3 In the
Drugs and Cosmetics Rules, 1945 (hereinafter referred to as said rules),
(1) in Part X-A, after
rule 122-DA, the following shall be inserted, namely:-,
122-DAA. Definition of
Clinical trial.- For the purpose of this Part, “Clinical trial”
means a systematic study of new drug(s) in human subject(s) to
generate data for discovering and / or verifying the clinical, pharmacological
(including pharmacodynamic and pharmacokinetic) and /or adverse effects with the
objective of determining safety and / or efficacy of the new drug. “.
(2) In the said rules
for Schedule Y, the following Schedule shall be substituted, namely :-
“SCHEDULE Y
s[See rules 122A, 122B, 122D, 122DA, 122DAA and 122E]
Requirements AND GUIDELINES
for permission to IMPORT AND / OR MANUFACTURE of New Drugs FOR SALE OR to
UNDERTAKE CLINICAL TRIALS
1. Application for permission.- (1) Application for permission to import or manufacture new
drugs for sale or to undertake clinical trials shall be made in Form 44
accompanied with following data in acccordance with the appendices, namely:-
(i) chemical and
pharmaceutical information as prescribed in item 2 of Appendix I; (ii) animal
pharmacology data as prescribed in item 3 of Appendix I and Appendix IV;
(a) specific pharmacological
actions as prescribed in item 3.2 of Appendix I, and demonstrating,
therapeutic potential for humans shalls be described according to the animal models
and species used. Wherever possible, dose-response relationships and ED 50s
shall be submitted. Special studies conducted to elucidate mode of action shall
also be described (Appendix IV);
(b) general pharmacological
actions as prescribed in item 3.3 of Appendix I and item 1.2 of Appendix IV;
(c) pharmacokinetic data
related to the absorption, distribution, metabolism and excretion of the test
substance as prescribed in item 3.5 of Appendix I. Wherever possible,
the drug effects shall be corelated to the plasma drug concentrations;
(iii)
animal toxicology data as
prescribed in item
4 of
Appendix I and Appendix III;
(iv) human Clinical Pharmacology Data as prescribed in items 5,6 and 7 of Appendix I and as stated below:-
(a)
for new drug substances discovered in India, clinical trials are required
to be carried out in India right from Phase I and data should be submitted as
required under items 1, 2, 3, 4, 5 (data, if any, from other countries) , and 9
of Appendix I;
(b) for new
drug substances discovered in countries other than India, Phase I data as
required under items 1, 2, 3, 4, 5 (data from other countries) and 9 of Appendix
I should be submitted along with the application. After submission of Phase I data
generated outside India to the Licensing Authority, permission may be granted to
repeat Phase I trials and/or to conduct Phase II trials and subsequently Phase
III trials concurrently with other global trials for that drug. Phase III trials
are required to be conducted in India before permission to market the drug in
India is granted;
(d) application for
permission to initiate specific phase of clinical trial should also accompany
Investigator’s brochure, proposed protocol (Appendix X), case record form, study
subject’s informed consent document(s) (Appendix V), investigator’s
undertaking (Appendix VII) and ethics committee clearance, if available,
(Appendix VIII);
(e) reports
of clinical studies submitted under items 5-8 of Appendix I should be in
consonance with the format prescribed in Appendix II of this Schedule. The study report
shall be certified by the Principal Investigator or, if no Principal
Investigator is designated, then by each of the Investigators participating in
the study. The certification should acknowledge the contents of the report, the
accurate presentation of the study as undertaken, and express agreement with the
conclusions. Each page should be numbered;
(v) regulatory status in other countries as prescribed in item 9.2 of Appendix I, including Information in respect of restrictions imposed, if any, on the use of the drug in other countries, e.g. dosage limits, exclusion of certain age groups, warning about adverse drug reactions,.etc. (item 9.2 of Appendix I). Likewise, if the drug has been withdrawn in any country by the manufacturer or by regulatory authorities, such information should also be furnished along with the reasons and their relevance, if any, to India. This information must continue to be submitted by the sponsor to the Licensing Authority during the course of marketing of the drug in India;
(vi)
the full prescribing
information should be submitted as part of the new drug application for
marketing as prescribed in item 10 of Appendix I. The prescribing information
(package insert) shall comprise the following sections: generic name;
composition; dosage form/s, indications; dose and method of administration; use
in special populations (such as pregnant women, lactating women, pediatric
patients, geriatric patients etc.) ; contra-indications; warnings; precautions;
drug interactions; undesirable effects; overdose; pharmacodynamic and
pharmacokinetic
properties; incompatibilities; shelf-life; packaging information; storage
and handling instructions. All package inserts, promotional literature and
patient education material subsequently produced are required to be consistent
with the contents of the approved full prescribing information. The drafts of label and
carton texts should comply with provisions of rules 96 and 97. After submission
and approval by the Licensing Authority, no changes in the package insert shall
be effected without such changes being approved by the Licensing Authority;
and
(vii) complete testing protocol/s for quality control testing together with a complete impurity profile and release specifications for the product as prescribed in item 11 of Appendix I should be submitted as part of new drug application for marketing. Samples of the pure drug substance and finished product are to be submitted when desired by the regulatory authority.
(2)
If the study drug is intended to be imported for the
purposes of examination, test or analysis, the application for
import of small quantities of drugs for such purpose should also be made in Form
12.
(3)
For drugs indicated in life threatening / serious diseases
or diseases of special relevance to the Indian health scenario, the
toxicological and clinical data requirements may be abbreviated, deferred or
omitted, as deemed appropriate by the Licensing Authority.
2. CLINICAL TRIAL
(1) Approval for clinical trial
(i)
Clinical trial on a new drug shall be initiated only after the permission
has been granted by the Licensing Authority under rule 21 (b),
and the approval obtained from the respective ethics committee(s). The Licensing
Authority as defined shall be informed of the approval of the respective
institutional ethics comittee(s) as prescribed in Appendix VIII, and the trial
initiated at each respective site only after obtaining such an approval for that
site. The
trial site(s) may accept the approval granted to the protocol by the ethics
committee of another trial site or the approval granted by an independent ethics
committee (constituted as per Appendix VIII), provided that the approving ethics
committee(s) is/are willing to accept their responsibilities for the study at
such trial site(s) and the trial site(s) is/are willing to accept such an
arrangement and that the protocol version is same at all trial sites.
(ii) All trial
Investigator(s) should possess appropriate qualifications, training and
experience and should have access to such investigational and treatment
facilities as are relevant to the proposed trial protocol. A qualified
physician (or dentist, when appropriate) who is an investigator or a
sub-investigator for the trial, should be responsible for all trial-related
medical (or dental) decisions. Laboratories used for generating data for
clinical trials should be compliant with Good Laboratory Practices. If services
of a laboratory or a facilities outside the country are to be availed, its/their
name(s), address(s) and specific services to be used should be stated in the
protocol to avail Licensing Authority’s permission to send clinical trial
related samples to such laboratory(ies) and/or facility(ies). In all cases,
information about laboratory(ies) / facilities to be used for the trial, if
other than those at the investigation site(s), should be furnished to the
Licensing Authority prior to initiation of trial at such site(s).
(iii) Protocol
amendments if
become necessary before initiation or during the course of a clinical
trial, all
such amendments should be notified to the Licensing Authority in writing along
with the approval by the ethics committee which has granted the approval for the
study. No
deviations from or changes to the protocol should be implemented without prior
written approval of the ethics committee and the Licensing Authority except when
it is necessary to eliminate immediate hazards to the trial Subject(s) or when
change(s) involve(s) only logistic or administrative aspects of the trial. All such exceptions
must be immediately notified to the ethics committee as well as to the Licensing
Authority.
Administrative and/or logistic changes in the protocol should be notified
to the Licensing Authority within 30 days.
(2) Responsibilities of
Sponsor.-
(i) The clinical
trial Sponsor is responsible for implementing and maintaining quality assurance
systems to ensure that the clinical trial is conducted and data generated,
documented and reported in compliance with the protocol and Good Clinical
Practice (GCP) Guidelines issued by the Central Drugs Standard Control
Organization, Directorate General of Health Services, Government of India as
well as with all applicable statutory provisions. Standard operating procedures should be
documented to ensure compliance with GCP and applicable regulations.
