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

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28clinical route at three dose levels should be done with highest dose havingobservable toxicity, mid-dose between high and low dose, and low dose. Thedoses should preferably be multiples of the effective dose and free fromtoxicity. Observation parameters should include cage-side observations, bodyweight changes, food/water intake, blood biochemistry, haematology, and grossand microscopic studies of all viscera and tissues.(iv) 90-Day repeated-dose toxicity studies: One rodent (15-30/sex/group) and onenon-rodent (4-6/sex/group) species are needed. Daily dosing by proposedclinical route at three graded dose levels should be done. In addition to thecontrol a “high-dose-reversal” group and its control group should be alsoincluded. Parameters should include signs of intoxication (general appearance,activity and behaviour etc), body weight, food intake, blood biochemicalparameters, hematological values, urine analysis, organ weights, gross andmicroscopic study of viscera and tissues. Half the animals in “reversal” groups(treated and control) should be sacrificed after 14 days of stopping thetreatment. The remaining animals should be sacrificed after 28 days of stoppingthe treatment or after the recovery of signs and/or clinical pathological changes– whichever comes later, and evaluated for the parameters used for the mainstudy.(v) (v) 180-Day repeated-dose toxicity studies: One rodent (15-30/sex/group) and one non-rodent (4-6/sex/group) species are needed.At least 4 groups, including control, should be taken. Daily dosing byproposed clinical route at three graded dose levels should be done.Parameters should include signs of intoxication, body weight, food intake,blood biochemistry, hematology, urine analysis, organ weights, gross andmicroscopic examination of organs and tissues.1.2 1.2 Male Fertility StudyOne rodent species (preferably rat) should be used. Dose selection should be done from theresults of the previous 14 or 28-day toxicity study in rat. Three dose groups, the highest one
29showing minimal toxicity in systemic studies, and a control group should be taken. Eachgroup should consist of 6 adult male animals. Animals should be treated with the testsubstance by the intended route of clinical use for minimum 28 days and maximum 70 daysbefore they are paired with female animals of proven fertility in a ratio of 1:2 for mating.Drug treatment of the male animals should continue during pairing. Pairing should becontinued till the detection of vaginal plug or 10 days, whichever is earlier. Females gettingthus pregnant should be examined for their fertility index after day 13 of gestation. All themale animals should be sacrificed at the end of the study. Weights of each testis andepididymis should be separately recorded. Sperms from one epididymis should be examinedfor their motility and morphology. The other epididymis and both testes should be examinedfor their histology.1.3 1.3 Female Reproduction and Developmental Toxicity StudiesThese studies (see Appendix I, item 4.4) need to be carried out for all drugs proposed to bestudied or used in women of child bearing age. Segment I, II and III studies (see below) are tobe performed in albino mice or rats, and segment II study should include albino rabbits also asa second test species.On the occasion, when the test article is not compatible with the rabbit (e.g. antibiotics whichare effective against gram positive, anaerobic organisms and protozoas) the Segment II data inthe mouse may be substituted.1.3.1 Female Fertility Study (Segment I): The study should be done in one rodent species (ratpreferred). The drug should be administered to both males and females, beginning asufficient number of days (28 days in males and 14 days in females) before mating.Drug treatment should continue during mating and, subsequently, during the gestationperiod. Three graded doses should be used, the highest dose (usually the MTD obtainedfrom previous systemic toxicity studies) should not affect general health of the parentanimals. At least 15 males and 15 females should be used per dose group. Control andthe treated groups should be of similar size. The route of administration should be thesame as intended for therapeutic use.
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 and 24: 2315. List of References16. Appendi
Page 25 and 26: 25whichever is higher) is recommend
Page 27: 27hours. Animals should be observed
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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