Trial Execution Consulting Associate, KCR Consulting

Malgorzata Michalak-Wojnowska

Disrupted clinical trials (CT) caused by low recruitment continue to rise.

 Together with the COVID-19 pandemic, the clinical research industry faced new challenges that irreversibly transformed the clinical landscape. Within one year (March 2020 - March 2021), around 1000 organizations involved in the conduct of CTs announced the discontinuation of planned and ongoing CTs. Low enrollment rates are the major cause of early termination and delays in initiation of subsequent CTs.

Effective patient enrollment is key to achieving the planned financial goals and milestone timelines. Patient recruitment and retention are a cornerstone of successful clinical research delivery. Despite obvious factors affecting the enrollment such as sites, investigators, or even patients’ interest in therapy access and/or therapy reimbursement status, competitive experimental therapies, phase of a CT, and overall clinical benefit, we may also distinguish other factors that are heavily influencing the enrollment.

The patients, their safety and their unmet clinical needs are at the heart of clinical research. Thus, clinical research revolves around patients and requires their active participation and attention to ensure its advancement. Patients may be reached by direct contact with their doctors or referrals or indirectly by Sponsors /CROs with the assistance of medical organizations, patient registries, hospitals, and pharmacies. Potential study participants may also individually seek information on active CTs in clinical trial registries and clinical trial recruitment websites. Nevertheless, methods listed above may not be sufficient and CT sponsors have also broadened their outreach with the use of social media channels. Regardless of the route of appealing to the prospect patients, an Ethics Committee/IRBs shall give a favorable opinion, before publishing, on the advertisement content and strategy,

 as any patient-facing materials are considered as a part of informed consent process, and the advertising in CTs realm is under control of applicable regulations.

As for the efficiency of study promotional efforts, interestingly, it was shown that CT promotion in newspapers did not increase the consent rates in contrast to digital marketing, which has proven to be an effective outreach tool.

 The other well-known and truly primary enrollment driver is the patient’s trust in a leading physician. Patients may seek the opinion of their physician on the participation in a CT or patients may be referred by their physician to a CT ongoing in a different but trusted site.

 However, this enrollment process bears the integral risk that patients unquestionably follow their physician’s advice not deeply reflecting on the impact of CT participation for themselves. Considering the above, an investigator is ethically obliged to inform the prospect participant about the differences between experimental intervention and standard treatment, and all available treatment options to the full extent without any vested interest, ensuring that the patient does not believe that the treatment he/she receives as part of his/her participation has been individually determined to be the best option for him/her.

Another widely utilized mean of attracting potential patient interest is the dissemination of information provision on the CT with the use of dedicated team. In this regard, Caldwell et al. observed that the information on CT covering topics of “how,” “when,” or “who” have not influenced the recruitment rates. This can be interpreted that the person of the study recruiter team might not contribute meaningfully to the recruitment process. However, the latest data confirms the importance of trust in gaining potential patient’s attention. It was observed that the lack of trust due to yet non-existent relationship with the trial team has been one of the reasons behind the recruitment failure.

The “believe” factor is another vital reason driving patient’s interest in the CT participation. Patient’s belief in the overall benefit potentially to be gained through the participation in the CT strengthens the willingness to consent to the study. The overall benefit may be defined as a chance to receive highly demanded treatment, better access to medical care, stable and comprehensively orchestrated therapeutic regimen or, simply, altruism—the perspective of ultimately contributing to others well-being.

 It must be strongly underlined that the vast majority of the patients have certain expectations regarding the participation in a CT. Especially in terms of the randomized CT (RCT), patients expect to be informed about the study outcomes, and to which arm they were randomized. Many of the patients want to be provided with the access to all kinds of data as soon as it is available (of course without compromising a trial), such as laboratory test results.

 The first study experience may affect their decision about future participation in CT and their recommendation to other patients on their involvement in CTs. Thus, tending to and being responsive to participants’ needs improves directly and indirectly retention and recruitment rates.

