home health visits; this model allows patients to remain compliant within the comfort of their homes. WebCOA is an alternative option allowing a patient to complete questionnaires at home under the control of site staff. WebCoA

 guarantees consistency in both protocol visit scheduling and patient adherence to protocol, while allowing patients in the trial to remain comfortably at home. This can be particularly helpful for patients who are in pain from multiple conditions or unable to travel to the site, as witnessed by Penny-Mary, a Canadian interviewee who has been living with multiple sclerosis, fibromyalgia and osteoarthritis for several years. She commented on the severe day-to-day impact on mobility of living with those three different conditions combined: 

“For walking I [usually] use a cane in the apartment. And if I go outside, I have a four-wheel walker [that] I use, cause otherwise it’s pretty hard yet moving anywhere.”

While digitalization methods offer much potential in facilitating increased access to, and alleviating patient burden in, clinical trials, it is important to look at how emerging technologies are perceived by clinical trial patients with multiple conditions.

Clinical trial patients with multiple chronic conditions rate digital solutions positively

The survey showed that overall, clinical trial patients with multiple chronic conditions rate well their experience of using digital solution in the context of a clinical trial.

This study also revealed that 26% of all participants were living with more than one condition. This is important when considering selection in a clinical trial: patients are generally considered for a clinical trial exploring one condition. Living with several might either exclude them from the study or they may experience additional challenges when participating in research.

Respondents were then asked about using electronic solutions. Among those who had already participated in a clinical trial (1/3 of total respondents), 71% had used at least one electronic device. Usage was spread across age ranges.

More than 85% of those patients, who had used at least one electronic device in a clinical trial, rated their experience of digital solutions as four or five, on a numerical scale from one (representing the worse experience) through five (representing the best experience). This ranking was independent of age or disease type. This very positive reaction towards use of digital solutions was voiced by Sheila K, an acromegaly patient from Italy, who claimed: 

“I am passionate [about] technology; it has been instrumental [in] improving mine and many patients’ lives!”

David, a UK patient living with neurology disorders, commented on how technology can help patients undergoing clinical trials by monitoring their day-to-day experiences: 

“When information on symptoms has to be provided every day, it’s much easier to provide it from home with digital tools rather than writing things down or having to go to the hospital.”

Interest in using these technologies to enable trial decentralization and support the effectiveness of traditional trials has exploded since the pandemic outbreak, driving innovation in a patient-centric manner. Since the study indicated significant patient satisfaction with digital technologies, the next step was to look at how receptive patients might be towards disruptive decentralized models.

How ready are patients for decentralized clinical trials?

COVID-19 meant that clinical trial patients could no longer be expected to attend on-site visits. Clinical trial digitalization grew due to the adjustments needed to enable them to continue while maintaining patient safety. Survey respondents were asked about having a say in the way their next clinical trial would be run. Three scenarios were proposed:

 Decentralized Clinical Trials (DCTs), relying on numerous locations, including using local laboratories and the patient’s home where many trial procedures can take place

, also called hybrid clinical trial, where part of the visits occurs at the clinical site, but some protocol procedures can also take place at the patient’s home

, where all the visits and study related procedures happen at site, as it used to work traditionally.

Although DCTs are not new, the ability to manage them more effectively with technology is a more 

. The increased use of technology allows several operating models to be envisioned. Clinical trials can now consist of a fully virtual approach, where patients can participate remotely and not have to visit a clinical site, or hybrid trials, a mix between traditional site visits, which may be required to complete an EKG or undergo a tumor biopsy and remote visits.

Regarding respondent preferences for either a fully home-based study (presented in the survey as corresponding to a DCT model where most of/all visits happen at home), a hybrid study (visits happen either on-site or at home in a hybrid manner) or a traditional site-based study (all visits happen at the clinical site), during COVID-19, 89% of patients said they preferred either a fully decentralized/home-based (47%) or a hybrid (42%) clinical trial model. This was true across every category of patient: neither age nor therapeutic condition had any impact on this result.

The fact that only 11% of patients interviewed prefer the traditional site visit model supports the hypothesis that the pandemic acted as a strong catalyst for modifying attitudes, patients became more ready to accept digitalization as the new norm in conducting clinical trials.

