Appendix II: Schedule y Requirements and guidelines on clinical trials for import and manufacture of new drug
For new drug substances discovered in other countries phase I trials are not usually allowed to be initiated in India unless phase I data as required under Item 5 of the said Appendix from other countries are available. However, such trials may be permitted even in the absence of phase I data from other countries if the drug is of special relevance to the health problem of India.
For new drug substances discovered in India, clinical trials are required to be carried out in India right from phase I as required from Item 5 of the said Appendix, through phase III as required under Item 7 of the said Appendix, permission to carry out these trials is generally given in stages, considering the data emerging from earlier phase.
Permission to carry out clinical trials with a new drug is issued along with a test license in Form 11.
It 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 approval granted to a protocol by the ethical committee of one institution will be applicable to the use of that protocol in other institutions, which do not have an ethical committee. In case none of the trial centres/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.
For new drugs having potential for use in children, permission for clinical trials in the paediatric age group is normally given after phase III trials as required under item 7 of the said Appendix, in adults are completed. However, if the drug is of value primarily in a disease of children, early trials in the paediatric age group may be allowed.
In all trials an informed, written consent is required to be obtained from each volunteer/patient in the prescribed form (See Appendix V), which must be signed, by the patient/volunteer and the chief investigator.
Most of the data under this heading (See Appendix I to Sch. Y, Item 2) are required with the application for marketing permission. When the application is for clinical trials only, information covered in item 2.1 to 2.3 of Appendix I will usually suffice.
In long-term toxicity studies the drug should be administered 7 days a week by the route intended for clinical use in humans. The number of animals required for these studies, i.e. the minimum number on which data should be available, is shown in Appendix IV to Sch. Y.
A control group of animals, given the vehicle alone, should always be included, and three other groups should be given graded doses of the drug; the highest dose should produce observable toxicity, the lowest dose should not cause observable toxicity, but should be comparable to the intended therapeutic dose in humans or a multiple of it, eg: 2.5x to make allowance for the sensitivity of the species; the intermediate dose should cause some symptoms, but not gross toxicity or death, and may be placed logarithmically between the other two doses.
The variables to be monitored and recorded in long-term toxicity studies include behavioral, physiological, biochemical and microscopic observations.
(a)Fertility studies: The drug should be administered to both males and females, beginning a sufficient number of days before mating. In females the medication should be continued after mating and the pregnant one should be treated throughout pregnancy. The highest dose used should not affect general health or growth of the animals. The route of administration should be the same as for therapeutic use in humans. The control and the treated group should be of similar size and large enough to give at least 20 pregnant animals in the control group of rodents and at least 8 pregnant animals in the control group of non-rodents. Observations should include total examination of the litters from both the groups, including spontaneous abortions, if any.
(b)Teratogenicity studies: The drugs should be administered throughout the period of organogenesis, using three dose levels. One of the doses should cause minimum maternal toxicity and one should be the proposed dose for clinical use in humans or multiple of it. The route of administration should be the same as for human therapeutic use. The control and the treated groups should consist of at least 20 pregnant females in case of non-rodents, on each dose used. Observations should include the number of implantation sites, resorptions if any; and the number of fetuses with their sexes, weights and malformations if any.
(c) Perinatal studies: The drug should be administered throughout the last third of pregnancy and then through lactation and weaning. The control of each treated group should have at least 12 pregnant females and the dose which causes low foetal loss should be continued throughout lactation weaning. Animals should be sacrificed and observations should include macroscopic autopsy and where necessary, histopathology.
4.Local toxicity: These studies (see Appendix I, Sch. Y, Item 4.5) are required when the new drug Is proposed to be used typically in humans. The drug should be applied to an appropriate site to determine local effects in a suitable species such as guinea pigs or rabbits, if the drug is absorbed from the site of applications, appropriate systemic toxicity studies will be required.
5.Mutagenicity and Carcinogenicity : These studies (see Appendix I, Sch. Y Item 4,6) 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. For carcinogenicity studies, at least two species should be used. These species should not have high incidence of spontaneous tumors and should preferably be known to metabolize the drug in the same manner as humans. At least three does levels should be used; the highest does should be sub-lethal but cause observable toxicity; the lowest does should be comparable to the intended human therapeutic does or a multiple of it, eg: 2.5x; to make allowance for the sensitivity of the species; the intermediate does to be placed logarithmically between the other two doses. A control group should always be included. The drug should be administered 7 days a week or a fraction of the life span comparable to the fraction of human life span over which the drug is likely to be used therapeutically. Observations should include macroscopic changes observed at autopsy and detailed histopathology.
4. Animal Pharmacology Specific pharmacological actions (see Appendix I to Sch. Y, Item 3.2) are those with therapeutic-potential for humans. These should be described according to the animal models and species used. Wherever possible, dose-response relationships and ED 50s should be given. Special studies to elucidate mode of action may also be described. General pharmacological action (see Appendix I to Sch. Y, Item 3.3) are effects on other organs and systems, especially cardiovascular, respiratory and central nervous systems.
