Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development

Phase 0 clinical trials, including microdosing, limit drug exposure in first-in-human studies to reduce risks, costs, and time in drug development. These exploratory trials, governed by ICH M3 guidelines, involve subtherapeutic doses—for small molecules, no greater than 100 μg or 1/100th of the NOAEL—and require sensitive analytical tools like LC-MS/MS. Evidence supports extrapolating pharmacokinetic and pharmacodynamic data from microdose to therapeutic doses, though validity depends on drug properties and modeling. Applications include studying metabolism, receptor binding, and local drug effects. Ethical advantages include reduced human and animal exposure. The term 'in humano' is proposed for such limited human testing. An increasing number of applications demonstrate the versatility of these approaches.

Study at a glance

Abstract

Increasing costs of drug development and ethical concerns about the risks of exposing humans and animals to novel chemical entities favor limited exposure clinical trials such as microdosing and other phase 0 trials. An increasing body of research supports the validity of extrapolation from the limited drug exposure of phase 0 approaches to the full, therapeutic exposure. An increasing number of applications and design options demonstrate the versatility and flexibility these approaches offer to drug developers. The pursuit of alternative approaches for first-in-human (FIH) trials arose in response to a decline in drug development productivity and as an attempt to reduce the costs and time spent identifying failed drugs.1 Such alternative approaches, variously named Exploratory Investigational New Drug applications (eIND), phase 0, and, under the current guidelines, Exploratory Clinical Trials, were established by regulatory authorities to reduce the risks to humans by limiting drug exposure during FIH trials.2, 3 Reduction in exposure and expected risks led to a reduction in preclinical testing, associated time and costs, drug manufacturing requirements, and promises to provide valuable human-based data prior to initiation of full-fledged INDs.4-6 Just how much better informed and more efficient these approaches are than traditional ones depends on the type of information provided, associated time and costs, available alternatives, and the validity of extrapolating modeling from the limited exposure to full-therapeutic dose exposure. The current, internationally harmonized, regulatory framework defining and governing microdosing and other phase 0 clinical trials is the International Conference on Harmonization (ICH) M3 Guidelines3. Under this framework phase 0 trials are FIH trials where the exposure to the drug is less than in phase I studies (i.e., less than maximal tolerated dose [MTD]), have no therapeutic purpose, and are not intended to assess tolerability. The five phase 0 approaches described in the guidelines form a spectrum of exposure from single, minimal (microdose) exposure to multiple doses into the anticipated therapeutic range (Table 1). Other approaches that meet the spirit of the guidelines are possible and early consultation with local regulators is recommended to help identify the optimal approach.2 The 2006 the US Food and Drug Administration (FDA) eIND guidance emphasizes the inherent flexibility in the regulations: “Existing regulations allow a great deal of flexibility in the amount of data that needs to be submitted with an IND application, depending on the goals of the proposed investigation, the specific human testing proposed, and the expected risks. The Agency believes that sponsors have not taken full advantage of that flexibility and often provide more supporting information in INDs than is required by regulations”.2 As a contribution to the body of definitions we propose the term “in-humano” to describe the type of limited testing in “exploratory clinical trials.” The term was coined during discussions on the occasion of microdosing symposium at the American College of Clinical Pharmacology (ACCP) annual meeting in 2013. Although limited, such brief and/or local drug interactions within humans may generate data of mechanistic and conceptual value not otherwise available prior to phase I studies. The term “in humano” testing uses the Latin terminology similar to “in silico,” “in vitro,” and “in vivo” testing, to indicate preclinical testing in humans, meaning that no clinical, (i.e., therapeutic or toxic) effects are expected. It is a step on the spectrum from human in vitro tissues, to studies in intact preclinical species, to studies in isolated intact human organs or tissues, to systemic subtherapeutic exposure in humans and finally, systemic therapeutic exposure in humans. In the case of microdosing (Approaches 1 and 2, Table 1) the dose is defined as no greater than 100 μg (for small molecules) or 1/100th of the No Observed Adverse Effect Level (NOAEL), whichever is the lower. With such low exposures no gross effects, therapeutic, toxic or radiotoxic when labeled with radioisotopes, are expected. As will be discussed later, however, pharmacological effects, both pharmacokinetic (PK) (e.g., absorption, distribution, metabolism, excretion [ADME]) and pharmacodynamic (PD) (e.g., receptor binding and displacement, production of intermediate metabolites, and modification of targets; Figure 1) may take place, and be detected with targeted approaches and sensitive analytical tools even if no gross effects are elicited in the organism as a whole. For microdosing approaches used to test proteins, a molar limit (30 nmol) is applied due to the large size of the molecules.2 The molar and mass definitions converge if the size of the test molecule is 3.3 kDa, when it is both 100 μg and 30 nmol. For any larger molecules the 100 μg definition of microdosing will be the more conservative one. As an illustration - the TGN1412 monoclonal antibody, at 150 kDa, was given at 0.1 mg/kg to six healthy volunteers and caused a cytokine storm and near fatal multiple organ failure within 24 h7. For a 45 kg individual the resulting 4.5 mg meets the molar definition of a microdose study (30 nmol x 150 kDa = 4.5 mg). However, were the 100 μg definition used the resulting dose would have been 45-fold lower. The limited systemic exposure of phase 0 studies may require more sensitive assays than conventional analytical tools. The three most commonly used techniques are liquid chromatography-tandem mass spectrometry (LC-MS/MS), positron emission and mass spectrometry (Table is by the most by and and require exposure is minimal and not require The advantage of is the to provide information about drug effects in time in the in of receptor binding and however, and from is the most and associated with the amount of and require the of for production of the radioisotopes, and the of such in to the clinical research the of and that be due to 100 and is in with the of no on The limited of and is of phase 0 study with six to is required drug development The of a phase 0 study from other clinical trials in most the of low low and the sensitive tools to drug The regulatory framework a initiation of phase 0 studies due to preclinical and manufacturing In other the phase 0 trials are similar to other FIH studies. is no therapeutic phase 0 trials allow the study of that are to drug development 1). of the (for both and receptor binding and displacement, and and clinical clinical that on exposure be with any of the phase 0 However, even with the most limited exposure of a microdose Table 1) the three be and, as will be in the depending on the (e.g., analytical tools (e.g., and (e.g., information may be phase 0 approaches on the validity of extrapolation from the to the full exposure of to be discussed in However, in the phase 0 provide information about test effects in humans. information the about the test on the individual development such information may a for a or provide valuable guidance for the phase I and phase that information however, the and time spent was to be the case in modeling and of microdosing the of the clinical framework more than a the in the have been testing of the validity of the and on of the microdose to therapeutic dose spectrum and development of modeling and tools to when may be an on drug development where the or of testing and early at informed been (Table The and 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