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Data Science and Statistics, University of Michigan

Study seeks to understand how different forms of data meet the needs of researchers. 

Establishing a Basis for Secondary Use Standards for Clinical Trials

In the world of clinical trials, patient recruitment remains a persistent challenge. Despite technological advancements, up to 80% of trials still fail to meet enrollment timelines, leading to delays and increased costs.

 At TrialScreen, we engage daily with sponsors, contract research organizations, and site management organizations striving to enhance recruitment dynamics for their projects. These discussions often revolve around whether to invest in data-focused or trust-based recruitment interventions. Understanding how both data and trust influence patient recruitment and retention is vital for improving operational outcomes.

The availability of rich patient data has transformed recruitment strategies. Electronic health record and real-world data now offer unprecedented insights into potential trial participants. Brett Kleger, CEO of Inspire, notes, “We’re seeing a shift toward more targeted, data-driven approaches. AI and machine learning are being leveraged to predict which patients are most likely to be eligible and interested in specific trials.”

However, data alone is not a panacea. Kleger cautions, “While data can tell us who might be eligible, it doesn’t necessarily tell us who will participate. There’s a human element that can’t be captured by algorithms alone.”

The importance of trust and relationships in clinical trial recruitment cannot be overstated. “When you think about going into a clinical trial, it’s mostly about the relationship that the patient has with the physician,” Kleger emphasizes. This highlights the critical role of site-patient relationships in both recruitment and retention.

Building trust, especially in communities with historical mistrust of clinical research, requires sustained effort. Community engagement and education are key to addressing misconceptions and increasing participation rates.

The future of effective clinical trial recruitment lies in the synergy between data-driven approaches and trust-building efforts. Kleger explains, “Data can inform where and how we build relationships. For instance, we can use data to identify communities with high prevalence of a condition, then tailor our outreach and education efforts to those specific populations.”

Elisa Cascade, chief product officer at Advarra and Association of Clinical Research Professionals board chair, adds nuance to this perspective. She notes, “While both data and trust relationships are important, they serve different purposes and likely vary based on the trial indication/design.”

For easily recruited studies, such as vaccine trials with broad inclusion criteria, trust relationships may suffice. However, in narrower indications like rare diseases, data becomes crucial for identifying potential candidates.

Cascade also notes the role of patient motivation: “One of the greatest drivers of clinical trial interest was a patient’s lack of satisfaction with their medication, including bothersome side effects. When you have patients who truly have unmet medical need and who are motivated to seek new options, data and relationships may play a lesser role.”

The following are practical strategies for balancing data and trust:

 Use big data to identify potential participants, but remember that eligibility doesn’t equal willingness.

 Invest in building trust with patients and communities, potentially partnering with patient advocacy groups or community leaders.

Use data insights to tailor communication and education efforts to specific patient populations.

 As Cascade notes, “If we refer the patient to a site, and the site fails to promptly follow-up, then that patient will never convert anyway.”

In rare disease, proactively build relationships with patient groups before study initiation.

The question of whether clinical trial recruitment is a data problem or a trust challenge is, in reality, a false dichotomy. Successful recruitment strategies must leverage the strengths of both approaches, tailored to the specific needs of each trial. By bridging the gap between data-driven insights and trust-based approaches, we can create more efficient, effective, and inclusive trials, ultimately accelerating the development of new therapies for patients in need.

, MD, is Co-Founder and Executive Chair, TrialScreen

* This is Stephenson’s first installment as a regular contributor to Applied Clinical Trials’ print and digital editions, where he will explore critical topics and challenges in patient recruitment, engagement, and diversity in global clinical trials. A physician, entrepreneur, and thought leader, Stephenson has founded disruptive initiatives such as Quintiles’ Global Late Phase Services, MediGuard, DrugDev,

1. Chaudhari, N.; Ravi, R.; Gogtay, N.J.; Thatte, U.M. Recruitment and Retention of the Participants in Clinical Trials: Challenges and Solutions. 

Understanding how the dynamics between the two play hand in hand in influencing patient recruitment and retention.


