Clinical trials offer people living with cancer the opportunity to try a new treatment while also helping the research community work towards defeating the disease. But could a selective recruitment approach be holding back both patients and scientists? Here, we investigate this complicated issue and learn what steps researchers at The Institute of Cancer Research, London, are taking to create meaningful change.
“You have cancer” are words nobody wants to hear, but hundreds of thousands of people receive this news every year. While everyone will react differently, the priority for most people will be to work with their oncologist on a care plan so that they can start treatment as soon as possible.
Either at this point or at a later stage, some people will be offered the chance to participate in a clinical trial. There are possible benefits and downsides to taking part, and each person will need to determine whether it is the right course of action for them.
A personal decision
For some patients, the opportunity to access an otherwise unavailable treatment that may be more effective than the standard of care is enough to convince them. Others find the idea of having extra tests, scans and checkups – a feature of some but not all clinical trials – reassuring. Altruism can also be a motivating factor, as trial participants are playing a part in improving cancer treatments for future generations.
Conversely, the risk of unexpected side effects can dissuade some people, while others might find the extra appointments unnerving or difficult to manage due to time or financial constraints. People invited to randomised blind trials may also be wary of committing their time when they do not know whether they will receive the standard treatment or the one under investigation.
Barriers to participation
Despite clinical trials not being the right choice for everyone, research carried out by scientists at The Institute of Cancer Research (ICR) found that approximately one in 10 UK adults with cancer have taken part in one. This relatively high number shows that many people are being given the option to participate. However, various barriers prevent this opportunity from being equal across all patients.
Logistical barriers
People who live in rural areas – particularly those with no vehicle and poor public transport services – may have limited geographical access to the clinical trial sites and be unable to commit to attending multiple appointments. Although many trials offer funding to support additional travel and required accommodation costs, the participant often has to cover these costs upfront before getting reimbursed.
Others might be tied to non-flexible working patterns or have health conditions that hinder mobility and make travel difficult. Although these issues are not inherent to clinical trials, they may dissuade people from joining studies that require additional in-person appointments.
Communication barriers
The 2021 Census revealed that 8.9 per cent of people aged three and over living in England and Wales did not have English as their main language. Of these people, 1.5 per cent felt they were unable to speak English well, and 0.3 per cent reported being unable to speak the language at all. While NHS hospitals provide access to interpreters and some trials provide patient information sheets translated into other languages, it is not always possible to give everyone a sufficient understanding of the details to allow them to give informed consent.
Another consideration is that 22,000 individuals primarily use British Sign Language (BSL) to communicate. In addition, statistics show that more than two million people in the UK have sight loss, with about 340,000 people registered blind or partially sighted. Although advances in digital technology have made communication easier for these populations, they are only helpful if trial organisers use them effectively.
Research-related barriers
Even if a great number of people were willing and able to take part in a study, scientists may not always be able to capitalise on this.
Low resources and insufficient personnel or funding can prevent clinical trial organisers from maximising their recruitment efforts. Or, more commonly, strict eligibility requirements – sometimes put in place by the company that owns the drug being tested – exclude a significant number of people. These requirements are known to be particularly stringent in oncology.
For instance, participants might need to have a specific type, subtype or stage of cancer, or they may need to fall within a specific age range. Often, people who have other serious health conditions or have survived another type of cancer already will be excluded, as will those on certain medications.
The move towards increasingly personalised and targeted treatments means that trial organisers often require participants to have specific genetic changes in their cancer. A person’s treatment history might also rule them out if they do not meet certain criteria, such as only having received one prior treatment or not having received any treatment in the past month.
Wider effects on cancer research
Clearly, inequality of opportunity is unfair to patients, which is partly why UK researchers are endeavouring to reduce it. They are also aware that treating only specific patient subgroups may limit the applicability of clinical cancer research findings to the broader population and slow the race to defeat the disease.
The approved uses of a drug, known as indications, are directly tied to its performance in the clinical trial setting. Therefore, if it is only tested in patients with a particular ethnicity, disease subtype or treatment history, these limitations will be included on the drug’s label. If other patients are given the drug, the efficacy and safety findings from the trial may not be directly applicable to them – even if they have the same type of cancer.
In a recent editorial published in European Urology, ICR researchers expressed their belief that the current model for oncology trials may not always accurately represent modern cancer care. They wrote:
“More inclusive study designs could ensure that trial outcomes better reflect the diversity of cancer patients and result in more effective, equitable and patient-centred treatments. This shift is both an ethical imperative and a scientific necessity for advances in oncology.”
