Healthy Volunteer Studies in the Development of Anticancer Drugs with Genotoxic Findings

Abstract

Background Recent scientific advances in cancer research have led to the development of immunomodulatory and molecularly targeted drugs with better safety profiles than chemotherapeutics, which makes it possible to include healthy volunteers (HVs) in clinical trials. In this study, we aimed to identify the number of marketing authorization applications (MAAs) that enrolled HVs in a clinical trial and to identify the number of anticancer drugs that were given to HVs despite a positive genotoxic finding. In addition, we evaluated the dose of anticancer drugs administered to HVs and the justification for proceeding with HV studies despite a positive genotoxic finding. Methods Publicly available information from the European Medicines Agency (EMA) website was used for this study. Anticancer drugs were identified using the human medicines highlights published by EMA between January 2010 and December 2019. EPARs were used to collect general information of the anticancer drugs, details on genotoxicity studies, and the enrollment of HVs in clinical trials. Results We identified 71 MAAs for small molecule anticancer drugs with a positive or negative CHMP opinion in the EU. Forty-eight anticancer drugs were studied in HVs, of which 12 anticancer drugs were administered to HVs despite positive genotoxic findings in the standard battery. Systematic and extensive genetic toxicology screening demonstrated the absence of genotoxic risks to the cell system. Conclusion We showed that despite a positive genotoxic finding, comprehensive genetic toxicology testing demonstrated the absence of risks to the cell system at the human exposure dose. Therefore, these anticancer drugs posed no harm to HVs.

Phase I crossover study of DNA‐protein kinase inhibitor peposertib in healthy volunteers: Effect of food and pharmacokinetics of an oral suspension

“…Notably, using healthy participants removes the ethical concern of administering subtherapeutic doses to patients with disease when studies of curative or palliative intent may be more appropriate. 16,19 In the absence of RT or CT, the constitutive level of DNA-PK is low in healthy volunteers and F I G U R E 2 Arithmetic mean plasma concentration-time course on linear and semi-logarithmic scales (36 h; pharmacokinetic analysis set). Note different value scales for y-axis in the linear-linear curves in (a,b); horizontal line refers to lower limit of quantification (5.00 ng/mL).…”

“…There is also lower risk of confounding by comorbidities or concomitant medications. Notably, using healthy participants removes the ethical concern of administering subtherapeutic doses to patients with disease when studies of curative or palliative intent may be more appropriate 16,19 . In the absence of RT or CT, the constitutive level of DNA‐PK is low in healthy volunteers and DNA‐PK mediated repair of double‐strand DNA damage is considered negligible.…”

“…Overall, healthy volunteers are being increasingly enrolled in pharmacological trials of drugs in oncologic indications for the development of small molecule therapeutics. 16 Nonclinical safety data showed that peposertib was not mutagenic or genotoxic in a standard battery of Note: Tablet fasted: 2 tablets of 50 mg peposertib under fasted conditions.…”

“…Additionally, as the half‐life of peposertib is short at ~5.5 h, 11 any risk to healthy volunteers, due to unexpected DNA damage upon peposertib exposure, was considered to be within acceptable limits of clinical pharmacology trials. These advantages have to be weighed against the fact that the pharmacokinetic and pharmacodynamic properties of the drug may not be identical in healthy volunteers and patients, in some cases, and that engagement of the drug target may have different safety consequences in patients 16 . Nonetheless, the case for using healthy volunteers is strengthened if the preclinical efficacious dose is equal to or less than the no observed adverse effect level (NOAEL) and the drug is non‐genotoxic.…”

“…Traditionally, anticancer drug development focused on chemotherapeutics, and these could not be administered to healthy volunteers due to ethical concerns over their toxic effects. However, the current immunomodulatory and molecularly targeted drugs are rarely genotoxic and have better safety profiles than chemotherapeutics, and can be administered to healthy volunteers 16 . Furthermore, the use of healthy volunteers instead of patients in clinical pharmacology studies (e.g., those evaluating food effects, drug–drug interactions, and thorough QT trials), is advantageous because recruitment can be faster and dropout rates are lower, rich sampling is easily possible, sampling can be more precisely timed, difficult pre‐analytical procedures are possible, and costs can be lower 17,18 .…”