Reviewing the role of healthy volunteer studies in drug development

Abstract

BackgroundWith the exception of genotoxic oncology drugs, first-in-human, Phase 1 clinical studies of investigational drugs have traditionally been conducted in healthy volunteers (HVs). The primary goal of these studies is to investigate the pharmacokinetics and pharmacodynamics of a novel drug candidate, determine appropriate dosing, and document safety and tolerability.Main bodyWhen tailored to specific study objectives, HV studies are beneficial to manufacturers and patients alike and can be applied to both non-oncology and oncology drug development. Enrollment of HVs not only increases study accrual rates for dose-escalation studies but also alleviates the ethical concern of enrolling patients with disease in a short-term study at subtherapeutic doses when other studies (e.g. Phase 2 or Phase 3 studies) may be more appropriate for the patient. The use of HVs in non-oncology Phase 1 clinical trials is relatively safe but nonetheless poses ethical challenges because of the potential risks to which HVs are exposed. In general, most adverse events associated with non-oncology drugs are mild in severity, and serious adverse events are rare, but examples of severe toxicity have been reported. The use of HVs in the clinical development of oncology drugs is more limited but is nonetheless useful for evaluating clinical pharmacology and establishing an appropriate starting dose for studies in cancer patients. During the development of oncology drugs, clinical pharmacology studies in HVs have been used to assess pharmacokinetics, drug metabolism, food effects, potential drug–drug interactions, effects of hepatic and renal impairment, and other pharmacologic parameters vital for clinical decision-making in oncology. Studies in HVs are also being used to evaluate biosimilars versus established anticancer biologic agents.ConclusionA thorough assessment of toxicity and pharmacology throughout the drug development process is critical to ensure the safety of HVs. With the appropriate safeguards, HVs will continue to play an important role in future drug development.

A Phase I Study to Assess the Effect of Speed of Injection on Pain, Tolerability, and Pharmacokinetics After High-volume Subcutaneous Administration of Gantenerumab in Healthy Volunteers

“…Moreover, the presence of AD pathologic findings was not necessary to evaluate the study objectives, and the inclusion of healthy volunteers avoids the dilemma of enrolling patients with AD into a safety trial in which they will likely receive a subtherapeutic dose. 34 However, because pain perception may be age dependent, enrollment was restricted to healthy volunteers aged 40e80 years, which is representative of the AD population. One limitation of our study is that gantenerumab was administered only into the abdomen, and pain levels after injection into the thigh are based solely on the placebo group; the perceived pain associated with subcutaneous injection of gantenerumab into other sites is unknown.…”

Pivotal Considerations for Optimal Deployment of Healthy Volunteers in Oncology Drug Development

“…Typically, early studies in NHVs comprise confinement to the CRU until discharge . Confinement allows for rich PK sampling schemes, including at “inconvenient” times, and allows for closer safety monitoring and management of safety events.…”

“…Typically, early studies in NHVs comprise confinement to the CRU until discharge. 61 Confinement allows for rich PK sampling schemes, including at "inconvenient" times, and allows for closer safety monitoring and management of safety events. Clinical pharmacology studies requiring crossover design and prolong washout can be very challenging in patients but are standard in NHVs.…”

Modulation of premotor cortex response to sequence motor learning during escitalopram-intake

“…In a double-blind, randomized controlled pharmaco-fMRI study, we administered 20 mg (to reach 80% serotonin transporter (5-HTT) occupancy) 37 of escitalopram, the most 5-HTT selective and rapid onset SSRI 38,39 or placebo, to healthy female participants undergoing parallel fMRI assessment and training on a variant of the sequential pinch force task (SPFT) 40 . Given reports of sex-differences in (i) motor learning 33,41,42 , (ii) fMRI responses during sequential motor control 43 , (iii) motor responses following SSRI-intake 33 , and (iv) sex hormone modulation of serotonin transporter density measures 44,45 and escitalopram responsivity 46,47 , we chose a healthy and young (to also control for the effects of pathology 48,49 and age 50 ) female sample on oral contraceptives, to avoid variance associated with sex and sex hormones on motor learning performance, fMRI response, serotonin transporter density, and SSRI responsivity. Our a priori hypotheses were (1) that one week of escitalopram intake would improve sequential motor performance relative to placebo, as assessed by performance in a temporal lag condition on the SPFT, calculated as the time difference between a computer controlled visual stimulus and participant control of a pinchforce device.…”