Phase I clinical trials of anticancer drugs in healthy volunteers: need for critical consideration.

Sir,

According to a popular belief, phase I clinical trials for anticancer drugs are not carried out in healthy volunteers for ethical reasons. Early anticancer drug trials are usually done in patients with advanced stage or refractory cancers. The dual purpose is to prevent healthy volunteers from being exposed to toxic drugs and a reasonable hope that at least some patients suffering from cancer will benefit from the investigational drug. In deviation from this convention, we observed a few completed and ongoing early clinical trials with anticancer drugs which include healthy volunteers and are registered with US Clinical Trials Registry.[1]

Safety assessment is the primary objective of phase I trials in general. However, the primary objective of most anticancer drug trials in healthy volunteers was observed to be pharmacokinetic evaluation and metabolic profiling, e.g. BMS-690514, a pan-HER inhibitor; dacomitinib (PF-00299804), HER 1,2,4 tyrosine kinase inhibitor; LY2584702, a serine threonine kinase inhibitor; GSK2256098, a focal adhesion kinase-1 inhibitor. Some studies were done for dose finding (e.g. transtuzumab) and formulation development (e.g. comparison of drug levels with tablet, liquid, and tablet dispersed formulation of dasatinib). Some phase I anticancer trials were done in healthy volunteers with safety as the primary objective (e.g. bosutinib, a tyrosine kinase inhibitor; 99mtc MIP 1404, a prostate-specific membrane antigen inhibitor; and Vitamin E d-tocotrienol). A few studies were also being done to assess the total recovery of radioactivity (e.g. [14C]dacomitinib).[1]

Pharmacodynamics is evaluated as a secondary objective in many of these studies [e.g. papatinib (HKI-272), an HER-2 inhibitor; 4 SC-203, a multitarget kinase inhibitor]. Healthy volunteers are also included in studies for cancer biomarker identification and diagnostic imaging, e.g. [18F] CP-18 PET tracer to identify high caspase-3 activity in breast cancer.[1]

Healthy volunteers are now being included in anticancer trials due to availability of non-cytotoxic anticancer drugs having considerably lower toxicity. The advantages of conducting healthy volunteer studies for anticancer drugs include investigation of bioavailability/pharmacokinetics, data not confounded by disease, reduction in patient exposure to ineffective drugs or doses, and rapid subject accrual in the study.[23] The hope to expedite drug development process is the probable driving force. However, the regulatory requirement for preclinical data is different when the new anticancer drug is to be used for phase I trial in cancer patients as compared to healthy volunteers.

Genotoxic studies, not required for early clinical trials in cancer patients, are essential for healthy volunteer studies, at least in vitro tests. In vivo tests, in addition, are desirable. In USA, a drug with positive in vitro genotoxicity may still be administered to healthy volunteers for single-dose studies if the in vitro results are not alarming, the drug does not belong to a known carcinogenic class structurally or mechanistically, and the trial participants are appropriately made aware of the results. Depending upon the perceived risk, trial permission is granted by the Food and Drug Administration on a case-to-case basis.[4]

Traditionally, 1/10th of the severely toxic dose in 10% rodents (STD10) or 1/6th of the highest non-severely toxic dose (HNSTD) in non-rodents is considered as an appropriate starting dose for cancer patients.[5] However, for anticancer trials in healthy volunteers, 1/10th of the human equivalent dose calculated from No Observed Adverse Effect Level (NOAEL) in the most sensitive species is used for oncology drug trial.[6]

To support early trials in healthy volunteers, the safety pharmacology studies should be conducted in accordance with ICH M3, S7A, and S7B.[7-9] Careful observation of effects on major organ systems, early identification and potential reversibility of preclinical toxicology, and early detection of adverse effects which may not be picked up by standard battery of tests (e.g. antibody formation) are important considerations. Clinical considerations while designing the study include: limited exposure to drug (maximum 1 or 2 doses), conservative dosing scheme, and cessation of exposure at the first evidence of toxicity in volunteers.[2]

Though inclusion of healthy volunteers in clinical trials for anticancer drugs offers certain advantages, extrapolation of results from these studies to cancer patients might be limited. The low-dose pharmacokinetics in healthy volunteers might be different than the therapeutic dose pharmacokinetics in cancer patients. Hence, cautious benefit risk assessment is needed to decide appropriateness of such study and serious preclinical and clinical concerns should be addressed while designing it.

Clinical research for cancer is increasing in India. However, we did not find any healthy volunteer study for anticancer drugs in the Clinical Trials Registry in India. The reason could be restriction on phase I studies for new drugs discovered outside India.[10] With improving research and development capacity and increasing importance of pharmacogenomics, more clinical trials are being done in India. Although inclusion of healthy volunteers is not a convention, increasing availability of safer anticancer drugs necessitates conscious rethinking by Indian clinical research professionals as well as the drug regulators.