First-in-man studies

Phase 1 trials are the first in man studies of a new drug in humans. These studies are usually carried out on small samples of subjects. The idea here is to determine the safety of the drug in a small and usually healthy volunteer study population. 

Preclinical animal studies are usually performed with simple formulations which are appropriate for the route investigated in the (nonhuman) species involved. While similar simple formulations or approaches (such as capsules) are also employed for first-in-man studies, as development proceeds, efforts are made to develop formulations which optimize bioavailability. This may lead to effects not seen in earlier animal (or, indeed, human) studies, a factor that should be kept in mind in both study design and interpretation. 

In addition to the first in man studies there are subsequent studies in healthy volunteers, which are performed in parallel to the phase II/III clinical development. These studies address issues like drug-drug interactions, special sub-populations (e.g. patients with liver and renal impairment), or bioavailability/bioequivalence issues. These studies are also conducted under the same well controlled conditions and therefore contribute rich data. 

The first tolerability studies in early clinical development always provide pharmacokinetic (PK) data over a considerable dose range. Especially the explorative first-in-man study with escalating single doses, or an explorative proof of principle study with escalating multiple doses provides a valuable basis for an exploratory assessment of dose linearity/ proportionality of drugs in humans. In addition such an assessment can directly help within the same study to optimize the dose selection and dose progression. Already in this early phase of the development, these data are going to support exposure-response relationships, and thus a potential submission (US FDA 2003, ICH E4 1994). 

The design of an exploratory assessment of dose linearity/proportionality during the conduct of a first-in-man study for candidate drug (XYZ1234) is presented below. For the purposes of simplicity, the description is limited to the collection, handling, and interpretation of pharmacokinetic data although clearly safety parameters are in the main focus. 

Single oral dose-escalation study, to study safety, tolerability, pharmacokinetics and pharmacodynamics of XYZ1234 in healthy male subjects (first-in-man study). 

The described evaluation provides a tool, also called online PK , which allows adjusting the dose in this first-in-man study on a very flexible basis. Consequently, this flexible dose-scheme is described already in the study protocol. The main prerequisite is, besides an adjustable dosing form, an immediate shipping and evaluation of the bioanalytical samples. 

PURPOSE AND RATIONALE In early clinical development the steps before entering into larger patient studies are typically an explorative first-in-man study with escalating single doses in healthy volunteers, an explorative proof-of-principle study with escalating multiple doses in healthy volunteers, and then a proof-of-concept with escalating... 

It would be unreasonable to study the pharmacokinetics of relatively toxic agents, at potentially therapeutic doses, in normal volunteers due to the near-certainty of the adverse events. Typically, this information can be gained in patients with diseases potentially responsive to these agents. Thus, the first-in-man studies in this case are phase II , using the classic nomenclature. Cytotoxic and antiviral drugs are two important classes of agent where this is commonly the case. 

For example, first-in-man studies and pivotal trials are more likely to be audited than phase IV trials, and external providers selected for the first time who are responsible for key areas in clinical trials should be audited with a higher priority than CROs with a long history and reliable performance. 

Grube E, Laborde JC, Gerckens U, etal. Percutaneous implantation of the CoreValve self-expanding valve prosthesis in high-risk patients with aortic valve disease the Siegburg first-in-man study. Circulation 2006 Oct 10 114(15) 1616-24. 

Working Party on Statistical Issues in First-in-Man Studies (2007) Statistical issues in flist-in-man studies. Journal of the Royal Statistical Society, Series A 170 517-579. 

Table 7.5 presents the basic guidance provided by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) for renal safety pharmacology evaluation of new drugs. These evaluations are noncore and therefore not required prior to first-in-man studies. It is essential that intact animals be used in such evaluations, but it must be kept in mind that there are species differences in responses [12,13] and that renal function is readily influenced by anesthesia [14,15]. 

Work in the late discovery phase after candidate selection involves the further characterization of the selected drug to allow prediction of clinical pharmacokinetic and metabolism properties, which may include prediction of efficacious human dose (Huang et al., 2008). These properties are important in the design of regulatory toxicology and first-in-man studies and can affect things such as choice of toxicology species, dose selection, and important metabolites to monitor in early studies (Walker et al., 2009 Zhu et al., 2009 Baillie, 2009). 

Malik M, Hnatkova K, Ford J, Madge D (2008) Near-thorough QT study as part of a first-in-man study. J Clin Pharmacol 48 1146-1157... 

He YL, Zhang Y, Yan JH et al (2013) High-quality triplicate electrocardiogram monitoring in a first-in-man study potential for early detection of drug-induced QT prolongation. Int J Clin Pharmacol Ther 51 948-957... 

Goh AS, Chung AY, Lo RH, Lau TN, Yu SW, Chng M, Satchithanantham S, Loong SL, Ng DC, Lim BC, Connor S, Chow PK et al (2007) A novel approach to brachytherapy in hepatocellular carcinoma using a phosphorus 32 brachytherapy delivery device - a first in man study. Int J Radiat Oncol Biol Phys 67(3) 786-792... 

A. Seth, P. Chandra, N.S. Chouhan, and A.S. Thakkar, A first-in-man study of sirolimus-eluting, biodegradable polymer coated cobalt chromium stent in real life patients, Indian Heart / 64 (6), 547-552, 2012. 

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