Diversity Lacking in Pancreatic Cancer Trials

From Let’s Win! Pancreatic Cancer
August 6, 2021

Pancreatic cancer trials are no exception. A recent study selected for presentation at the annual Digestive Disease Week 2021 conference clearly shows the magnitude of the problem.

Researchers analyzed data from 8,429 participants in 207 clinical trials in the U.S. for treatments for pancreatic ductal adenocarcinoma on ClinicalTrials.gov, the national registry of clinical trial data. Gender was reported in 99 percent of the trials, while race and ethnicity were reported in 49.3 percent and 34.7 percent of trials respectively. In all, 54.8 percent of trial participants were male, and 45.2 percent were female.

According to the data, minorities were substantially underrepresented:

  • Black patients comprised 8.2 percent of trial participants vs. 12.4 percent of cases
  • Hispanic patients represented 6 percent of trial participants vs 8.5 percent of cases
  • Asian or Pacific Islander patients represented 2.4 percent of trial participants vs 3.3 percent of patients
  • American Indians and Alaska Native patients represented 0.3 percent of trial participants compared to 0.4 percent of cases

On the flip side, White patients were overrepresented, making up 84.7 percent of the total trial participants, while they account for 82.3 percent of the total U.S. pancreatic cancer incident cases.

“We knew there was an issue and we knew there were going to be disparities, but when we looked at the numbers we were a little shocked. Anyone who isn’t White is underrepresented in these trials,” says lead investigator Kelly Herremans, M.D., a general surgery resident and surgical oncology research fellow at the University of Florida, Gainesville, who presented the abstract “Trials and tribulations: Diversity and inclusion in pancreatic ductal adenocarcinoma clinical trials.”

The hypothesis for the study stemmed from what was being seen in the clinic. “As a surgical oncologist who concentrates his academic and clinical practice on pancreatic cancer, I was seeing mostly White people coming in the door while pancreatic cancer disproportionately affects Black Americans,” explains surgical oncologist Jose Trevino, M.D., Chair of the Division of Surgical Oncology at the VCU School of Medicine and Surgeon-in-Chief at VCU Massey Cancer Center, Virginia Commonwealth University, Richmond.

Trevino admits this contradictory scenario spurred a lot of questions. “I started asking myself if this was a result of socioeconomics, lack of transportation, or that minorities don’t always trust the healthcare system,” he notes. Trevino’s research focuses on pancreatic cancer biology, tumor microenvironment, cancer cachexia, and novel therapeutics and how they relate to pancreatic cancer health equity. “When you see the numbers, the disparity in recruitment is just so stark.”

Asking the Tough Questions

Lack of diversity in clinical trials is often attributed to reluctance to participate due to historic wrongs, such as the infamous 1932 USPHS Syphilis Study at Tuskegee that left Black men untreated for many years to study the long-term impact of syphilis. But research has shown that Black patients are just as willing as White patients to be part of a clinical trial, Herremans says. Plus, Black patients get pancreatic cancer more often, are diagnosed at younger ages, and die sooner, she adds.

Which, of course, begs the question: Why then is there such underrepresentation?

The research team is currently in the process of trying to answer that question. “It’s clearly multifactorial,” Herremans explains. “But one reason may be due to the fact there are so few Black or Hispanic oncologists, for example, which can influence referral patterns.”

Other troubling reasons for the lack of minority enrollment may be due to systemic racism, provider biases that interfere with recruitment as well as study inclusion criteria. Those biases can create impediments to enrollment, such as turning away patients with obesity and diabetes, which are more prevalent in minority populations.

“As doctors who deal with cancer patients every day, we need to start looking at ourselves,” says Trevino. “I’m a surgeon. Dr. Herremans is a surgeon. If something goes wrong in the operating room the first person we look at is ourselves and ask what did we do wrong? We don’t blame the tools or the system because we can’t exclude the possibility that we made a mistake.

“So when you think of it that way, we need to ask ourselves why is the accrual so poor?”

Because of higher rates of diabetes and heart disease among minority patients, they often don’t meet eligibility requirements for trials, Trevino explains. “Many trials are designed for the healthiest of pancreatic cancer patients. That’s going to immediately exclude many minority participants and that just doesn’t make sense.”

Both Trevino and Herremans admit some of the questions they will ask as their research progresses may be uncomfortable. “We’re going to be asking tough questions, and venture into areas that people have stayed away from, and then hopefully find ways to better meet the needs of all cancer patients,” Trevino says. “That’s the way that change occurs.”

Why Diversity Matters

Clinical trials are the foundation of approval for any new cancer chemotherapeutic agent. Without demographic diversity among those who participate in trials, researchers won’t have a clear understanding of how the drug may work in different populations.

Numerous variables, including age, sex, and ethnicity, among others, can influence how an individual may react to a drug. For example, a 2014 study published in the journal Clinical Pharmacology & Therapeutics found marked differences as to how different ethnicities reacted to about 20 percent of drugs approved from 2008 to 2013.

