By Stacey Kusterbeck
Early phase oncology clinical trials demand a lot from participants but offer uncertain benefits in return. Many cancer patients enrolled in these studies undergo numerous procedures, some of which pose significant risk; others travel hundreds of miles at their own expense. “Increasingly, early phase trials are requiring hospitalization to observe for adverse effects after the first doses of the study medication,” reports Manish R. Sharma, MD, co-director of clinical research at START Midwest. Sharma is a medical oncologist and clinical pharmacologist who focuses on development of new cancer drugs.
Given the significant burdens of early phase oncology trials, researchers may worry about violating their ethical obligation to “do no harm” to patients. “It’s important to balance the quality and quantity of data required to ensure that an investigational therapy is safe and effective against the demands that we put on patients,” underscores Colt Williams, MD, FACP, a hematologist/oncologist with Cancer Care Specialists in Carson City, NV, and assistant professor of medicine at University of Nevada School of Medicine.
Transportation burden is a top consideration. “Unfortunately, access to clinical trials remains largely centralized, with access limited to academic medical centers,” says Williams. For some patients in sparsely populated states, participation may entail traveling very long distances.
Many Phase I oncology trials have stringent pharmacokinetic monitoring requirements. For participants, that means multiple clinic visits, often many days in a row, with blood drawn hours after each administration of the medication. “The participation demands can be high, even for patients [who] live in the same city as the clinical trial center,” acknowledges Williams.
Although these requirements are necessary for researchers to fully understand a drug’s performance, there usually are ways to reduce the burden on participants. “Researchers should make every effort to minimize the number of clinic visits, hospital stays, and procedures necessary to achieve the objectives of the study,” urges Sharma.
Allowing longer monthly visits to the clinical center can be easier than shorter, more frequent visits. “Researchers should place themselves in the position of their patients when designing study protocols. Imagine the time off work, the time away from family, and the logistics of travel that may be needed,” says Williams.
These are some other important ethical considerations for researchers with early phase oncology trials:
- Patient selection. The primary objective of early phase oncology trials is safety and tolerability. “But eligibility criteria are often overly strict and written with efficacy considerations in mind,” says Sharma. For example, many trials exclude patients with modest chronic kidney disease and exclude patients with any brain metastases, even if small and asymptomatic. Many trials also exclude individuals with too many lines of prior therapy for advanced disease, even though many of these patients potentially could benefit from the treatment. “Researchers should design studies to be more inclusive of real-world advanced cancer patients, to the extent that this can be done without excessive risk to those patients,” advises Sharma.
- Potential exposure to subtherapeutic doses. In dose escalation studies, the first few doses of the study medication may be subtherapeutic, with little chance of benefit. “Researchers should use pre-clinical data and real-time pharmacokinetic data to select doses that are close to the estimated therapeutic range and should design studies with intra-patient dose escalation so that exposure to lower doses is minimized,” says Sharma.
- Slot allocation. Sponsors often open early phase oncology trials at multiple sites. Thus, a large number of sites are competing for a small number of slots during the dose escalation part of the study. “In many cases, the slot allocation plan involves putting patients on a waiting list for future slots,” says Sharma. Many of these patients never enroll in the study because they get additional standard of care therapy, enroll in a different study, or have declining performance status and no longer are eligible. “Sponsors should limit the number of sites during dose escalation and should assign slots to sites in a rotation, so that sites can identify the best candidate and enroll patients in the study in a timely manner,” says Sharma.
- Financial toxicity. Researchers have an ethical obligation to inform prospective participants of the potential financial costs of participating in early phase clinical trials, argues Williams and colleagues in a recent paper.1 “IRBs (Institutional Review Boards) should consider financial toxicity as a concern with as much validity as physical side effect toxicity. There are clear measures in place for preventing, documenting, and managing physical side effects. We believe these same measures should be applied to financial toxicity,” says Williams.
Williams was lead author of a 2023 study interviewing 16 oncology patients who were actively participating in Phase I clinical trials to better understand financial toxicity from the perspective of the patient.2 The interviews revealed these key themes that recurred in the majority of participants:
- the burden of travel;
- a willingness to pursue treatment despite financial risk;
- fear of destitution;
- financial toxicity equaling physical toxicity;
- changes in food spending;
- reluctance to confide in the study investigator about financial toxicity;
- difficulty navigating financial aid.
“Our study revealed that our patients may be suffering in more ways than they let on during their clinic visits and only reveal the extent of their financial toxicity after carefully establishing rapport and repeated direct questioning,” says Willams. “It demonstrates the humanity of our patients. These are real people trying to balance their mortgage, career, car payment, and children while finding the time and money to be able to travel to receive treatment.”