(ii)
Sponsors are required to submit a status report on the
clinical trial to the Licensing Authority at the prescribed periodicity.
(iii)
in
case of studies prematurely discontinued for any reason including lack of
commercial interest in pursuing the new drug application, a summary report
should be submitted
within 3 months. The summary report should provide a brief
description of the study, the number of patients exposed to the drug, dose and
duration of exposure, details of adverse drug reactions (Appendix XI), if any,
and the reason for discontinuation of the study or non-pursuit of the new drug
application;
(iv) Any unexpected serious adverse
event (SAE) (as defined in GCP Guidelines) occurring during a clinical trial
should be communicated promptly (within 14 calendar days) by the Sponsor to the
Licensing Authority and to the other Investigator(s) participating in the study
(see Appendix XI).
(3) Responsibilities of the
Investigator(s).- The Investigator(s) shall be responsible for the conduct of
the trial according to the protocol and the GCP Guidelines and also for
compliance as per the undertaking given in Appendix VII. Standard operating procedures are required to be documented
by the investigators for the tasks performed by them. During and
following a subject’s participation in a trial, the investigator should ensure
that adequate medical care is provided to the participant for any adverse
events. Investigator(s) shall report all serious and unexpected
adverse events to the Sponsor within 24 hours and to the Ethics Committee that
accorded approval to the study protocol within 7 working days of their
occurance.
(4) Informed Consent.-
(i) In all trials, a freely given, informed, written consent is
required to be obtained from each study subject. The Investigator must provide
information about the study verbally as well as using a patient information
sheet, in a language that is non-technical and understandable by the study
subject. The
Subject’s consent must be obtained in writing using an ‘Informed Consent
Form’. Both
the patient information sheet as well as the Informed Consent Form should have
been approved by the ethics committee and furnished to the Licensing
Authority. Any
changes in the informed consent documents should be approved by the ethics
committee and submitted to the Licensing Authority before such changes are
implemented.
(ii) Where a subject is not able to give informed consent (e.g. an unconscious person or a minor or those suffering from severe mental illness or disability), the same may be obtained from a legally acceptable representative (a legally acceptable representative is a person who is able to give consent for or authorize an intervention in the patient as provided by the law(s) of India). If the Subject or his/her legally acceptable representative is unable to read/write – an impartial witness should be present during the entire informed consent process who must append his/her signatures to the consent form.
(iii) A checklist of essential
elements to be included in the study subject’s informed consent document as well
as a format for the Informed Consent Form for study Subjects is given in
Appendix V.
(5) Responsibilities of the
Ethics Committee.-
(i) It is the responsibility of the ethics committee that
reviews and accords its approval to a trial protocol to safeguard the rights,
safety and well being of all trial subjects. The ethics committee should exercise
particular care to protect the rights, safety and well being of all vulnerable
subjects participating in the study, e.g., members of a group with hierarchical
structure (e.g. prisoners, armed forces personnel, staff and students of
medical, nursing and pharmacy academic institutions), patients with incurable
diseases, umemployed or impoverished persons, patients in emergency situation,
ethnic minority groups, homeless persons, nomads, refugees, minors or others
incapable of personally giving consent. Ethics committee(s) should get document
‘standard operating procedures’ and should maintain a record of its proceedings.
(ii) Ethics Committee(s)
should make, at appropriate intervals, an ongoing review of the trials for which
they review the protocol(s). Such a review may be based on the periodic
study progress reports furnished by the investigators and/or monitoring and
internal audit reports furnished by the Sponsor and/or by visiting the study
sites.
(ii) In case an ethics
committee revokes its approval accorded to a trial protocol, it must record the
reasons for doing so and at once communicate such a decision to the Investigator
as well as to the Licensing Authority.
(6) Human
Pharmacology (Phase I) .-
(i)
The objective of studies in this Phase is the estimation of
safety and tolerability with the initial administration of an investigational
new drug into human(s). Studies in this Phase of development usually
have non-therapeutic objectives and may be conducted in healthy volunteers
subjects or certain types of patients. Drugs with significant potential toxicity
e.g. cytotoxic drugs are usually studied in patients. Phase I trials
should preferably be carried out by Investigators trained in clinical
pharmacology with access to the necessary facilities to closely observe and
monitor the Subjects.
(ii) Studies conducted in
Phase I, usually intended to involve one or a combination of the following
objectives:-
(a) Maximum tolerated
dose: To
determine the tolerability of the dose range expected to be needed for later
clinical studies and to determine the nature of adverse reactions that can be
expected. These studies include both single and multiple dose
administration.
(b) Pharmacokinetics, i.e.,
characterization of a drug's absorption, distribution, metabolism and excretion.
Although these studies continue throughout the development plan, they should be performed
to support formulation development and determine pharmacokinetic parameters in
different age groups to support dosing recommendations.
(c) Pharmacodynamics:
Depending on the drug and the endpoints studied, pharmacodynamic studies and
studies relating to drug blood levels (pharmacokinetic/ pharmacodynamic studies)
may be conducted in healthy volunteer Subjects or in patients with the target
disease. If there are appropriate validated indicators of activity and potential
efficacy, pharmacodynamic data obtained from patients may guide the dosage and
dose regimen to be applied in later studies.
(d) Early Measurement of Drug
Activity: Preliminary studies of activity or potential therapeutic benefit may
be conducted in Phase I as a secondary objective. Such studies are generally
performed in later Phases but may be appropriate when drug activity is readily
measurable with a short duration of drug exposure in patients at this early
stage.
(7) Therapeutic exploratory
trials (Phase II).-
(i)
The primary objective of Phase II trials is to evaluate the
effectiveness of a drug for a particular indication or indications in patients
with the condition under study and to determine the common short-term
side-effects and risks associated with the drug. Studies in Phase II should be
conducted in a group of patients who are selected by relatively narrow criteria
leading to a relatively homogeneous population. These studies should be closely
monitored. An
important goal for this Phase is to determine the dose(s) and regimen for Phase
III trials.
Doses used in Phase II are usually (but not always) less than the highest
doses used in Phase I.
(ii) Additional
objectives of Phase II studies can include evaluation of potential study
endpoints, therapeutic regimens (including concomitant medications) and target
populations (e.g. mild versus severe disease) for further studies in Phase II or
III. These objectives may be served by exploratory analyses, examining subsets
of data and by including multiple endpoints in trials.
(ii)
If the application is for conduct of clinical trials as a
part of multi-national clinical development of the drug, the number of sites and
the patients as well as the justification for undertaking such trials in India
shall be
provided to the Licensing Authority.
(8) Therapeutic confirmatory
trials (Phase III).-
(i) Phase III
studies have primary objective of demonstration or confirmation of therapeutic
benefit(s).
Studies in Phase III are designed to confirm the preliminary evidence
accumulated in Phase II that a drug is safe and effective for use in the
intended indication and recipient population. These studies should be intended to provide
an adequate basis for marketing approval. Studies in Phase III may also further
explore the dose-response relationships (relationships among dose, drug
concentration in blood and clinical response), use of the drug in wider populations, in
different stages of disease, or the safety and efficacy of the drug in
combination with other drug(s).
(ii) For drugs intended
to be administered for long periods, trials involving extended exposure to the
drug are ordinarily conducted in Phase III, although they may be initiated in
Phase II. These studies carried out in Phase III complete the information needed
to support adequate instructions for use of the drug (prescribing
information).
(iii) For new drugs
approved outside India, Phase III studies need to be carried out primarily to
generate evidence of efficacy and safety of the drug in Indian patients when
used as recommended in the prescribing information. Prior to conduct of
Phase III studies in Indian subjects, Licensing Authority may require
pharmacokinetic studies to be undertaken to verify that the data generated in
Indian population is in conformity with the data already generated abroad.
(iv) If the application
is for the conduct of clinical trials as a part of multi-national clinical
development of the drug, the number of sites and patients as well as the
justification for undertaking such trials in India should be provided to the
Licensing Authority along with the application.
(9) Post Marketing Trials (Phase IV).-
Post Marketing trials are studies (other than routine
surveillance) performed after drug approval and related to the approved
indication(s).