Respondent feedback on clinical trial digitalization indicated that its advantages, such as its convenience and ability to help patients overcome logistical hurdles, were well perceived and appreciated, to the extent of improving opportunities for wider patient populations to join a clinical trial. David summed up what many patients expressed: 

“In multiple sclerosis, where you have a severely progressive disease, you might not even want to volunteer for a clinical trial, because of the travel and logistics burden. Digitalization of the research will allow recruitment of more severely [ill] patients or [those] living in remote areas."

Although our investigation did not enquire about replacing telephone calls with on-site visits, Penny-Mary was insightful on this subject: 

“I actually have had several phone calls with my doctors, I was not impressed at all, I had [the] feeling that he was rushing and wanted to get off the phone quickly. Whereas if you're there in person, you can say “wait a minute [I’ve] got more questions.” I would actually rather go to the site. However, if this is not an option, then when you can see their faces with the computer system it is better because we can see each other, and so that's a good one too 

Our study confirms other conclusions, including that the flexibility and safety that virtual options offer patients no longer need debating. Digitalization solutions enable high-quality results without encompassing many of the site-specific challenges that impact the patient, the sponsor and/or investigators. Evolving towards decentralization will require technology readiness of all clinical trial stakeholders. Site organizations and IT infrastructure will require development in order to fully embrace the massive switch to digital trials. Securing data privacy or handling large volumes of data still require further adaptation and work. Although the industry has probably made a decade of progress in one year under the catalyst effect of the pandemic, there are still technical issues in implementing digital trials that require further industry effort.

Nevertheless, digitalization options do create a somewhat disruptive way of running trials. We must acknowledge that specific patient groups may experience difficulties in a remote environment, some patients, for example, may miss human contact, which remains key in healthcare. Other examples are teenagers who might be less inclined to report promptly, so their compliance might be poor in remote settings, or patients whose condition or disability would make using digital technologies challenging (e.g., inflammatory disease in finger joints). Thus, further research in specific patient populations is necessary to characterize patient preferences in those groups.

In summary, patient reluctance is no longer the limiting factor when it comes to digitalizing clinical trials. Clinical study participants are satisfied overall with the technology used to collect data and are open to new ways or running clinical trials, across age ranges and conditions, according to this study conducted by Kayentis. It seems that trials fueled by helpful technologies that are conducted in part or entirely remotely will become the new industry standard. Despite this, incentivizing the adoption of digital technologies across the board remains crucial for complete adoption and efficient use of these solutions. As technology adoption grows and matures, collaborative work across clinical trial stakeholders will help improve digital technologies options, modernize clinical site organizations, and optimize clinical trials access to patients, enabling technology to open the door to a smooth clinical trial experience.

https://kayentis.com/plan-a-successful-web-back-up-strategy-for-your-clinical-trials/

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Digitalization has been progressively facilitating increased access to trials by helping alleviate logistical burdens, but not much is known about how these tools can address the needs of patients with multiple chronic conditions.

Digitalization Trends in Tackling the Complexity of Clinical Trials for Patients with Multiple Health Conditions

	Digital solutions have without a doubt improved both the quality and the quantity of data collected in clinical trials. The positive impact that eClinical Outcome Assessment (eCOA) has had on the success of clinical trials is no longer disputed 

, and this is in addition to increasing preference among end-users for digital data reporting. The annual eCOA adoption growth rate has been reported to be 16%, yet less than 25% of all possible studies incorporate eCOA

, primarily due to misperceptions of the risk factors associated with implementing eCOA and eCOA backup solutions.Contrary to popular belief, e-devices are rarely damaged; they seldom need replacing. And unlike paper, the volume and quality of digital data collection are significantly higher, thereby adding value to the study. Given the wide use of digital technologies in society today, apprehension about implementing eCOA and creating an eCOA back-up plan is unwarranted. Rather, with the choice of eCOA back-up solutions now available, implementing an eCOA back-up plan that safeguards, as well as optimizing data collection, has become a streamlined process readily adaptable to the specifics of any project.

e-device failures are the exception rather than the rule

	Even though cases where e-devices fail are quite rare, significantly limiting the overall risk of losing data, a robust back-up solution remains necessary. eCOA back-up solutions enable clinical sites and sponsors to guard against two types of potential electronic device failures: permanent failure (through theft or breakage); temporary failure (through a connectivity issue, forgotten password, or loose electrical cable, etc.). 

an investigation6into the use of electronic devices (using real data from several studies across multiple therapeutic areas of various duration and complexity, and with different eCOA device models) revealed that e-devices are rarely stolen or broken at sites, with less than two per cent (<2%) of e-devices requiring replacement and more than 90 per cent (>90%) of sites never needing to make a replacement.