Pharmacokinetic data help relate drug effect to plasma concentration and should be given to the extent available.
5. Human/Clinical Pharmacology trials (Phase I) The objective of phase I of trials (see Appendix I, Sch. Y, Item 5) is to determine the maximum tolerated dose in humans; pharmacodynamic effects, adverse reactions, if any, with their nature and intensity; and pharmacokinetic behaviors or the drug as far as possible. These studies are carried out in healthy adult males, using clinical, physiological and biochemical observations. At least 2 subjects should be used on each dose.
Phase I trials are usually carried out by investigators trained in clinical pharmacology and having the necessary facilities to closely observe and monitor the subjects. These may be carried out at one or two centers.
6. Exploratory trials (Phase II) In phase II trial (see Appendix I to Sch. Y, Item 6) a limited number of patients are studied carefully to determine possible therapeutic uses, effective dose range and further evaluation of safety and pharmacokinetics. Normally 10-12 patients should be studied at each dose level. These studies are usually limited to 3-4 centers and carried out by clinicians specialized on the concerned therapeutic areas and having adequate facilities to perform the necessary investigations for efficacy and safety.
7. Confirmatory trials (Phase III)
The purpose of these trials (see Appendix I to Sch. Y, Item 7) is to obtain sufficient evidence about the efficacy and safety of the drug in a larger number of patients, generally in comparison with a standard drug and/or a placebo as appropriate. These trials may be carried out by clinicians in the concerned therapeutic areas, having facilities appropriate to the protocol. If the drug is already approved/marketed in other countries, phase III data should generally be obtained on at least 100 patients distributed over 3-4 centres primarily to confirm the efficacy and safety of the drug, in Indian patients when used as recommended in the product monograph for the claims made.
If the drug is a new drug substance discovered in India and not marketed in any other country, phase III data should be obtained on at least 500 patients distributed over 10-15 centers. In addition, data on adverse drug reactions observed during clinical use of the drug as recommended and to provide a report on its efficacy and adverse drug reactions in the treated patients. The selection of clinicians for such monitoring and supply of drug to them will need approval of the licensing authority under Rule-21 of Drugs & Cosmetics Rules.
8. Special Studies (A) These include studies on solid oral dosage forms, such as, bioavailability and dissolution studies. These are required to be submitted on the formulations manufactured in the country. (See Appendix I, Items 8.1 and 8.2) (B) These include studies to explore additional aspects of the drug, eg: use in elderly patients or patients with renal failure, secondary or ancillary effects, interactions, etc. (See Appendix I to Sch. Y, Item 8.1 and 8.2).
9. Submission of Reports (Appendix II to Schedule Y)
The reports of completed clinical trials shall be submitted by the applicant duly signed by the investigator within a stipulated period of time. The applicant should do so even if he is no longer interested to market the drug in the country unless there are sufficient reasons for not doing so.
10. Regulatory status in other counties It is important to state if any restrictions have been placed on the use of the drug in any other country, eg: dosage limits, exclusion of certain age groups, warnings about adverse drug reaction, etc. (See Appendix I, Sch. Y, Item 9.2) Likewise, if the drug has been withdrawn from any country especially by a regulatory directive such information should e furnished along with reasons and their relevance, if any, to India (See Appendix I, Item 9.1(d)).
11. Marketing Information
The product monograph should comprise the full prescribing information necessary to enable a physician to use the drug properly. It should include description, actions, indications, dosage precaution, drug interactions, warnings and adverse reactions. The drafts of label and carton texts should comply with provisions of Rules 96 and 97 of the said rules.
Appendix I to Schedule Y Data required to be submitted with application for permission to market a new drug
1. Introduction A brief description of the drug and the therapeutic class to which it belongs.
2. Chemical and pharmaceutical information 1. Chemical name; code name or number, if any; non-proprietary or generic name, if any; physio-chemical proportion. 2. Dosage form and its composition. 3. Specifications of active and inactive ingredients. 4. Tests for identification of the active ingredient and method of its assay. 5. Outline of the method of manufacture of the active ingredient. 6. Stability data.
3. Animal pharmacology 1. Summary. 2. Specific pharmacological actions. 3. General pharmacological actions. 4. Pharmacokinetics, absorptions, distribution, metabolism, excretion.
4. Animal toxicology (See Appendix III and IV to Sch. Y) 1. Summary 2. Acute toxicity 3. Long term toxicity 4. Reproduction studies 5. Local toxicity 6. Mutagenicity and carcinogenicity
5. Human/clinical pharmacology (Phase I) 1. Summary. 2. Specific pharmacological actions. 3. General pharmacological actions. 4. Pharmacokinetics, absorptions, distribution, metabolism, excretion.
6. Exploratory clinical trials (Phase II) 1. Summary 2. Investigator wise reports.
7. Confirmatory clinical trials (Phase III)
8. Special studies
9. Regulatory status in other countries
(a) Marketed (b) Approved (c) Under trial, with phase (d) Withdrawn, if any, with reasons
10. Marketing information
Notes I: All items may not be applicable to all drugs, for explanation, see text of Schedule Y. II: For requirements of data to be submitted with application for clinical trials see text of Schedule Y, Section I and also Appendices II and III to Sch. Y.
