Oncology Clinical Trials: Considerations and Challenges

While clinical trials are becoming more complex, oncology trials have generally had a greater level of complexity than trials in many other disease spaces.

Despite this, the number of oncology trials worldwide has increased dramatically over the past two decades. According to Statista, from 2000 to 2018, the number of clinical trials initiated in oncology worldwide increased from about 500 to 2,300 per year. As per a February 2022 World Health Organization (WHO) report, clinical trials involving malignant neoplasms had the most number of registered trials at 104,491 followed by trials for neuropsychiatric conditions at 78,060.

As of December 11, 2022, ClinicalTrials.gov has over 93,000 registered oncology trials.

Some of the inherent challenges of oncology trials include long time to completion, enrollment hurdles, mammoth amounts of generated data and the frequent involvement of a large number of investigative sites and countries.

Many aspects of oncology clinical trials can be complex, from the study design to the data analysis involved. Below is a review of some of the key challenges and considerations in oncology clinical trials.

Regulatory Considerations

One of the keys to a robust trial design that leads to successful trial initiation and culmination is to engage with regulatory bodies early. This is particularly important at the initial stages of trial design to ensure the study meets regulatory requirements, which can change at any given time. Therefore, it is important to be up to speed with US Food and Drug Administration (FDA) guidance documents for example and to have early discussions and engagement with regulators.

The FDA Oncology Center of Excellence (OCE) provides regulatory resources for oncology trials. This includes guidance documents on eligibility criteria, patient-reported outcome (PRO) measures and clinical trial design strategies among many others. The Center is dedicated to patient-centric regulatory decision-making by conducting expedited reviews of medical products for oncologic and hematologic malignancies. It also leads research and educational outreach programs to advance the development and regulation of medical products for patients.

Under the regulatory arm of the OCE, there are initiatives like Project Orbis, which provides a framework for the concurrent submission and review of oncology products among international partners.

Being up to date on regulatory guidelines and programs specific to oncology trials is important in both the early stages of trial design through to the regulatory submission of a product.

Study Design Considerations

Clinical trial designs are optimized to the specific patient populations and therapies involved. In oncology, patients entering trials have almost often than not been treated with either one or more prior therapies. Some of the treatments, such as intensive chemotherapy, can often make patients quite ill and unable to meet trial eligibility criteria. These types of challenges must be considered at the study design stage.

The COVID-19 pandemic has accelerated the adoption of a variety of different trial models, most notably decentralized trials and trials with off-site components. Decentralized and/or hybrid study designs allow for greater patient and site flexibility, where patients can receive treatments and submit samples locally, and practitioners can monitor patients remotely and more often. However, oncology trials often involve complex investigational products (IP) and drugs that can have specific storage and administration requirements, limiting their use to clinical sites with specialized storage and staff. Could alternative delivery and administration occur at community-based network sites?

Moreover, what are common issues encountered in virtual visits, telemedicine and patient-reported outcomes (PRO)? There could also be technological challenges for patients based on the level of familiarity they have with digital tools or functional ability when partaking in remote trial delivery and monitoring. The logistics of off-site trial management must be incorporated in the study design planning stage.

Site Challenges in Oncology Clinical Trials

Oncology trials are often multi-site and can span several countries. This is often a need due to limited patient populations. While multi-center trials are necessary in many oncology trials to meet enrollment targets, it can often be difficult to maintain consistency in trial procedures across sites. Important questions to ask in this regard include: Are all sites sufficiently staffed and equipped to manage potential complexities at all trial steps? Are there site-of-care restrictions and lack of specialized care at sites?

Some sites may not be equipped with advanced imaging or digital data collection tools, for example, which could compromise collected patient data. And if patients cannot visit their local site, they may have to travel to sites further from them, which poses a burden to patients and their caregivers and could result in trial dropout.

Given these challenges, how can trial consistency be ensured across sites with respect to the administration of treatments, sample collection, data collection and data analysis? There is also the consideration of interpreting large and inter-site datasets.

This begs the question whether some aspects of trial care and delivery can be done at hospitals with lower-level accreditation. Would this compromise patient care and data integrity? Striking a balance between optimizing patient access and robust site trial delivery is an important consideration in oncology clinical trials.

Restrictive Eligibility Criteria

Oncology clinical trials are often criticized for having strict eligibility criteria in many cases. This is especially true for trials evaluating targeted therapies, which have strict inclusion criteria based on levels of a given biomarker.

Biomarkers are important at almost every stage of a trial, from initial patient stratification to endpoint monitoring and outcome measures. How can restrictive eligibility criteria be overcome to avoid excluding patients that could potentially benefit from a treatment? Should there be more flexible biomarker ranges versus strict thresholds/cut-offs? Can patients be evaluated on a case-by-case basis, or would this be too time and cost intensive? Given all of these considerations, how should eligibility criteria be optimized?

Inclusion and exclusion criteria can also impact trial diversity. For example, a given biomarker may be more prevalent (i.e., a given gene mutation) or expressed at higher levels (an abnormal protein that a drug is designed to target) in a certain racial demographic or gender. While it makes sense that a drug could be best suited for a given target population based on the molecular profile of their cancer, for example, having a diverse patient cohort is always beneficial even if it is for control purposes.

Oncology Clinical Trial Diversity

While it is encouraging that clinical trial diversity is not a mere afterthought anymore and has become an important aspect in clinical trial design, studies show that there are still systemic level challenges in achieving optimal trial diversity, particularly in oncology trials.

Patients from certain socioeconomic, racial and age demographics may not be too aware of how their participation in clinical research can be important. The onus of this falls on practitioners to inform and educate patients about clinical trials.

Participation in oncology trials can be even more of a challenge as cancer as a disease is still often associated with a lot of stigma and fear in many cultures. This impedes conversations around the disease and treatment itself, and even more about participation in trials. Therefore, culturally appropriate communication is important to help educate patients about oncology trials. This can include communication in different languages, and the presence of practitioners from diverse ethnic and community backgrounds in healthcare and clinical research. Patients tend to be more at ease and can be more trusting if their healthcare provider is someone that they can relate to.

Moreover, mistrust of medical systems among some communities such as Black, Native American and Hispanic peoples continues to be a grave issue. Many people from these backgrounds feel they are not listened to or taken seriously when they enter a medical establishment.

The solution to this is to directly address the problem of medical mistrust, discrimination and bias in healthcare communities. How can preconceived notions and biases be erased in medical systems? How do we come up with tangible and concrete solutions that undo conscious and subconscious prejudices? This must involve training early on in educational pathways, with examples and images of diverse patient populations in textbooks and training manuals to dealing with diverse patients during training, for example. While we are seeing some of these changes being implemented, much more awaits to be done.

The complexity of oncology clinical trials warrants the need for robust study designs and early planning, which includes early engagement with regulators. Regulators like the FDA have specific programs and resources for oncology studies that sponsors and investigators should make themselves familiar with early on. The unique challenges of oncology trials may often warrant novel approaches and solutions to ensure that the trial is a success.