First in human trials

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... 

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. 

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

Calculation of the starting dose in first-in-human trials with biopharmaceuticals requires a good understanding of the science behind both the mechanism of action and the mechanism of toxicity of the test article. The FDA has provided an algorithm in its MRSD guidance to calculate a human equivalent... 

What starting dose should be used for the first-in-humans trial ... 

The prediction of human PK from precUnical in vitro and in vivo data remains an important goal in the drug discovery and development process to obtain an early estimate of efficacious human dose, dosing regimen, and safety window prior to first-in-human trials. From a clinical study perspective, under-prediction of human exposure would lead to safety concerns because actual exposures would be greater than expected, and inversely. The primary focus in the literature has been on the estimation of basic PK parameters such... 

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. 

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... 

The first clinical human trials using magnetic hyperthermia were reported by Liibbe, et al. [70, 129, 137, 190] who used 100-nm starch-coated iron-oxide particles bound with epirubicin for treatment of advanced solid cancers. Jordan recently reported positive results from ongoing trials of advanced cancer patients who received magnetic nanoparticle hyperthermia in conjunction with conformal external beam radiation therapy [191]. The therapy was well tolerated by the patients and significant increases in the length and quality of life were observed. 

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. 

Pharmacokinetic data were collected as well as pharmacodynamic measurements of platelet aggregation support (ristocetin cofactor activity) and cuticle wound blood flow. An important component of these studies was the suitability of the model. These models were chosen because of the biochemical deficiency of the particular factors and the parallel clinical syndromes. Such in vivo data can help in determining activity and dosing when such a product is first used in human trials. The Refacto molecule was also studied in rats and monkeys to determine its no observed adverse effect level, that was more than 10 times normal circulating levels. The major toxicity observed was the development of antibodies to the molecule that blocked activity and resulted in an acquired hemophilia syndrome. Similar findings were demonstrated when plasma-derived material was injected into monkeys [20]. 

One such delivery system known as PMED (particle-mediated epidermis delivery) was the first to show that DNA vaccines could produce a humoral response in human trials [44,45], Also this method was associated with an increased response in patients that had not responded to the HBV protein vaccine [20,45,46],... 

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

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