First in man

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. 

A decision tree approach for the development of first human dose. FTIM = first in man CIC = chemical in capsule CIB = chemical in bottle CICIB = chemical in cap- [Pg.35]

It should be noted that our proposal goes considerably beyond the current proposal of FDA to create a looser Phase 0 stage for first-in-man pharmacokinetic and similar activities. Our proposal would cover all early human studies through clinical proof-of-concept, which usually occurs in Phase 2a. Only in the large pivotal studies (Phases 2b-3), when there is more assurance that the drug candidate has a solid chance of getting to an NDA submission, would the full formal IND filing be necessary. (These proposals are the opposite of what has been introduced by the EC Clinical trial Directive, see Chapter 17.)... 

The rationale for this proposal is that first-in-man and other early studies are of small size and are relatively safe when performed by experienced investigators and that entities and... 

A myriad of preclinical and first-in-man clinical studies suggest that cell therapy has a positive effect on cardiac and vascular repair. In fact, in most studies, the tested cell types were found to be effective, even in the absence of the evidence of robust cell engraftment. This unexpected outcome defines how little we actually understand at present about the underlying mechanism ) of cell-mediated repair, We attribute much repair to direct participation of the transplanted cells in angiogenesis or myogenesis, but in truth, despite promising clinical outcomes, relatively little clinical data exist to support this contention. 

Skowasch M, Hein R, Buescheck F etal. Non-Implant Closure of Ratent Foramen Ovale First-in-Man Results. Am J Cardiol 2005 96(suppl 7A) 101 H. 

Preliminary Preclinical First in man Refine dose ranging evaluation (Lab/Animal Dose range Tests)... 

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. 

European Medicines Agency—Committee for Medicinal Products for Human Use (CHMP). Guideline on Strategies to Identify and Mitigate Risks for First-in-Man Human Clinical Trials with Investigational Medicinal Products. EMEA/CHMP/ SWP/2836707/2007. 19 July 2007. http //www.emea.europa.eu/pdfs/human/swp/ 2836707enfin.pdf... 

Overall the ICH S7A guideline is successfully implemented in the pharmaceutical world. The core battery is in general performed prior to First in Man . The guideline increases the visibility of safety pharmacology within companies and increases focus by regulatory agencies. 

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. 

---