In a recent blog, we described the complexity and uniqueness of Phase I clinical trials, outlining the fact that some Phase I trials recruit healthy volunteers while others enroll participants with specific health conditions. In this blog, we will dive deeper into Phase I oncology trials, discussing what makes them unique and what IRBs need to know as they review Phase I clinical trials for participants with a cancer diagnosis.
When searching clinicaltrials.gov, there are over 3,900 interventional Early Phase and Phase I oncology clinical trials currently recruiting participants. Phase I clinical trials typically enroll up to 30 participants and are designed to evaluate the safety of a new investigational product, such as a drug. They may also be designed to evaluate new routes of administration of currently approved drugs, for example, changing a medication from an infusion to a pill or testing an approved FDA agent in a different population or for a new indication. Phase I oncology clinical trials may offer novel, experimental treatments to patients who have tried an approved therapy, or the standard of care, to cure or alleviate their disease. While clinical trials may be considered as an option in the treatment plan for patients with cancer, it is important to bear in mind that the trials address and evaluate experimental agents.
Phase I Trial Design
Study participants for Phase I oncology trials are divided into groups called cohorts. The experimental therapy is typically tested in a cohort at a pre-determined lower dosage (based on pre-clinical data) to determine the therapy’s side effects. If the participants receiving the experimental therapy either do not experience side effects, or the effects are mild to moderate, the dosage increases with the next cohort. This cycle is repeated with each cohort until the study investigators find the maximum tolerated dose (MTD): the highest dose at which they can provide the experimental therapy without causing severe side effects.
Once the MTD is identified, it is used to set the dosage for subsequent trials. If during the course of treating a cohort, a participant has a dose-limiting toxicity (DLT), or severe adverse reaction as defined by the study protocol, the research investigators/sponsor will stop exposing participants at that dose level. If the researchers/sponsor finds the experimental treatment is safe to use at a specified dose, participants respond well to the treatment (i.e., there are preliminary data showing the experimental therapy had a positive effect on the cancer), and only mild to moderate side effects were observed, the study can advance to a Phase II clinical trial. According to BIO’s Industry Analysis Report, it is estimated that approximately 48.8% of all Phase I oncology clinical trials proceed to Phase II.
Managing Phase I Clinical Trials
Given the complexity of Phase I clinical trials, many large academic medical centers and cancer centers have a dedicated unit or department to manage the studies. Individuals enrolling in Phase I oncology trials must meet strict inclusion/exclusion criteria and are monitored closely for adverse side effects resulting from the therapy. They typically have more frequent study visits and blood draws than participants in later phase research.
Many research institutions also have committees to review the science described in Phase I clinical trial protocols to ensure the study is rigorous, based on prior research outlined in the literature, and aims to answer an important scientific question.
Considerations for the Institutional Review Board (IRB)
IRBs are responsible for protecting the safety, rights, and welfare of human subjects who participate in research. IRBs must ensure the protocol includes pre-clinical data to support a proposed Phase I clinical trial. Phase I oncology trials do not typically involve a placebo; instead, they compare a new experimental therapy to the current standard of care for individuals with cancer.
Safety monitoring is a significant concern in Phase I clinical trials. Investigators/sponsors must clearly outline all risks to the participants, expected toxicities of the experimental treatment, study stopping rules (or the criteria by which a study would be stopped), and a plan to include how adverse/serious adverse events and unanticipated problems will be captured and reported.
Safety monitoring for Phase I trials should also include the extent to which safety monitoring of participants will continue following the discontinuation of the experimental therapy. As with other clinical trials, the informed consent document for individuals enrolling in Phase I oncology trials should clearly describe the purpose of the research, a description of the study design and procedures to be performed, risks to participants, any cost they may incur as a result of trial participation, alternatives to participating, and information regarding the experimental nature of the study.
The federal regulations require IRBs to be “sufficiently qualified through the experience and expertise of its members,” and IRB members must possess “professional competence to review the specific research activities.” Therefore, IRBs must ensure they include medical oncologists on their committees if they are reviewing oncology clinical trials.
Most Phase I oncology trials require the sponsor/sponsor-investigator to submit an investigational new drug (IND) application to the FDA prior to recruiting subjects. Most IRBs require a copy of the IND approval letter or the IND number issued by the FDA prior to final approval of a research protocol.
Oncology clinical trials that include a gene therapy component must also be reviewed by an institutional biosafety committee (IBC) to mitigate risks to the research participants as well as researchers and their research team.