First in Human studies

The number of new chemical entities (NCEs) approved by the U.S. FDA has dropped in the last decade (41) and the average success rate, from the first-in-human studies to registration, is only 11% (42). The lack of drug efficacy and safety account for around 30% of the failures in the clinic (42). Thus, the ability to determine drug safety and efficacy early in the discovery process should help in reducing the failure rate during the costly development studies, and in the end it would produce better and safer drugs (43). 

Use of these semisolid and solid approaches can potentially alleviate the chemical stability problems sometimes observed for liquid-Llled formulations, and may eventually offer the possibility of development of a tablet dosage form using conventional equipment. Liquid lipid-based formulations, however, generally afford the greatest enhancement of bioavailability for water-insoluble drugs, as well as affording more rapid development for First-in-Human studies. Any decisions on the best formulation route would have to be evaluated on a case-by-case basis. 

First in-human study the estrogen and stents to eliminate restenosis-1 trial... 

Parasrampuria D, de Boer P, Desai-Krietger D, et al. Single-dose pharmacokinetics and pharmacodynamics of RWJ 67657, a specific p28 MAP kinase inhbitor a first-in-human study, J Clin Pharmacol 2003 43(4) 406-13. 

The scope of this book covers the entire clinical development continuum from selection of lead candidate to first-in-human studies to ultimate product... 

Before any agent can enter into first-in-human studies, a battery of preclinical toxicological studies are required. The major goals of these preclinical... 

Some features of a Phase I study are invariant others have changed considerably over time. On a periodic basis, a set of new investigators enters the field, and almost everyone is inclined to reinvent the design features of Phase I studies. First-in-human studies are an extraordinary opportunity to integrate pharmacokinetic (PK), pharmacodynamic (PD), and toxicology information while launching the new molecule on a path for rational clinical development (1). Above all, this is a major domain for application of the principles of clinical pharmacology. 

The data in Table 31.1 for iododeoxydoxorubicin (I-Dox) were obtained during first-in-human studies conducted by Gianni et al. (8). There was greater exposure to the parent drug in mice, and to the hydrox-ylated metabolite (I-Dox-ol) in humans. Overall, there was a 50-fold difference in the relative AUC exposure ratios (metabolite parent drug) for humans and... 

During first-in-human studies with the investigational anticancer drug penclomedine, it was discovered that exposure to parent drug concentrations was less than 1% of the exposure to its... 

In studies conducted on diseases mainly affecting pediatric patients, the development will be entirely in pediatric patients. However, in addition to the appropriate usual toxicology and neonate animal toxicology, the first-in-humans studies for toxicity and safety are usually done in healthy adult volunteers. Clearly, however, drugs such as the surfactants would yield no useful data from adult testing. For these unique pediatric situations, new measurements and end points may need to be developed and validated. Frequently, the FDA will involve an advisory panel to help determine what these might be. 

The primary objective of first-time-in-human (first-time-in-man or first-in-human) studies is the identification of a suitable dose or dose range for further study, based on the safety and toierabiiity of the substance. These are volunteer subject-based dose-escalation studies that are traditionally small and time-lagged. These studies offer the first opportunity to learn about the drug in humans and serve as a bridge from animal to human. They provide opportunity for confirming the prediction of pharmacokinetics from animals and to learn about the safety of the drug, if the study is appropriately designed. 

First-in-human studies (SAD MAD) Microdosing Human ADME Drug-drug interaction... 

For nonclinical studies, ISR should be conducted at least once in each species, preferably in the first toxicology study. This could be a validation activity. Guidance was to follow the recommendations from the 2007 white paper [10]. Evaluation of ISR in clinical studies was recommended for all bioequivalence/ comparability studies and, where applicable, for the first-in-human study and diseased patient population studies. 

The report made 21 recommendations regarding such trials, which it would be pointless to repeat here. However, some brief discussion of issues can be attempted. The first is that it was established that there was no global, easily interrogated central database recording serious adverse reactions in first in human studies. The recommendation was... 

A further recommendation was that prior to beginning first-in-human studies a document should be prepared outlining in some detail an assessment of risk based on preclinical studies and other general background information and that this should be available to all parties concerned treating physicians, insurers, regulators and, of course human subjects. 

There is also a demand for a universal detector that will allow quantification of drug metabolites without the need for radioisotopes or authentic reference standards. Online coupling of LC with inductively coupled plasma mass spectrometry (LC/ICPMS) offers the ability to quantify metabolites. ICPMS is an element-specific detector with almost uniform response independent of molecular structure. The response is only related to the molar content of the detected element (Axelsson et al., 2001). Unfortunately, the use of ICPMS for metabolite profiling and identification is limited to compounds containing specific elements such as P, I, F, Br, S, and selected metals. We predict that in not too distant future technologies will be available to reliably detect, identify, and quantitate major human metabolites routinely from first-in-human studies. 

---