3 In the Drugs and Cosmetics Rules, 1945 - amam-ayurveda.org

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24Appendix IIIANIMAL TOXICOLOGY (NON-CLINICAL TOXICITY STUDIES)1. General PrinciplesToxicity studies should comply with the norms of Good Laboratory Practice (GLP). Briefly,these studies should be performed by suitably trained and qualified staff employing properlycalibrated and standardized equipment of adequate size and capacity. Studies should be doneas per written protocols with modifications (if any) verifiable retrospectively. Standardoperating procedures (SOPs) should be followed for all managerial and laboratory tasksrelated to these studies. Test substances and test systems (in-vitro or in-vivo) should beproperly characterized and standardized. All documents belonging to each study, including itsapproved protocol, raw data, draft report, final report, and histology slides and paraffin tissueblocks should be preserved for a minimum of 5 years after marketing of the drug.Toxicokinetic studies (generation of pharmacokinetic data either as an integral component ofthe conduct of non-clinical toxicity studies or in specially designed studies) should beconducted to assess the systemic exposure achieved in animals and its relationship to doselevel and the time course of the toxicity study. Other objectives of toxicokinetic studiesinclude obtaining data to relate the exposure achieved in toxicity studies to toxicologicalfindings and contribute to the assessment of the relevance of these findings to clinical safety,to support the choice of species and treatment regimen in nonclinical toxicity studies and toprovide information which, in conjunction with the toxicity findings, contributes to the designof subsequent non-clinical toxicity studies.1.1 Systemic Toxicity Studies1.1.1 Single-dose Toxicity Studies: These studies (see Appendix I item 4.2) should becarried out in 2 rodent species (mice and rats) using the same route as intended forhumans. In addition, unless the intended route of administration in humans is onlyintravenous, at least one more route should be used in one of the species to ensuresystemic absorption of the drug. This route should depend on the nature of thedrug. A limit of 2g/kg (or 10 times the normal dose that is intended in humans,
25whichever is higher) is recommended for oral dosing. Animals should beobserved for 14 days after the drug administration, and minimum lethal dose(MLD) and maximum tolerated dose (MTD) should be established. If possible,the target organ of toxicity should also be determined. Mortality should beobserved for up to 7 days after parenteral administration and up to 14 days afteroral administration. Symptoms, signs and mode of death should be reported, withappropriate macroscopic and microscopic findings where necessary. LD 10 andLD 50 should be reported preferably with 95 percent confidence limits. If LD 50 scannot be determined, reasons for the same should be stated.The dose causing severe toxic manifestations or death should be defined in the case ofcytotoxic anticancer agents, and the post-dosing observation period should be to 14days. Mice should first be used for determination of MTD. Findings should then beconfirmed in rat for establishing linear relationship between toxicity and body surfacearea. In case of nonlinearity, data of the more sensitive species should be used todetermine the Phase I starting dose. Where rodents are known to be poor predictors ofhuman toxicity (e.g., antifolates), or where the cytotoxic drug acts by a novelmechanism of action, MTD should be established in non-rodent species.1.1.2 1.1.2 Repeated-dose Systemic Toxicity Studies: These studies (see Appendix I,item 4.2) should be carried out in at least two mammalian species, of which oneshould be a non-rodent. Dose ranging studies should precede the 14-, 28-, 90- or180- day toxicity studies. Duration of the final systemic toxicity study will depend onthe duration, therapeutic indication and scale of the proposed clinical trial. (see Item1.8). If a species is known to metabolize the drug in the same way as humans, itshould be preferred for toxicity studies.In repeated-dose toxicity studies the drug should be administered 7 days a week by theroute intended for clinical use. The number of animals required for these studies, i.e.the minimum number of animals on which data should be available, is shown in Item1.9.Wherever applicable, a control group of animals given the vehicle alone should beincluded, and three other groups should be given graded doses of the drug. The
Page 4 and 5: 42. CLINICAL TRIAL(1) Approval for
Page 7 and 8: 7(5) Responsibilities of the Ethics
Page 9 and 10: 9study and to determine the common
Page 11 and 12: 11(1) Geriatrics.-Geriatric patient
Page 13 and 14: 13(viii)For clinical trials conduct
Page 15 and 16: 15(ii) Evaluation of the effect of
Page 17 and 18: 172.6. 2.6. Stability Studies (for
Page 19 and 20: 198.2. 8.2. Bio-availability / Bio-
Page 21 and 22: 21brief description of the trial de
Page 23: 2315. List of References16. Appendi
Page 27 and 28: 27hours. Animals should be observed
Page 29 and 30: 29showing minimal toxicity in syste
Page 31 and 32: 31One male and one female from each
Page 33 and 34: 33taken. Formulation in volume comp
Page 35 and 36: 35the same route in a batch of 4 ma
Page 37 and 38: 37(i) (i) In-vitro exposure (with a
Page 39 and 40: 39At least three dose levels should
Page 41 and 42: 41Female Reproduction and Developme
Page 43 and 44: 43Reaction(pH)• • Bilepigments
Page 45 and 46: 45Allergenicity/Hypersensitivity te
Page 47 and 48: 47Specific and general pharmacologi
Page 49 and 50: 49These include ventricular contrac
Page 51 and 52: 511.6 Application Of Good Laborator
Page 53 and 54: 5313. Statement that participation
Page 55 and 56: 55Signatory’s Name: _____________
Page 57 and 58: 57Appendix VIIUNDERTAKING BY THE IN
Page 59 and 60: 59(ix) I agree to promptly report t
Page 61 and 62: 612. Format for Approval of Ethics
Page 63 and 64: 63Appendix IXSTABILITY TESTING OF N
Page 65 and 66: 65(i) Study conditions for drug sub
Page 67 and 68: 67Previous clinical work with the n
Page 69 and 70: 69d. Possible drug interactionse. C
Page 71 and 72: 71Appendix XIData Elements for repo
Page 73: 73(F.No. X-11014/1/2003-DMS & PFA)(

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