Adverse events are key elements in defining risks in clinical trials. The quality of identifying, reporting, and eventually forecasting adverse events is crucial for participant protection and ethics assessment. Issues of reporting and problems with accurate attribution of adverse events as related — or not — to the study drug have been identified and frequently described in the literature. A new study by FisherReference Fisher1 addresses the lesser known problem of interpretation of adverse events by healthy volunteers.
Accounts of Adverse Events by Healthy Volunteers
Preclinical research answers basic questions about the safety of new medicinal products, but it does not guarantee that new agents are equally safe in humans. To develop new and sufficiently safe drugs, the recruitment of healthy volunteers is essential. However, the transition from preclinical to clinical stage is a critical turning point and can pose risks of mild to severe adverse events. Although the incidence of serious adverse events is low, they can occasionally occur as they did in the Phase I clinical trial of BIA 10-2474 in 2016 in France, in which one healthy participant died and six were hospitalized.Reference Chen, Sinaii, Bedarida, Gregorio, Emanuel and Grady2
It is known that healthy volunteers do pay attention to the risks associated with study interventions, potential side effects, and burdens of participation in a trial; the majority express preferences for low risk studies.3 However, the risks associated with the occur-rence of how adverse reactions are accounted for by Phase I trial participants was unknown. Such data are provided in new research by Fisher.4
This qualitative study, including 131 healthy volunteers, evaluated the subjective assessment of bodily changes in terms of harm. Most participants interpreted their experiences of having adverse events during Phase I trials as insignificant or not concerning. Others viewed adverse events as imagined, fabricated, or psychosomatic, meaning that they were generated by the participant's mind. There were times when volunteers acknowledged the bodily changes as real and painful, but according to them, they were caused by some factor other than the study drug. Their interpretations minimize, deny or re-attribute the cause of adverse events to downplay the possibility and magnitude of experienced harm.5 The main reason to do so is the motivation to earn money for enduring interventions, which can be very unpleasant, uncomfortable, or risky.Reference Różyżska6 The tendency to delink the experience of adverse events from being harmed results also from the clinical trial environment. Participants compare their bodily changes to the greater risks outlined in informed consent forms or try to explain that the adverse events they experience are the result of some lifestyle changes (e.g., caffeine withdrawal) during the trial period.7 There are also instances of dual enrollment, in which volunteers ignore both restrictions and potential harms related to participation in more than one trial at a time.
These factors, taken together, can indicate that Phase I trials are, in general, considered safe by healthy volunteers. Adverse events are underestimated and, in some cases, can even be unreported.
Accounts of Adverse Events in Phase I Trials in Oncology
Some Phase I trials must be conducted with sick participants because various tested drugs are too toxic or potentially too dangerous for healthy volunteers. The largest area of such research is Phase 1 in oncology, which aims not only to evaluate the safety and dosage of a new compound but also demonstrate preliminary evidence of efficacy.
It is known that healthy volunteers do pay attention to the risks associated with study interventions, potential side effects, and burdens of participation in a trial; the majority express preferences for low risk studies. However, the risks associated with the occurrence of how adverse reactions are accounted for by Phase I trial participants was unknown. Such data are provided in new research by Fisher.
Phase I studies in oncology include participants with advanced cancer who usually have exhausted standard therapeutic options. The advancement of the disease and very strict entry conditions ensure that, unlike in Phase I with healthy volunteers, participants of cancer Phase I trials are rarely serial participants. Their motivations for participation, expectations of the benefit/risk ratio, and accounts of adverse events also differ from healthy volunteers. While the motives of the latter are mostly economic, sick participants often hope for the direct therapeutic benefit or enhanced care from researchers-physicians. Sometimes patients can also misunderstand the probability of direct benefit or harm that may result from participating in research by underestimating risks, overestimating benefits, or both.
As in studies with healthy volunteers, adverse events in Phase I in oncology pose some problems with interpretation. The National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 defines an adverse event as “any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure.” Adverse events are assessed on a 5 grade (severity) scale, in which grade 1 is a mild symptom and grade 5 is death caused by the adverse event. Clear categorization of adverse events most likely helps with severity classifications. But the core of the interpretation problem of adverse events in Phase I cancer trials is the difficulty to accurately attribute adverse events as related — or not — to the study drug, to the disease, co-morbid illness, or to a combination of all three.Reference Eaton, Iasonos, Gounder, Pamer, Drilon, Vulih, Smith, Ivy, Spriggs and Hyman8 This can be one of the reasons why adverse events in cancer Phase I trials are not always reported in a clear manner. For example, in our recent meta-research calculating risk and benefit in pediatric Phase I trials in oncology, there was no explicit information about drug-related deaths (grade 5 adverse events) in 100 among 170 of analyzed studies.Reference Waligora9
Conclusion
Data from various research suggest that potential harms occurring in Phase 1 trials are most likely underestimated by the participants and there is the possibility that some adverse events are unreported. While the issues of reporting of adverse events could be solved by technical solutions, problems with interpretation of adverse events need more advanced techniques and should be further discussed.
