Safety studies, nonclinical

Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals Notice Stability testing of new drug substances and products Stability testing Stability testing... 

Anon., Guideline on the evaluation of control samples in nonclinical safety studies checking for contamination with the test substance, CPMP/SWP/1094/04, London, 17 March 2005. 

The above table also reflects the marketing recommendations in all three ICH regions except that a chronic nonrodent study is recommended for clinical use > 1 month Source Taken from the ICH M3 guideline. Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals, November 1997 and updated November 2000, Available at http //www.fda.gov/cder/guidance. 

The Government of India has established the National GLP Compliance Monitoring Authority (India GLP), adopting the OECD quality system of the principles of GLP, for inspection, monitoring, and accreditation of test facilities in India for conducting nonclinical and environmental safety studies. Currently, India enjoys the full member status of OECD for GLP. India is a member of the OECD Test Guidelines program. 

Currently 23 Indian laboratories have been accredited by the Indian national GLP compliance monitoring authority as per the provisions of the OECD Principles of GLP to conduct nonclinical health and environmental safety studies. The Indian system of GLP inspection, accreditation, and monitoring of test facilities was started in 2004 (India GLP). 

ICH (2009) Harmonised Tripartite Guideline M3(R2). Guidance on nonclinical safety studies for the conduct of human cKnical trials and marketing authorization for pharmaceuticals... 

ICH (2009) Gmdance on nonclinical safety studies for the conduct of hmnan clinical trials and marketing authorization for pharmaceuticals ICH M3(R2). http //www.ich. org/fileadmin/Public Web Site/ICH Products / Giudehnes /Multidisciplinary/M 3 R2/Step4/M3 R2 Gmdeline.pdf. Accessed 29 Jan 2012... 

The animal species chosen for the later nonclinical safety studies should be responsive to the pharmacodynamic action(s). If the standard laboratory species are not responsive, the applicant should justify the choice of species selected or any supplementary tests if these are deemed appropriate. 

Table 3 indicates the preclinical safety studies for CAPTISOL (25) conducted as of 2005. The strategic safety plan for CAPTISOL was designed based on the guidelines discussed in the 1990s by the International Pharmaceutical Excipients Council which resulted in the May 2005 issuance of the FDA Guidance (26) Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients. These studies and others in the CAPTISOL Drug Master File have delineated the safety of CAPTISOL (SBE7-P-CD) for parenteral, ophthalmic, oral, nasal, and inhalation administration. 

Food and Drug Administration (FDA) (2000). Nonclinical safety studies for the conduct of human clinical trials for pharmaceuticals, Guideline, I. H. T. FDA, Washington, DC. 

M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals... 

In this context the term nonclinical is often used interchangeably with preclinical, particularly to define the preclinical studies performed after a product has advanced into the clinic (and thus is no longer in the preclinical development phase). Diverse studies are performed at different times to answer specific questions that only become relevant during particular phases of clinical development for example, carcinogenicity studies are done to answer questions that ultimately arise at the end of lifetime administration to patients. Based on the explicit objective of safety studies to reveal or exclude potential adverse effects before they occur in healthy subjects or patients, the term preclinical will be used throughout this book to highlight the importance of the data to be derived prior to the specific clinical phase they are designed to support. 

If a sponsor has conducted phase 1 trials outside of the United States and believes that there are adequate human safety studies already available, it may not be necessary to conduct any phase 1 trials in the United States. In such a case, the sponsor would prepare an IND and include in the initial IND submission a clinical protocol for phase 2 or 3. This IND, because it will involve exposure of more patients to the drug for the purposes of safety testing as well as efficacy evaluations, will require a greater level and depth of manufacturing and nonclinical data. The next section will describe the requirements for such an advanced-stage IND. 

A variety of items within an NDA serve as assurance that the information in the application is correct and reliable. Each nonclinical toxicology or safety study should have a QA statement indicating compliance with the GLP regulations. If a laboratory conducting one or more of the studies has not provided a QA statement in the report, the NDA should explain the omission. In current general practice by pharmaceutical firms and contract laboratories, GLP regulations are also applied to the analysis of the drug in plasma, serum, or urine samples from clinical studies. 

Provide quantitative compositions and lot numbers of each finished dosage form used in nonclinical safety studies, clinical studies, and stability during the investigational phases of development for the drug product. In addition, formulation differences should be explained, and each formulation should be cross-referenced to the study or studies in which it was used. 

The guidelines on repeated dose toxicity studies (Data d-2 in Table 1) were revised in April 1999 as follows based on the ICH M3/Nonclinical Safety Studies for the Conduct Clinical Trials and S4/Repeated dose Toxicity Studies in Nonrodents. The studies already started before the revised guidelines could be applied under the previous guidelines issued in 1993. 

The standardized guidelines have been compiled to cover test methods in animal studies and in vitro studies on absorption, distribution, metabolism cind excretion in the Notification No. 496 of the PAB in 1998. The guidelines can be applicable for the drugs to be submitted after October 1999. The following principles should be considered in order to select the most appropriate methods bcised on the characteristics of test substance. It is required that the exposure data related to toxicological studies be obtained before the first human study and other pharmacokinetic data before the completion of Phcise I study in principle in accordance with the guidelines on nonclinical safety studies for conducting clinical trials (Notification No. 1019 of the PAB, 1998). 

The design of a nonclinical safety study should use the most appropriate species and take into account the clinical route of administration, the dose, and the dosing schedule. In the clinic, the dosing schedule is usually episodic, either weeks or months apart. In the animal studies, this dosing period can be reduced to approximately 2 to 3 weekly intervals (see Sections 19.2.4 and 19.2.5). 

Toxicology studies conducted specifically to support juvenile or elderly populations are not evident in the published literature. The general practice is to support such populations with standard nonclinical safety studies (as discussed previously) and clinical data generated in adults. 

In 1981, the OECD Principles of GLP were finalized and led to the OECD Council Decision on the Mutual Acceptance of Data (MAD) which states that Data generated in the testing of chemicals in an OECD member country in accordance with OECD Test Guidelines and OECD principles of Good Laboratory Practice shall be accepted in other member countries for purposes of assessment and other uses relating to the protection of man and the environment . The OECD recommended in 1983 that implementation of GLP compliance should be verified by laboratory inspections and study audits. The EC later ratified the OECD principles and a number of Directives (e.g., 2004/9/EC, 2004/10/EC) indicates that tests must be carried out in compliance with the principles of GLP and that also that EU Member States must incorporate into their laws the requirement for all nonclinical safety studies to be conducted in compliance with GLP, and that premises conducting such studies must be inspected by a national authority. 

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