APPENDIX I to Schedule YI Format for submission of Clinical Trial Reports ….Title of the trial ….Name of the investigator and institution ….Objectives of the trial ….Design of study: open, single-blind or double-blind, non-comparative or comparative; parallel group or crossover. ….Number of patients, with criteria for selection and exclusion; whether written informed consent, was obtained. ….Treatments given: drugs and dosage forms: regimens; method of allocations of patients to the treatments; method of verifying compliance, if any. ….Observations made before, during and at the end of the treatment, for efficacy and safety , with methods used. ….Results: exclusions and dropouts, if any, with reasons; description of patients with initial comparability of groups where appropriate; clinical and laboratory observations on efficacy and safety; adverse drug reactions. ….Discussions of results: relevance to objectives, correlation with other reports data, if any; guidance for further study, if necessary. ….Summary and conclusion. APPENDIX III to Schedule Y Animal toxicity requirements for clinical trials and marketing of a new drug
** Number and/or duration of application commensurate with duration of use Abbreviations: sp- species; wk- week; d- day; h- hour; mo- month; MP – Marketing Permission; exp- exposure I, II, III – Phases of clinical trial (see Appendix I, item No. 5-8). Note : (1) Animal toxicity data available from other countries are acceptable and do not need to be repeated/duplicated in India. (2) Requirements for fixed dose combinations are given in Appendix VI.
APPENDIX IV to Schedule Y Number of animals for long term toxicity studies
APPENDIX V to Schedule Y Patient consent form for participation in a Phase I Clinical Trial This clinical trial involves the study of a new ……………………….….. agent in volunteers/patients suffering from ……………………….. The drug which will be administered to volunteers/patients has been found to be safe in animal toxicity tests and other experimental data. The volunteers/patients will be required to undergo, if necessary, all routine examinations including taking of X-ray, ECG, EEG etc. at intervals. The volunteers/patients may be asked to collect stool and urine, and there may be need to draw blood or any other body fluid on several occasions to test the effects of concentrations of the drugs. The volunteers/patients are free to withdraw from the trial at any stage.
Authorisation I have read/been briefed on the above project summary and I voluntarily agree to participate in the project. I understand that participation in this study may or may not benefit me. Its general purpose, potential benefits, possible hazards, and inconveniences have been explained to my satisfaction. I hereby give my consent for this treatment.
Signature or thumb impression
Name of the volunteer/patient
Date: Signature of Chief Investigator
Patient consent form for participation in Phase II and Phase III Clinical Trial
I ………………………………… exercising my free power of choice, hereby give my consent to be included as a subject in the clinical trial of a new drug, namely …………………………. for the treatment of ……………………….. . I understand that I may be treated with this drug for the diseases. I am suffering from ………………………….. . I have been informed to my satisfaction, by the attending physician the purpose of the clinical trial and the nature of drug treatment and follow up including the laboratory investigation to monitor and safeguard my body function.
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.
Signature of the patient
Date: Signature of the attending physician
APPENDIX VI to Schedule Y Data requirements of Fixed Dose Combinations
Fixed Dose combinations (FDC) fall into four groups and their data requirements accordingly
(a) The first group of FDC includes those in which one or more of the active ingredients is a new drug. Such FDC are treated in the same way as any other new drug , both the clinical trials and for marketing permission (see Rule 122-E, Item (a)).
(b) The second group of FDC includes those in which active ingredients already approved/marketed individually are combined for the first time, for a particular claim and where the ingredients are likely to have significant interaction of a pharmacodynamic or pharmacokinetic nature (see Rule 122-E, item (c)). For permission to carry out clinical trials with such FDC, a summary of available pharmacological, toxicological and clinical data on the individual ingredients should be submitted, along with the rationale for combining them in the proposed ratio. In addition, acute toxicity data (LD 50) and pharmacological data should be submitted on the individual ingredient as well as their combinations in the proposed ratio. If clinical trials have been carried out with the FDC in other countries, reports of such trials should be submitted. If the FDC is marketed abroad, the regulatory status in other countries should be stated. (See Appendix I, Item 9). For marketing permission, the reports of clinical trials carried out with the FDC in India should be submitted. The nature of trials depending on the claims to be made and the data already available.
(c) The third group of FDC includes those which are already marketed, but in which it is proposed either to change the ratio of active ingredients or to make a new therapeutic claim.
(d) The fourth group of FDC includes those whose individual active ingredients have been widely used in particular indication for years, there concomitant use is often necessary and no claim is proposed to be made other than convenience, and a stable acceptable dosage form and the ingredients are unlikely to have significant interaction of a pharmacodynamic or pharmacokinetic nature.
No additional animals or human data are generally required for these FDC, and marketing permission may be granted if the FDC has an acceptable rationale.
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