These trials go beyond the prior demonstration of the drug’s safety,
efficacy and dose definition. These trials may not be
considered necessary at the time of new drug approval but may be required by the
Licensing Authority for optimizing the drug's use. They may be of any type but
should have valid scientific objectives. Phase IV trials include additional
drug-drug interaction(s), dose-response or safety studies and trials designed to
support use under the approved indication(s), e.g. mortality/morbidity studies,
epidemiological studies etc.
3. Studies in special
populations:
Information supporting the use
of the drug in children, pregnant women, nursing women, elderly patients,
patients with renal or other organ systems failure, and those on specific
concomitant medication is required to be submitted if relevant to the clinical
profile of the drug and its anticipated usage pattern. Any claim sought to be
made for the drug product that is not based on data submitted under preceding
items of this Schedule should be supported by studies included under this item
of the Schedule
(Appendix I, item 8.3).
(a) the
disease intended to be treated is characteristically a disease of aging; or
(b) the
population to be treated is known to include substantial numbers of geriatric
patients; or
(c) when
there is specific reason to expect that conditions common in the elderly are
likely to be encountered; or
(d) when
the new drug is likely to alter the geriatric patient's response (with regard to
safety or efficacy) compared with that of the non-geriatric patient.
(ii) If the new drug is for diseases predominantly or
exclusively affecting paediatric patients, clinical trial
data should be generated in the paediatric population except for initial safety
and tolerability data, which will usually be obtained in adults unless such
initial safety studies in adults would yield little useful information or expose
them to inappropriate risk.
(iii) If the new drug is intended to treat serious or
life-threatening diseases, occurring in both adults and paediatric patients, for
which there are currently no or limited therapeutic options, paediatric
population should be included in the clinical trials early, following
assessment of initial safety data and reasonable evidence of potential benefit.
In circumstances where this is not possible, lack of data should be justified in
detail.
(iv) If the new drug has a
potential for use in paediatric patients – paediatric studies should be
conducted.
These studies may be initiated at various phases of clinical development
or after post marketing survelliance in adults if a safety concern exists. In cases where
there is limited paediatric data at the time of submission of application – more
data in paediatric patients would be expected after marketing authorisation for
use in children is granted.
(v) The paediatric studies
should include -
(a)
clinical trials,
(b)
relative bioequivalence comparisons of the paediatric
formulation with the adult formulation performed in adults, and
(c)
definitive pharmacokinetic studies for dose selection
across the age ranges of paediatric patients in whom the drug is likely to be
used. These
studies should be conducted in the paediatric patient population with the
disease under study.
(vi) If the new drug is a
major therapeutic advance for the paediatric population – the studies should
begin early in the drug development , and this data should be submitted with the
new drug application.
(vii) Paediatric Subjects are
legally unable to provide written informed consent, and are dependent on
their parent(s)/ legal guardian to assume responsibility for their participation
in clinical studies. Written informed consent should be obtained from the
parent/ legal guardian. However, all paediatric participants should be informed
to the fullest extent possible about the study in a language and in terms that
they are able to understand. Where appropriate, paediatric participants should
additionally assent to enrol in the study. Mature minors and adolescents should personally
sign and date a separately designed written assent form. Although a
participant’s wish to withdraw from a study must be respected, there may be
circumstances in therapeutic studies for serious or life-threatening diseases in
which, in the opinion of the Investigator and parent(s)/ legal guardian, the
welfare of a pediatric patient would be jeopardized by his or her failing to
participate in the study. In this situation, continued parental/ legal guardian
consent should be sufficient to allow participation in the study.
(viii)For clinical trials
conducted in the paediatric population, the reviewing ethics committee should
include members who are knowledgeable about pediatric, ethical, clinical and
psychosocial issues.
(3)
Pregnant or nursing women.-
(i) Pregnant or nursing women
should be included in clinical trials only when the drug is intended for use by
pregnant/nursing women or foetuses/nursing infants and where the data generated
from women who are not pregnant or nursing, is not suitable.
(ii) For new drugs intended
for use during pregnancy, follow-up data (pertaining to a period appropriate for
that drug) on the pregnancy, fetus and child will be required. Where applicable,
excretion of the drug or its metabolites into human milk should be examined and
the infant should be monitored for predicted pharmacological effects of the
drug.
(2) Post
Marketing Surveillance.-
(i) Subsequent to
approval of the product, new drugs should be closely monitored for their
clinical safety once they are marketed. The applicants shall furnish Periodic
Safety Update Reports (PSURs) in order to-
(a) report all the relevant
new information from appropriate sources;
(b)
relate these data to patient exposure ;
(c) summarize the market
authorization status in different countries and any significant variations
related to safety; and
(d) indicate whether changes
should be made to product information in
order to optimize the use of the product.
(ii) Ordinarily all
dosage forms and formulations as well as indications for new drugs should be
covered in one PSUR. Within the single PSUR separate presentations of data for
different dosage forms, indications or separate population need to be given.
(iii) All relevant
clinical and non-clinical safety data should cover only the period of the report
(interval data). The PSURs shall be submitted every six months for the first two
years after approval of the drug is granted to the applicant. For subsequent two
years – the PSURs need to be submitted annually. Licensing authority may extend
the total duration of submission of PSURs if it is considered necessary in the
interest of public health. PSURs due for a period must be submitted
within 30 calendar days of the last day of the reporting period. However, all
cases involving serious unexpected adverse reactions must be reported to the
licensing authority within 15 days of initial receipt of the information by the
applicant. If
marketing of the new drug is delayed by the applicant after obtaining approval
to market, such data will have to be provided on the deferred basis beginning
from the time the new drug is marketed.
(iv) New studies
specifically planned or conducted to examine a safety issue should be described
in the PSURs.
(v) A PSUR should be
structured as follows:
(a)
A title page stating: Periodic safety update report for the
product, applicant’s name, period covered by the report, date of approval of new
drug, date of marketing of new drug and date of reporting;
(b)
Introduction,
(c) Current
worldwide market authorization status,
(d) Update
of actions taken for safety reasons,
(e) Changes
to reference safety information,
(f)
Estimated patient exposure,
(g)
Presentation of individual case histories,
(h)
Studies,
( I) Other
information,
(j) Overall
safety evaluation,
(k)
Conclusion,
(l) Appendix
providing material relating to indications, dosing, pharmacology and other
related information.
(5) Special studies:
Bioavailability / Bioequivalence Studies.-
(i)
For drugs approved elsewhere in the world and absorbed systemically,
bioequivalence with the reference formulation should be carried out wherever
applicable.
These studies should be conducted under the labeled conditions of
administration. Data on the extent of systemic absorption may be required for
formulations other than those designed for systemic absorption.
(ii) Evaluation of the effect
of food on absorption following oral administration should be carried out. Data from
dissolution studies should also be submitted for all solid oral dosage forms.
(iii) Dissolution and
bioavailability data submitted with the new drug application must provide
information that assures bioequivalence or establishes bioavailability and
dosage correlations between the formulation(s) sought to be marketed and those
used
for clinical trials during
clinical development of the product. (See items 8.1, 8.2 and 8.3 of Appendix I,).
(iv) All
bioavailability and bioequivalence studies should be conducted according to the
Guidelines for Bioavailability and Bioequivance studies as prescribed.
Note.- The data requirements stated in this Schedule are expected
to provide adequate information to evaluate the efficacy, safety and therapeutic
rationale of new drugs (as defined under rule 122-E) prior to the permission for
sale.
Depending upon the nature of new drugs and disease(s), additional
information may be required by the Licensing Authority. The applicant shall
certify the authencity of the data and documents submitted in support of an
application for new drug. The Licensing Authority reserves the right to
reject any data or any document(s) if such data or contents of such documents
are found to be of doubtful integrity.
APPENDIX I
DATA TO BE SUBMITTED ALONG
WITH THE APPLICATION TO CONDUCT CLINICAL TRIALS / IMPORT / MANUFACTURE OF NEW
DRUGS FOR MARKETING IN THE COUNTRY.
1.
Introduction
A brief description of the
drug and the therapeutic class to which it belongs.
2.
Chemical and pharmaceutical information
2.1.
