2. INDEX
1. Introduction
2. History
3. Institutional Ethics Committee
4 Terms of reference andreviewprocedures
5. General statement
6. General Ethical Principles
7. 12 Basic Principles
8. Specific Ethical Principles
9. Submissionof application
10. Check list for protocol
11. Decision-making
12. Recordkeeping
13. Quality Assurance
14. Guidelines for Drug Trials
15. Guidelines for Vaccine Trials
16. Principles of Human Genetic Research
17. Appendix I - The Nuremberg Code
18. Appendix II - The Declarationof Helsinki
19. Bibliography
3. ABBREVIATIONS
CDSCO : Central Drugs Standard ControlOrganization
CECHR : Central Ethics Committee on Human Research
CIOMS : Council for InternationalOrganization of Medical Sciences
DTAB : Drugs Technical Advisory Board
FDA : Food and Drug Administration
FDC : Food, Drug and Cosmetic Act
GCP : Good Clinical Practice
ICH : InternationalConference on Harmonization
ICMR : Indian Council of Medical Research
ICH GCP 6.0 : DocumentE6 of the ICH guidelines, Conserving GCP
IEC : InstitutionalEthics Committee
SOP : Standard Operating Procedure
WHO : World Health Organization
QA : Quality Assurance
4. INTRODUCTION
Advances in the Biomedical Science and Technology and their application in
the practice of medicine are provoking someanxiety among the public and
society with new ethical problems. Society is expressing its concern about whatit
fears would be abuses in scientific investigation and biomedical technology. The
new advances in science and medicine are a cause for celebration and jubilations,
but at the same time, they need careful evaluation of risks againstbenefits and it
raises somedelicate and difficult issues of ethics. These need to be dealt with
extreme sensitivity of human values with utmostcare, and development of
ethical guidelines for the clinical research. In view of the complexity of the
subject, the guidelines can neither be exhaustive nor be static. They need to be
updated, consistentwith the change in the realms of science and technology.
HISTORY
The firstInternationalCode of Ethics for Research involving human
subjects ‘The Nuremberg Code’ was a responseto the cruelties committed by
Nazi Research Physicians revealed at the Nuremberg war crimes trials. Thus, it
was to prevent any repetitions by physician of such attacks on the rights and
welfare of human beings that human research ethics came into being. The
Nuremberg (1947) laid down standards for carrying outhuman experimentations,
emphasizing the subject’s voluntary consent. World Medical Association (1964)
took a step further to reassuresociety by adopting the ‘Declaration of Helsinki’,
which laid down the ethical guidelines for research involving human subjects.
The Indian Council of Medical Research (ICMR), New Delhi had broughta
document in February 1980, ‘Policy Statementof EthicalConsiderationsinvolved
5. in Research on Human Subject’ prepared by the Ethical Committee which is being
used ,not only by ICMR, but also by Research Institutions, GovernmentAgencies,
Non-governmentAgencies. However, need to update this was required keeping
in view the modern biology and recent developments in different medical fields.
Therefore, the Central Ethics Committee on Human Research (CECHR) was
constituted to consider various issues related to ethical, social and legal aspects.
The Committee identified the following major areas and set up sub-Committees
of experts for drawing up a set of guidelines related to clinical evaluation of drugs,
epidemiological research, human genetic research, transplantation research,
assisted reproductivetechnologies and many more. Itwas proposed that these
guidelines be updated periodically, paripasu, with the development of the area of
medical science. In view of the circumstances of developing countries in regard to
the applicability of ‘Nuremberg Code and Declaration of Helsinki’, the Council for
InternationalOrganizations of Medical Sciences (CIOMS) and theWorld Health
Organization (WHO) undertook and issued the proposed international guidelines
for biomedical research involving human subjects (1982). Thepurposeof
proposed guidelines was to indicate the ethical principles that should guide the
conduct of biomedical research involving human subjects, as set in
the ‘Declaration of Helsinki’ which could be applied effectively and efficiently in
developing countries.
Good Clinical Practice (GCP) is an ethical and scientific quality standard for
designing, conducting and recording trials that involvethe participation of human
subjects. Compliance with this standard provides assuranceto public that the
rights, safety and well-being are protected, consistentwith principles in
the ‘Declaration of Helsinki’. A need was however felt to develop our own Indian
guidelines to ensureuniformequality of clinical research throughoutthe country
and to generate data for registration for new drugs beforeuse in Indian
population. An Expert Committee set by Central Drugs Standard Control
Organization (CDSCO) in consultation with experts has formulated the GCP
guidelines for clinical data generation on drugs. TheDrug Technical Advisory
Board (DTAB), the highest Technical Body under D&C Act, has endorsed adoption
6. of GCP guidelines for streamlining the clinical studies in India which would be
usefulto Research Institutions, Investigators, InstitutionalEthics Committee (IEC)
in providing desired direction, protection of rights and welfare of human subjects
of biomedical research.
INSTITUTIONAL ETHICS COMMITTEE (IEC)
Ø “InstitutionalEthics Committee (IEC) is an independent body constituted of
medical / scientific professionals and non-medical/ non-scientific members
whoseresponsibility is to ensurethe protection of the right, safety, and well-
being of human subjects involved in a trial and to provide public assuranceof that
protection.
