This action might not be possible to undo. Are you sure you want to continue?
2 [SCHEDULE Y REQUIREMENT AND GUIDELINES ON C LINICAL TRIALS FOR IMPORT MANUFACTURE OF NEW AND DRUG. 1. Clinical Trials. 1.1. Nature of . - The clinical trials required to be car ried out in the countr y b trials efore a new d rug is approved for marketing depend on the status of the drug in other countries. If drug the is already approved/marketed, Phase III trials as required under Item 7 of Appendix 1 usually are required. If the drug is not approved/marketed trials are generally allowed to be initiated at one phase earlier to the phase of trials in other countries. For new drug substances discovered in other countries phase I trials are not usually allowed be initiated in India unless Phase I data as required under Item 5 of the said Appendix from to other countries are available. However, such trials may be permitted even in the absence of Phase I data other countries if the drug is of special relevance to the health problem of from India. For new dru g substances discovered in India, clinical trials are required to be carried out India right from phase I as required under Item 5 of the said Appendix though Phase III in as required und er Item 7 of the said Appendix, permission to carry out these trials is generally given in stages, considering the data emerging from earlier phase. 1.2. Permission for trials. Permission to initiate clinical trials with a new drug may obtained -by applying in Form 12 be a test licence (TL) to import or manufactur e the drug for under the Rules. Data appropriate for the various phases of clinical trials to be carried out should accompany the application as per format given in Appendix I (items 1-4). In addition, the protocol for proposed trials, case report forms to be used, and the names of investigators and institutions be submitted for approval. The investigators selected should possess should also qualifications appropriate and ex perience and should have such investigations facilities as are germane to the proposed trials protocol. Permission to carry out clinical trials with a new drug is issued along with a test licence Form in __________________________________________________________________ 11. 1 Omitted as per G.O.I. Notification No. GSR 673(E) dt __ 188.8.131.523. Ins. by G.O.I. Notification No. GSR 944(E) dt It 21.9.1998. is desirable that protocols for clinical trials be reviewed and approved by the institution’s ethical committee. Since such committees at present do not exist in all institutions, the granted approvalto a protocol by the ethical committee of one institution will be applicable to use of that protocol in other institutions which do not have an ethical committee. In case none of the trial centers/institutions has an ethical committee, the acceptance of the protocol by the investigator and its approval by the Drugs Controller (India) or any officer as authorized by him to do so will be adequate to initiate the trials.
1. Most of the data under the heading (See Appendix I. reasons for this should be 50s stated. 3. LD 50s should be reported preferably with 95 per cent confidence limited. item 2) ar e required with the application for marketing permission. If a species is known to and the drug in the same way as humans. Acute toxicity studies (See Appendix I item 4. the minimum number on which data should be available. of which one should be a non rodent. In addition. Mortality should be looked for up to 72 hours after p arenteral administration and up to 7 days after oral administration. Responsibilities of Sponsors are required to submit to Sponsor/Investigator. at least one more route should be used to ensure systemic absorption of drug. information item 2. 2.e. if LD cannot be determined. 3.2 Long term toxicity: Long term toxicity see appendix 1. However. permission for clinical trials in the paediatric age group is normally given after phase III trials as required under item 7 of the Appendix in adults are completed. Animal Toxicology. it should be ( metabolize preferred. Chemical and pharmaceutical information. if the drug is of value primarily in a disease said of children. completed. unexpected or serious adverse drug reaction (ADR) detected during a trial should be promptly communicated by the sponsor to the licensing authority under Rule 21 and the other investigators . When the application is for clinical trials only. signsmode of death should be reported. written consent required to be obtained from each volunteer/patient in the prescribed Forms (See Appendix V) which must be signed by the patient/volunteer and the chief investigator. The number of animals required for these studies. or terminated. Acute Toxicology.2) should be carried out in at least two species usually mice and rats using the same route as intended for humans. Any unusu al. the licensing authority as given under Rule 21 an annual status report on each clinical trial. ongoing. reason for this should be stated. 1. with appropriate macroscopic and microscopic and findings where necessary. the this route may dep end on the nature of the drug. item 1. is shown in Appendix IV. early trials in the paediatric age group may be allowed. .550 For new drugs having potential for use in children.3) should ( be carried out in at least tow mammalian species. In case a trial is terminated.3 of Appendix I will usually covered in suffice. 3. The duration will depend on whether the application is for marketing permission or for clinical of study trial.1 to 2. on the phase of trials see Appendix III).in the latter case. In all trials an informal. In long-term toxicity studies the drug should be administered 7 days a week by the route intended for clinical use in humans. i. namely. Symptoms.3.