Information on active
ingredients
Drug information (Generic
Name, Chemical Name or INN)
2.2.
Physicochemical Data
a. Chemical name
and Structure
Empirical formula
Molecular weight
b. Physical
properties
Description
Solubility
Rotation
Partition coefficient
Dissociation constant
2.3.
Analytical Data
Elemental analysis
Mass spectrum
NMR spectra
IR spectra
UV spectra
Polymorphic identification
2.4.
Complete monograph
specification including
Identification
Identity/quantification of
impurities
Enantiomeric purity
Assay
2.5.
Validations
Assay method
Impurity estimation method
Residual solvent/other
volatile impurities (OVI) estimation method
2.6.
Stability Studies (for details
refer Appendix IX)
Final release
specification
Reference standard
characterization
Material safety data sheet
2.7.
Data on Formulation
Dosage form
Composition
Master manufacturing
formula
Details of the formulation
(including inactive ingredients)
In process quality control
check
Finished product
specification
Excipient compatibility
study
Validation of the analytical
method
Comparative evaluation with
international brand(s) or approved Indian brands, if applicable
Pack presentation
Dissolution
Assay
Impurities
Content uniformity
pH
Force degradation study
Stability evaluation in market
intended pack at proposed storage conditions
Packing specifications
Process validation
When the application is for
clinical trials only, the international non-proprietary name (INN) or generic
name, drug category, dosage form and data supporting stability in the intended
container-closure system for the duration of the clinical trial (information
covered in item nos. 2.1, 2.3, 2.6, 2.7) are required.
3.
Animal Pharmacology (for details refer Appendix IV)
3.1.
Summary
3.2.
Specific pharmacological
actions
3.3.
General pharmacological
actions
3.4.
Follow-up and Supplemental Safety Pharmacology
Studies
3.5.
Pharmacokinetics: absorption,
distribution; metabolism; excretion
4.
Animal Toxicology (for details refer Appendix III)
4.1.
General Aspects
4.2.
Systemic Toxicity Studies
4.3.
Male Fertility Study
4.4.
Female Reproduction and
Developmental Toxicity Studies
4.5.
Local toxicity
4.6.
Allergenicity/Hypersensitivity
4.7.
Genotoxicity
4.8.
Carcinogenicity
5.
Human / Clinical pharmacology (Phase I)
5.1.
Summary
5.2.
Specific Pharmacological
effects
5.3.
General Pharmacological
effects
5.4.
Pharmacokinetics, absorption,
distribution, metabolism, excretion
5.5.
Pharmacodynamics / early
measurement of drug activity
6.
Therapeutic exploratory trials (Phase II)
6.1.
Summary
6.2.
Study report(s) as given in
Appendix II
7.
Therapeutic confirmatory trials (Phase III)
7.1.
Summary
7.2.
Individual study reports with
listing of sites
and Investigators.
8.
Special studies
8.1.
Summary
8.2.
Bio-availability /
Bio-equivalence.
8.3 Other studies e.g.
geriatrics, paediatrics, pregnant or nursing women
9.
Regulatory status in other countries
9.1.
Countries where the drug
is
a. Marketed
b. Approved
c. Approved as IND
d. Withdrawn, if any, with
reasons
9.2.
Restrictions on use, if any,
in countries where marketed /approved
9.3.
Free sale certificate or
certificate of analysis, as appropriate.
10. Prescribing information
10.1. Proposed full prescribing
information
10.2. Drafts of labels and
cartons
11. Samples and Testing Protocol/s
11.1. Samples of pure drug substance
and finished product (an equivalent of 50 clinical doses, or more number of
clinical doses if prescribed by the Licensing Authority), with testing
protocol/s, full impurity profile and release specifications.
NOTES:
(1)
All items may not be applicable to all drugs. For
explanation, refer text of Schedule Y.
(2)
For requirements of data to be submitted with
application for clinical trials refer text of this Schedule.
APPENDIX I-A
DATA REQUIRED TO BE SUBMITTED
BY AN APPLICANT FOR GRANT OF PERMISSION TO IMPORT AND / OR MANUFACTURE A NEW DRUG ALREADY
APPROVED IN THE COUNTRY.
1. Introduction
A brief description of the
drug and the therapeutic class
2. Chemical and pharmaceutical
information
2.1 Chemical name, code name
or number, if any; non-proprietary or generic name, if any, structure;
physico-chemical properties
2.2 Dosage form and its
composition
2.3 Test specifications
(a) active ingredients
(b) inactive ingredients
2.4 Tests for identification
of the active ingredients and method of tis assay
2.5 Outline of the method of
manufacture of active ingredients
2.6 Stability data
3. Marketing information
3.1 Proposed package insert / promotional literature
3.2 Draft specimen of the label and carton
4. Special studies conducted
with approval of Licensing Authority
4.1 Bioavailability /
Bioequivalence and comparative dissolution studies for
oral dosage forms
4.2 Sub-acute animal toxicity studies for intravenous infusions and
injectables
Appendix II
1.
Title Page:-
This page should contain
information about the title of the study, the protocol code, name of the
investigational product tested, development Phase, indication studied, a brief
description of the trial design, the start and end date of patient accrual and
the names of the Sponsor and the participating Institutes (Investigators).
2. Study Synopsis
(1 to 2 pages): A brief overview of the study from the protocol development to
the trial closure should be given here. This section will only summarize the
important conclusions derived from the study.
4.
List of Abbreviations and Definitions
5.
Table of contents
6.
Ethics Committee:
This section should document
that the study was conducted in accordance with the ethical principles of
Declaration of Helsinki. A detailed description of the Ethics Committee
constitution and date(s) of approvals of trial documents for each of the
participating sites should be provided. A declaration should state that EC
notifications as per
Good Clinical Practice Guidelines issued by Central Drugs Standard
Control Organization and Ethical Guidelines for Biomedical Research on Human
Subjects, issued by Indian Council of Medical Research have been followed.
7.
Study Team:
Briefly describe the
administrative structure of the study (Investigators, site staff, Sponsor/
designates, Central laboratory etc.).
8.
Introduction:
A brief description of the
product development rationale should be given here.
9.
Study Objective:
A statement describing the
overall purpose of the study and the primary and secondary objectives to be
achieved should be mentioned here.
10.
Investigational Plan:
This section should describe
the overall trial design, the Subject selection criteria, the treatment
procedures, blinding / randomization techniques if any, allowed/ disallowed
concomitant treatment, the efficacy and safety criteria assessed, the data
quality assurance procedures and the statistical methods planned for the
analysis of the data obtained.
11. Trial Subjects
A clear
accounting of all trial Subjects who entered the study will be given here.
Mention should also be made of all cases that were dropouts or protocol
deviations. Enumerate the patients screened, randomised,
and prematurely discontinued. State reasons for premature discontinuation of
therapy in each applicable case.
12.
Efficacy evaluation
The results of evaluation of
all the efficacy variables will be described in this section with appropriate
tabular and graphical representation. A brief description of the demographic
characteristics of the trial patients should also be provided along with a
listing of patients and observations excluded from efficacy analysis.
13.
Safety Evaluation
This section should include
the complete list
13.1 all serious adverse
events, whether expected or unexpected and
13.2 unexpected advese events
whether serious or not (compliled from data received as per Appendix XI).
The comparison of adverse
events across study groups may be presented in a tabular or graphical form. This
section should also give a brief narrative of all important events considered
related to the investigational product.
14.
Discussion and overall Conclusion
Discussion of the important
conclusions derived from the trial and scope for further development.
15. List of References
16.
Appendices
a. Protocol and
amendments
b. Specimen of
Case Record Form
c. Investigators’
name(s) with contact addresses, phone, email etc.
d. Patient data
listings
e. List of trial
participants treated with investigational product
f.
Discontinued
participants
g. Protocol
deviations
h.
CRFs of cases involving death and life threatening adverse event
cases
i.
Publications
from the trial
j.
Important
publications referenced in the study
k.
Audit
certificate, if available
l.
Investigator’s certificate that he/she has read the report and that the
report accurately describes the conduct and the results of the study.
Appendix III
ANIMAL TOXICOLOGY
(NON-CLINICAL TOXICITY STUDIES)
1.
