First-in-human

Schelman WR, Sandhu SK, Moreno GV et al (2011) First-in-human trial of a poly(ADP)-ribose polymerase (PARP) inhibitor MK-4827 in advanced cancer patients with antitumor activity in BRCA-deficient tumors and sporadic ovarian cancers (soc). J Clin Oncol 29 abstr 3102... 

FTIH trials are discussed in the Guideline on strategies to identify and mitigate risks for first-in human clinical trials with investigational medicinal products, EMEA/CHMP/SWP/28367/07issued by the European Medicines Agency (EMEA), in 2007. 

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. 

Figure 2.10. The microdosing strategy for candidate selection offers the greatest benefit when a stop-development decision is made. This is because the exploratory IND does not forego the submission of a traditional IND to continue testing in the clinic. (IND, Investigational new drug mths, months FIH, First-in-human clinical study Ph1, Phase 1 clinical studies Ph2, Phase 2 clinical studies.)...

Liu X, Huang Y Hanet C, et al. Study of antirestenosis with the BiodivYsio dexamethasone-eluting stent (STRIDE) a first-in-human multicenter pilot trial. Catheter Cardiovasc Interv 2003 60(2) 172-178. 

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

Beginning of Phase I clinical trials (first in humans). 

This discussion understandably cannot address whether the results of the preclinical studies that were conducted would support the proposed clinical trials (e.g., the proposed first-in-human dose). For that reason, or for other reasons, a development project team might choose to request a pre-IND meeting or an earlier meeting. 

TABLE 14.1 A first-in-human single-dose, dose-escalation study of biologic X, a putative TLR ligand and immune-response modifier in healthy volunteers... 

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 first in human trial (FIH) for cell-based therapies is in patients often with no available alternative therapies rather than in normal volunteers. These are also populations where clinical effects are less easy to manifest themselves and where adverse events may be difficult to distinguish from disease-associated events. The surgical procedures and use of immunosuppressants may also contribute to the adverse event profile. Therefore it is even more important to understand the nature and extent of the pathological process underlying the disease symptoms of the patients enrolled in the early clinical trials. 

Four-week toxicology studies in rodent and nonrodent The four-week studies are designed for subchronic exposure of rodents and nonrodents to the test article. These studies also look at reversibility of any toxicity observed. Many times these are the pivotal studies used to support the first in human dosing. Toxicokinetic assessments are generally included in repeat-dose toxicity studies. When testing biopharmaceuticals, studies also include assessment and characterization of immune response (immunogenicity). 

Science and Judgment in Establishing a Safe Starting Dose for First-in-Human Trials of Biopharmaceuticals... 

Examples of Estimations of First-in-Human Doses for Protein... 

Guideline on Strategies to Identify and Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products [5]... 

The lowest resulting HED was chosen (0.3 mg/kg) and a 10-fold margin was applied to estimate the first-in-human dose of 0.03 mg/kg. 

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