The highest dose used should not affect general treated health or growth of the animals. if any. the intermediate dose should cause some symptoms. c. b. if any.The drug should be administered throughout the last studies. Reproduction studies see Appendix I. weights and malformations. physiological. one of them being a non-rodent if possible. Fertility Studies.3. species should generally be used. but should be comparable to the intended therapeutic dose in humans of a multiple of it. the groups. Observations should include the number of implantation sites. The route of administration should be the same as human therapeutic use. the highest dose should produce toxicity. The control and the treated group should consist for of least 20 pregnant females in case of non-rodents. the observable lowest dose should not cause observable toxicity. The dru g should be administered throughout the p . resorptions any. biochemical. Teratogenicity studies. using three dose levels. if and the number of foetuses with their sexes. Animals foetal should be sacrificed and observations should include macroscopic autopsy and where necessary. and microscopic observations.g. The control of each third of pregn group treatedshould have at least 12 pregnant females and the dose which causes low loss should be continued throughout lactation weaning. 3. a. The variables to be monitored and recorded in long-term toxicity studies should include behavioral.551 A control group of animals given the vehicle alo ng should always b e included and thr ee other groups should be given graded dose of th e drug.5 to make allowance for the sensitivity of the species. histopathology.4) n eed to ( be carried out only if the new drug is proposed to be studied or used in women or childbearing Two age. ancy and then through lactation of weaning. beginning a sufficient number of days before mating. Perinatal . and may be placed logarithmically between the other two doses. 2.organogenesis. e. but not gross tox icity or death. The control and the treated group should be similar large enou gh to give at least 20 pregnant animals in the control size and group of rodents and at least 8 pregnant animals in the control group of nonObservations should include total examination of the litters from both rodents. Reproduction studies. including spontaneous abortions. item 4. In females the medication continued after mating and the pregnant one should be should be throughout pregnancy. . The drug should be administered to both males and females. The route of administration should be the same as for therapeutic use in humans. on each dose at used. One of the doses should eriod of minimum maternal toxicity and one should be proposed dose for clinical use cause in humans or a multiple of it.
5 Mutagenicity and Carcinogenicity.5 X. the lowest dose should be comparable to the intended human therapeutic dose or a multiple of it. Wherever possible. item 4. These studies are carried out in healthy adult males. At least three dose level should be used. 2. at least two species should be used. Special studies elucidate mode of action may also be to described. These species should not have a For high incidence of spontaneou s tumors and should preferably be known to metabolize the drug in the manner as humans. General pharmacological action ( see Appendix I.5) are required to be carried out if the drug or its metabolite is related to a known carcinogen or when the nature and action of the drug is such as to suggest a carcinogenic/mutagenic potential. least At 2 subjects should be used on each dose.4. These may be car riedat one or two centers. The objective of phase I of trials ( see Appendix I.2) are those with ( for humans. pharmacodynamic effects.3) are effects on other organs and systems. Local toxicity. out . respiratory and central nervous systems. to make intermediate dose to be logarithmically between the other two doses. 4. 5 Human/Clinical Pharmacology (Phase I). The drug should be applied to an appropriate site to determine local effects in a suitable species such as guinea pigs or rabbits. These studies ( see Appendix 1. if an y.552 3. the highest dose should same be sublethal out cause observable toxicity. item 4. and pharmacokinetic behaviour of the drug as far as possible. with their nature and intensity. 3. e. Observations should macroscopic changes observed at autopsy and detailed include histopathology. using clinical. These studies ( see Appendix I. A control group should always be included. specially cardiovascular. carcinogenicity studies. Pharmacokinetic data help relate drug effect to plasma concentration and should be given the to extent available. item 3. The placed drug be administered 7 days a week or a fraction of the life span comparable to the fraction should of human life span ov er which the drug is likely to be used therapeutically. Animal pharmacology. item 3.5) are required when the new drug is proposed to be used topically in humans. if the drug absorbed from the site of applications. appropriate systemic toxicity studies will be is required. physiological and biochemical observations. Specific pharmacological actions seeAppendix I. These should be described according to the animal models and species therapeuticpotential used. item 5) is to determine the maximum tolerated dose in humans.g. Phase I trials are usually carried out by investigators trained in clinical pharmacology and having the necessary f acilities to closely observe and monitor the subjects. adverse reactions. dose-response relationships and ED 50s should be given.
