Eligibility Criteria in Clinical Trials
Giovanni Monopoli, senior project manager, reflects on what he learned about the eligibility criteria at an American Society of Clinical Oncology (ASCO) conference presentation in 2017.
At the American Society of Clinical Oncology (ASCO) 2017 conference, ASCO and Friends of Cancer Research (FoCR) collaborated with the U.S. Food and Drug Administration (FDA) and other stakeholders to present the Modernizing Eligibility Criteria Project, which aims to evaluate clinical trial entrance criteria that may unnecessarily restrict clinical trial access. The session provided recommendations for a more rational approach to determine inclusion and exclusion criteria, which helps to expand the number and diversity of patients in clinical trials and result in a more suitable population of patients.
Eligibility criteria in clinical trials
In 2016, ASCO, FoCR, the FDA, patient advocacy groups and others involved in the industry formed working groups to develop recommendations for a more nuanced approach to determining eligibility. These groups prioritized assessments on criteria for patients with brain metastases, organ dysfunction, history of prior malignancy, HIV and those younger than age 18.
Patients with brain metastases
The working group identiﬁed treated/stable, active and leptomeningeal disease as the three key populations in brain metastases patients. In most circumstances, the working group encourages including patients with treated/stable brain metastases in prospective clinical trials of all phases, unless there is a compelling rationale for exclusion. In cases of speciﬁc safety concerns, speciﬁc criteria should be designed rather than excluding all patients with brain metastasis.
A framework of key considerations for patients with active brain metastases were developed, depending on disease characteristics, trial design and investigational product. The panel recommended that such patients not be automatically excluded because this is a population of patients with a great need for innovative interventions.
For patients with leptomeningeal disease, inclusion of separate cohorts in early phase and later phase trials are recommended if central nervous system activity is expected and when relevant to the speciﬁc disease type.
Expanding eligibility early in drug development to include patients with brain metastases is important because this is an area of high clinical need and would be most valuable in settings where brain metastases are common in the intended-use population, such as melanoma, breast cancer and lung cancer. The working group recommends that in such disease settings, the inclusion of patients with brain metastasis should be the default position.
Patients with comorbidities
According to the comorbidities panel, eligibility should be based on creatinine clearance rather than serum creatinine levels when considering a patient’s renal function. If renal toxicity and clearance are not of direct treatment-related concern, then patients with creatinine clearance values lower than 30 mL/min should be included in trials. Inclusion of patients with mild to moderate hepatic dysfunction may be possible when the totality of the available nonclinical and clinical data indicates such inclusion is safe.
Regarding cardiac function, the working group includes patients with cardiovascular dysfunction when the totality of the available nonclinical and clinical data, including pharmacokinetic and pharmacodynamic data, supports the safety of such patients. Alongside close collaboration with cardiology, ejection fraction values should be used with an investigator assessment of a patient’s risk for heart failure to decide eligibility.
Including patients with prior malignancies is recommended, especially when the risk of the prior malignancy interfering with either safety or efﬁcacy endpoints is very low. Patients with a previously treated malignancy should be eligible to participate if all treatment of that malignancy was completed at least two years before registration and the patient has no evidence of the disease.
Patients with a clinically stable concurrent malignancy that does not require tumor-directed therapies should be allowed to participate in a trial for another cancer that requires treatment. Patients with laboratory parameters out of normal range due to hematologic disease should be included in trials.
Disease-speciﬁc comorbidities thought to be unaffected by the study agents and otherwise treated in practice should not exclude patients. These comorbidities might include peripheral neuropathy or bone symptoms in multiple myeloma,including these patients will increase the number and diversity of patients in clinical trials and result in a more appropriate population of patients.
Patients with HIV
The HIV working group emphasized a straightforward and uniform evaluation of the suitability of a patient with HIV across all studies. The major risks to be mitigated in developing eligibility criteria in cancer studies in the HIV-patient population include avoidance of drug-drug interactions between cancer therapies and HIV therapies. To avoid adverse events related to competing infectious morbidity the group suggests using approaches for patients with other chronic medical conditions and appropriate consideration of eligibility criteria related to the degree of HIV-associated immunosuppression that may be acceptable for a given study.
