North American Enrollment in Clinical Trials: An Emerging Issue for Regulatory Approval

On May 20, 2025, the FDA had a meeting of its Oncologic Drug Advisory Committee (ODAC).¹ The meeting reviewed STARGLO, a phase 3 clinical trial that compared glofitamab plus gemcitabine and oxaliplatin to rituximab plus gemcitabine and oxaliplatin in patients with relapsed or refractory diffuse large B-cell lymphoma.¹ In a surprising vote, ODAC voted 8 to 1 against the applicability of the STARGLO trial’s results to the US population.²

The main issue presented to ODAC was that although the study demonstrated an overall survival (OS) benefit, only 25 North American patients were enrolled in the trial.¹ In patients from the Asian region (excluding Australia), the median progression-free survival (PFS) was 20.4 months for glofitamab plus gemcitabine and oxaliplatin versus 2 months for rituximab plus gemcitabine and oxaliplatin.¹ In the rest of the world, the median PFS was 9.2 months for glofitamab plus gemcitabine and oxaliplatin versus 7.8 months for rituximab plus gemcitabine and oxaliplatin. In the Asian region, the median OS was not estimable for glofitamab plus gemcitabine and oxaliplatin versus 8.2 months in rituximab plus gemcitabine and oxaliplatin.¹ In the rest of the world, the median OS was 21.2 months for glofitamab plus gemcitabine and oxaliplatin versus 27.8 months for rituximab plus gemcitabine and oxaliplatin.¹ Even when excluding the OS data, which could be confounded by subsequent therapy, the pooled non-Asian patient data (ie, in United States, Europe, Australia) found glofitamab plus gemcitabine and oxaliplatin did not have significantly longer PFS than with rituximab plus gemcitabine and oxaliplatin.¹

The Asian population had more lenalidomide exposure and only 2 of the 131 patients previously received CAR-T therapy compared with 19 of 143 patients from the rest of the world.¹ In the United States, CAR-T therapy is standard of care second- or third-line therapy, whereas there is limited or no access to CAR-T therapy in Asia.³ Was this an explanation for why PFS was so much longer in the Asian region compared with the rest of the world? For the patients who received previous CAR-T therapy, glofitamab plus gemcitabine and oxaliplatin (N=13) and rituximab plus gemcitabine and oxaliplatin (N=8) had nearly identical PFS rates of 8.4 months and 7.8 months, respectively.⁴ Is there no difference in outcomes in countries with wide access to CAR-T? ODAC ultimately voted against the applicability of STARGLO to a US population.² Based on the available data, ODAC could not conclude with certainty that glofitamab plus gemcitabine and oxaliplatin was superior to rituximab plus gemcitabine and oxaliplatin in US patients.²

On July 17, 2025, ODAC met again, this time regarding the DREAMM-7 and DREAMM-8 trials.⁵ Both trials examined different combinations of belantamab mafodotin with other agents for the treatment of multiple myeloma. This time, ODAC voted 5 to 3 against the risk-benefit profile of the DREAMM-7 trial and 7 to 1 against the risk-benefit profile of the DREAMM-8 trial.⁶ A key issue discussed was that it was difficult to interpret the risk-benefit profile of belantamab mafodotin because of low US enrollment.⁶ The United States, for example, travels the longest distance per capita in cars, trucks and motorcycles.⁷ It is possible that the ocular adverse events could be more impactful on a US population, as patients would be unable to drive if they cannot see. Less than 5% of the patient population in both trials was from the United States, and even fewer of the patients were Black, even though 20% of patients with multiple myeloma are Black.⁶ The control arm in the DREAMM-7 trial, which consisted of patients receiving daratumumab plus bortezomib and dexamethasone, was also considered an inferior control arm, because the study enrolled patients without previous exposure to immunomodulatory drugs but did not add them to the control arm.⁵ The combination of daratumumab, bortezomib, lenalidomide, and dexamethasone was superior to daratumumab plus bortezomib and dexamethasone in a phase 3 trial.⁸

These decisions come as we are seeing decreasing proportions of US patients in oncology clinical trials⁹ It is not unusual to see multinational trials that have ≤10% of the clinical trial population originate from the United States.¹⁰ The FDA must decide whether the primary end point would still apply to the US population based on small trial subgroups. The recent decisions from the FDA and ODAC suggest that a lack of US representation could prevent a therapy from being approved.