Recruiting Clinical Trial Participants: How to Balance Data and Trust

If clinical trial enrollment is improving, it’s a secret well hidden. PubMed is chock full of studies that bemoan the little progress, if any, of trial sites reaching their desired accrual numbers. The HHS Office of the Inspector General, in its May report that looked at enrollment of underrepresented groups in NIH-funded trials, said, in general, that“the NIH monitors clinical trial enrollment but has had limited success spurring improvement.”

In all fairness, Sisyphus had an easier task. Successful clinical trial enrollment might be a numbers game, but it’s a game involving people, and what attracts one person to sign a consent form might barely interest another. Older patients often stay away because they are sicker and, therefore, reluctant to travel to trial sites;

 younger patients with little means need child care and transportation. Some want technology, others think that “smartphone or tablet use during studies disrupt[ed] their daily routines.”

To be sure, numerous, disparate studies are showing just how complicated it can be to get patients to sign on the dotted consent form line. “A wide range of strategies and tactics are needed to reduce barriers to participation and improve retention,” wrote Sine et al. of the 12,451 responses they received to an online global survey.

Perhaps the widest need of all: The use of everyday plain language is not, at least judging by the literature, in wide use. Patients want the kind of communication that allows them to comprehend their disease, the trial process itself, what is expected of them, and what they can expect from the trial.

“It’s a deterrent [from participation] when you don’t know what you are reading,” said one oncology patient during a Center for Information and Study on Clinical Research Participation webinar.

When the concept of health literacy was introduced years ago, the hope was that people would be better able to understand what they were hearing or reading about their situation, aided by simpler language. But health literacy best practices have not been universally adopted, so access to comprehensible materials has remained elusive.

To address this, health literacy advocates have essentially redefined the term. Initially, says Sylvia Baedorf Kassis, MPH, program director, multi-regional clinical trials, Center of Brigham and Women’s Hospital and Harvard (MRCT Center), the health literacy definition was focused on a person’s ability to access, understand, and use health information to make decisions. In the last few years, she says, the concept has expanded. There is still personal health literacy, but now there is organizational health literacy, which “makes it incumbent on the communicators to provide clear communication. The system needs intervention; there is an obvious reason people don’t understand it,” says Baedorf Kassis.

No longer just patient-directed, health literacy is now provider-directed, too. Further, says Baedorf Kassis, that once simple definition of health literacy now encompasses more of what clear, understandable health-related communication requires, taking into account not only words, but also numeric information, cultural humility, and understanding overarching social determinants of health.

Another factor that needs consideration, she says, is cognitive decline in the elderly, especially those whose childhood IQ scores were low to begin with.6 A patient’s emotional state also affects his or her ability to absorb the information being shared, adds Baedorf Kassis. Healthcare professionals in various roles have tried to address the problem, from creating plain language clinical trial templates, developing plain language glossaries that can be downloaded (The AMA’s includes words such as ableism, whiteness, and weathering), and even hiring patient advocacy employees who oversee writing of all patient-focused documents to ensure that they are health literacy accessible.7To support clear communication, for example, the MRCT Center has developed a downloadable Clinical Research Glossary. “Since April, the downloads are in the 1,000s. Folks are coming and using it,” says Baedorf Kassis.

Most potential clinical trial patients want more from their physicians. They want their physicians to give them the particulars of the trial—in a calm setting, not the emergency room—and once enrolled, they want trial staff who know how to communicate with them.

How one patient with diabetes, for example, interprets their illness and its complications is not how another patient understands it.

This patient attachment to his physician is nothing new. A 2008 survey that asked cancer patients about knowledge of clinical trials, found that the more patients knew about the trial and its benefits to them, the more they felt their physicians’ support, and “when the physician invited the patient to participate (20% of the time), three of four patients” accepted.

­ Other patient surveys have found that patients are increasingly more interested in leaning on their physicians to learn about trials.