Dr Tarek Taha, an honorary researcher in the Division of Clinical Studies at the ICR and first author of the editorial, said:
“Research on pivotal clinical trials that led to drug approvals has shown that fewer than 10 per cent of cancer patients met the eligibility criteria for participation. The problem is that the nine in 10 people excluded – which typically includes older people and people with other health conditions – actually comprise the majority of cancer cases.
“Arguably, these trials will be overestimating the benefits of the intervention being tested and potentially underestimating the risks. We’ve seen before that new drugs can end up performing less well than expected once they become available in clinics.”
Senior author Professor Johann De Bono, Regius Professor of Cancer Research at the ICR and Director of the Adult Drug Development Unit at the ICR and The Royal Marsden NHS Foundation Trust, agreed:
“Specific details, such as a laboratory blood test abnormality, can be enough to prevent patients from joining a clinical trial, usually to minimise safety concerns. Some of these patients have exhausted their other treatment options and would be willing to risk the uncertainties of experimental therapies.
“While valid safety concerns and regulatory requirements cannot be overlooked, eligibility criteria are often too stringent. If we are not testing how a drug can perform against more complex cases, we are undermining the relevance of the trial outcomes for the wider population of cancer patients.”
Competing priorities
Cancer researchers are usually driven by a strong desire to help people living with cancer. Understandably, they want to maximise the likelihood of a drug that works being approved so that it can save and extend lives. This can contribute to the disconnect between clinical trial cohorts and real-world patient populations, as one way to increase the chances of an intervention performing well is to be cautious when setting the eligibility criteria.
People with other health conditions and those for whom other treatments have been ineffective might be less likely to respond well to the trial drug, and this could skew the results towards an underperformance. If this prevented the drug from reaching the market, people who would have done well on the treatment would never get to benefit from it.
Researchers must also consider safety, particularly in early-stage trials, when the potential side effects of the drug are not yet clear. Unfortunately, this again can restrict eligibility to prioritise people who, aside from the cancer, are in good health and have not already tried multiple other treatments. These criteria also make it more likely that older people will not be accepted onto the trial.
Equity, diversity and inclusion (EDI)
Image credit: Gerd Altmann from Pixabay
A particularly pressing issue is that trial cohorts often fail to represent the breadth of the eligible patient population. For instance, although the UK is a multicultural country, the diversity within different areas still varies significantly. A trial that takes place in an ethnically homogenous region and recruits locally may unintentionally exclude some ethnic groups, despite cancer affecting them too.
The historical mistreatment of some ethnic populations – whether that be in the UK or abroad – has also led to a widespread mistrust of healthcare professional among certain communities.
Some people belonging to LGBTQIA+ communities might also have had negative past experiences when seeking healthcare and fear that their gender identity would not be accepted or acknowledged as a clinical trial participant. This is a risk because data collection processes often use ‘sex’ and ‘gender’ interchangeably. In addition, clinical trial organisers might not always think to extend trial invitations to transgender people, even though – for example – transgender women may still have a prostate cancer risk, and ovarian cancer can affect transgender men who have retained their ovaries.
A person’s socioeconomic position can also affect their likelihood of taking part in a clinical trial. People who live in a deprived area are more at risk of certain health conditions, including cardiovascular and respiratory disease, and some may have poorer access to healthcare. Individuals with a low income might find that financial barriers prevent them from participating in a trial while those with a lower level of education might not be able to advocate for themselves effectively or understand the trial well enough to provide informed consent.
A lack of data
Currently, it is difficult to quantify the extent to which researchers are incorporating, or failing to incorporate, EDI into cancer clinical trials. This is primarily because there is no standardised approach to demographic data collection. Some teams might record the participants’ ethnicity but not their level of education or employment status while others might do the opposite.
Without access to sufficient information, it is difficult to determine which groups of people are frequently underrepresented and how researchers should tailor their recruitment interventions going forwards.
A priority for the ICR
Scientists at the ICR have led and co-run many important cancer clinical trials, several of which have resulted in new drug approvals or changes to standard clinical practice. As a result, the Clinical Trials and Statistics Unit at the ICR (ICR-CTSU) is internationally recognised for its clinical trial research expertise.
Being among the leaders in this field, it is crucial that the ICR is continually striving to refine trial protocols to set a high bar globally. While the clinical trial teams are also committed to improving the efficiency, sustainability and impact of their trials, they are very focused on EDI.
Mindful of the current lack of data, the researchers’ prime concern is to assess their current practice and try to identify any underrepresented groups.