In most cases, a back-up solution is only needed temporarily 

when a password is forgotten or when a device runs out of battery. The occurrences of these incidences can be greatly minimized with recurrent training and strong preparation of both the study site and the patients. 

	It is important to approach an eCOA back-up solution as an integral part of the study design and not just as an ‘add-on’ to a clinical trial. Given the wide choice of electronic options now available, and in order to adhere to the recent recommendations from the competent authorities as well as the specialized organizations such as the C-Path Institute PRO and ePRO Consortiums, an efficient back-up solution should not be paper-based. 

Wider choice of eCOA back-up solutions enable a better adapted eCOA backup plan to meet project needs

	It has been well-documented that paper-based approaches result in untimely, unreadable, missing or often illogical data, all of which can have a very deleterious effect on data quality

. It has also been strongly discouraged by the C-Path’s institute ePRO Consortium

to use paper as a back-up solution. “We s

trongly discourage the mixing of paper and electronic field-based instruments and suggest that mixing of only electronic modes be considered for clinical trials and only after equivalence has been established

	Selecting a well-adapted electronic back-up solution can be quite simple as long as it is anticipated and implemented with a well-coordinated project plan. It can be extensively supported by eCOA solution vendors and eCOA experts, and will also be facilitated by detailed review of the four existing options to characterize them and evaluate their advantages and drawbacks:

consists of making sure that, before site initiation, one or several spare devices will be supplied onsite, in accordance to the specifics of each project and the site’s recruitment projections. The spare device is an easy and frequently used backup solution, but implies additional budget that is to be considered upfront.

The provision of a spare device at the country level 

where another device can be provided quickly, either by an eCOA provider support or by another local site that has spare devices. This solution is similar to having spare devices onsite, but requires preparation, such as anticipating potential shipment delays, that are to be considered upfront of the study. This option tends to incur delays and may not work everywhere; however it remains a cheaper back-up option than maintaining spare devices on each site and so may be the preferred option should the budget influence eCOA backup solution choices.

The availability of a web portal data entry

that could be accessible on the site, as well as on the premises of patients’ homes, so that patients can complete their ePROs and e-diaries in a user-friendly environment. This solution does not add cost or complexity to a trial. It can more readily deployed in most countries now, given the expanded access to computers and the internet. However, developing alternative solutions will still be required to address the needs of patients without access to a home computer.

patient’s own personal device in a BYOD manner 

can be a very convenient and well-adapted back-up solution. The convenience for patients using their own devices can be significant: 

		It eliminates the learning curve to use a new device

		It removes the need to keep track of an additional device

		It increases a level of comfort by not having to collect or return a provisioned device to the site.

	However, deployment of this type of solution does not come without the technical challenge of ensuring that the solution will work in a standard manner on different types of devices-should several patients request this solution. It could also increase the burden for the site’s staff, having to verify the upload of the application and access to the patient’s questionnaires or e-diaries. It can be a fair reason for a team opting out of this option.

	There now seems to be sufficient eCOA backup solutions available for each clinical team to find a tailored plan that will satisfy the requirements for each project and therefore secure patient and clinical data collection.

An eCOA backup solution has to remain a temporary solution

	It is important to note that back-up solutions should only be deployed in the specific circumstances. This is where the original designed solution cannot be used because of device failure, loss or impossibility of use, and is a temporary solution. The timeframe should be limited, and it should never replace the original solution. 

	Using a back-up solution-as an alternative data capture for a significant period of time-would lead to significant “mix mode” of patients’ data capture which may complicate the audit trails, lead to potential lack of comparability of the data and so may potentially jeopardize the validity of the clinical trial. The FDA states in their PRO Guidance, that they “i

ntend to review the comparability of data obtained when using multiple data collection methods or administration modes within a single clinical trial to determine whether the treatment effect varies by methods or modes.”

(FDA, 2009). Although technology makes mixed modes of data collection feasible operationally, clinical trial designs need to consider the sources of error variance in the PRO data, and only sufficiently tested PRO collection modes should be considered.