Another huge boulder to roll up that hill: Journal articles advocating health literacy practice in the clinic go back decades—as do efforts by many federal agencies and professional organizations. But, according to various published reports, it doesn’t appear as if physicians, or medical schools in general, are adopting plain language ways.

“I don’t see them asking for help,” says Baerdorf Kassis. “This speaks to organizational and systemic issues that need to be addressed.”

 on physicians’ attitudes regarding health literacy found most blamed “dysfunctions within the healthcare system, staff shortages, managing a large number of patients, limited time, work-related stress, cultural and socio-economic barriers, medical jargon, and language barriers.” A survey of community pharmacists in poorer sections of southwest Georgia, published in 2023 article in 

, found they had no health literacy training, and most didn’t know that their lack of knowledge about health literacy kept them from screening their patients for their own health literacy levels.

Can we dismantle the hierarchy between patient and physician to allow for good communication? asks Baedorf Kassis. Researchers do not want to confuse patients, she believes. “I think it is hard to unlearn what you learned and to remember what it is like to have a beginner’s mindset. Medical professionals learn a scientific, technical language, so simplifying takes practice. But we need to meet patients where they are.”

She adds: “Doctors aren’t resisting on purpose. Medical professionals have learned medical and scientific language, so it takes practice.”

 is a Freelance Writer for Medical, Clinical Trials, and Pharma Information

1. Department of Health and Human Services. Office of Inspector General. Plans and Enrollment Often Fell Short for Underrepresented Groups in a Sample of NIH-Funded Clinical Trials. May 28, 2024. 

https://oig.hhs.gov/reports/all/2024/plans-and-enrollment-often-fell-short-for-underrepresented-groups-in-a-sample-of-nih-funded-clinical-trials/

2. Buttgereit, T.; Palmowski, A.; Forsat, N.; et al. Barriers and Potential Solutions in the Recruitment and Retention of Older Patients in Clinical Trials-Lessons learned from Six Large Multicenter Randomized Controlled trials. 

3. de Bruin, A. Latest CISCRP Patient Survey Reveals Diversity Gaps, Yields 5 Tips For Improvement. 

https://www.clinicalleader.com/doc/latest-ciscrp-patient-survey-reveals-diversity-gaps-yields-tips-for-improvement-0001

4. Sine, S.; de Bruin, A.; Getz, K. Patient Engagement Initiatives in Clinical Trials: Recent Trends and Implications. 

https://doi.org/10.1007/s43441-021-00306-8

5. Center for Information and Study on Clinical Research Participation. Tools of the Trade for Patient-Centric Clinical Development. YouTube. 

https://www.youtube.com/watch?v=YVAoZkBwP9M

6. Murray, C.; Johnson, W.; Wolf, M.S.; Deary; I.J. The Association Between Cognitive Ability Across the Lifespan and Health Literacy in Old Age: The Lothian Birth Cohort 1936. 

https://www.sciencedirect.com/science/article/abs/pii/S0160289611000535

7. Empowering Patients on Clinical Trials Day and Beyond. Galapagos. May 20, 2024. 

https://www.glpg.com/stories/empowering-patients-on-clinical-trials-day-and-beyond/

8. Briel, M.; Speich, B.; von Elm, E.; Gloy, V. Comparison of Randomized Controlled Trials Discontinued or Revised for Poor Recruitment and Completed Trials with the Same Research Question: A Matched Qualitative Study. 

https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-019-3957-4

9. Williams, C.P.; Senft Everson, N.; Shelburne, N.; Norton, W.E. Demographic and Health Behavior Factors Associated with Clinical Trial Invitation and Participation in the United States. 

https://pubmed.ncbi.nlm.nih.gov/34586365/

10. Albrecht, T.L.; Eggly, S.S.; Gleason, M.E.; et al. Influence of Clinical Communication on Patients’ Decision-Making on Participation in Clinical trials. 

. 2008. 26 (16), 2666-26673.J1;26(16):2666-73. 

https://pubmed.ncbi.nlm.nih.gov/18509178/

With universal adoption of health literacy best practices slow going over the years, advocates are redefining the term to encompass much more of what health-related communication requires beyond simply words.