Rebecca Lewis, Clinical Trials Programme Manager at the ICR-CTSU, explained:
“We need to identify the populations not being included before we can make meaningful differences to inclusion. Then, we need to establish interventions that facilitate participation by interested members of those groups. Currently, we don’t know what will work due to insufficient UK data on trial inclusivity. There is a danger of directing limited resources in unhelpful directions if we don’t take these steps first.”
Current ICR-CTSU projects
The ICR-CTSU has already instigated two projects designed to provide more information about who is joining clinical trials in the UK. The first, INTERACT, aims to identify any groups who have not participated in past ICR trials while also assessing the EDI of current cancer trials at selected pilot sites.
The second, DISTINCT, has developed a standard set of questions to ask study participants about their personal characteristics to help make the ICR’s research more inclusive in the future. The project team has consulted patients and other members of the public about the proposed questions and will refine them based on the feedback received.
Alongside these projects, Georgiana Synesi, a PhD student in the ICR-CTSU, has evaluated cancer trial eligibility criteria from trials across the UK to check for any systemic exclusion of particular groups of patients. She is following this up with a study called REPRESENT, which will use a range of methods – including interviews with cancer patients and the staff responsible for trial enrolment – to explore who is invited to join trials and the reasons why people do or do not accept.
Introducing change
At the same time as gathering more data, researchers at the ICR-CTSU have taken proactive steps towards improving EDI in future cancer trials. The team has updated trial material templates to remove gendered phrases, added statements to encourage teams to consider whether any groups are disproportionately affected by the disease in question and included a reminder to avoid overly restrictive eligibility criteria.
Next, the researchers plan to increase accessibility by lowering financial barriers and building a better understanding of translation needs. They will assess the impact of these measures to gauge their effectiveness.
A team based at the Drug Development Unit has already made progress in reducing the economic burden associated with clinical trial participation. The researchers have developed an upfront payment management process so that participants no longer have to cover their expenses upfront and wait weeks to be reimbursed.
An ongoing process
The ICR-CTSU team knows there is much more work to be done in this area, but it is realistic about what might be achievable. Rebecca said:
“EDI is complex, and there is unlikely to be a one-size-fits-all solution. The ultimate aim is to try to ensure that everyone for whom trial participation is appropriate is invited to take part and that they have sufficient information, knowledge and support to make an informed decision.”
Georgiana said:
“I don’t think we can ever get to a place where every individual who wants to can access a clinical trial. Eligibility criteria primarily exist to ensure that people who receive a treatment will benefit without incurring undue safety risks, and sometimes these cannot be avoided. We also need to consider the integrity of clinical research and accept that some people will not be open to being randomly allocated to a treatment.
“However, I hope we can get to a place where groups of people aren’t being excluded due to their identities. This needs to be addressed both with patients and with medical professionals. We need to acknowledge that it is a privilege to have the social and financial support to join a clinical trial and that currently, not everybody has that.”
Challenges specific to cancer clinical trials
All clinical trials have eligibility criteria, so the challenge of recruiting a cohort of participants that accurately represents the patient population is not unique to cancer. However, the complexity of the disease can make this harder to achieve.
Georgiana said:
“The treatment protocols for cancer can be complex and have a heavy participation burden because of the need to attend regular appointments. This can result in people being unintentionally excluded, such as those with caregiving responsibilities or limited financial resources.”
Rebecca added:
“Particular issues with eligibility criteria restrictions arise where comorbidities that are more prevalent in certain populations are automatically excluded, or where arbitrary upper age limits are used as a proxy for fitness."
Closing the gap
Once the ICR-CTSU scientists have more information at their fingertips, they can take proactive steps to try to bridge the gap between clinical trials and real-world practice.
One possible solution proposed in the editorial is to include a more diverse group of patients in later trial stages, such as those that take place following a drug’s approval. The authors also believe that clinical trial teams will need to proactively recruit participants from underserved groups.
Professor Emma Hall, Director of the ICR-CTSU and Deputy Head of the Division of Clinical Studies at the ICR, said:
“Ultimately, we want to give as many cancer patients as possible the best chance of surviving and thriving. Key ways to achieve this are to offer more people the opportunity to try new treatments in a clinical trial setting and to approve new treatments based on how well they work for ‘real-world’ patients rather than a ‘cherry-picked’ cohort.
“Our team is fully committed both to uncovering factors contributing to unequal access to clinical trials and to addressing them as quickly as possible so that we can benefit people living with cancer and get crucial insights into the disease, which will accelerate cancer research as a whole.”