Regarding patients’ attraction to particular study designs, not surprisingly, the non-inferiority clinical studies (with active treatments arms) show higher recruitment rates than the placebo-controlled ones.

 The open-label trials also gain more traction among potential participants, but such a design often represents methodological challenges and thus is less favored by study sponsors.

Patient centricity in a new standard of operations in clinical research

For more than a decade, there has been an increasing discussion on patient-focused CT designs.

Patient-centric strategies are evolving and re-shaping the recruitment and retention space. Patient centricity is defined as considering all needs and concerns raised by patients, patient organizations and regulators in the process of drug development. Patient satisfaction and treatment outcomes that matter to patients must be at the focus of drug developers and investigators.

Patient centricity requires active engagement from all parties and keeping in focus the outcomes essential to most patients. Such an approach results in strengthening of recruitment and retention and enriches clinically relevant evidence-based policy. Increased and continuous participation of stakeholders can enhance compliance between clinical research assumptions and patient priorities. However, the inclusion of all expectations in the study protocols is very challenging, often not feasible and, consequently, such studies cannot realize patient centric approach to full extent.

One of the barriers weakening a possibility of successful enrollment is insufficient awareness of the health problem being studied. It was observed that strategies with focus on disease’s education, engage prospect patients and translate into the significantly increased consent rates. Such strategies include questionnaires related to studied health problem, learning sessions, videos, and interactive programs.

Other successful patient-centric strategies place at their core extending patients’ awareness and involving local communities. The communities’ engagement may boost public local awareness of available medical care and clinical research, and ultimately leads to increased and diverse recruitment.

Strengthening diversity in clinical research

Due to numerous barriers among ethnic groups, the limited diversity is being observed. Those potential barriers may be language, culture and logistic-related issues (e.g. transportation) or may result from insufficient education on prophylactics, treatment options and CTs.

Indigenous people of Australia, Canada, New Zealand, and United States are disproportionately affected by chronic diseases and experience suboptimal therapeutic effects from the approved treatments for such diseases. As often genetic variations can influence clinical response to administered treatment, there are potential risks and harm when applying data from poorly diversified studies to Indigenous populations.

Ethnical discrepancies affect clinical data as the data do not reflect the entire population, and consequently pose regulatory risks to product labeling, and limit the access of ethnical minorities to experimental interventions.

 The diversification gap may result from a high concentration of CTs in large academic medical centers in big cities, thereby limiting access to the rural population due to transportation barriers such as distance related to high/-er costs of participation (time necessary to travel, day off at work, secure childcare, costs of traveling).

Volume of ethnic minorities-specific CTs or efforts behind the inclusion of people from ethnic minorities in general population studies are low. It is crucial to enhance the representation of ethnical minorities people in clinical studies to ensure that collected clinical evidence is applicable to their clinical care.

To address this gap, FDA in November 2020 released guidance to improve clinical trial diversity, and in April 2022 a new draft guidance on diversity plans was announced. FDA recommends developing and submitting a Race and Ethnicity Diversity Plan to the agency early in clinical development. For drugs, the plan should be submitted to the relevant IND at earliest possibility during drug development but no later than when a sponsor is seeking feedback regarding the applicable pivotal trials (often the End-Of-Phase II). FDA may request periodic DP updates provisions. The diversity plan should be also included in the Marketing Authorization Application.

The FDA initiative is the milestone in area of diversifying the clinical trial participation and surely will become the powerful inspiration for similar actions to take place across the world.

Decentralization with the goal of enhanced recruitment, retention, and diversity

Recruitment and retention may face challenges at every single level of clinical research pathway starting from patients flow through various investigators, private sites, excellence centers, public medical institutions, and ending at the level of the public health care systems.

The most crucial factors influencing recruitment at the patient level are incapacity to consent, little understanding of the importance of research (which also strongly impacts the retention), fear of side effects or not receiving treatment considered as the best standard care. The retention process may be affected by impairments related to prior disease, problems with transportation, lack of family support, change of address, side effects of experimental treatment, and poor memory of scheduled study visits.