In Focus: Addressing the Health Literacy Roadblock in Patient Recruitment

Patient-centricity has become a guiding principle for clinical research and treatment evaluation. There is a strong movement in clinical research to actively involve patients at the center of decision-making, with their preferences, quality of life, and individual values increasingly recognized as key elements in assessing treatment success. The net treatment benefit (NTB) embodies this patient-centered approach by allowing integration of diverse clinical outcomes into a single comprehensive metric. By prioritizing outcomes based on patient input, NTB offers a more personalized and transparent way to evaluate treatment effects, empowering patients to play an active role in their healthcare journey.

NTB is a measure of treatment effects estimated from generalized pairwise comparisons (GPC), a statistical method that stems from the well-known Mann-Whitney Wilcoxon non-parametric test.

 The primary innovation of GPC is to provide a global assessment of treatment effects through the hierarchical integration of any type of outcomes, such as efficacy, safety, and quality of life. By allowing the integration of multiple outcomes within a single analysis, this approach can overcome the limitations of traditional methods that focus on a single primary endpoint. Indeed, analyzing outcomes hierarchically rather than marginally better reflects their interactions and dependencies.

An advantage of GPC is that its logic is quite simple. The approach sequentially compares each clinical outcome based on a predefined list of priorities. For instance, in a cancer trial, overall survival may be the highest-ranked outcome, followed by cancer progression outcomes, treatment-related adverse events, and quality of life measures. It also allows the use of thresholds of clinical relevance that define a minimum clinical difference required for classifying two pairs. Once the priorities and thresholds are specified, each patient from the experimental arm is compared with all possible patients from the control arm, starting with the highest-priority outcome. The possible outcomes of these comparisons are classified as a “favorable” (if the patient in the experimental group fares better), “unfavorable” (if the control patient does better), or “neutral” (if there is no significant difference between the two patients).

If a pair is classified as neutral, the comparison moves to the next outcome, which might be toxicity or quality of life. Each pair initially classified as “neutral” is then compared on the next outcome and reclassified as “favorable,” “unfavorable,” or “neutral.” This continues until all hierarchical outcomes have been considered. The NTB can be calculated as the difference between the probability of being favorable to the experimental treatment and the probability of being favorable to control. This creates an easily interpretable absolute metric where a NTB value greater than zero indicates that the experimental treatment provides a net benefit over the control treatment, while a value less than zero indicates net harm.

This emerging class of statistical analysis is sometimes referred to as hierarchized composite outcome and is gaining increased traction in clinical research. One of the most recognized is an alternative estimator called the win ratio (WR). However, as a relative measure, the WR has several limitations. First, it lacks transparency in illustrating how individual outcomes contribute to the overall treatment effect, making it difficult to understand the specific factors driving the observed benefit or harm. Moreover, the WR disregards neutral pairs by assuming they behave similarly to classified pairs, which can be misleading if this assumption does not hold. Recently, two treatments have been approved by FDA’s cardiovascular division using GPC and the WR, the most well-known being tafamidis.

In contrast, the NTB provides a clearer understanding of treatment effects by explicitly detailing each outcome’s contribution. This makes NTB a more transparent and patient-centered approach, ensuring that each relevant clinical outcome is considered and that the overall estimate reflects a comprehensive picture of patient impact. Recent case studies have demonstrated the benefits of NTB in highlighting differences across a wide range of patient-relevant outcomes, ultimately leading to more informed and patient-aligned decision-making in clinical trials.

The NTB can also address some of the shortcomings associated with non-inferiority trials. As discussed in a recent published paper in 

, non-inferiority trials often face criticism for relegating outcomes such as toxicity and cost to secondary considerations, and for setting very narrow statistical margins that can make it difficult for alternative, potentially patient-friendlier treatments to demonstrate equivalence. These trials frequently require large sample sizes and expensive resources to prove that an alternative is “not worse” than the standard, even when the clinical differences are minimal.