General Principles
Toxicity studies should comply
with the norms of Good Laboratory Practice (GLP). Briefly, these studies should be performed by
suitably trained and qualified staff employing properly calibrated and
standardized equipment of adequate size and capacity. Studies should be
done as per written protocols with modifications (if any) verifiable
retrospectively.
Standard operating procedures (SOPs) should be followed for all
managerial and laboratory tasks related to these studies. Test substances and
test systems (in-vitro or in-vivo) should be properly characterized and
standardized.
All documents belonging to each study, including its approved protocol,
raw data, draft report, final report, and histology slides and paraffin tissue
blocks 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 of the
conduct of non-clinical toxicity studies or in specially designed studies)
should be conducted to assess the systemic exposure achieved in animals and its
relationship to dose level and the time course of the toxicity study. Other
objectives of toxicokinetic studies include obtaining data to relate the
exposure achieved in toxicity studies to toxicological findings 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 to provide information which, in conjunction with the toxicity
findings, contributes to the design of subsequent non-clinical toxicity
studies.
1.1
Systemic Toxicity Studies
1.1.1 Single-dose Toxicity
Studies: These
studies (see Appendix I item 4.2) should be carried out in 2 rodent species
(mice and rats) using the same route as intended for humans. In addition, unless
the intended route of administration in humans is only intravenous, at least one
more route should be used in one of the species to ensure systemic absorption of
the drug. This
route should depend on the nature of the drug. A limit of 2g/kg (or 10 times the
normal dose that is intended in humans, whichever is higher) is recommended for
oral dosing.
Animals should be observed 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 be
observed for up to 7 days after parenteral administration and up to 14 days
after oral administration. Symptoms, signs and mode of death should be reported,
with appropriate macroscopic and microscopic findings where necessary. LD10 and LD50 should be
reported preferably with 95 percent confidence limits. If LD50s cannot be determined, reasons for the same should
be stated.
The dose causing severe toxic
manifestations or death should be defined in the case of cytotoxic anticancer
agents, and the post-dosing observation period should be to 14 days. Mice should first
be used for determination of MTD. Findings should then be confirmed in rat for
establishing linear relationship between toxicity and body surface area. In case of
nonlinearity, data of the more sensitive species should be used to determine the
Phase I starting dose. Where rodents are known to be poor predictors
of human toxicity (e.g., antifolates), or where the cytotoxic drug acts by a
novel mechanism of action, MTD should be established in non-rodent species.
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 one should be a non-rodent. Dose ranging studies should precede the
14-, 28-, 90- or 180- day toxicity studies. Duration of the final systemic toxicity study
will depend on the duration, therapeutic indication and scale of the proposed
clinical trial. (see Item 1.8). If a species is known to metabolize the drug in
the same way as humans, it should be preferred for toxicity studies.
In repeated-dose toxicity
studies the drug should be administered 7 days a week by the route 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 Item 1.9.
Wherever applicable, a control
group of animals given the vehicle alone should 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 . To make allowance
for the sensitivity of the species the intermediate dose should cause some
symptoms, but not gross toxicity or death, and should be placed logarithmically
between the other two doses.
The parameters to be monitored
and recorded in long-term toxicity studies should include behavioral,
physiological, biochemical and microscopic observations. In case of
parenteral drug administration, the sites of injection should be Subjected to
gross and microscopic examination. Initial and final electrocardiogram and
fundus examination should be carried out in the non-rodent species.
In the case of cytotoxic
anticancer agents dosing and study design should be in accordance with the
proposed clinical schedule in terms of days of exposure and number of
cycles. Two
rodent species may be tested for initiating Phase I trials. A non-rodent
species should be added if the drug has a novel mechanism of action, or if
permission for Phase II, III or marketing is being sought.
For most compounds, it is
expected that single dose tissue distribution studies with sufficient
sensitivity and specificity will provide an adequate assessment of tissue
distribution and the potential for accumulation. Thus, repeated dose tissue
distribution studies should not be required uniformly for all compounds and
should only be conducted when appropriate data cannot be derived from other
sources. Repeated dose studies may be appropriate under certain circumstances
based on the data from single dose tissue distribution studies, toxicity and
toxicokinetic studies. The studies may be most appropriate for compounds which
have an apparently long half life, incomplete elimination or unanticipated organ
toxicity.
Notes:
(i) Single Dose
Toxicity Study:
Each group should contain at least 5 animals of either sex. At least four
graded doses should be given. Animals should be exposed to the test
substance in a single bolus or by continuous infusion or several doses within 24
hours. Animals
should be observed for 14 days. Signs of intoxication, effect on body weight,
gross pathological changes should be reported. It is desirable to include histo-pathology of
grossly affected organs, if any.
(ii)
Dose-ranging Study: Objectives of this study include the
identification of
target organ of toxicity and establishment of MTD for subsequent studies.
(a)
Rodents: Study should be performed in one rodent
species (preferably rat) by the proposed clinical route of administration. At least four
graded doses including control should be given, and each dose group as well as
the vehicle control should consist of a minimum of 5 animals of each sex. Animals should be
exposed to the test substance daily for 10 consecutive days. Highest dose should
be the maximum tolerated dose of single-dose study. Animals should be
observed daily for signs of intoxication (general appearance, activity and
behaviour etc), and periodically for the body weight and laboratory
parameters.
Gross examination of viscera and microscopic examination of affected
organs should be done.
(b)
Non-rodents: One male and one female are to be taken for
ascending Phase MTD study. Dosing should start after initial recording
of cage-side and laboratory parameters. Starting dose may be 3 to 5 times the
extrapolated effective dose or MTD (whichever is less), and dose escalation in
suitable steps should be done every third day after drawing the samples for
laboratory parameters. Dose should be lowered appropriately when
clinical or laboratory evidence of toxicity are observed. Administration of
test substance should then continue for 10 days at the well-tolerated dose level
following which, samples for laboratory parameters should be taken. Sacrifice, autopsy
and microscopic examination of affected tissues should be performed as in the
case of rodents.
(iii) 14-28 Day
repeated-dose toxicity studies: One rodent (6-10/sex/group) and one
non-rodent (2-3/sex/group) species are needed. Daily dosing by proposed clinical route at
three dose levels should be done with highest dose having observable toxicity,
mid-dose between high and low dose, and low dose. The doses should preferably be
multiples of the effective dose and free from toxicity. Observation
parameters should include cage-side observations, body weight changes,
food/water intake, blood biochemistry, haematology, and gross and microscopic
studies of all viscera and tissues.
(iv) 90-Day
repeated-dose toxicity studies: One rodent (15-30/sex/group) and one
non-rodent (4-6/sex/group) species are needed. Daily dosing by proposed clinical route at
three graded dose levels should be done. In addition to the control a
“high-dose-reversal” group and its control group should be also included. Parameters should
include signs of intoxication (general appearance, activity and behaviour etc),
body weight, food intake, blood biochemical parameters, hematological values,
urine analysis, organ weights, gross and microscopic study of viscera and
tissues. Half
the animals in “reversal” groups (treated and control) should be sacrificed
after 14 days of stopping the treatment. The remaining animals should be sacrificed
after 28 days of stopping the treatment or after the recovery of signs and/or
clinical pathological changes – whichever comes later, and evaluated for the
parameters used for the main study.
(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 by proposed 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 and microscopic examination of organs and
tissues.
1.2 Male Fertility Study
One rodent species (preferably
rat) should be used.
Dose selection should be done from the results of the previous 14 or
28-day toxicity study in rat. Three dose groups, the highest one showing
minimal toxicity in systemic studies, and a control group should be taken. Each group should
consist of 6 adult male animals. Animals should be treated with the test
substance by the intended route of clinical use for minimum 28 days and maximum
70 days before 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 be continued till the
detection of vaginal plug or 10 days, whichever is earlier. Females getting
thus pregnant should be examined for their fertility index after day 13 of
gestation. All
the male animals should be sacrificed at the end of the study. Weights of each
testis and epididymis should be separately recorded. Sperms from one
epididymis should be examined for their motility and morphology. The other
epididymis and both testes should be examined for their histology.