e.2 and 8. having facilities appropriate to the protocol. use in patientselderly or patients with renal failure. interactions. items 8.553 6. Normally 10-12 patients should be studied at each dose level. These are required to be submitted on the formulations manufactured in the country. item 7) is to obtain sufficient evidence about the efficacy and safety of the drug in a larger number of patients. such data may be collected through clinicians who give consent written to use the drug as recommended and to provide a report on its efficacy and adverse during in the treated p atients. The purpose of these trials ( see Appendix I. These include studies on solid oral dosage form.3).g. In addition. In phase II trial ( see appendix I. Explanatory trials (Phase II). The reports of completed clinical trials shall be submitted by the applicant duly signed by the investigator with a stipulated period of time. If the drug is already approved/marketed in other countries. B. Submission of Reports (Appendix II). If the drug is a new drug substance discovered in India and not marketed in any other country. A. etc. effective dose range and further evaluation of safety and pharmacokinetics. The applicant should do so even if he is no longer interested to market the drug in the countr y unless there are sufficient reasons for not doing so. These include studies to explore additional aspects of the drug. generally in comparison with s atandard drug and/or a placebo as appropriate.3). ( see Appendix I. 3. Th ese trials may be carried out by clinicians in the concerned therapeutic areas. These studies are usually limited to 3-4 centres and carried out by clinicians specialized in the concerned therapeutichaving adequate facilities to perform the necessary investigations for efficacy and areas and safety. item 6) a limited number of patients are studies carefully to determine possible therapeutic use. Special Studies. in Indian patients when used as recommend ed in the product monograph for the claims made. 2. 1. phase III data should gen erally obtained on at least 100 patients distributed over 3-4 centres primarily to confirm the efficacy and safety of the drug. phase III data should be obtained at least 500 patients distributed over 10-15 centres. . The selection of clinicians for such monitoring and supply of reactions drug to them will need approval of the licensing authority under Rule 21. data on adverse drug reactions observed durin g clinical use of the drug should be collected in 1000-2000 patients. secondary or ancillar y effects. bio-availability and dissolution studies. such as. See ( Appendix 8.2 and 8. Confirmatory trials (Phase III).
etc. warnings and adverse reactions. if any.I. e.O. INTRODUCTION . Likewise. exclusion of certain age groups.2).] period *[12 _______________________________________________________________________ ___Ins. dosage precaution. Notification No. It is important to state if any restrictions have been placed on the use of the drug in other countr y.g. by G. drug interactions. 900(E) dt * 12. item 9. On approval of a new drug. warnings about adverse any drug reaction. ( See Appendix I.12. The drafts of label and carton texts should comply with provisions of Rules 96 and 97 of said rules. item 9. APPENDIX I Data required to be submitted with application for permission to market a New Drug 1. It should include description. a indications. the Post-marketing surveillance study. India ( See appendix I. 5. dosage limited. the importer or the manufactu rer shall conduct post-marketin g surveillance study of that new drug after getting the protocols and the names of the approved by investigators the Licensing Authority as defined under clause (b) of Rule 21 during the initial of two years of marketing. The product monograph should comprise the full prescribing information necessary enable to ph ysician to use the drug properly.554 4. actions. directive.1 to (d).2001. if the dru g has been withdrawn fro m any country specially by a regulatorysuch information should be furnished along with reasons and their relevance. Regulatory status in other countries. Marketing information.
if any.1.4.555 A brief description of the drug and the therapeutic class to which it belongs. 5.1. 2. physio-chemical proportion. Tests 2. 6. Summary Investigatorwise 6. Pharmacokinetics. Summary 3. 6. 5.1.. 7. Chemical name.2. absorption. assay. structure.3 General pharmacological actions.3. 2. ANIMAL PHARMACOLOGY 3. Mutagenicity and Carnicogenicity. excretion. metabolism. ANIMAL TOXICOLOGY ( SeeAppendix III and IV) 4. EXPLANATORY CLINIC AL TRIALS (PHASE II) . code name or number. 5. CONFIRMATORY CLINICAL TRIALS (PHASE III) 7.2 4.3 General Pharmacological effects. 4.3 Specifications of active and inactive ingredients. for identification of the active ingredient and method of its 2.5. SPECIAL STUDIES . excretion. HUMAN/CLINICAL PHARMACOLOGY (PHASE I). Summary Pharmacological effects. 5. 2. 3.4 Studies.1. Outline of the method of manufacture of the active ingredient. Pharmacokinetics.2 Dosage form and its composition. distribution. Toxicity Long Term Toxicity Reproduction 4. if any. non-proprietary or generic name. distribution. Summary Acute 4.4. Summary Investigatorwise 7.1. 3.2 Specific 184.108.40.206 reports.6 Stability data 3.2 reports 8. 2. metabolism.5 Local Toxicity 4. CHEMICAL AND PHARMACEUTICAL INFORMATION. Specific pharmacolo gical actions. 2. 4.1. absorption.