Some CROs avail themselves to deploy the Clinical Trial Educator (CTE), who may oversee the stable retention and recognize and mitigate potential enrollment barriers. Such person in particular manages communication of medical information with patients, caregivers, and investigators. Adequate education about research and medical care may be one of the key factors to successful recruitment and retention through a better understanding of the patient’s care pathway. Such a solution fortifies patient-centric focus of clinical research.

The retention barriers like transportation problems, change of address, compromised memory of planned study visits, limited family support, may be overcome by the means of study decentralization or study’s hybrid design. Such cases e.g. rely on mobile nurse or other mobile health providers to support the visits’ conduct, or patient concierge services to facilitate the patient’s travel to the clinical site. These solutions strengthen the trials’ perception of being patient centric and secure the retention by limiting participation burden, elevating patients’ comfort—all without compromising study design or data quality.

A mobile study nurse or other mobile health professional carry out off-site visits and perform study-related assessments and data collection. The visits, if performed regularly by the same professional/-s, reinforce trust, engagement, and patient’s attention. In the case of hybrid or traditional trial designs that require on-site visits, patient concierge services may depreciate participation burden outcomes by customizing travel-related tasks such as transportation and visit arrangements, travel bookings, or travel reimbursement.

Another role established in clinical research environment with the goal of patient centricity and enhanced retention is Chief Patient (Experience) Officer (CPO or CXO). Such a professional ensures that the level of care a patient receives meets the patient’s expectations and among others may be responsible for partnering with advocacy groups to gain patients’ insights, setting up decentralized clinical trials, instilling “Quality by Desing” processes in order to reflect patients’ input at the research and commercial levels setting up the visits to after-care consultations, sharing trial results with the participants, creating new ways in order to enhance the diversity, and being involved in patient-facing technologies development.

Recent years show the progressive enablement of home-based participation in a CT. This translates into increased rates of recruitment, better level of retention and foremost boost in diversity,

 making CTs easily accessible and effortless for patients who have problems related to distance to the clinical site and travel logistics.

It is stipulated that the research decentralization may contribute to the increase in patient diversity. This promising vision maybe tinted by the limitations on CTs execution imposed by the imaging-based procedures. A solution here may be expansion of imaging facilities beyond the investigational site. Those off-site imaging facilities may operate under the supervision of a central imaging facility which would also be accountable for imaging reading. Such an approach requires careful planning and proactive identification of centers open for yet unconventional operation to support thereby efforts of boosting patients’ inclusivity and diversity. The planning of imaging expansion should keep in focus solutions that are simple, user-friendly and scalable, thus can be seamlessly deployed at multiple sites.

Other tools used to support patient retention

Not surprisingly, communication and engagement of the site staff are crucial for recruitment and retention. Patients report that they expect clear and useful information from the study staff to make the participation-related decisions.

 Different forms of reminders (e.g. Christmas cards or text messages) are utilized to encourage patients’ motivation and compliance with the study plan. Interestingly, according to Coleman et al. Christmas cards do not improve retention rates. No difference in retention was observed between receivers and non-receivers of those cards. The authors recommend a solution called SWAT (Study Within A Trial) to build an evidence base to support the selection of recruitment and retention techniques.

 An embedded non-interventional study within a clinical trial to measure various engagement tools is a feasible solution to be used across multiple trials aiming to test the same hypotheses. By examining different ways of recruitment, it may result in customized enrollment and participant engagement strategies in the future CTs. It is worth mentioning that the SWAT strategy reinforces patient centricity. Nevertheless, it is worth highlighting that, reminders about upcoming visits/procedures are still expected by the patients and may contribute to retention.