Clinical trials that are submitted for FDA approval must do more to recruit patients in the United States so the FDA and US clinicians can better assess the efficacy and safety of experimental agents in US patients. If not, there is a real risk that new drug approvals could be delayed or denied. Here are several suggestions for trial design changes that could help improve US clinical trial enrollment.

Improved Control Arms

Multinational trials often must consider the therapies available in every country to determine the appropriate control arm. However, this often leads to a substandard control arm for US patients, even if the control arm may be appropriate for a multinational trial. For example, second-generation Bruton tyrosine kinase (BTK) inhibitors are the most prescribed BTK inhibitors for chronic lymphocytic leukemia in the United States.¹¹ However, in many Central and Eastern Europe countries, these second-generation BTK inhibitors are not reimbursed.¹² Fam-trastuzumab deruxtecan, which is recommended for the treatment of HER2-low breast cancer in the United States, is not recommended for use in patients with HER2-low breast cancer in the United Kingdom.^13,14

US patients may not want to risk being randomized to a substandard control arm, and it may be unethical for trial investigators in the Unites States to randomize patients to a substandard control arm.¹⁵ This can lead to low clinical trial enrollment in the United States. Clinical trials may need to strengthen their control arms to enroll more US patients. Innovative trial design, such as varying the control arm depending on the country, could be considered. In the DeLLphi-304 trial, for example, the control arm varied depending on the patient’s country of enrollment.¹⁶

Crossover Trial Design

The accelerated approval program in the United States allows drugs to reach market based on surrogate end points from single-arm trials.¹⁷ This is a double-edged sword, because although this allows US patients to access novel treatments faster, it can affect clinical trial enrollment. If a novel agent is available commercially through accelerated approval, some patients may want the guarantee of receiving a novel agent versus having the risk for being randomized to the control arm and never receiving the new therapy. This would affect trials involving that novel agent as well as other trials that are investigating agents with similar mechanisms of action.

Crossover trial design, in which patients who are randomized to the control arm of a trial are allowed to cross over to the experimental arm after disease progression, could help mitigate this issue. First, this trial design maintains equipoise for clinical trials after accelerated approval of a drug, because the single-arm trials used for accelerated approval do not address crossover. Second, this trial design gives patients who are randomized to the control arm the opportunity to still receive the experimental agent. Giving every patient the chance to receive the experimental agent may help maintain patients’ interest in a clinical trial.

Multiple Experimental Arms

Clinical trials are not limited to 1 control arm and 1 experimental arm. Although trials with multiple experimental arms can be more difficult to design, there are benefits. One benefit is that having multiple experimental arms in a trial allows the testing of multiple hypotheses. Patients are more likely to be randomized to an experimental arm, which could encourage US patients to enroll in a trial, and these trials may generate comparative data between experimental arms, thereby producing new hypotheses.

Platform trials, such as the STAMPEDE trial in prostate cancer, can enroll patients faster and answer more questions than typical clinical trials.¹⁸

Broader Inclusion Criteria

Recently, the Journal of Clinical Oncology encouraged authors to improve trial representativeness and have broader inclusion criteria.¹⁹ Clinical trials often have a homogenous, relatively healthy population, which makes it easier to detect an effect from the experimental arm. However, that may also limit patient enrollment in clinical trials. Expanding inclusion criteria could increase clinical trial participation in the United States and make the trial more applicable for patient populations that are often excluded from clinical trials. It may make more sense, for example, to use a geriatric assessment instead of a simple age cutoff in clinical trials to enroll older adults who are otherwise healthy.

In summary, US patient representation in clinical trials has been declining over time. This issue has caused ODAC and the FDA to question the applicability of some clinical trials to a US population. Clinical trials seeking approval from the FDA may need to make changes in their trial design to increase US enrollment.

Dr Tai is Oncology Pharmacist, Corewell Health William Beaumont University Hospital, Royal Oak, MI.

References

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