Precautionary steps can help simplify the implementation of an eCOA back-up plan 

	To implement the right eCOA back-up plan requires taking a few well thought through steps:  

: the manner in which patients adapt to the back-up plan will very much depend on their health condition and age. Age is less of a barrier to eCOA primary and back-up solutions now as people’s familiarity with mobile device technologies, including the elderly, has increased. Thus, evidence shows that they can be integrated into elderly patients’ lives more seamlessly

, as long as precautions are taken. Well-designed and customized training, and well-trained 24/7 available multi-language support teams may likely provide the adequate resources and support to the patients for them to accept the electronic back-up strategy more easily. 
		 

geographical characteristics of your study

: on top of the characteristics of the patient population, the eCOA technology implementation and the back-up solution should consider the locality and the prevalence of technology used in each geographical location to determine the modality and specification of the provisioned devices, as well as the optimum back-up strategy.
		 

: align the level of investment of your back-up plan to the purpose of the data that is being collected: is it for a primary or secondary endpoint? Is the data critical for efficacy or safety assessment that it will justify 100% of data should necessarily be collected? 
		 

primary question of your protocol and goal of your research in selecting a back-up plan

: you may not need the same type of back-up solution should your study be an efficacy and safety registration study, or an epidemiology research. The analysis conducted upfront of the study start will positively impact the decision on the back-up solution to develop. 
		 

Consider the operational aspects of your trial: 

the clinical site organization and the site’s staff experience will also influence your choice. Sites with decades of expertise in clinical trials and experience with using digital solutions will likely be at ease at adopting any back-up strategy, whilst less experienced sites may need the simplest solution. Also, the skillset of the site’s staff, the infrastructure of the hospital are parameters to be considered before developing your back-up plan.
		 

what is the eCOA data being collected for? Who is the patient population? Where is the study being conducted? How are the patients visiting the sites? How likely is the site staff to control deployment of the eCOA solution on site?… All these are questions that, when answered, will facilitate the eCOA back up strategy selection and implementation.

Apprehension about digital technologies seems unÂ­Â­Â­Â­Â­warranted. Continued education of all parties, shared experience and learnings of clinical trial stakeholders, and reference to existing regulations and recommendations from the authorities do represent a strong avenue to support eCOA implementation and electronic back-up solution strategies. 

Implementing a complete eCOA strategy, including an adapted backup solution, creates a way to support both the industry stakeholders in their collection of clinical data, and the patients and the sites who generously provide them. 

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https://www.ncbi.nlm.nih.gov/pubmed/25300613

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https://www.ncbi.nlm.nih.gov/pubmed/17161749

Yeomans A. The future of ePRO platforms. Appl Clin Trials 2014. 

www.appliedclinicaltrialsonline.com/appliedclinicaltrials/article/articleDetail.jsp?id=833920&pageID=1

Outcomes in Focus:  Best Practices for eCOA. Applied Clinical Trials 2018

http://www.appliedclinicaltrialsonline.com/outcomes-focus-best-practices-ecoa


		https://c-path.org/wp-content/uploads/2018/05/2018_Session3-eCOA_FINAL.pdf 	

White Paper “Challenges of back-up solutions in eCOA studies” by Kayentis 

https://kayentis.com/challenges-of-back-up-solutions-in-ecoa-studies/

Data quality and power in clinical trials: a comparison of ePRO and paper in a randomized trial

https://www.taylorfrancis.com/books/e/9781315580142/chapters/10.4324/9781315580142-10

Coons SJ.: ePRO Systems Providers: Clearly Defining the roles of Clinical Trial Teams and ePRO System Providers, ISPOR 2013, 16, Issue 4, Pages 457–458

https://doi.org/10.1016/j.jval.2013.04.006

Eremenco et al. PRO Data Collection in Clinical Trials Using Mixed Modes: Report of the ISPOR PRO Mixed Modes Good Research Practices Task Force.  Value in Health 2014, 17: 501-516

Watson C.: Mobile, the Future of Patient Reported Outcomes. Appl Clin Trials 2015.

http://www.appliedclinicaltrialsonline.com/mobile-future-patient-reported-outcomes

Given the wide use of digital technologies in society today, apprehension about implementing eCOA and creating an eCOA back-up plan is unwarranted.

Estelle Haenel

Articles

Digitalization Trends in Tackling the Complexity of Clinical Trials for Patients with Multiple Health Conditions

eCOA Back-up Solutions: Perception vs Reality