ABSTRACT
Food products in the United States (U.S.), including dietary supplements, may contain live microorganisms and can be promoted for general health, nutritional, or structure/function claims. In contrast, such preparations used with the intention of having a preventive or therapeutic effect in humans are regulated by the Food and Drug Administration (FDA) in the U.S. as biological products, specifically as live biotherapeutic products (LBPs). Discussion of considerations in the early development of LBPs may aid in preparation of an Investigational New Drug Application (IND) that is designed to collect clinical data to support marketing approval of a LBP in the U.S. for a specific clinical use. Product information is an important component of an IND to support a proposed clinical study.
Subject(s)
Biological Products/biosynthesis , Biological Products/therapeutic use , Drug Approval , Probiotics/standards , Biological Products/chemistry , Drug Approval/legislation & jurisprudence , Drug Design , Humans , United States , United States Food and Drug Administration/legislation & jurisprudenceABSTRACT
A sponsor developing a vaccine or related product for clinical study in the U.S. must submit an Investigational New Drug Application (IND) to the Food and Drug Administration (FDA). Evaluation of information submitted to the IND may prompt a clinical hold, for reasons described in 21 CFR 312.42. Our review of clinical hold letters issued to sponsors during a 2-year period identified the most often cited reason for a clinical hold, insufficient information (21 CFR 312.42 (b) (1) (iv)), and indicated that the majority of INDs were specifically deficient in clinical information. In addition, sponsors who sought formal pre-IND advice decreased the likelihood of their resulting IND being placed on clinical hold.
Subject(s)
Clinical Trials as Topic/legislation & jurisprudence , Investigational New Drug Application/legislation & jurisprudence , United States Food and Drug Administration/legislation & jurisprudence , Vaccines/adverse effects , Clinical Trials as Topic/methods , Humans , Investigational New Drug Application/methods , United States , Vaccines/therapeutic useABSTRACT
The previously isolated hemiplegic, induction-negative, repression-positive mutants, H80R and Y82C, were found to be defective in the binding of arabinose. Randomization of other residues close to arabinose in the three-dimensional structure of AraC or that make strong interactions with arabinose yielded induction-negative, repression-positive mutants. The induction and repression properties of mutants obtained by randomizing individual residues of the N-terminal arm of AraC allowed identification of the domain with which that residue very likely makes its predominant interactions. Residues 8-14 of the arm appear to make their predominant interaction with the DNA-binding domain. Although the side-chain of residue 15 interacts directly with arabinose bound to the N-terminal dimerization domain, the properties of mutant F15L indicate that this mutation increases the affinity of the arm for the DNA-binding domain.