1.3
Female Reproduction and Developmental Toxicity Studies
These studies (see Appendix I,
item 4.4) need to be carried out for all drugs proposed to be studied or used in
women of child bearing age. Segment I, II and III studies (see below) are
to be performed in albino mice or rats, and segment II study should include
albino rabbits also as a second test species.
On the occasion, when the test
article is not compatible with the rabbit (e.g. antibiotics which are effective
against gram positive, anaerobic organisms and protozoas) the Segment II data in
the mouse may be substituted.
1.3.1 Female
Fertility Study (Segment I): The study should be done in one rodent
species (rat preferred). The drug should be administered to both males and
females, beginning a sufficient number of days (28 days in males and 14 days in
females) before mating. Drug treatment should continue during mating
and, subsequently, during the gestation period. Three graded doses should be used, the
highest dose (usually the MTD obtained from previous systemic toxicity studies)
should not affect general health of the parent animals. At least 15 males and 15
females should be used per dose group. Control and the treated groups should be
of similar size.
The route of administration should be the same as intended for
therapeutic use.
Dams should be allowed to
litter and their medication should be continued till the weaning of pups. Observations on
body weight, food intake, clinical signs of intoxication, mating behaviour,
progress of gestation/ parturition periods, length of gestation, parturition,
post-partum health and gross pathology (and histopathology of affected organs)
of dams should be recorded. The pups from both treated and control groups
should be observed for general signs of intoxication, sex-wise distribution in
different treatment groups, body weight, growth parameters, survival, gross
examination, and autopsy. Histopathology of affected organs should be
done.
1.3.2 Teratogenicity Study (Segment II): One rodent
(preferably rat) and one non-rodent (rabbit) species are to be used. The drug
should be administered throughout the period of organogenesis, using three dose
levels as described for segment I. The highest dose should cause minimum
maternal toxicity and the lowest one should be proportional to the proposed dose
for clinical use in humans or a multiple of it. The route of administration should be the
same as intended for human therapeutic use.
The control and the treated
groups should consist of at least 20 pregnant rats (or mice) and 12 rabbits, on
each dose level.
All foetuses should to be subjected to gross examination, one of the
foetuses should be examined for skeletal abnormalities and the other half for
visceral abnormalities. Observation parameters should
include: (Dams) signs of intoxication, effect on body weight, effect on food
intake, examination of uterus, ovaries and uterine contents, number of corpora
lutea, implantation sites, resorptions (if any); and for the foetuses, the total
number, gender, body length, weight and gross/ visceral/ skeletal abnormalities,
if any.
1.3.3 Perinatal Study (Segment III): This study is
specially recommended if the drug is to be given to pregnant or nursing mothers
for long periods or where there are indications of possible adverse effects on
foetal development.
One rodent species (preferably rat) is needed. Dosing at levels
comparable to multiples of human dose should be done by the intended clinical
route. At
least 4 groups (including control), each consisting of 15 dams should be
used. The drug
should be administered throughout the last trimester of pregnancy (from day 15
of gestation) and then the dose that causes low foetal loss should be continued
throughout lactation and weaning. Dams should then be sacrificed and
examined as described below.
One male and one female from
each litter of F1 generation (total 15 males and
15 females in each group) should be selected at weaning and treated with vehicle
or test substance (at the dose levels described above) throughout their periods
of growth to sexual maturity, pairing, gestation, parturition and
lactation.
Mating performance and fertility of F1
generation should thus be evaluated to obtain the F2 generation whose growth parameters should be
monitored till weaning. The criteria of evaluation should be the same
as described earlier (3.4.1).
Animals should be sacrificed
at the end of the study and the observation parameters should include (Dams)
body weight, food intake, general signs of intoxication, progress of gestation/
parturition periods and gross pathology (if any); and for pups, the clinical
signs, sex-wise distribution in dose groups, body weight, growth parameters,
gross examination, survival and autopsy (if needed) and where necessary,
histopathology.
1.4 Local toxicity
These studies (see Appendix I,
item 4.5) are required when the new drug is proposed to be used by some special
route (other than oral) in humans. The drug should be applied to an appropriate
site (e.g., skin or vaginal mucous membrane) to determine local effects in a
suitable species.
Typical study designs for these studies should include three dose levels
and untreated and/ or vehicle control, preferably use of 2 species, and
increasing group size with increase in duration of treatment. Where dosing is
restricted due to anatomical or humane reasons, or the drug concentration cannot
be increased beyond a certain level due to the problems of solubility, pH or
tonicity, a clear statement to this effect should be given. If the drug is
absorbed from the site of application, appropriate systemic toxicity studies
will also be required.
Notes:
(i)
Dermal toxicity study: The study should be done in rabbit and
rat. Daily
topical (dermal) application of test substance in its clinical dosage form
should be done.
Test material should be applied on shaved skin covering not less than 10%
of the total body surface area. Porous gauze dressing should be used to hold
liquid material in place. Formulations with different concentrations
(at least 3) of test substance, several fold higher than the clinical dosage
form should be used.
Period of application may vary from 7 to 90 days depending on the
clinical duration of use. Where skin irritation is grossly visible in
the initial studies, a recovery group should be included in the subsequent
repeated-dose study.
Local signs (erythema, oedema and eschar formation) as well as
histological examination of sites of application should be used for evaluation
of results.
(ii) Photo-allergy or dermal
photo-toxicity: It should be tested by Armstrong/ Harber Test in guinea
pig. This test
should be done if the drug or a metabolite is related to an agent causing
photosensitivity or the nature of action suggests such a potential (e.g., drugs
to be used in treatment of leucoderma). Pretest in 8 animals should screen 4
concentrations (patch application for 2 hours ±15 min.) with and without UV
exposure (10 J/cm2). Observations
recorded at 24 and 48 hours should be used to ascertain highest nonirritant
dose. Main
test should be performed with 10 test animals and 5 controls. Induction with the
dose selected from pretest should use 0.3 ml/patch for 2 hour ±15 min. followed
by 10 J/cm2 of UV exposure. This should be
repeated on day 0, 2,4,7,9 and 11 of the test. Animals should be challenged with the
same concentration of test substance between day 20 to 24 of the test with a
similar 2-hour application followed by exposure to 10 J/cm2 of UV light. Examination and grading of erythema and
oedema formation at the challenge sites should be done 24 and 48 hours after the
challenge. A
positive control like musk ambrett or psoralin should be used.
(iii) Vaginal
Toxicity Test:
Study is to be done in rabbit or dog. Test substance should be applied topically
(vaginal mucosa) in the form of pessary, cream or ointment. Six to ten animals
per dose group should be taken. Higher concentrations or several daily
applications of test substance should be done to achieve multiples of daily
human dose. The minimum duration of drug treatment is 7 days (more according to
clinical use), Subject to a maximum of 30 days. Observation parameters should include
swelling, closure of introitus and histopathology of vaginal wall.
(iv) Rectal
Tolerance Test:
For all preparations meant for rectal administration this test may be
performed in rabbits or dogs. Six to ten animals per dose group should be
taken.
Formulation in volume comparable to human dose (or the maximum possible
volume) should be applied once or several times daily, per rectally, to achieve
administration of multiples of daily human dose. The minimum duration of application is 7 days
(more according to clinical use), Subject to a maximum of 30 days. Size of
suppositories may be smaller, but the drug content should be several fold higher
than the proposed human dose. Observation parameters should include
clinical signs (sliding on backside), signs of pain, blood and/or mucus in
faeces, condition of anal region/sphincter, gross and (if required) histological
examination of rectal mucosa.
(v)
Parenteral Drugs: For products meant for intravenous or
intramuscular or subcutaneous or intradermal injection the sites of injection in
systemic toxicity studies should be specially examined grossly and
microscopically.
If needed, reversibility of adverse effects may be determined on a case
to case basis.
(vi) Ocular toxicity
studies (for products meant for ocular instillation): These studies
should be carried out in two species, one of which should be the albino rabbit
which has a sufficiently large conjunctival sac. Direct delivery of drug onto the cornea in
case of animals having small conjunctival sacs should be ensured. Liquids, ointments,
gels or soft contact lenses (saturated with drug) should be used. Initial single dose
application should be done to decide the exposure concentrations for
repeated-dose studies and the need to include a recovery group. Duration of the
final study will depend on the proposed length of human exposure Subject to a
maximum of 90 days. At least two different concentrations
exceeding the human dose should be used for demonstrating the margin of
safety. In
acute studies, one eye should be used for drug administration and the other kept
as control. A
separate control group should be included in repeated-dose studies.