 This “nested dolls” approach towards trials allows to verify the seemingly self-evident assumptions on utilized recruitment measures. In the three-arm, embedded randomized trial “REducing Falls with ORthoses and a Multifaceted podiatry intervention” (REFORM) it has been tested if the distribution of the optimized information sheet will have a positive impact on the enrollment rates. The study included 6900 participants over the age of 65, where first arm (n=2298) received “standard” REFORM information sheet, second arm (n=2301) received a ‘bespoke user-tested’ information sheet that was re-written for a lay audience, re-organized into subsections, had graphic design input and underwent user testing, and the third arm (n=2301) received a ‘template-developed’ information sheet written by three research fellows with more than 12 years’ experience of recruiting patients to a range of randomized trials. Cockayne et al. have not observed any significant increase in the success rate in enrolling patients between arms.

Furthermore, Caldwell et al. noted that all the strategies aiming at explaining the CT process instead of having focus on disease or explanation about treatment, had no effect on the consent rates. Above examples showcase that the efforts placed educational activities concentrated on the patient’s health problem have stronger impact on patients’ interest and recruitment than focusing on the process of clinical trials exclusively.

COVID-19 pandemic inevitably has accelerated the adoption of remote solutions in the conduct of CTs—from allowing for electronic ICF through introducing the decentralized CT (DCTs) design.

 Despite all excitement, not all CTs are suitable for decentralized modus operandi.

Decentralized and hybrid CTs have greater potential of patients’ inclusivity and diversity despite of their nowadays operational challenges. They can abolish the conventional participation burdens related to patient’s recruitment by facilitating broader and bespoke reach-out, allowing for active participation by limiting needs for travel for on-site visits. This is all possible as many measures are deployed in parallel leading to ease of access to healthcare services, imposing less stress on patient related to circumstances of the visit to medical institution and transportation, tailored educational means to learn more about the study, study-related procedures and more prominent possibilities of recording patients’ experiences and satisfaction via mobile apps. Bringing studies to patients’ homes create an excellent opportunity to increase the diversity by increasing the chance to recruit people who live in distant regions and do not have access to clinical networks/organizations or are not aware of clinical research.

The remote model improves participants’ compliance to the study procedures and in parallel positively impacts the quality of life. In addition, it is suggested that it lessens the burden on the on-site study team due to decreasing the number of patients’ on-site visits and potential exposure to risks related to infectious diseases.

The remote study design faces few substantial challenges: a) regulatory (e.g., related to existing differences in country-level regulations, b) technological (e.g., securing patients data’s codification, ensuring ease of use of the digital platform/-s for a lay recipient), c) logistic (e.g. successful, proper and timely IMP transportation to the participant’s home, accounting for legal and safety aspects).The clinical research organizations progressively embrace one-stop shop solutions by using a single technology platform for all study participants, where patients are exposed to only one tool from the point of pre-study entry (education/ prescreening), through e-consent for study enrollment to long-term follow-up at the end of patient’s study journey. These tools can collect patient feedback and/or enable study-related communication—all heading towards honing comfortable, interactive, and patient centric solution.

The COVID-19 pandemic has underscored socioeconomic differences in relation to the implementation and utilization of digitalization in clinical research. From economic stance, least developed countries are experiencing serious challenges in deploying and utilizing remote solutions. In addition, the sole reliability on telemedicine may pose a substantial problem in the recruitment of older people in low-income countries, where the access to technology, digital tools, and foremost internet connection remains limited in specific social groups.

Last but not least, DCTs are associated with additional expenses at initial stages related to the costs of implementation and integration with current operations. However, they hold promise of being truly cost- and time-efficient following successful deployment across all processes integral to remote mode of clinical trials’ operations.

Improving recruitment, retention, and diversity may be accomplished mainly by diminishing participation barriers through having in focus patient centricity and considering at least partial decentralization of CTs whenever deem feasible. Such solutions may seem challenging especially in area of securing anonymization, data quality and integrity. Yet, at the same time, they improve those key elements and deliverables of CTs. Moreover, resultant acceleration in optimalization efforts in clinical e-tools dedicated to data obtainment and processing ensures real-time data collection, seamless issue tracking, and on-time reporting. The whole process might require additional engagement, resources, and modification to clinical teams, but it translates into the decrease in participation burden, sites’ workload, and the number of mandatory patients’ on-site visits.

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