Non-Clinical Studies

The majority of non-clinical studies are undertaken in the pre-clinical phase of drug development. These studies serve both to guide the developer and satisfy the regulatory authorities. The objectives of this phase can be summarised as follows ... 

Physical, Chemical, and Pharmaceutical Properties and Formulation Non-clinical Studies Non-clinical Pharmacology... 

Non-Clinical Study Reports Toxicological and Pharmacological Tests 111... 

CFR 601.28 Distribution data Current labelling CMC new information New non-clinical studies New clinical data Status report on post-approval study commitments, e.g. paediatric studies Minor supplementary changes... 

During product development, many of the initial non-clinical studies were undertaken in GAA knockout mice (i.e. mice devoid of a functional GAA gene), which serves as an animal model for Pompe s disease. The mice proved useful in assessing the pharmacodynamic effect of Myozyme on glycogen depletion and helped establish appropriate dosage regimens. The mice were also used to evaluate pharmacokinetics and biodistribution of GAA following its administration at clinically relevant doses. 

Guidelines for General Pharmacology Studies — Japanese Guidelines for Non-clinical Studies of Drugs manual 1995... 

Doses selected for safety pharmacology studies are typically based on the criteria established in the ICH S7A guidance.25 Doses should exceed those projected for clinical efficacy and at the upper limit be bound by (1) adverse pharmacodynamic effects in the safety pharmacology study (2) moderately adverse effects in other non-clinical studies that follow a similar route and duration of dosing or (3) limit of solubility/toxicity. In the absence of adverse effects, the maximum administrable dose can be used. If nonreusable animals enter the study, then the maximum tolerated dose may be appropriate. Most importantly, the doses/concentrations should establish the dose/concentration-response relationship of the adverse effect. 

The integrated risk assessment is the stepwise and holistic evaluation of non-clinical study results in conjunction with any other relevant information and should be scientifically based and individualized for an NCE. Such an assessment can contribute to the design of clinical investigations and the interpretation of their findings. 

Anon., Guidelines for general pharmacology studies-Japanese guidelines for non-clinical studies of drugs manual 1995 (pp. 71-80), Eds., Nippo Yakuji, Ltd. 

CTD consists of four modules, preceded by a Module 1 that is region-specific and includes administrative and prescribing information. Module 2 comprises of CTD summaries and overviews of the quality, non-clinical and clinical data. Module 3 contains data on quality. Module 4 consists of the non-clinical study reports and Module 5 comprises the clinical study reports. There are guidelines on the details to be included in each module and these are summarised in Box 17.2. The non-clinical and clinical overviews and summaries are equivalent to the previous Expert Reports submitted under sections IC2 and IC3 respectively of part I, data. 

Module 4 Non-clinical study reports Table of contents Study reports Literature references... 

Requires FDA to issue guidance describing when abbreviated reports may be submitted in lieu of full reports for clinical and non-clinical studies required to be included in an NDA. 

An outline of the data from non-clinical studies must be submitted to the PMDA with the protocol for the proposed clinical study before commencing the clinical trial. A notification is required for each protocol. The list of items required for Clinical Trial Plan Notification is shown in Table 23.4. Furthermore, supplementary data must be added on entry to subsequent clinical phases, that is, general clinical trials and comparative trials. Such data are reviewed by the PMDA, and for this purpose the sponsor must wait for 30 days after submitting the initial notification before executing a contract with the medical institute. For a subsequent notification, the review period is reduced to 14 days. The notification also... 

If not, which species has (or have) been chosen for non-clinical studies and why... 

Scull, J. R. Outsourcing analytical testing for non-clinical studies. Contr Pharm Jan JFeb. 20-24 (2000). 

Nakazawa T, Kai S, Kawai M, Maki E, Sagami F, Onodera H, Kitajima S, Inoue T. Points to Consider regarding safety assessment of biotechnology-derived pharmaceuticals in non-clinical studies (English Translation). J Toxicol Sci 2004 29 497-504. 

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