Proof-of-concept studies

Gu X, Simons KJ, Simons FER Administration by sublingual tablet feasible for the first aid treatment of anaphylaxis A proof-of-concept study. Diophar Drug Dispos 2002 23 213-216. 

Zarate, C. A., Payne, I. L., Singh, J. et al. Pramipexole for bipolar II depression a placebo-con trolled proof of concept study. Biol Psych. 56 54-60, 2004. 

Skyler JS, Cefalu WT, Kourides IA, Landschulz WH, Balagtas CC, Cheng S-L, Gelfand RA (2001) Efficacy of inhaled human insulin type a diabetes mellitus a randomized proof-of-concept study. Lancet 357 331-335. 

Phase I studies evaluate the pharmacokinetics and safety of the drug in a small number (tens) of healthy volunteers. Phase I studies are sometimes conducted in a small patient population (Proof of Concept studies) with a specific objective such as the validation of the relevance of preclinical models in man. The purpose of these studies may be the rapid elimination of potential failures from the pipeline, definition of biological markers for efficacy or toxicity, or demonstration of early evidence of efficacy. These studies have a potential go/no-go decision criteria such as safety, tolerability, bioavailability/PK, pharmacodynamics, and efficacy. Dosage forms used in Phase I or Proof of Concept studies must be developed with the objectives of the clinical study in mind. 

Measurements of the trCCR-rate have also been applied to small pep-tidic ligands. In a proof-of-concept study we have studied the STAT-6 bound conformation of an IL-4 receptor-derived peptide [9]. For this study a chemically synthesized N/ C-labelled tetrapeptide was used in conjunction with NHCH dipole-dipole CCR and /nhc dipole-CSA CCR experiments. 

Liu et al. [140] have also used this interface for an electrochemical immunosensor for small molecules (Figure 1.26). In this sensor, one end of the molecular wire is attached to ferrocene dimethylamine with a covalent link formed between one of the amine group son the ferrocene and the carboxyl group on the wire. To the other amine is attached the antibody-binding epitope for the antibody, in this proof-of-concept study the epitope is biotin. Electron transfer can be readily achieved to the ferrocene molecule but upon antibody binding to this interface, the electrochemical signal is dramatically reduced. 

Proof-of-concept studies in patients (Phase II) Preclinical support... 

At a slightly lower risk is to develop a compound for a condition where therapeutic agents have been identified and proof of concept-studies completed, which validate the approach. In such... 

The filing of a full IND, with a formal coordinated writeup of all the supporting data, while necessary 40 years ago, is now an unnecessary requirement in the early-stage clinical programs of most large pharmas and CROs that do this work today. It is a barrier to the easy access to human studies that is needed for proof-of-concept studies (Phases 1 and 2a). There has been very little trouble in the past 20 years with early INDs filed by responsible individuals, corporations and institutions. The system can now be safety adjusted to recognise this fact, by scaling back the IND requirements for responsible entities, based on what has been learned in the past 40 years. 

Horvath D. (2001b) ComPharm—Automated comparative analysis of phar-macophoric patterns and derived QSAR approaches, novel tools in high throughput drug discovery. A proof-of-concept study applied to farnesyl protein transferase inhibitor design. In M Diudea (ed), QSPR/QSAR Studies by Molecular Descriptors, pp. 395-439, Nova Science Publishers, New York, USA. 

A rat anti-mouse VEGFR2 (Flkl) monoclonal antibody (DClOl) was developed by ImClone Systems (New York, NY, www.imclone.com) using conventional hybridoma technique [194] to conduct proof-of-concept studies. 

In a proof-of-concept study in which Saito et al. [60] intravenously injected LacZ reporter gene-transfected MSCs into healthy rats, the MSCs preferentially engrafted in the bone marrow. When injected into rats subjected to repetitive periods of ischemia/reperfusion, however, the MSCs engrafted in the infarcted regions of the heart, where they participated in angiogenesis and expressed cardio-myocyte-specific proteins. When injected into rats 10 days after myocardial injury, MSCs preferentially homed to damaged myocardium. 

