One year ago, the approval of the first COVID-19 vaccine was fuelling debate in the oncology community about whether it was safe to immunise patients with cancer. Despite their increased risk of severe infection or death from COVID-19, patients receiving immunosuppressive therapy or under active anticancer treatment were excluded from vaccine trials – raising questions about overly restrictive eligibility criteria in clinical research.
Dr. Luis Castelo-Branco, Medical Oncologist, ESMO Scientific and Medical Division (SMD) Fellow, first author of a recent ESMO Open editorial advocating for broader inclusion criteria for oncology studies (ESMO Open 2021 Oct;6(5):100237), explains: “The main driver for exclusion criteria is the need for a harmonised population with minimal confounding factors for the final outcomes. But restricting inclusion makes results less generalisable, including to the significant proportion of patients with comorbidities. For these vulnerable groups further studies are then required, translating into more time and resources.”
In medical oncology, some trials of immune checkpoint inhibitors excluded, for instance, elderly patients, those with auto-immune diseases, patients with HIV, or treated with high dose of corticosteroids, even though these groups represent a significant proportion of patients with cancer.
We need to find innovative ways to be more inclusive without affecting the quality of research.
"Exclusion criteria should be clearly justified and based on best available evidence that patients are either at higher risk of severe, unacceptable, toxicity or they are likely to experience significantly lower efficacy,” says Castelo-Branco.
He suggests that when designing clinical trials, the potential public health impact of an innovative drug on different subpopulations should be carefully considered and assessing precise epidemiology data for unmet need may lead to broader, evidence-based inclusion criteria.
“Instead of exclusions due to age or the presence of certain comorbidities, clinically relevant and valid tools with pre-defined but not very restrictive thresholds assessing frailty or disease severity should be more used to identify patients who can be included on a case-by-case basis.
Parallel cohorts may be an option for assessing safety and efficacy in groups who might otherwise be excluded, and if patients must be excluded, it should be planned how to get evidence about these groups from complementary studies beyond that randomised control trial,” adds Castelo-Branco.
Real-world studies may provide further evidence to address unmet needs in some patient populations. Recently, the US Food and Drug Administration (FDA) expressed a willingness to evaluate drug approval on the basis of real-world evidence to expedite access to new cancer treatments. However, some concerns remain about the quality of such data which requires that well-defined, appropriate variables are included, as discussed in a previous article on the topic.
Inclusiveness in EU guidance updates
At a European level, a step towards greater inclusiveness in clinical trials comes in the draft update of the International Council for Harmonisation (ICH) E6 Good Clinical Practice guidance, which is expected to go out to public consultation in Summer 2022 (ICH, April 2021).
“The participant selection process should be representative of the anticipated population who are likely to use the medicinal product in future clinical practice,” explained Dr. Fergus Sweeney, European Medicines Agency (EMA), at a recent ESMO webinar on Clinical Trials Regulation.
The draft guidance states that, when designing a trial, the scientific goal and purpose should be carefully considered so that particular patient populations are not unnecessarily excluded. Recently updated ICH guideline E8 General Considerations for Clinical Studies also highlighted the role of special populations in clinical research (ICH, October 2021)
“In the past, elderly, pregnant and lactating patients may have been protected by exclusion from clinical trials but the E8 guidelines recognise that these populations may be better protected by good and carefully managed inclusion in research so we have good results to support use of medicines,” said Sweeney.
At the ESMO webinar, Dr. Tanja Spanic, Chair of the ESMO Patient Advocates Working Group, stressed the importance of patient involvement to make trial design more meaningful and relevant, as recommended by the recently published Principles of Successful Patient Involvement in Cancer Research (Federal Ministry of Education and Research, September 2021).
“Patients should be involved at an early stage, not just sitting around the table, but in decision making with voting rights. Some research organisations already have permanent patient panels or advisory boards that provide counsel on project design, and this needs to become much more common,” said Spanic.
“Picking a random patient just to tick the box that there is a patient representative at the table makes no sense and won’t give positive results. There are plenty of patient groups with expert knowledge or who can nominate the most appropriate person to advise on any specific research project,” she added.
Ensuring meaningful surrogate endpoints
With surrogate endpoints increasingly used in clinical trials to accelerate and broaden access to innovative therapies, Castelo-Branco stresses the need for strong correlations with clinically meaningful outcomes – validated for each situation in which they are used.
“What may be a good surrogate endpoint in one disease and for one medicine may not be good for others and it is important that evidence based on surrogate endpoints is matched by results of subsequent confirmatory trials. For example, although median progression-free survival (PFS) is generally a good surrogate for overall survival, it has not been a great indicator of benefit with immunotherapy in several metastatic cancers,” Castelo-Branco points out.
Earlier this year, accelerated approval for at least six indications for immunotherapies for advanced or metastatic cancers in the USA were withdrawn following disappointing results of confirmatory trials (Targeted Therapies in Oncology 2021; 10 (8)). In contrast, Castelo-Branco highlights the recent very promising results of the Phase III DESTINY-Breast03 trial of trastuzumab deruxtecan in metastatic breast cancer, presented at the ESMO Congress 2021, which showed a 72% reduction in risk of progression compared to trastuzumab emtansine.
“These are striking findings and the fact that they are based on PFS should not delay access to this new standard of care worldwide. However, the use of such endpoints is complex and requires continuing reassessment by regulatory authorities and dialogue with investigators, the pharmaceutical industry and patient representatives,” concludes Castelo-Branco.