Unique Ethical Issues in Phase I Oncology Studies
Oncology research represents a significant percentage of all clinical research, reflecting the fact that cancer continues to be a leading cause of mortality and morbidity worldwide. At the same time, we’ve made significant treatment advances for different types of cancers in the past decade, and the death rate from cancer is declining in the United States.
Phase I oncology trials play an essential role in assessing investigational therapeutic safety and determining whether they are promising candidates for further exploration. They also raise unique ethical challenges that sponsors, investigators, and institutional review boards (IRBs) should anticipate and ensure are adequately addressed.
Vulnerability in Phase I Oncology Research
Participants in Phase I oncology trials are typically sick and suffering from the cancer being studied. This is unlike Phase I research in other disease areas, which typically enrolls healthy volunteers. Phase I oncology protocols usually require individuals to have advanced disease and/or to have failed available treatments in order to be eligible. As a result, individuals eligible for Phase I oncology studies are often in very difficult and vulnerable situations, which itself merits additional sensitivity, and the possibility for additional safeguards, from researchers and IRBs.
Phase I oncology studies give very sick individuals with few or no other options an opportunity to access investigational therapies. Nonetheless, they are often first-in-human studies to evaluate for safety, not primarily for efficacy. Because of this, care is needed to ensure “therapeutic misconception” avoidance in participants, which involves assuming research is more similar to clinical care than it actually is, and (as a result) a tendency to overestimate the benefits of research participation.
Participants in Phase I oncology trials should have a realistic understanding of the risks and benefits and understand the investigational therapies evaluated have not been shown to be effective. Design consent forms (including recruitment materials) with this aim in mind, avoiding overly promissory statements about personal benefit. While consent forms often state, “you may or may not benefit,” the likelihood of sustained personal benefit on a novel Phase I study is vanishingly small.
Study Design and Monitoring
Phase I oncology studies are typically designed to assess for safety, which they do by monitoring adverse event (AE) occurrence and frequency. They also pursue aims relevant for future studies, such as determining the maximum tolerated dosage of an investigational drug. Phase I oncology trials often have distinctive designs allowing them to accomplish both of these aims efficiently, with the fewest number of participants possible and in relatively short time frames.
For example, in a standard 3+3 dose escalation study with an objective of identifying the maximum tolerated dose (MTD), cohorts of three participants are given a starting dosage of an investigational drug. If none of the initial three participants experience toxicity, the dose is escalated to the next level. If, by contrast, two or three participants experience toxicity, no further dose escalations take place and this is considered the MTD. If only one participant experiences a toxicity, three additional participants are dosed at that level. If any of those additional three (i.e., more than one participant out of six) experience toxicity, no additional dose escalations take place and this is considered the MTD; if not (i.e., if only one out of six experiences toxicity), the dose is escalated. This process continues for each subsequent dose until an MTD is reached.
In first-in-human oncology studies, where the drug has not been previously tested in humans, some form of staggered or sentinel dosing is usually ethically advisable. This will involve dosing one or two participants, followed by a time delay and observational period before additional participants are dosed. Sentinel dosing can be limited to the first participants dosed in the entire study, or employed within each dose cohort; which approach is best will depend on the nature of the study and therapy being evaluated. By limiting the number of participants simultaneously exposed to a drug with unknown risks, sentinel dosing minimizes damages in worst-case scenarios, which unfortunately do occur, if rarely, in first-in-human studies. Sentinel dosing can be difficult for studies with novel antibodies, which may have long half-lives, and careful assessment is needed in these studies to arrive at reasonable dosing windows and timelines.
Due to participants in Phase I oncology trials being sick, and the potential for toxicity and unknown risks, robust safety monitoring plans are needed. These will typically include both routine assessments and blood labs, the details of which will vary depending on the study. Take care when balancing the need for monitoring assessments and data collection requiring blood samples against the fact that certain oncology populations may have low hemoglobin or platelet counts, potentially resulting in a need for transfusions. Sponsors and investigators should consider these factors, with efforts made to accomplish study objectives with the least amount of blood collection possible in these populations.
Whereas many Phase I non-oncology studies will mandate a pause for a subject death, that may not be the case for Phase I oncology studies, even first-in-human Phase I oncology studies. This may reflect the precarious nature of participants’ health, the likelihood a terminal event is unrelated to study procedures, and other factors. The IRB should read the definition of serious adverse events (SAEs) carefully when reviewing these studies.
Phase I oncology studies are designed to yield basic data about safety and other parameters in people suffering the condition under study. Increasingly, these studies leverage complex designs in an attempt to accomplish their objectives efficiently and on tight timelines; for example, by moving seamlessly from Phase I to Phase II or allowing for greater flexibility in adjustments to dosage, sample size, and other features.
Everyone can agree speeding therapeutic advances in oncology is a worthy goal. At the same time, care is needed to ensure such advances do not happen at the expense of the rights or interests of participants in these studies. The research community can ensure this does not happen by recognizing the vulnerability of Phase I oncology participants, being forthright and realistic about the risks and expected personal benefits of these studies, and taking care to ensure they are well-designed with robust mechanisms for promoting participant safety and minimizing risks.