Treatment effects on surrogate endpoints therefore do not necessarily translate into treatment effects on clinical endpoints and the validity of the surrogate depends not only on the variable itself but also on the disease area and the mode of action of the treatment. Establishing new valid surrogates is very difficult. Fleming and DeMets conclude that surrogates are extremely valuable in phase II proof of concept studies but they question their general use in phase III confirmatory trials. 

Proof-of-concept studies, and pilot-scale and full-scale demonstrations, have been successfully completed for a variety of contaminants, and additional full-scale applications are planned. Berkeley Environmental Restoration Center is currently seeking commercial licensees for SEE. The technology is commercially available through SteamTech Environmental Services and Integrated Water Resources, Inc. 

This chapter illustrated the broad spectrum of uses for plant-derived vaccines and therapeutic proteins. Many of the biopharmaceuticals listed in this chapter were developed in transgenic tobacco or potato plants. While tobacco is not ideal for the expression of vaccine proteins nor is raw potato ideal for oral consumption, they are both relatively easy to work with and have been well characterized, making them useful for proof-of-concept studies. The use of plants for production systems and delivery vehicles holds great promise for future biopharmaceutical development. Proteins can be produced in plants while remaining biologically functional they can be scaled up for large production and purified inexpensively and with relative ease. The following chapters describe the many attributes of plant-made biopharmaceuticals in more detail. 

Kohl, T., Hitzeroth, 1.1., Stewart, D., Varsani, A., Govan, V.A., Christensen, N.D., Williamson, A.-L., and Rybicki, E.R (2006). Plant-produced cottontail rabbit papillomavirus LI protein protects against tumor challenge a proof-of-concept study. Clin. Vaccine Immunol. 13(8) 845-853. 

Proof-of-concept studies with a new compound are recommended provided... 

Skyler, IS., W.T. Cefalu, I.A. Kourides, W.H. Landschulz, C.C. Balagtas, S.L. Cheng, and R.A. Gelfand, Efficacy of inhaled human insulin in type I diabetes mellitus a randomised proof-of-concept study. Lancet, 2001.357(9253) 331-5. 

Steiner, S., Pfutzner, A., Wilson, B.R., Harzer, O., Heinemann, L., and Rave, K. (2002). Technosphere (TM)/Insulin - proof of concept study with a new insulin formulation for pulmonary delivery. Exp. Clin. Endocrinol. Diabetes, 110, 17-21. 

The overall process, illustrated in Scheme 10.4, intercepts the racemate (2) by crystallization from heptane. After separation of the enantiomers using the MCC process, the radafaxine free base is converted to the desired salt directly on treatment with anhydrous HCl. Any mixed fractions from the MCC separation are combined with the epimerized R,R)-enantiomer and fresh racemate for processing, hence generating further radafaxine free base for conversion to the hydrochloride salt. These results were subsequently confirmed in a Proof of Concept study performed on the medium- to large-scale in-house MCC equipment prior to scale-up. 

Data from the evaluation and Proof of Concept studies indicated that the anticipated process benefits could be realized, and, with the inclusion of the racemization process, the expected environmental benefits could also be achieved. For example, this procedure avoided the use and recovery of DTTA, the desired (S,S)-enantiomer could be isolated in >90% yield, and a productivity of 5 kg of racemate per kg of CSP per day could be achieved (an above-average value for MCC). Solvent recovery and re-use for the MCC was predicted to be >99.5%, and the only solid waste would be the spent/exhausted CSP. 

Kidron M, Dinh S, Menachem Y, Abbas R, Variano B, Goldberg M, Arbit E, Bar-On H. A novel per-oral insulin formulation proof of concept study in non-diabetic subjects. Diabetic Med 2004 21 354-7. 

Guevara-Aguirre, J., et al. 2004. Oral spray insulin in treatment of type 2 diabetes A comparison of efficacy of the oral spray insulin (Oralin) with subcutaneous (SC) insulin injection, a proof of concept study. Diabetes Metab Res Rev 20 472. 

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