 The NTB, on the other hand, can transform this approach by incorporating multiple outcomes into a superiority benefit-risk analysis, offering a more nuanced and holistic assessment. By prioritizing and integrating different endpoints, NTB helps redefine the evaluation from simply establishing non-inferiority to understanding the full spectrum of benefits and risks, thereby supporting more patient-centered, cost-effective, and meaningful treatment decisions.

Incorporating patient preferences into NTB

One of the most powerful aspects of NTB is its ability to accommodate patient preferences directly into the clinical trial design and analysis. In the traditional trial framework, only outcomes such as overall survival or disease-free survival are used for market approval, while others—such as quality of life, symptom burden, or adverse effects—are secondary considerations. This approach can fail to reflect what truly matters to patients, particularly when dealing with chronic conditions where long-term side effects or daily functioning may outweigh the benefit of the former outcomes. By focusing solely on clinical endpoints, traditional methods may overlook the nuanced needs and desires of patients, limiting the comprehensiveness of the treatment effect evaluation.

The NTB, however, can be estimated based on the outcomes that are most important to individual patients. This patient-centric approach empowers individuals by giving them a voice in the evaluation process. It enables patients to express their preferences and offers a more personalized view of treatment effects. For example, patients may prioritize quality of life and minimal side effects over overall survival, depending on their unique circumstances. By allowing for such individual differences, NTB provides a more holistic understanding of treatment benefits that align closely with patients’ lived experiences.

To facilitate the incorporation of patient preferences, software tools designed to elicit these preferences are essential. These tools can help quantify and integrate patient values, allowing researchers to develop personalized NTB metrics. Such tools exemplify how patient input can be incorporated into the NTB methodology, transforming the traditionally rigid framework of clinical trials into one that is more adaptable to individual patient needs. The FDA currently encourages medical researchers to engage with patients as early as the design phase of clinical trials,4 underscoring the importance of understanding patient priorities from the outset.

Furthermore, relevant methods are needed to elicit patient preferences in the context of treatment effect measures. Current tools and techniques, such as surveys, discrete choice experiments, or conjoint analysis, offer promising approaches but still lack standardization across the industry. While the FDA, in past guidance documents, acknowledges that “quantitative patient preference assessment is an active and evolving research area,”

 no standard process has been validated yet. This lack of standardized tools poses a challenge, as pharmaceutical companies may be hesitant to invest in patient-focused methodologies without clear regulatory frameworks.

Significant efforts are needed from the industry to address this unmet need and support patient-focused clinical research. This includes developing and validating standardized methods to elicit patient preferences and ensuring these methods are robust enough to be used in regulatory submissions. By taking these steps, the industry can foster a more patient-centered approach to clinical trials, ultimately leading to treatments that better reflect patient needs and enhance their quality of life.

is Clinical Trial Solutions Analyst; and 

is Senior Trial Design Lead; all with One2Treat

1. Buyse, M. Generalized Pairwise Comparisons of Prioritized Outcomes in the Two‐Sample Problem. 

https://pubmed.ncbi.nlm.nih.gov/21170918/

2. Maurer, M.S.; Schwartz, J.H., Gundapaneni, B., et al. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. 

https://www.nejm.org/doi/full/10.1056/NEJMoa1805689

3. Tannock, I. F.; Buyse, M.; De Backer, M.; et al. The Tyranny of Non-Inferiority Trials. 

https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(24)00218-3/abstract

FDA Patient-Focused Drug Development Guidance Series for Enhancing the Incorporation of the Patient’s Voice in Medical Product Development and Regulatory Decision Making 

https://www.fda.gov/drugs/development-approval-process-drugs/fda-patient-focused-drug-development-guidance-series-enhancing-incorporation-patients-voice-medical

Patient Preference Information - Voluntary Submission, Review in Premarket Approval Applications, Humanitarian Device Exemption Applications, and De Novo Requests, and Inclusion in Decision Summaries and Device Labeling

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-preference-information-voluntary-submission-review-premarket-approval-applications

How the inclusion of measures centered on net treatment benefit can drive an effective multifaceted approach. 