Determine eligibility through assessing present and historic CD4+ T-cell counts, reviewing any history of potential AIDScomplications, and evaluating the use of effective antiretroviral therapy. Speciﬁc eligibility criteria may vary based on the study’s objectives.
The working group uses criteria to deﬁne a patient sufﬁciently healthy from the HIV perspective to participate in almost any oncology study. These criteria are focused on immune function and measures related to HIV therapy.
Once eligibility is established, manage the HIV infection as part of standard of care and not dictated by the protocol, unless the protocol has speciﬁc objectives regarding HIV outcomes.
Patients of a minimum age
The minimum age working group proposed including pediatric-specific cohorts in dose-finding studies with the presence of strong scientific rationale, such as preclinical data. Opening enrollment of a pediatric cohort in the Phase I setting should occur when sufﬁcient data in adults exist to guide dosing and toxicity monitoring, just before any cohort expansion at the recommended Phase II dose. Alternatively, a pediatric cohort could be treated as a separate stratum and escalated independently of adults until defining an age-appropriate dose for the speciﬁc age group. Rationale could be based on an understanding of the mechanism of the disease.
Younger age groups present additional considerations, so it may be appropriate to use staged enrollment starting with older children once initial adult safety and toxicity data are known. In later stages of drug development, the group proposed that trials in diseases that span adult and pediatric populations should enroll pediatric patients, particularly patients 12 and older. Where growth and development could be adversely affected based on nonclinical or early clinical data, a more restrictive age cutoff may be appropriate or more stringent monitoring may be incorporated. In some cases, include patients younger than 12 years old. A serious adverse event in the pediatric population may appropriately interrupt or halt development in that population without affecting drug development in adults, unless there is evidence that the safety signal may also apply to adults. Conversely, should pediatric patients tolerate a higher dose than adults, recommendations of the group will facilitate identiﬁcation of that scenario and sufficient dosing in each patient population. Others, including the FDA, have suggested the inclusion of patients aged 12 through 17 in disease-specific trials.
Criteria impact on patient participation
The Modernizing Eligibility Criteria Project and its working groups advocate for a culture shift in the approach to inclusion and exclusion criteria. The groups will continue to pursue a broad implementation of this rational approach to eligibility with the FDA working with clinical trial sponsors to implement these recommendations.
All stakeholders in the clinical research industry know how the eligibility criteria may be a major barrier to patient enrollment. Expanding the eligibility criteria would allow faster accrual and earlier access to new therapies as it would contribute significantly decreasing the clinical trials duration. In addition, more complete safety and efficacy data could be collected by using a bigger population and drugs that may not be effective could potentially be identified earlier during the development phase. Lastly, the clinical trials results could more easily be generalized to “real-word” patients and more patients could gain earlier access to investigational agents.
Historically, eligibility criteria were appropriately put in place because of concerns over safety in selected populations but, nowadays, clinical trial protocols are not always based on a rational analysis of entry criteria. Despite years of recognition of this issue, inclusion and exclusion criteria remain prohibitive for some patient populations. Of approximately 300 commercial investigational new drug applications submitted to the FDA’s Office of Hematology and Oncology Products in 2015:
- Only 3.7 percent included pediatric patients
- 60 percent required Eastern Cooperative Oncology Group performance status of 0–1
- 77 percent excluded known, active or symptomatic central nervous system or brain metastases
- 47 percent allowed treated or stable brain metastases
- 84.2 percent excluded patients with known or active HIV
- With only 1.7 percent allowing patients to enroll with adequate CD4 counts.
Multiple stakeholders realize that taking a more rational approach to eligibility criteria will result in improved patient benefit, so this initiative is expected to produce positive results in the coming years.
Obviously, mitigation factors are to be taken into account for potential risks arising when expanding eligibility criteria such as variability of the outcome due to the larger sample size needed, more complicate attribution of adverse events, increased safety monitoring may be needed.
Giovanni Monopoli is a senior project manager with PPD.