That’s because tumor biology plays a role. “What we do know is that patients with African ancestry have different rates of both somatic and germline mutations when compared to other subgroups,” Herremans explains. “They are going to respond differently to therapies.

“I’m completing a precision medicine fellowship right now, and the bulk of the subject matter is how patient biology impacts therapeutics. Everyone is unique. Patients of different ancestries may metabolize things differently based on enzymes. So there has to be adequate representation of different races and ethnicities in clinical trials because without that we just don’t know how that particular drug is going to act in all patients.”

Both researchers are hopeful there will be change sooner rather than later. “There are regulations that are supposed to help with this problem, and everyone is talking about the issue. I think it’s just time that we all just need to work together, move forward, and make changes that need to be made,” Herremans notes.

Precision medicine will also be a game-changer. “I am Mexican, but that means I’m probably a mix of Portuguese, Spanish, and Indigenous American ancestry,” says Trevino. “We’re all a mix of something. Ideally, we will get to the day when therapies are based on individual patient genomics. We’re not quite there yet, but when we are it will be a beautiful day.”


ASCO and Friends of Cancer Research Recommend Expanding Patient Access to Cancer Clinical Trials by Further Broadening Eligibility Criteria

from www.ASCO.org
February 9, 2021


Working to broaden clinical trial eligibility criteria ASCO and Friends of Cancer. SCORThe American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (Friends) jointly issued new recommendations to further efforts to broaden eligibility criteria in cancer clinical trials with the goal of making clinical trials more accessible to patients. The joint recommendations are detailed in a series of articles published in Clinical Cancer Research, a journal of the American Association for Cancer ResearchThe series provides a comprehensive examination of eligibility criteria for cancer clinical trials with recommendations to address five specific areas: treatment washout periods, concomitant medications, prior therapies, laboratory reference ranges and test intervals, and patient performance status.

“Clinical trial access must be recognized as a health equity issue. Overly restrictive eligibility criteria without scientific justification has led to an underrepresentation of older adults, racial/ethnic and sexual/gender minorities, and patients with well-managed comorbidities,” said ASCO President Lori J. Pierce, MD, FASTRO, FASCO. “We’re proud to continue our collaboration with Friends of Cancer Research to make eligibility criteria less restrictive so that clinical trial populations can be more inclusive and representative of cancer patient populations and improve results for all patients.”

Trial eligibility criteria are designed to protect participant safety and define an appropriate study population. However, overly restrictive eligibility criteria can limit the participation of patients in a clinical trial who share critical characteristics with those likely to be treated based on the study’s results. These restrictions make it hard for clinicians to fully understand how a more diverse patient population typically seen in clinical practice will respond to a therapy post-approval. Overly restrictive eligibility criteria can also reduce patient access to potentially life-prolonging novel treatments and slow down the generation of research results. Using recommendations made by ASCO and Friends in 2017, a new analysis of data from CancerLinQ Discovery® (CancerLinQ’s deidentified real-world data product for researchers) found that expanding just three common eligibility criteria—renal function measures, presence of brain metastases, and history of prior malignancy—increases the percentage of lung cancer patients potentially eligible for clinical trials almost twofold.

To address this issue, ASCO and Friends worked with stakeholders throughout the cancer research community to develop evidence-based, consensus recommendations that are focused on expanding eligibility criteria to make trial populations more reflective of the general cancer population, reduce clinical trial complexity, and exclude patients from trials only where it is warranted due to safety concerns. Implementation of the recommendations, ASCO and Friends assert, can expedite patient recruitment, accelerate learning, decrease trial ‘failure rate’ due to slow enrollment, increase opportunities for patient participation and benefit, and make trial results more generalizable to the population that would use the treatment in routine clinical care.

“As new cancer therapies are being developed, we must think broadly about how eligibility criteria are determined.” said Jeff Allen, PhD, President & CEO of Friends of Cancer Research. “We need to find an optimal balance between improving patient access to clinical trials and the methods used for robust evaluation of safety and efficacy of new therapies. Modernizing eligibility criteria for enrollment will bring more trials to more patients, and ultimately help inform the optimal use of new medicines more quickly.”

The recommendations published today were developed by stakeholders from ASCO, Friends, academic and community research sites, the Food and Drug Administration (FDA), National Cancer Institute (NCI), patient advocates and advocacy groups, NCI National Clinical Trials Network Groups, and the pharma-biotech industry.

New Recommendations Build on Ongoing Work to Expand Eligibility Criteria and Simplify Trial Operations

In 2016, ASCO, Friends, and FDA formed a collaboration to address overly restrictive cancer clinical trial eligibility criteria. Project leadership selected five criteria that commonly lead to the exclusion of specific patient populations from clinical trials (brain metastases, minimum age for enrollment, HIV status, organ dysfunction, and prior or concurrent malignancies) and tasked multi-stakeholder working groups with recommending less restrictive eligibility criteria addressing these five factors. An ASCO-Friends Joint Research Statement and supporting working group papers were published in the Journal of Clinical Oncology in 2017.