556 8. 220.127.116.11. 4.O. Notes (1) All items may not be applicable to all drugs.MARKETING INFORMATION. 8. Notification No. 9. 4. Dosage from its composition . 9. ________________________________________________________________________ ___ * Ins. INTRODUCTION A brief description of the drug and the therapeutic class. (2) For requirements of data to be submitted with application for clinicalrials see text of Schedule Y. Summary 8. see text : of Schedule Y. 10. Chemical name. Drafts 4. *[APPENDIX 1-A [See Rules 122-A and 122B) Data required to be submitted by an applicant for grant of permission to import manufacture an already approved new drug.3 Investigatorwise reports. physico-chemical properties. Restrictions on use. (d) Withdrawn.2 Bioavailability and dissolution studies. GSR 900(E) dt 12.3. CHEMICAL AND PHARMACEUTICAL INFORMATION. code name or number. with testing protocol. if any. with reasons.2. for ex planation. if any.3 Free sale certificate from country of origin. Sample of pure drug substance. if any. with phase.1. Section 1 and also Appendices II and t III.2. non-proprietary or generic name. 1. 2. Countries where – (a) Marketed (b) Approved. 2. 9.2001.2. structure. 9. by G.I.1. in countries where marketed/approved. if any. Proposed product monograph of labels and cartons. REGULATORY STATUS IN OTHER COUNTRIES. (c) Under trial.
Sub-acute animal toxicity studies for intravenous infusions and injectables. whether written. 4. 4. clinical and laboratory observations on efficacy and safety. with reasons. with criteria selection and exclusion. Bioavailability/Bioequivalance and comparative Dissolution Studies. 3.557 2. if any. Marketing information. method of verifying compliance.2. Stability data. description of patients with initial comparability of groups where appropriate. 2. ___ Treatments given – drugs and dosage forms. (b) Inactive ingredients 2.2 Draft specimen of the label and carton. dosage regimens. 3. Special studies conducted with approval o f Licensing Authority. ] APPENDIX II ___ Title of the trial ___ Name of investigator and institution ___ Objectives of the trial ___ Design of study: Open. drug reactions.1 Proposed package insert/promotional literature 3. Test specifications. arallel group or crossover. Tests for identification of the active ingredients and method of its assay. if any ___ Observations made before. single-blind or double blind. with methods used. ___ Results : exclusions and dropouts. adverse Format for submission of clinical Trial Reports.1.3. p ___ Number of patients. Outline of the method of manufacture of active 2. for efficacy and safety.5.4. was informed obtained. clinical patients with initial comparability of groups where approp riate. ingredients. method of allocation of patients to treatments. during and at the end of treatment. consent. non-comparative or comp arative. 4. (a) active ingredients. . for oral dosage form.6.
3 mo MP 2 sp. 3 wk. Route of administration Duration of Phase Long term Human toxicity administratio requirements. guidance for further study. 4 wk Up to 3 wk III 2 sp. if any. number and duration of applications with duration of commensurate use. Graded doses. correlation with other reports/data. if necessar y. then 2 wk observation III: MP 1 sp. III 1 sp. ___ Summary conclusion. Up to 3 mo I. single 24h exp. Up to 6 mo Over 3 mo Inhalation (general Anaesthetics) Aerosole use I: III MP 5d(3h/d) 4 sp. III 1-2 sp. Oral or Parenteral or Transdermal Up to 2 wk I. II 1-2 sp. 3 mo III: MP 2 sp. dailyapplications . 6 mo Repeated or Chronic I. I: II Irrigation test. II 2 sp . I. relevance to objectives. Dermal long Short term or Term application Ocular or Otic or Nasal Single or Applications Multiple .558 ___ Discussion of results . II 2 sp. as in clinical use. 3h/exp. II 2 sp. n 1 2 3 4 Single dose of several I-III MP 2 sp. 2 wk doses in one day. and APPENDIX III Animal toxicity requirements for clinical trials and marketing of a New Drug. Up to 4 wk III MP 2 sp. Up to 6 (2 exp/d) wk MP 1-2 sp. 24 (2 exp/d) wk I: II 1 sp.
