Pharmacological and Toxicological Data

The licensee of our SOAz patent namely Otsuka Chemical Co., was in charge of filling the pharmacological and toxicological file necessary for future marketing of a new anticancer drug. 

Such an impressive check-list is given here with the aim of showing the long 

Although we are obliged not to disclose too much about the data already obtained by Otsuka, owing to the secrecy requested by the patent agreement, we may claim that SOAz does not induce any nephrotoxicity or hepatotoxicity or cardiotoxicity. 

Moreover, phase 1 clinical trials started on May 21, 1981 at the Institut Jean-Godinot in Reims, France, with Dr. P. Coninx as supervisor. These trials will allow us to make a more precise determination of the LD value for humans, i.e., the highest non-lethal dose which can be inoculated within mono and polyinjections protocols or schedules without any redhibitory side-effects for the patients. 

Meanwhile, some phase 2 trials have already been performed on some naturally cancerous dogs, bearing tumors which are histologically close to the corresponding human ones, namely, osteolytic osteosarcomas and fibrosarcomas (bone cancers). Let us give some details about the protocol of treatment we used in the case of a dog weighing 70 kg and suffering from an acute osteolytic osteosarcoma (expected survival time less than 2 weeks on March 26, 1981). 

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Chemistry (or biology, as appropriate) manufacturing, and control detail Pharmacology and toxicology data... 

A Sponsor submits a clinical trial application to the Competent Authority in each member state where the trials are to be conducted. The Competent Authority has 60 days to review and approve or reject the application. Application is in prescribed forms and covers the proposed clinical trial protocol, manufacturing, and quality controls on the drug, and supporting data, such as (1) chemical, pharmaceutical, and biological data, (2) nonclinical pharmacological and toxicological data, and (3) clinical data and previous human experience. The supporting data are submitted in the Common Technical Document (CTD) format (see Section 7.11). 

Guideline Section 2 specifies that only mammalian species are to be used in the studies to be described. The rat is noted as being generally the most practical choice. A second species is traditionally required, and the rabbit is the preferred choice. Other species or a second rodent species may be used on a case-by-case basis. Note 5 associated with Section 2 points out that a single species can be sufficient if kinetic, pharmacological, and toxicological data show it to be a relevant model for the human. However such a complete set of data are very rarely available prior to the time such studies are needed. 

Investigational New Drug (IND) application. The IND petition requires full disclosure of where and how the NME is manufactured and controlled for quality and stability. It also contains proposed analytical methods, pharmacology and toxicology data, and evidence of desired effects in disease models. The application lists proposed chnical investigators and contains complete human subject protocols. Under current regulations the FDA must provide a written response to the sponsor within 30 days after submission. The lack of a timely response is tacit approval for the sponsor to proceed to the clinic. 

PrecUnical data are compiled in the Investigational New Drug (IND) application—a request for permission to initiate human studies—and submitted to the FDA for approval. The IND application requires full disclosure of all the precUnical study results as well as where and how the drug itself is manufactured and formulated to ensure quality and stability. The IND also contains pharmacology and toxicology data, evidence of desired and unwanted... 

Starting with this hypothetical structure-activity relationship, the syntheses and biological investigations of 210-215 and decamethonium iodide were carried out130,13 U As an example, the synthesis of 212 is described in Scheme 26. The pharmacological and toxicological data are given in Table 20 and Table 21, respectively. 

A more effective interpretation of pharmacological and toxicological data may usually be made if the ADMEs of the drug and its metabolites are well defined (see section 8.4). Tissue distribution data is usually obtained using single dose studies but repeated dose studies should be undertaken when ... 

The ICH reproductive toxicology guidance considers the acceptability of a single species if it can be shown by means of pharmacological and toxicological data that the species selected is a relevant model for humans. ICH further states that there is little value in using a second species if it does not show the same similarities [31]. 

Generation of metabolic profiles especially by use of radiolabeled test compounds in preclinical development makes sure that the animal model allows a qualitative and/or quantitative prediction to human. This is crucial for proof of validity of pharmacological and toxicological data obtained in animal models for humans. 

A description and analysis of each clinical pharmacology study of the biologic, including a brief comparison of the results of the human studies with the animal pharmacology and toxicology data. 

It is necessary to submit proof or publications, if the plant sources concerned have no pharmacological and toxicological data this is specially important in cases, when specific indications are claimed. 

The regulatory procedure involved is a so-called Clinical Trial Authorization appH-cation (CTA) and consists, in addition to a Clinical Trial Protocol (CTP) and Investigator s Brochure (IB), of an Investigational Medicinal Product Dossier (IMPD) in CTD format. The IMPD consists of quality data, nonclinical pharmacology and toxicology data, clinical trial and previous human experience data, and an overall risk-benefit assessment. A copy of the CTA is sent to each EU Member State where the study is conducted, as well as to the Ethics Committees for approval. These also have to be notified in case of any amendments, study termination and adverse reactions. The contents of the IMPD are case specific and may be simplified or even replaced by the... 

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