Phase I clinical trials are usually conducted in healthy volunteers to assess the tolerability of a new medicinal entity, estimate the maximum tolerated dose and study its pharmacokinetics. Anti-cancer drugs have the potential to cause serious toxicities; hence, Phase I oncology trials are conducted in patients suffering from cancers refractory to chemotherapeutic interventions. Such patients are terminal but have a good performance status, relatively normal energy and activity levels. But the concern is: Do Phase I oncology studies conform to the ethical requirements for a favourable benefit-risk ratio?
Many Phase I trials are conducted with novel therapies less toxic than chemotherapy, e.g., vaccines, immune modulators and anti-angiogenesis factors. In such studies, the benefit-risk ratio may be more favorable than chemotherapy trials. The overall response rate in 460 Phase I oncology trials was 10.6% and the toxic death rate was 0.49% (Horstmann E et al 2005). However, most Phase I oncology patients receive low doses to minimize toxicity. Such biologically inactive doses are unlikely to benefit the patients. A review of US Food and Drug Administration’s approval of anti-cancer drugs shows that such low response rates — 10% — are acceptable for routine medical care and can be accepted in clinical trials.
In a clinical trial setting, the evaluation of risks and benefits is the responsibility of the ethics committee members, who are healthy individuals. They are likely to consider Phase I oncology trials unfavorably. However, cancer patients are typically willing to endure intensive chemotherapy with substantial adverse effects for a 1% chance of cure. Although response rates are low, most patients in Phase I oncology trials are motivated to participate by hopes for stabilisation, reduction in tumour size, or a cure for their cancer. Altruism – a desire to benefit others – may also be a factor.
Informed consent (IC) of cancer patients to participate in Phase I studies with an unfavorable risk-benefit ratio is widely considered to be suggestive of deficiencies in disclosure or comprehension in the IC process or as indicative of their vulnerability and the clouding of judgment due to an incurable illness. Studies of IC processes have showed that the majority of participants were satisfied with IC process and reported comprehension of most, or all, information imparted about the Phase I trial in which they participated. But only 31% remembered the objectives of Phase I trial. As such studies are often conducted weeks or months after the Phase I study, they tend to assess the recollection of information as opposed to the participant’s understanding of the study process. The participants are likely to remember information relevant to them and not the whole informed consent document. Patients suffering from serious and terminal illnesses also obtain information about clinical trials and alternative treatments outside of the consent process. Terminally ill cancer patients do routinely make major decisions, e.g., preparing their wills. These patients therefore don’t seem to lack the capacity to provide informed consent for taking part in a clinical trial.
Phase I studies are critical to the development of novel anti-cancer agents. The researchers should offer an opportunity for participation in Phase I trials by providing the necessary information to make informed decisions.
Writer is a consultant on clinical research & development from Mumbai.