As a result of efforts by ASCO and Friends to disseminate and encourage implementation of those recommendations, in September 2018 NCI revised protocol template language based on the recommendations, stating that the updated criteria should be implemented where possible in active protocols and included in future Experimental Therapeutics Clinical Trials Network and National Clinical Trials Network trial protocols. Additionally, in July 2020, FDA released four final guidance documents recommending broadening eligibility criteria related to brain metastasesHIV and Hepatitis B/C infectionsorgan dysfunction and prior/concurrent malignancies, and minimum age requirements.

ASCO and Friends will continue to work closely with FDA, NCI, trial sponsors, institutional review boards (IRBs), contract research organizations (CROs), and patient groups to disseminate the latest recommendations, share analyses, and help to successfully implement changes in protocols to broaden eligibility criteria appropriately.

More detailed information on each article is provided below. 


ASCO-Friends Joint Research Statement

Overview: This article provides an overview of the ASCO and Friends eligibility criteria initiativeoutlines goals and rationale, and describes the process used to develop the recommendations. The article also provides a summary of the working groups’ recommendations.

Washout Periods and Concomitant Medications

Background: Washout periods for prior treatments and interventions limit timely accrual and may prevent patient enrollment without adding safety measures or preventing misinterpretation of efficacy results. Excluding patients who require concomitant medications (other medications taken by the patient that are unrelated to the investigational treatment) for other illnesses or supportive care management limits understanding of the investigational agent’s tolerability and dosing in those likely to receive the treatment post-approval and excludes many older patients with co-morbid illnesses.

This working group recommends the use of less restrictive requirements for prior therapy washout periods and concomitant medication in most instances. Specifically:

  • Time-based washout periods should be removed from protocol eligibility criteria in most cases.
  • Relevant clinical and laboratory parameters should be used in place of time-based washout periods to address safety considerations.
  • Potential trial participants should have recovered from clinically significant adverse events of their most recent therapy/intervention prior to enrollment.
  • Concomitant medications use should only exclude patients from trial participation when clinically relevant known or predicted drug-drug interactions or potential overlapping toxicities will impact safety or efficacy.

Performance Status

Background: Performance status (PS) is one of the most common eligibility criteria, often limiting clinical trial populations to highly functional and minimally symptomatic individuals who do not reflect the populations afflicted with the disease. Existing PS tools are inherently subjective and invite bias, and PS does not reliably predict outcomes for older adults.


  • Patients with reduced PS should be included unless there is a scientific and/or clinical rationale for exclusion justified by established safety considerations. PS eligibility criteria should be continually re-evaluated and modified throughout the clinical development process to reflect accumulated safety data of the investigational treatment.
  • Investigators should consider alternate trial designs, such as pre-specified cohorts with lower PS that are exempt from the primary analysis, to encourage inclusion of these patients.
  • Investigators should consider additional assessments to better characterize the functional status of ECOG PS2 patients and patients aged ≥65.

Laboratory Tests

Background: Laboratory test-related eligibility criteria may exclude a significant portion of patients from clinical trials unnecessarily and can have disproportionate impact on patients according to age, gender, race, and ethnicity.

The proposed recommendations help guide appropriate use of laboratory tests and testing intervals to safely enable increased clinical trial accrual and provide more relevant data that better mirror oncology patient populations. Specifically, the article recommends:

  • Laboratory test results should only be used as exclusion criteria when scientifically justified and when abnormal test results confer safety concerns.
  • Laboratory reference values should account for potential normal variations due to race, ethnicity, age, sex, and gender identity.
  • Routine re-assessment of laboratory test-based exclusion criteria should be conducted during the course of clinical research and drug development.
  • Investigators should consider increasing the intervals between protocol-specified tests to help reduce patient burden and rely more on routine clinical testing.

Prior Therapies

Background: A patient’s prior therapies—including number or type—are often used either as exclusion or inclusion criteria for enrollment into clinical trials.

The multi-stakeholder working group has recommended:

  • Patients should be eligible for clinical trials regardless of the number or type of prior therapies and without a requirement to have received a specific therapy prior to enrollment unless there is a scientific or clinical rationale.
  • Prior therapy could be used to determine eligibility in the following cases:
    • If the agents being studied target a specific mechanism or pathway that could potentially interact with a prior therapy.
    • If the study design requires that all patients begin protocol-specified treatment at the same point in the disease trajectory.
    • In randomized clinical studies, if the therapy in the control arm is not appropriate for the patient due to previous therapies received.
  • Trial designers should consider conducting evaluation separately from the primary endpoint analysis for participants who have received prior therapies.

CancerLinQ Discovery Analysis

Overview: An analysis of real-world data from the CancerLinQ® Discovery database shows that expansion of three common eligibility criteria—renal function measures, presence of brain metastases, and history of prior malignancy—increases the number of patients with lung cancer in the dataset analyzed who are potentially eligible to enroll in a trial almost two-fold. This analysis was conducted in a population with advanced non-small cell lung cancer, although the paper suggests that the findings are likely applicable to other advanced malignancies.