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Adverse events are key elements in defining risks in clinical trials. The quality of identifying, reporting, and eventually forecasting adverse events is crucial for participant protection and ethics assessment. Issues of reporting and problems with accurate attribution of adverse events as related — or not — to the study drug have been identified and frequently described in the literature. A new study by FisherReference Fisher1 addresses the lesser known problem of interpretation of adverse events by healthy volunteers.
Accounts of Adverse Events by Healthy Volunteers
Preclinical research answers basic questions about the safety of new medicinal products, but it does not guarantee that new agents are equally safe in humans. To develop new and sufficiently safe drugs, the recruitment of healthy volunteers is essential. However, the transition from preclinical to clinical stage is a critical turning point and can pose risks of mild to severe adverse events. Although the incidence of serious adverse events is low, they can occasionally occur as they did in the Phase I clinical trial of BIA 10-2474 in 2016 in France, in which one healthy participant died and six were hospitalized.Reference Chen, Sinaii, Bedarida, Gregorio, Emanuel and Grady2
It is known that healthy volunteers do pay attention to the risks associated with study interventions, potential side effects, and burdens of participation in a trial; the majority express preferences for low risk studies.3 However, the risks associated with the occur-rence of how adverse reactions are accounted for by Phase I trial participants was unknown. Such data are provided in new research by Fisher.4
This qualitative study, including 131 healthy volunteers, evaluated the subjective assessment of bodily changes in terms of harm. Most participants interpreted their experiences of having adverse events during Phase I trials as insignificant or not concerning. Others viewed adverse events as imagined, fabricated, or psychosomatic, meaning that they were generated by the participant's mind. There were times when volunteers acknowledged the bodily changes as real and painful, but according to them, they were caused by some factor other than the study drug. Their interpretations minimize, deny or re-attribute the cause of adverse events to downplay the possibility and magnitude of experienced harm.5 The main reason to do so is the motivation to earn money for enduring interventions, which can be very unpleasant, uncomfortable, or risky.Reference Różyżska6 The tendency to delink the experience of adverse events from being harmed results also from the clinical trial environment. Participants compare their bodily changes to the greater risks outlined in informed consent forms or try to explain that the adverse events they experience are the result of some lifestyle changes (e.g., caffeine withdrawal) during the trial period.7 There are also instances of dual enrollment, in which volunteers ignore both restrictions and potential harms related to participation in more than one trial at a time.
These factors, taken together, can indicate that Phase I trials are, in general, considered safe by healthy volunteers. Adverse events are underestimated and, in some cases, can even be unreported.
Accounts of Adverse Events in Phase I Trials in Oncology
Some Phase I trials must be conducted with sick participants because various tested drugs are too toxic or potentially too dangerous for healthy volunteers. The largest area of such research is Phase 1 in oncology, which aims not only to evaluate the safety and dosage of a new compound but also demonstrate preliminary evidence of efficacy.
It is known that healthy volunteers do pay attention to the risks associated with study interventions, potential side effects, and burdens of participation in a trial; the majority express preferences for low risk studies. However, the risks associated with the occurrence of how adverse reactions are accounted for by Phase I trial participants was unknown. Such data are provided in new research by Fisher.
Phase I studies in oncology include participants with advanced cancer who usually have exhausted standard therapeutic options. The advancement of the disease and very strict entry conditions ensure that, unlike in Phase I with healthy volunteers, participants of cancer Phase I trials are rarely serial participants. Their motivations for participation, expectations of the benefit/risk ratio, and accounts of adverse events also differ from healthy volunteers. While the motives of the latter are mostly economic, sick participants often hope for the direct therapeutic benefit or enhanced care from researchers-physicians. Sometimes patients can also misunderstand the probability of direct benefit or harm that may result from participating in research by underestimating risks, overestimating benefits, or both.
As in studies with healthy volunteers, adverse events in Phase I in oncology pose some problems with interpretation. The National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 defines an adverse event as “any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure.” Adverse events are assessed on a 5 grade (severity) scale, in which grade 1 is a mild symptom and grade 5 is death caused by the adverse event. Clear categorization of adverse events most likely helps with severity classifications. But the core of the interpretation problem of adverse events in Phase I cancer trials is the difficulty to accurately attribute adverse events as related — or not — to the study drug, to the disease, co-morbid illness, or to a combination of all three.Reference Eaton, Iasonos, Gounder, Pamer, Drilon, Vulih, Smith, Ivy, Spriggs and Hyman8 This can be one of the reasons why adverse events in cancer Phase I trials are not always reported in a clear manner. For example, in our recent meta-research calculating risk and benefit in pediatric Phase I trials in oncology, there was no explicit information about drug-related deaths (grade 5 adverse events) in 100 among 170 of analyzed studies.Reference Waligora9
Conclusion
Data from various research suggest that potential harms occurring in Phase 1 trials are most likely underestimated by the participants and there is the possibility that some adverse events are unreported. While the issues of reporting of adverse events could be solved by technical solutions, problems with interpretation of adverse events need more advanced techniques and should be further discussed.