Slit-lamp examination should
be done to detect the changes in cornea, iris and aqueous humor. Fluorescent dyes
(sodium fluorescein, 0.25 to 1.0%) should be used for detecting the defects in
surface epithelium of cornea and conjunctiva. Changes in intra-ocular tension should be
monitored by a tonometer. Histological examination of eyes should be
done at the end of the study after fixation in Davidson’s or Zenker’s fluid.
(vii)
Inhalation toxicity studies: The studies are to be undertaken in one
rodent and one non-rodent species using the formulation that is to be eventually
proposed to be marketed. Acute, subacute and chronic toxicity studies
should be performed according to the intended duration of human exposure. Standard systemic
toxicity study designs (described above) should be used. Gases and vapors
should be given in whole body exposure chambers; aerosols are to be given by
nose-only method.
Exposure time and concentrations of test substance (limit dose of 5mg/l)
should be adjusted to ensure exposure at levels comparable to multiples of
intended human exposure. Three dose groups and a control (plus vehicle
control, if needed) are required. Duration of exposure may vary Subject to a
maximum of 6 hours per day and five days a week. Food and water should be withdrawn during the
period of exposure to test substance.
Temperature, humidity and flow
rate of exposure chamber should be recorded and reported. Evidence of
exposure with test substance of particle size of 4 micron (especially for
aerosols) with not less that 25% being 1 micron should be provided. Effects on
respiratory rate, findings of bronchial lavage fluid examination, histological
examination of respiratory passages and lung tissue should be included along
with the regular parameters of systemic toxicity studies or assessment of margin
of safety.
1.5 Allergenicity/ Hypersensitivity:
Standard tests include guinea
pig maximization test (GPMT) and local lymph node assay (LLNA) in mouse. Any one of the two
may be done.
Notes:
(i)
Guinea Pig Maximization Test: The test is to be
performed in two steps; first, determination of maximum nonirritant and minimum
irritant doses, and second, the main test. The initial study will also have two
components. To
determine the intradermal induction dose, 4 dose levels should be tested by the
same route in a batch of 4 male and 4 female animals (2 of each sex should be
given Freund’s adjuvant). The minimum irritant dose should be used for
induction.
Similarly, a topical minimum irritant dose should be determined for
challenge.
This should be established in 2 males and 2 females. A minimum of
6 male and 6 female animals per group should be used in the main study. One test and one
control group should be used. It is preferable to have one more positive
control group.
Intradermal induction (day 1) coupled with topical challenge (day 21)
should be done.
If there is no response, re-challenge should be done 7-30 days after the
primary challenge.
Erythema and oedema (individual animal scores as well as maximization
grading) should be used as evaluation criteria.
(ii) Local Lymph
Node Assay:
Mice used in this test should be of the same sex, either only males or
only females.
Drug treatment is to be given on ear skin. Three graded doses, the highest being maximum
nonirritant dose plus vehicle control should be used. A minimum of 6 mice
per group should be used. Test material should be applied on ear skin
on three consecutive days and on day 5, the draining auricular lymph nodes
should be dissected out 5 hours after i.v. 3H-thymidine or bromo-deoxy-uridine (BrdU). Increase in 3H-thymidine or BrdU incorporation should be used as
the criterion for evaluation of results.
1.6 Genotoxicity
Genotoxic compounds, in the
absence of other data, shall be presumed to be trans-species carcinogens,
implying a hazard to humans. Such compounds need not be Subjected to long-term
carcinogenicity studies. However, if such a drug is intended to be administered
for chronic illnesses or otherwise over a long period of time - a chronic
toxicity study (up to one year) may be necessary to detect early tumorigenic
effects.
Genotoxicity tests are in vitro and in vivo tests
conducted to detect compounds which induce genetic damage directly or
indirectly. These tests should enable a hazard identification with respect to
damage to DNA and its fixation.
The following standard test
battery is generally expected to be conducted:
(i) A test
for gene mutation in bacteria.
(ii) An in vitro test with cytogenetic evaluation of
chromosomal damage with mammalian cells or an in vitro
mouse lymphoma tk assay.
(iii)
An in vivo test for chromosomal damage using
rodent hematopoietic cells.
Other genotoxicity tests e.g.
tests for measurement of DNA adducts, DNA strand breaks, DNA repair or
recombination serve as options in addition to the standard battery for further
investigation of genotoxicity test results obtained in the standard battery.
Only under extreme conditions in which one or more tests comprising the standard
battery cannot be employed for technical reasons, alternative validated tests
can serve as substitutes provided sufficient scientific justification should be
provided to support the argument that a given standard battery test is not
appropriate.
Both in-vitro and in-vivo
studies should be done. In-vitro studies should include Ames’
Salmonella assay and chromosomal aberrations (CA) in cultured cells. In-vivo studies
should include micronucleus assay (MNA) or CA in rodent bone marrow. Data analysis of CA
should include analysis of ‘gaps.’
Cytotoxic anticancer
agents:
Genotoxicity data are not required before Phase I and II trials. But these studies
should be completed before applying for Phase III trials.
Notes:
Ames’ Test (Reverse mutation
assay in Salmonella):
S. typhimurium tester strains such as TA98, TA100, TA102, TA1535, TA97 or
Escherichia coli WP2 uvrA
or Escherichia coli WP2 uvrA (pKM101) should be used.
(i)
In-vitro exposure (with and without metabolic
activation, S9 mix) should be done at a minimum of 5 log dose levels. “Solvent” and
“positive” control should be used. Positive control may include
9-amino-acridine, 2-nitrofluorine, sodium azide and mitomycin C, respectively,
in the tester strains mentioned above. Each set should consist of at least three
replicates. A
2.5 fold (or more) increase in number of revertants in comparison to spontaneous
revertants would be considered positive.
(ii)
In-vitro cytogenetic assay : The desired level of toxicity for in vitro cytogenetic tests using cell lines should be
greater than 50% reduction in cell number or culture confluency. For lymphocyte
cultures, an inhibition of mitotic index by greater than 50% is considered
sufficient. It should be performed in CHO cells or on human lymphocyte in
culture.
In-vitro exposure (with and without metabolic activation, S9 mix) should
be done using a minimum of 3 log doses. “Solvent” and “positive” control should be
included. A
positive control like Cyclophosphamide with metabolic activation and Mitomycin C
for without metabolic activation should be used to give a reproducible and
detectable increase clastogenic effect over the background which demonstrates
the sensitivity of the test system. Each set should consist of at least three
replicates.
Increased number of aberrations in metaPhase chromosomes should be used
as the criteria for evaluation.
(iii)
In-vivo micronucleus assay: One rodent species (preferably mouse) is
needed. Route
of administration of test substance should be the same as intended for
humans. Five
animals per sex per dose groups should be used. At least three dose levels, plus “solvent”
and “positive” control should be tested. A positive control like mitomycin C or
cyclophosphamide should be used. Dosing should be done on day 1 and 2 of study
followed by sacrifice of animals 6 hours after the last injection. Bone marrow from
both the femora should be taken out, flushed with fetal bovine serum (20 min.),
pelletted and smeared on glass slides. Giemsa-MayGruenwald staining should be done
and increased number of micronuclei in polychromatic erythrocytes (minimum 1000)
should be used as the evaluation criteria.
(iv) In-vivo
cytogenetic assay:
One rodent species (preferably rat) is to be used. Route of
administration of test substance should be the same as intended for humans. Five
animals/sex/dose groups should be used. At least three dose levels, plus “solvent”
and “positive” control should be tested. Positive control may include
cyclophosphamide.
Dosing should be done on day 1 followed by intra-peritoneal colchicine
administration at 22 hours. Animals should be sacrificed 2 hours after
colchicine administration. Bone marrow from both the femora should be
taken out, flushed with hypotonic saline (20 min.), pelletted and resuspended in
Carnoy’s fluid.
