Schedule Y

Schedule Y is defined as the clinical trials as the requirements and guidelines for the import and manufacture of new drugs for sale or clinical trials. It describes the details of the application process for conducting clinical trials; the responsibilities of the sponsor, investigators, and the Independent Ethics Committee.

Clinical Trials

Nature of Trials:

The clinical trials required to be carried out in the country before a new drug is approved for marketing depend on the status of the drug in other countries. If the drug is already approved/marketed, Phase II 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 to be initiated in India unless Phase 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 under 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 the earlier phase.

Permission for Trials:

Permission to initiate clinical trials with a new drug may be obtained by applying in Form 12 for a test license (TL) to import or manufacture the drug under the Rules. Data appropriate for the various phases of clinical trials to be carried out should accompany the application as per the format given. In addition, the protocol for proposed trials, case report forms to be used, and the names of investigators and institutions should also be submitted for approval. The investigators selected should possess appropriate qualifications and experience and should have such investigations facilities as are germane to the proposed trial’s protocol. Permission to carry out clinical trials with a new drug is issued along with a test license in Form 11.

Protocols for clinical trials should 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 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.

For new drugs having potential for use in children, permission for clinical trials in the pediatric 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 pediatric age group may be allowed.

Responsibilities of Sponsor/Investigator:

Sponsors are required to submit to the licensing authority as given under Rule 21 an annual status report on each clinical trial, namely, ongoing, completed, or terminated. In case a trial is terminated, the reason for this should be stated. Any unusual, 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. In all trials informal, written consent is required to be obtained from each volunteer/patient in the prescribed Forms which must be signed by the patient/volunteer and the chief investigator.

Chemical and Pharmaceutical Information: Most of the data under the heading are required with the application for marketing permission.

Animal Toxicology

Acute Toxicology:

Acute toxicity studies should be carried out in at least two species usually mice and rats using the same route as intended for humans. In addition, at least one more route should be used to ensure systemic absorption of the drug; this route may depend on the nature of the drug. Mortality should be looked at for up to 72 hours after parenteral administration and up to 7 days after oral administration. Symptoms, signs, and mode of death should be reported, with appropriate macroscopic and microscopic findings where necessary. LD50s, should be reported preferably with 95 percent confidence limited, if LD50s cannot be determined, reasons for this should be stated.

Long Term Toxicity:

Long-term toxicity should be carried out in at least two mammalian species, of which one should be a non-rodent. The duration of study will depend on whether the application is for marketing permission or for the clinical trial, and in the latter case, on the phase of trials. If a species is known to metabolize the drug in the same way as humans, it should be preferred.

In long-term toxicity studies, the drug should be administered 7 days a week by the route intended for clinical use in humans. A control group of animals given the vehicle along should always be included and three other groups should be given a graded dose 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 of a multiple of it, e.g. 2.5 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 should include behavioral, physiological, biochemical, and microscopic observations,

Reproduction Studies:

Reproduction studies need to be carried out only if the new drug is proposed to be studied or used in women of childbearing age. Two species should generally be used, one of them being a non-rodent if possible.

  • 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 the 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 a 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 a total examination of the litters from both groups, including spontaneous abortions if any.

  • Teratogenicity Studies: The drug 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 a proposed dose for clinical use in humans or a multiple of it. The route of administration should be the same as for human therapeutic use. The control and the treated group 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.
  • Perinatal Studies: The drug should be administered throughout the last third of pregnancy and then through lactation of weaning. The control of each treated group should have at least 12 pregnant females and the dose which causes low fetal loss should be continued throughout lactation weaning. Animals should be sacrificed and observations should include macroscopic autopsy and where necessary, histopathology.

Local Toxicity:

These studies are required when the new drug is proposed to be used topically 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.

Mutagenicity and Carcinogenicity:

These studies 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 a high incidence of spontaneous tumors and should preferably be known to metabolize the drug in the same manner as humans. At least three dose levels should be used; the highest dose should be sublethal out cause observable toxicity, the lowest dose should be comparable to the intended human therapeutic dose or a multiple of it, e.g. 2.5 X; to make intermediate dose 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.

Animal Pharmacology:

Specific pharmacological actions 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 ED50, should be given. Special studies to elucidate the mode of action may also be described. General pharmacological actions 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.

Human/Clinical Pharmacology (Phase I):

The objective of phase I of trials is to determine the maximum tolerated dose in humans; pharmacodynamic effects, adverse reactions, if any, with their nature and intensity; and pharmacokinetic behavior of 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 have the necessary facilities to closely observe and monitor the subjects. These may be carried out at one or two centers.

Explanatory trials (Phase II):

In the phase II trial, a limited number of patients are studied carefully to determine possible therapeutic use, 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 in the concerned therapeutic areas and having adequate facilities to perform the necessary investigations for efficacy and safety.

Confirmatory Trials (Phase III):

The purpose of these trials 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 centers 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 from at least 500 patients distributed over 10-15 centers. In addition, data on adverse drug reactions observed during clinical use of the drug should be collected in 1000-2000 patients, such data may be collected through clinicians who give written consent to use the drug as recommended and to provide a report on its efficacy and adverse during reactions in the treated patients. The selection of clinicians for such monitoring and supply of the drug to them will need the approval of the licensing authority under Rule 21.

Special Studies:

  • 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.
  • These include studies to explore additional aspects of the drug, e.g. use in elderly patients or patients with renal failure, secondary or ancillary effects, interactions, etc.

Submission of Reports:

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.

Regulatory Status in Other Countries:

It is important to state if any restrictions have been placed on the use of the drug in any other country, e.g. dosage limited, exclusion of certain age groups, warnings about adverse drug reaction, etc.

Likewise, if the drug has been withdrawn from any country, especially by a regulatory directive, such information should be furnished along with reasons and their relevance, if any, to India.

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.

Post-marketing Surveillance Study:

On approval of a new drug, the importer or the manufacturer shall conduct a post-marketing surveillance study of that new drug after getting the protocols and the names of the investigators approved by the Licensing Authority as defined under clause (b) of Rule 21 during the initial period of two years of marketing.

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