Clinical trials may be one of the very last bastions of a non-customer-focused approach within the pharmaceutical industry. Protocols, which have remained substantively unchanged for over 30 years, often impose an immense burden on patient participants, largely due to the frequency of site visits. Across the board, from rheumatology to neurology, outcomes that matter most to patients, have traditionally not been captured in clinical trials. Underpinning this dearth of patient-centricity is, of course, the highly regulated nature of clinical development and the need to generate standardized data sets in support of regulatory submissions. Also contributing, however, may be a rather deeply ingrained mindset that patients are “lucky” to be given access to an investigational therapy, rather than sponsors being the ones who are fortunate to enroll them.

At this year’s Reuters Pharma Clinical 2021, I joined over 500 global leaders in clinical research as they discussed many of these issues under the theme, “rebuild clinical trials in the image of patient need.”

How do we increase the diversity of clinical trials?

In recent years, an increasingly-discussed goal has been improving the diversity of clinical trial enrollment so that study populations better reflect the likely end-users of the drug. The release in November of FDA’s final guidance on strategies to increase participation of underrepresented populations in trials (“Enhancing the Diversity of Clinical Trial Populations—Eligibility Criteria, Enrollment Practices, and Trial Designs Guidance for Industry”) has given added impetus to these efforts. According to FDA principal deputy commissioner and acting chief information officer Dr. Amy Abernathy, there are several types of chronically underserved communities. People of certain racial and ethnic backgrounds, including the Black and Latin American communities, are perhaps the most obvious. While the lack of racial and ethnic diversity in trials has been apparent for some time, it’s been brought into sharper focus by the COVID-19 pandemic, which severely impacted those communities and exacerbated pre-existing disparities in access to health care. In a separate panel, Jenn Horonjeff, PhD, who is founder and CEO of Savvy Cooperative, stressed the importance of pharmaceutical companies engaging with those communities in culturally-sensitive ways. She considers it paramount that sponsors acknowledge and address the historical injustices that have caused mistrust in medicine and clinical research before making efforts to enroll patients from those communities. Dr. Charlotte Jones-Burton from Otsuka stressed the importance of employing individuals who belong to the community, engaging with the communities early to understand what works for them and what does not, and building a long-term partnership:

“We have to make sure that we keep the patient at the center of what we’re doing, and that we form lasting relationships, not just have transactions, with the communities that we want to be included in our trials. And that should be reflective of the diseases that we’re trying to eradicate.”
– Charlotte Jones-Burton, MD, VP, Clinical Development, Nephrology, Otsuka

Another underserved population is those living in rural communities. The preponderance of trial sites at academic medical centers, which are – at least within the US – typically located on the coasts or in Chicago, can often present insurmountable financial and logistic barriers to those in rural locations. Finally, many individuals are denied access to trials because of eligibility criteria that exclude potentially medically-complex individuals, including older patients (>65-year olds) and those with comorbidities. Dr. Abernethy urged sponsors to carefully rethink the standard eligibility criteria of their trials and consider whether there are actually data to support exclusion based on, for example, older age or HIV status.

Entering a new age of decentralized clinical trials (DCTs): opportunities and challenges.

While DCTs (ie, trials that include innovative technologies or processes to enable participation outside of traditional clinical settings) certainly mesh with the zeitgeist of our pandemic times, the roots of this evolution in trial design can be traced back 17 years. However, the need to deliver healthcare remotely and maintain continuity of ongoing trials during the pandemic infused new energy into this field. One of the highlights of this year’s Pharma Clinical was a multidisciplinary panel, comprising sponsor, CRO, DCT expert, and patient advocate, that addressed the challenges and opportunities around practical implementation of DCTs.