Once again the cells should be pelletted and dropped on clean glass
slides with a Pasteur pipette. Giemsa staining should be done and increased
number of aberrations in metaPhase chromosomes (minimum 100) should be used as
the evaluation criteria.
1.7 Carcinogenicity
(see Appendix I, item 4.8)
Carcinogenicity studies should
be performed for all drugs that are expected to be clinically used for more than
6 months as well as for drugs used frequently in an intermittent manner in the
treatment of chronic or recurrent conditions. Carcinogenicity studies are also to be
performed for drugs if there is concern about their carcinogenic potential
emanating from previous demonstration of carcinogenic potential in the product
class that is considered relevant to humans or where structure-activity
relationship suggests carcinogenic risk or when there is evidence of
preneoplastic lesions in repeated dose toxicity studies or when long-term tissue
retention of parent compound or metabolite(s) results in local tissue reactions
or other pathophysiological responses. For pharmaceuticals developed to treat
certain serious diseases, Licensing Authority may allow carcinogenicity testing
to be conducted after marketing permission has been granted.
In instances where the
life-expectancy in the indicated population is short (i.e., less than 2 - 3
years) - no long-term carcinogenicity studies may be required. In cases where
the therapeutic agent for cancer is generally successful and life is
significantly prolonged there may be later concerns regarding secondary cancers.
When such drugs are intended for adjuvant therapy in tumour free patients or for
prolonged use in non-cancer indications, carcinogenicity studies may be / are
needed.
Completed rodent carcinogenicity studies are not needed in advance of the
conduct of large scale clinical trials, unless there is special concern for the
patient population.
Carcinogenicity studies should
be done in a rodent species (preferably rat). Mouse may be employed only with proper
scientific justification. The selected strain of animals should not
have a very high or very low incidence of spontaneous tumors.
At least three dose levels
should be used.
The highest dose should be sub-lethal, and it should not reduce the life
span of animals by more than 10% of expected normal. The lowest dose
should be comparable to the intended human therapeutic dose or a multiple of it,
e.g. 2.5x; to make allowance for the sensitivity of the species. The intermediate
dose to be placed logarithmically between the other two doses. An untreated
control and (if indicated) a vehicle control group should be included. The drug
should be administered 7 days a week for a fraction of the life span comparable
to the fraction of human life span over which the drug is likely to be used
therapeutically.
Generally, the period of dosing should be 24 months for rats and 18
months for mice.
Observations should include
macroscopic changes observed at autopsy and detailed histopathology of organs
and tissues.
Additional tests for carcinogenicity (short-term bioassays, neonatal
mouse assay or tests employing transgenic animals) may also be done depending on
their applicability on a case to case basis.
Note:
Each dose group and concurrent
control group not intended to be sacrificed early should contain atleast 50
animals of each sex.
A high dose sattelite group for evaluation of pathology other than
neoplasia should contain 20 animals of each sex while the sattelite control
group should contain 10 animals of each sex. Observation parameters should include signs
of intoxication, effect on body weight, food intake, clinical chemistry
parameters, hematology parameters, urine analysis, organ weights, gross
pathology and detailed histopathology. Comprehensive descriptions of benign and
malignant tumour development, time of their detection, site, dimensions,
histological typing etc. should be given.
1.8 Animal toxicity requirements for clinical trials and
marketing of a new drug.
|
Systemic Toxicity
Studies | |||
|
Route of
administration |
Duration of proposed
human administration |
Human Phase(s) for which
study is proposed to be conducted |
Long term toxicity
requirements |
|
Oral or Parenteral or
Transdermal |
Single dose or several
doses in one day, Upto 1wk |
I,II,III |
2sp,2wk |
|
|
> 1 wk but upto
2wk |
I,II,III |
2sp;4wk |
|
|
> 2 wk but upto
4wk |
I,II,III |
2sp;12wk |
|
|
Over 1mo |
I,II,III |
2sp;24wk |
|
Inhalation (general
anaesthetics, aerosols) |
Upto 2 wk |
I,II,III |
2sp;1mo; (Exposure time
3h/d, 5d/wk) |
|
|
Upto 4wk |
I,II,III |
2sp;12wk, (Exposure time
6h/d, 5d/wk) |
|
|
> 1 4wk |
I,II,III |
2sp;24wk, (Exposure time
6h/d, 5d/wk) |
|
Local Toxicity
Studies | |||
|
Dermal |
Upto 2 wk |
I,II |
1sp;4wk |
|
|
|
III |
2sp;4wk |
|
|
> 2 wk |
I,II,III |
2sp;12wk |
|
Ocular or Otic or
Nasal |
Upto 2 wk |
I,II |
1sp;4wk |
|
|
|
III |
2sp;4wk |
|
|
> 2 wk |
I,II,III |
2sp;12wk |
|
Vaginal or Rectal |
Upto 2 wk |
I,II |
1sp;4wk |
|
|
|
III |
2sp;4wk |
|
|
> 2 wk |
I,II,III |
2sp;12wk |
|
Special Toxicity
Studies | |||
|
Male Fertility
Study: ·
Phase I, II, III in male
volunteers/patients | |||
|
Female Reproduction and
Developmental Toxicity Studies: ·
Segment II studies in 2 species; Phase II, III
involving female patients of child-bearing age. ·
Segment I study; Phase III involving female patients
of child-bearing age. ·
Segment III study; Phase III for drugs to be given to
pregnant or nursing mothers for long periods or where there are
indications of possible adverse effects on foetal development. | |||
|
Allergenicity/Hypersensitivity: ·
Phase I, II, III - when there is a cause of concern
or for parenteral drugs (including dermal application) | |||
|
Photo-allergy or dermal
photo-toxicity: ·
Phase I, II, III - if the drug or a metabolite is
related to an agent causing photosensitivity or the nature of action
suggests such a potential. | |||
|
Genotoxicity: ·
In-vitro studies - Phase I ·
Both in-vitro and in-vivo - Phase II, III | |||
|
arcinogenicity: ·
Phase III - when there is a cause for concern, or
when the drug is to be used for more than 6 months. | |||
Abbreviations: sp-species;
mo-month; wk-week; d -day; h-hour; I, II, III - Phases of clinical trial;
|
Note: |
1.Animal toxicity data
generated in other countries may be accepted and may not be asked to be
repeated/duplicated in India on a case to case basis depending upon the
quality of data and the credentials of the laboratory (ies) where such
data has been generated. 2. Requirements for
fixed dose combinations are given in Appendix VI. |
|
|
|
1.9
Number of animals required for repeated-dose toxicity studies
|
|
14-28 days |
84-182 days | ||||||
|
Group |
Rodent (Rat) |
Non-rodent (Dog or Monkey) |
Rodent (Rat) |
Non-rodent (Dog or Monkey) | ||||
|
|
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 |
2.0
Laboratory parameters to be included in toxicity studies.
Haematological parameters
|
·
Haemoglobin |
·
Total RBC Count |
·
Haematocrit |
· Reticulocyte Count |
|
·
Total WBC Count |
·
Differential WBC Count |
·
Platelet Count |
·
Terminal Bone Marrow Examination |
|
·
ESR (Non-rodents only) |
· General Blood Picture: A special mention of abnormal and
immature cells should be made. | ||
|
· Coagulation Parameters (Non-rodents only): Bleeding
Time, Coagulation Time, Prothrombin Time, Activated Partial Thromboplastin
Time | |||
Urinalysis Parameters
|
·
Colour |
·
Appearance |
·
Specific Gravity |
·
24-hour urinary output |
|
·
Reaction (pH) |
·
Albumin |
·
Sugar |
·
Acetone |
|
·
Bile pigments |
·
Urobilinogen |
·
Occult Blood |
|
|
· Microscopic examination of urinary sediment. | |||
Blood Biochemical
Parameters
|
·
Glucose |
·
Cholesterol |
·
Triglycerides |
·
HDL Cholesterol (Non-rodents only) |
|
·
LDL Cholesterol (Non-rodents only) |
·
Bilirubin |
·
SGPT (ALT) |
·
SGOT (AST) |
|
·
Alkaline Phosphatase (ALP) |
·
GGT (Non-rodents only) |
·
Blood Urea Nitrogen |
·
Creatinine |
|
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