To prevent financial harm to study participants, IRBs can evaluate any financial aid that might be available. IRBs also can consider asking for longitudinal documentation of financial toxicity. “Financial toxicity is more likely to become severe the longer a patient remains in the study,” explains Williams.
In early phase oncology trials, costs are divided into standard of care costs and research-related costs. Standard of care costs are billed to a patient’s insurance, whereas research-related costs are paid for by the study sponsor. “Informed consent documents should clearly outline the expenses that will be considered standard of care on a particular study,” says Sharma.
Sponsors can help by paying for participants’ hotel and travel expenses whenever possible. “Researchers should make sure that sponsors are supplying all study medications to avoid situations where a patient’s insurance might deny coverage for the medication and to avoid out-of-pocket expenses even when coverage is approved,” adds Sharma.
Informed consent. “IRBs should hold researchers accountable for disclosing in the informed consent document the full burden of clinic visits, procedures, and costs that are required to participate in the study,” says Sharma. Consent forms should make it clear that optional procedures (such as optional tumor biopsies) have no direct benefit to the patient, and that these can be declined without any repercussions, says Sharma.
“Researchers should clearly articulate which phase the clinical trial is in, its respective goals inherent to that stage (such as determining if a drug is safe, finding the correct dose, or determining if the drug is effective), and what’s expected from study participants,” says Williams.
IRBs should make sure that information in informed consent materials is clear enough for an average person to understand. Many study participants may know little or nothing about how clinical trials work in general, let alone early phase oncology trials. “If somebody has been with an IRB for several years, that person may end up learning so much medicine through the process that their level of medical education is higher than the average community member,” observes Leon Budrie, MD, MBA, an assistant professor in the Department of Critical Care at MD Anderson Cancer Center. To address this, it is helpful for IRBs to include the perspective of a patient.
Therapeutic misconception. Budrie recently overheard a patient, who had enrolled in an oncology clinical trial with a good outcome, encouraging a friend with a different type of cancer to join a clinical trial “because clinical trials are lifesaving.”
The well-meaning but misleading remark made Budrie wonder how much patients really understand what they are consenting to when joining an early phase oncology trial. “Even for healthcare providers, if you are not really engaged in clinical trials, you may have only a vague idea of what they are. But some people are really not familiar with clinical trials at all,” observes Budrie.
Some patients wrongly assume that medical decisions in the clinical trial will be made solely for the individual patient’s benefit instead of for the purpose of research. “Typically, participants in these studies have reached a point where they have exhausted all other treatment options. Because they are at this stage where anything else would be a dead end, they might see the trial as a last hope for a cure — not a future cure, but a cure for themselves,” says Budrie. Researchers should be clear that patients understand they may not get any benefit personally from the study. Researchers could put it this way, says Budrie: “This could be a potential cure for you right now. This could be a potential cure in the future. But right now, all we are really doing is to see if this is safe and if it has any potential to be established as a cure.”
Patient autonomy. Assuming a patient is fully informed, and has decision-making capacity, researchers must respect the patient’s decision on whether or not to participate — even if they disagree with that decision. “We all make decisions based on different things, regardless of whether it looks logical or rational. We try as best as possible to be sure that patients are making decisions not because of a misrepresentation of the information. And then, to some extent we have to allow people to do what they want,” says Budrie.
The possibility that patients may feel pressured to participate. Patients may be reluctant to disappoint their physician, their family, or their community. “Even for someone in good health, making a decision on whether to participate in a clinical trial is a daunting challenge. In poor health, in the last few weeks or months of your life, it is much more challenging,” says Budrie.
Clinicians can take the pressure off by reminding patients that what is most important is how they want to spend the time they have left. Patients may realize that they do not want to spend that time going back and forth to the clinic for monitoring and blood draws — regardless of how important the early phase oncology trial is. “A goals of care conversation should be happening in conjunction with the informed consent process,” says Budrie. “We should be asking, ‘How does study participation fit into the patient’s overall goals for the rest of their time?’”
References
1. Meyer LE, DeMartino ES, Williams C. Financial toxicity in early phase oncology clinical trials: A review and ethical analysis. Ethics Hum Res. 2025;47(2):26-33.
2. Williams C, Meyer L, Kawam O, et al. The faces of financial toxicity: A qualitative interview study of financial toxicity in advanced cancer patients in Phase I oncology trials. Mayo Clin Proc Innov Qual Outcomes. 2023;7(6):524-533.
Early phase oncology clinical trials demand a lot from participants but offer uncertain benefits in return.
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