Craig Lipset is a long-time champion and pioneer of DCTs who recently founded the Decentralized Trials & Research Alliance (DTRA), an initiative that promotes collaboration to accelerate their adoption. Lipset commended the efforts of stakeholders to ensure trial continuity throughout 2020: regulators for providing FAQs and guidance documents, technology and service partners for bringing new solutions, sponsors for their rapid implementation of protocol changes, and both investigators and patients for their willing embrace of new technologies, such as videos for virtual visits. He believes that elements of DCTs (eg, remote data collection, video visits) that were once viewed as introducing risk into trials have, since the start of the pandemic, been perceived more as a risk mitigation strategy. Having witnessed the value of DCTs during the pandemic, the clinical research community is increasingly embracing DCT models and sponsors are proactively considering their feasibility for upcoming studies.

Novartis Institutes for BioMedical Research (NIBR) has a long-term commitment to DCTs which, its Global Head of Clinical Innovation Sam Hariry explained, is due to an understanding of their advantages beyond risk mitigation. These include better trial participation, increased trial diversity, and the potential for better data to be collected in more meaningful environments. Going forward, Hariry favors a phased approach to DCT implementation, starting in early Phase 2 programs and gradually increasing integration into later-stage trials. Expanding on the theme of better data, Munther Baara (Vice President of Product Strategy and Innovation at EDETEK Inc) explained how DCTs can enable a paradigm shift for sponsors and sites. DCTs avoid the siloed collection of different modalities of data, which occurs in traditional trials. Data can be collected in a single location, analyzed and interpreted more rapidly, and shared with the sponsor, the site, and the patient at a much earlier stage.

Of course, the advantages of DCTs extend beyond the potential for richer, more meaningful data sets. Grace Cordovano (CEO of Enlightening Results), a board-certified patient advocate working in oncology, spoke powerfully of the benefits to patients and caregivers. She believes that DCTs can remove many of the geographic, logistic, and economic barriers to trial participation (eg, travel time and expense, requirement to take days off work) and may help to increase trial participation earlier in the patient journey. They will also help to increase the diversity of patients enrolled in trials. Cordovano refuted the suggestion that oncology patients may be less receptive to DCTs than those with other health conditions:

“In oncology, people want to live their best lives where they are. They don’t want to be a patient. They want to be a parent going to their son’s soccer game. They want to be an executive, successful in their work. They want to be a grandparent continuing with their retirement. They are a person with goals and aspirations and wishes, and they want to live with dignity and quality of life. And that’s where technology and DCTs can help bridge those gaps.”
– Grace Cordovano, PhD, BCPA

Based on his work with DTRA, of which Stand Up To Cancer and the American Cancer Society are member organizations, Craig Lipset concurred and advised that, “The oncology community is not willing to be left behind when it comes to decentralized trials. Sponsors with oncology therapeutic portfolios should know that, and not think that this is just a tool for those in dermatology or in other primary care indications.”

While the broad consensus from Pharma Clinical 2021 is that DCTs have a bright future and are here to stay even after the pandemic is under control, several barriers to their widespread adoption remain. The lack of an agreed lexicon and standardized definition for “decentralized clinical trial” is one such barrier. While most people would agree that a trial without physical study sites and only digital engagement is a DCT, most studies will adopt a hybrid model with an a la carte selection of “decentralizing” solutions. These will encompass digital tools to capture consent, personal wearables and medical devices for remote monitoring, direct-to-patient distribution of medication, and use of local labs and imaging centers. Understandably, any discussion of DCTs includes a heavy focus on technology. However, it’s important to understand that technology is a critical enabler of decentralization, not a measure of it:

“The measure [of trial decentralization] is not how much technology did you just drop into your study. It’s easy to say I’ve introduced e-consent and e-PRO and wearables, but my visit schedule hasn’t changed. And the patients are still coming in and out for all the other stuff involved in the trial. It’s just now they’re going home with a gadget and something on their wrist. You didn’t actually decentralize much of anything from the patient’s experience.”
– Craig Lipset, Co-Chair of the Decentralized Trials & Research Alliance (DTRA)

Additional obstacles or challenges to the adoption of DCTs at scale include the following:

• Cultural and resource barriers that still exist in many organizations. Shifting from the long-held status quo of a product-oriented approach to a service-oriented, patient-centric mentality can be challenging. Even when senior leadership is supportive, it will be critical to provide already-stretched clinical teams with adequate resources.

