New active substance

The development of a single enantiomer as a new active substance should be described in the same manner as for any other new chemical entity. Studies should be carried out with the single enantiomer, but if development began with the race-mate then these studies may also be taken into account. Chiral conversion should be considered early on so that enantiospecific bioanalytical methods may be developed. These methods should be described in chemistry and pharmacy part of the dossier. If the opposite enantiomer is formed in vivo, then it should be evaluated in the same way as other metabolites. For endogenous human chiral compounds, enantiospecific analysis may not be necessary. The enantiomeric purity of the active ingredient used in preclinical and clinical studies should be stated. 

New active substances for treatment of AIDS, cancer, diabetes, neurodegenerative disorders, (and from 2008) autoimmune or other immunological disorders and viral diseases. 

Industry has to decide which of the existing active substances it will support and supply the necessary data to the competent authorities. Data must also be submitted on any new active substances (not on the market on 14 May 2000). 

Bachem produces biochemical and pharmaceutical compounds, and offers complementary services on a proprietary technology platform. Although, oriented to the Health Sector, it supports synthetic methods from customers for defined target structures up to the registration of new compounds. Consequently, R D activities are also a strong part of Bachem business that encourages collaborations with technology partners to produce new active substances. 

Medicinal products with a new active substance for treatment of ... 

The metabolism of taxol by Eucalyptus perriniana cell suspension cultures has been recently reported to induce hydrolyses of ester bonds at C-13, C-10 and C-2 [222]. At this moment only very few data have been published about the microbial metabolism of taxoid compounds only site specific hydrolyses of acyl side-chains at C-13 or C-10 by extracellular and intracellular esterases of Nocar-dioides albus SC13,911 and N. luteus SC13,912, respectively, have been reported [223]. On the other hand, Hu et al. [224-226] have recently described some fungal biotransformations of related natural taxane diterpenes extracted from Chinese yews or their cell cultures, in order to obtain new active substances or precursors for hemisynthesis. The taxadiene 145, a 14 -acetylated derivative... 

The Directive requires an authorization process for biocidal products containing active substances listed in positive lists (Annexes I, lA, and IB of the Directive 98/8/EC). In relation to biocides, existing active substances are substances, which have been on the EU Market for biocidal purposes before 14 May 2000. An active substance, which was not on the market before 14 May 2000 is regarded as a new active substance and has to be approved by the Member States before it will be entered on the positive hsts. 

The reader is referred to one of several texts giving detailed accounts of clinical pharmacokinetics. However, an understanding of the basic concepts is essential in order to appreciate how pharmacokinetic data can provide insight into the physiological processes, which determine the time course of a drug in the body, and implications this has for the toxicity and therapeutic efficacy of drugs, particularly the new active substances in development. 

It is reasonable that data should be required to demonstrate whether the response of patients to a new active substance is likely to change or be changed by concomitant medication. However, there is clearly a huge number of potential drug combinations, and some rational selection is required. To assist with the selection of drug combinations for which data are required, the following seven questions at least should be asked. 

In the development of most new active substances, it is required to investigate the disposition of the compound and its metabolite(s) and their rates and routes of elimination. This is generally carried out with radiolabelled compound, usually In the United Kingdom, approval of the Administration of Radioactive Substances Advisory Committee (ARSAC) is required for administration of radiolabelled compound to man. The purpose of the submission is to demonstrate that the dose of absorbed radiation is minimised by administration of the lowest dose that is consistent with meeting the objectives of the study. In general, the estimated absorbed radiation dose should be less than 500 xSv, but higher amoimts are permissible if they can be justified. The estimate is based on tissue distribution of radioactivity in animals and the pharmacokinetics in animals and man. 

There are three possible specific objectives for comparator trials to show superiority, equivalence or non-inferiority of the new active substance. Each is governed by statistical and regulatory guidelines. - 2... 

Table 15.5 Median numbers (range) of volunteers and patients exposed to new active substances during premarketmg studies ...

RawUns MD, Jefferys DB. Study of United Kingdom product licence apphcations containing new active substances. BMJ 1991 302 223-5. 

A typical dossier for a new active substance (NAS) included 4—6 volumes of administrative (previously known as Part 1), 6-10 volumes of pharmaceutical (Part 11), 20 0 volumes of phar-macotoxicological (Part 111), and 60-100 volumes of clinical (Part IV) data - each volume being approximately 400 pages. As stated above, it is now mandatory to submit the dossier in the CTD format. 

New active substance (this is also defined further)... 

Medicinal products intended for administration to human beings, containing a new active substance which, on the date of entry into force of the Regulation, was not authorised by any Member State for use in a medicinal product intended for human use... 

First, the Office of Conformity Audit will conduct a compliance review to ensure that the dossier meets the standards of GCP, GLP and reliability. The GCP compliance check is based on the inspection of both study sites and sponsor. For the submission of new active substance usually four study sites are inspected. If the pivotal studies are conducted overseas, the inspection may be conducted by MHLW instead of PMDA. 

For FTIH trials, all applications should include a summary of projected free plasma concentrations of the new active substance (NAS) in humans and a brief description of any pharmacokinetic modelling programs used to generate the estimates. A comparison with the concentrations obtained in the nonclinical toxicity studies and projected safety margins should be given. In the same section, an estimate of the extent of the intended pharmacological or pharmacodynamic response at the expected plasma concentrations should be included, with a list of the assumptions used in deriving that estimate. 

For most new active substances, a meeting will be held with the concerned regulatory agencies before submission of the dossier to allow the assessors to comment on the important points to cover in the dossier and to give advice on the presentation of the data. 

Rational drug design - use of high resolution molecular imaging techniques (NMR, x-ray crystallography) to identify the active site of the target molecule and construct an new active substance which binds to this active site. 

Krayenbuhl JC, Vozeh S, Kando-Ostreicher M, et al. Drug-drug interactions of new active substances mibefradil example. Eur J Clin Pharmacol 1999 55 559-565. 

Neuropeptide research will in all probability allow the development of new active substances that are more effective, more specific, and safer than the psychopharmaceuticals in current use. 

Taking all these costs together, it is clear that marketing a biocidal active substance or a product based on it, in the EU, is a major commitment and one that will not be undertaken lightly. This is certainly true for new active substances and we shall not be seeing many of these, if any, in future. However it is also true of the existing actives and products on the EU market. These are very much in the majority and this brings us to the transitional measures already mentioned several times. 

Q1B Photostability testing of New Active Substances and Medicinal Products CPMP/ICH/279/95 Step 5... 

---