volunteers/patients suffering from in ………………………………………………………………. number and duration 1 sp. APPENDIX IV Number of animals for long term Toxicity Studies.III – Phases of clinical trial see Appendix I. I.559 MP 1 sp. mo-month. The drug which will be administered to volunteers/patients has been found to be safe in animal toxicity tests and other experimental data. of applications commensurate with duration of use. agent ……………. (2) Requirements for fixed dose combinations are giv en in Appendix VI.5-8).day. ( item No. exp-ex posure. Abbrevations Marketing Sp-species. d. h-hour.. MPPermission.26 Weeks (rats) NonRodents (dogs) (Rats) : Group Rodents Rodents NonRodents (dogs) M F M F M F M F Control 6 – 10 6 – 10 2 –3 2 –3 15 –30 15 –30 4—6 4 —6 Low dose 6 – 10 6 – 10 2 –3 2 –3 15 –30 15 –30 4—6 4 —6 Intermediate dose 6 – 10 6 – 10 2 –3 2 –3 15 –30 15 –30 4—6 4 —6 High dose 6 – 10 6 – 10 2 –3 2 –3 15– 30 15 30 4—6 4—6 APPENDIX V Patient consent form for participation in a Phase I Clinical Trial The clinical trial involves the study of a new …………. The volunteers /patients will be required to . number and or duration Vaginal or Rectal Multiple Single or Application I : II III : MP of application commensurate with duration of use.(1) Animal tox icity data available from other countries are acceptable and not need to be repeated/duplicated in e do India. 2 6 Weeks 7 .II.week. wk. Not : .
and th ere may be n eed to draw blood or any other body fluid on several occasions to test the effects of concentrations the of drug. at intervals. The volunteers/patients are f ree to withdraw from the trial at any stage. namely………………. Signature of the attending physician. . and inconveniences have been Its explained to my satisfaction.. I am suffering from ……………………… I have been informed to my satisfaction. Authorisatio n I have read/been briefed on the abov e project summary and I voluntarily agree participate in the project.. Signature of Chief Investigator Date: Patient consent form for participation in Phase II and Phase III Clinical Trial: I……………………………. by attending ph ysician the purpose of the clinical trial and the nature of drug treatment and the follow up including the laboratory investigation to monitor and safeguard my body functions. I understand that participation in this study may or may not benefit to me. exercising my free power of choice. Name of the volunteer/patient Signature or thump impression of the volunteer/patient. ECG. EEG etc. I hereby give my consent for this treatment. possible hazards. if necessary. Date: …………. potential benefits. I understan d that I may be treated with this drug for the the diseases. I am also aware of my right to opt out of the trial at any time during the course of the trial without having to give the reasons for doing so. The volunteers/patients may be asked to collect stool and urine. hereby give my consent to be included as a subject in the clinical trial of a n ew drug. all routine examinations including taking of X-ray. Signature of the patient Date: APPENDIX VI Fixed Dose Combination (FDC) fall into four groups and their data requirements accordingly.560 undergo. general purpose. for treatment of ……………………..
actual toxicity data (LD 50) and pharmacological d ata should be submitted on the individual ingredients as well as th eir combination in the proposed ratio. In addition. . No additional animal or human data are generally required for these FDC. The of trails will depend on the claims to be made and the data already nature available. and a stable acceptable dosage from the ingredients are unlikely to have significant interaction of a pharmacodynamic or pharmacokinetic nature. and the reports of trials should be submitted to obtain a marketing permission. for a particular claim and a where the ingredients are likely to have significant interaction of a pharmacodynamic or pharmacokinetic 122-E. If been the is mark eted abroad. the reports of clinical trails carried out with the FDS in India should be submitted. toxicological and clinical data on the ingredients individual should be submitted. both the clinical a trialsfor marketing permission SeeRule 122-E. the appropriate rationale should be submitted to obtain a permission for the clinical trials. ( For marketing permission. their concomitant use is often necessary and no claim is proposed to be made other than convenience. For permission to carry out clinical trials with such nature ( see Rule summary ofFDC. The nature of trials depending on the claims to be made and the data already available. and permission marketing may be granted if the FDC has an acceptable rationale. (d) The fourth group of FDC includes those whose individual active ingredients have widely been used in particular indication for years. (c) The third group of FDC includes those which are already marketed. item (a). If the clinical trials have carried out with the FDC in other countries. drug. with rationale for combining them in the proposed ratio. the regulatory status in other countries should be FDC See Appendix . Such FDC are treated in the same way as any other new. For such FDC.561 (a) The first group of FDC includes those in which one or more of the active ingredients is new drug. reports of such trials should be submitted. item 9). item (c)). stated. but in which it proposed either to change the ratio of active ingredients or to make a new therapeutic is claim.) and ( (b) The second group of FDC includes tho se in which active ingredients alread ypproved/marketed individually are combined for the first time. a available pharmacological.
This action might not be possible to undo. Are you sure you want to continue?
We've moved you to where you read on your other device.
Get the full title to continue listening from where you left off, or restart the preview.