• Deployment of technology in the real world, which is always challenging. Allowing patients to capture data using their own personal devices can further improve the accessibility of trials but may require the services of a specialist vendor to assist with technological integration and implementation.

• Concerns that collecting large, real-time data sets in DCTs may put sponsors at a disadvantage with regulators compared with companies running traditional trials. The ability to continuously monitor patient safety (and also biomarker and efficacy) data using digital tools is an undeniable advantage that DCTs have over traditional trials, which provide a mere “snapshot” of data from each study visit. However, this may be seen as a double-edged sword if the DCT identifies safety events earlier and if sponsors are penalized by regulators as a result. This is an area that will benefit from further dialogue with regulatory authorities and their therapeutic area review teams around the world.

• Rapidly evolving, but highly variable global regulatory environment. Guidance from regulatory authorities continues to evolve. While their willingness to consider new approaches is welcome, the ongoing ambiguity and inconsistency will impede the wider rollout of decentralized trial models.

Though none of these obstacles are insurmountable, successfully addressing almost all of them could benefit from a greater partnership among key stakeholders. Organizations such as DTRA will no doubt play a critical role in fostering the necessary collaboration.

The role of digital transformation strategies to enhance the recruitment, retention, and output of clinical trials

On my evening runs along the Brooklyn, New York waterfront, I’ve been noticing more Apple Watches and Fitbits than ever before. The rising popularity of these consumer wearables has been paralleled by a sharp increase in the use of digital technologies, including wearables, in clinical trials. At the time of writing this article, a search of found as many as 1,066 active or completed studies that include wearable devices. Leaders within the industry include Janssen Pharmaceuticals, who have used Apple Watch for the early detection and diagnosis of atrial fibrillation in a clinical study, and AbbVie who have a 5-year record of integrating wearables into clinical trials, including in atopic dermatitis and Parkinson’s disease.

In a lively panel discussion of the advantages to clinical trials of incorporating patient-driven digital transformation strategies, the expert panelists – representing pharmaceutical companies, a CRO, and patient organizations – achieved unanimity on the following recommendations:

• Technology has already started to play a major role in improving clinical trial recruitment, but it cannot be the only approach to enrolling diverse patient populations. In 2019, Otsuka, Pfizer, Sanofi, and Novartis partnered with Verily, an Alphabet company, in their groundbreaking Project Baseline initiative, which is collecting an unprecedented volume of health data from a large group of participants. Through a combination of digital marketing, electronic health records (EHRs), and use of wearables, these partnerships are helping to boost trial recruitment and also lead the industry towards increasingly patient-centric trial designs. Although Project Baseline aims to include a racial and ethnic distribution that is representative of the US, digital approaches do not work for all patients, so trial recruitment will continue to require multimodal outreach. Working with patient advocacy groups and organizing focus groups at an early stage in clinical development is recommended if sponsors are to fully understand how best to engage with those communities.

• Incorporating technology into trials does not negate the need for personal interaction. It’s important not to forget the human element of trials. Given the fatigue that trial participants often experience, introducing them to the study team and enabling them to feel they can interact with the team, is an important part of any trial retention strategy.

• Digital tools, such as wearables, help engage patients and make them active participants in the management of their disease; however, sponsors have a duty to ensure timely data return that conforms to health literacy principles. The panel agreed that many patients would prefer to receive their health data from wearable devices in real-time, rather than at the end of the study. Enabling timely access to data can sometimes allow patients to see patterns that help them better understand their condition. Patients may also be able to provide context that can help investigators interpret the data. Data should be returned to patients in digestible chunks with sufficient explanation and support for them to understand it. Finally, the industry must make greater efforts to funnel data back into patient’s health records. Each of these steps are essential to creating a more patient-centric clinical research environment.