Enhancing Empowerment in Patient-Focused Research 

Advarra has published results from its 2024 Site-Sponsor-CRO Collaboration Survey. Results include responses from over 200 stakeholders within sites, sponsors, and CROs. The full report highlights three distinct barriers that prevent greater collaboration, ultimately delaying clinical trial execution.

Survey respondents agreed on the importance of communication. However, over half of the respondents from sites and 43% from sponsors/CROs ranked the need for improved communication as important or very important. Additionally, results showed a much higher percentage of sites are initiating daily/weekly communication compared to sponsors/CROs.

"Sites, sponsors, and CROs have good intentions, but they often work in siloes, isolated from the daily concerns of one another, which—over time—creates friction and slows trials," Christine Senn, vice president of site-sponsor innovation, Advarra, said in a press release. "With strong relationships across stakeholders, Advarra is uniquely positioned to create common ground to drive innovation and advance clinical research."

Responses indicated staffing issues as an area needing improvement. In particular, respondents from sites indicated they are seeking better education and training for inexperienced clinical research associates.

In terms of technology and its role in enabling collaboration, about half of the site and sponsor/CRO respondents expressed that better technology would improve their relationships with each other. Despite this, only 29% of site respondents agreed or strongly agreed that sponsor/CRO technology solutions deliver their promised value.

Based on the results of the survey, Advarra identified key actions that can be taken to improve stakeholder relationships. These action items include:

Optimize reporting, visibility, and feedback

Earlier in October, Senn authored an article about site-sponsor collaboration on 

. In the article she wrote, “It may not be easy, but the path forward must start with improving processes, communication, and technology to reduce the time and effort required for study startup. We are better together than apart. Only by committing to be part of our theoretical village, can the industry productively collaborate and come together to accelerate study activation and improve the overall efficiency of clinical research.”

The full report from Advarra can be downloaded 

1. Advarra Publishes 2024 Site-Sponsor-CRO Collaboration Survey Results to Improve Clinical Research. News release. Advarra. November 12, 2024. Accessed November 13, 2024. 

https://www.prnewswire.com/news-releases/advarra-publishes-2024-site-sponsor-cro-collaboration-survey-results-to-improve-clinical-research-302302070.html

2. Senn C. From Isolation to Integration: Improving Site-Sponsor Collaboration in Clinical Trial Startup. 

 October 24, 2024. Accessed November 13, 2024. 

https://www.appliedclinicaltrialsonline.com/view/integration-improving-site-sponsor-collaboration-clinical-trial-startup

Over 200 stakeholders highlighted challenges such as communication, training, and improving technology.

Advarra Publishes Latest Site-Sponsor-CRO Collaboration Survey Results

In the first part of this roundtable discussion, a panel of experts introduce themselves and highlight the challenges industry is seeing with underrepresentation of racial and ethnic groups in clinical trials.

Peer Exchange: The Importance of Improving DE&I in Clinical Trials (Episode 1)

In this roundtable discussion, industry experts gathered to address the state of achieving greater diversity in clinical research. The group highlighted a variety of topics including current challenges they are seeing, the use of technology, and more.

Moderated by Otis Johnson, PhD, MPA Co-Founder & Principal Consultant, Trial Equity, the panel featured key insights from Sophia McLeod, Sr. Director, Government Relations, ACRO; Erin Stern, PharmD, Research Support Pharmacist, Mayo Clinic; and Caitlin Brown, PharmD, Neurocritical Care and Emergency Medicine Clinical Pharmacist, Mayo Clinic.

Brown highlighted the progress in women's representation, but also noted challenges with racial and ethnic groups due to historical mistrust, access, eligibility criteria, and language barriers. McLeod emphasized the importance of early diversity planning in protocol design and community engagement. Stern discussed the logistical challenges of decentralized trials and the need for better technology integration. The panel agreed on the necessity of consistent funding, community involvement, and ethical artificial intelligence use to enhance DE&I in clinical research.

Peer Exchange: The Importance of Improving DE&I in Clinical Trials

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