Ø All proposals on biomedical researches involving human subjects should be
cleared by InstitutionalEthics Committee (IEC), to safeguard the welfare of the
rights of the subjectinvolved.
Ø The sponsor and / or investigator should seek the opinion of Institutional
Ethics Committee regarding suitability of the protocol, methods and documents to
be used in recruitment of subjectsand obtaining theirinformed consent including
adequacy of the information being provided to the subjects. The Ethics
Committee is entrusted not only with the initial view of the proposed research
protocols prior to the initiation of the projects butalso have a continuing
responsibility of regular monitoring for the compliance of the ethics of the
approved programmetill the same are completed. Such an ongoing review is in
accordancewith the‘Declaration of Helsinki’.
7. BASIC RESPONSIBILITIES OF IEC:
1. To protect the dignity, rights and` well-being of potential research
participants.
2. To ensure that universalethical values and InternationalScientific
Standards areexpressed in terms of local community values and customs.
3. To assistin the development and the education of a research
community responsive to local health care requirements.
SALIENT FEATURES OF IEC:
1. Multidisciplinary and multi-sectorial in composition
2. Independent
3. Competent
TERMS OF REFERENCE AND REVIEW PROCEDURES:
1. The IECshould be awareof their role and responsibilities as
Committee Members.
2. Each Committee should haveits own operating procedures available
with each member
3. Any change in the regulatory requirement should be broughtto the
notice of members, keeping in view the National and Internationaldevelopments.
8. 4. The terms of references should include a statement on terms of
appointment with reference to
a. the duration of the term of membership
b. the policy for removal/ replacement
c. the resignation procedureetc.
5. The ethical review should be done through formal meetings and
discussion should notbe taken through circulation of proposals.
6. Every research proposalon human subjects should be reviewed
scientifically, evaluated in terms of risks and benefits with proper justification
7. Scientific evaluation should be done completely prior to ethical
review
8. The Committee should evaluate for the adequacy of documentation
to ensure privacy confidentiality and legal aspects.
9. All proposals on biomedical researches involving human subjects
should be cleared by an appropriately constituted InstitutionalEthics Committee
(IEC), to safeguard the welfare of the rights of the subjectinvolved.
10. The sponsor and / or investigator should seek the opinion
of Institutional Ethics Committee regarding suitability of the protocol, methods
and documents to be used in recruitment of subjects and obtaining their informed
consentincluding adequacy of the information being provided to the subjects.
The Ethics Committees are entrusted not only with the initial view of the
proposed research protocols prior to the initiation of the projects but also have a
continuing responsibility of regular monitoring for the compliance of the ethics of
the approved programmetill the same are completed. Such an ongoing review is
in accordancewith the ‘Declaration of Helsinki’.
11. Interim review :can be resorted to instead of waiting for the
scheduled time of the meeting and decisions can be taken urgently and should be
broughtto the notice of the main committee for the following reasons :
9. a. Re-examinations of a proposalalready examined by the IEC
b. Research study of a minor nature such as examination of case records etc.
c. An urgent proposalof national interest.
GENERAL STATEMENT:
Medical and related research using human beings as subjects mustnecessarily
ensurethat:
1. The PURPOSE of research should be directed towards the increase of
knowledgeabout human condition and for the betterment of all.
2. The research is CONDUCTED in a conducivemanner. The dignity, well
-being, transparency and fair professionaltreatment should be maintained.
3. EVALUATION mustbe done at all stages ensuring the safety of human
life.
GENERAL ETHICAL PRINCIPLES:
All research involving human subjects should be conducted in accordance
with three basic ethical principles, namely respectfor person, beneficence and
justice. The present guidelines are directed at the application of these principles
to research involving human subjects.
10. (A) RESPECT FOR PERSONS includes at least two fundamental ethical
considerations, namely
1. Respect for autonomy
Itincludes the idea that an individual is free to chooseand to act. Both rational
capacity and freedomfromconstraintare necessary elements. “Respect for
persons” includes respecting the decisions of autonomous beings.
2. Protectionfor those withimpairedor diminishedautonomy
Itmeans a recognition by the commission that these people are not capable of
self determination at all times and in all circumstances.
(B) BENEFICENCE – includes the ethical obligation to maximize benefits and
minimize harms and wrongs.
(C) JUSTICE – In the ethics of research involving human subjects the principle
primarily refers to distributivejustice, which means equitable distribution of both
burden and the benefits of participation in research.
TWELVE BASIC PRINCIPLES:
(Common to all areas of biomedical research)
1 All biomedical researches on human subjects should be absolutely
essential after a due consideration of all alternatives for the advancementof
knowledgeand human beings (Principle of Essentiality).
2 The concept of voluntariness and informed consent shallapply to the
community as a whole and to each individual member who is subjectof
research (Principle of voluntariness andInformedConsent).
3 Irrespectiveof the socio-economic status and educational levels, research
subjectshould be fully appraised of all risks arising as a resultof
research (Principle of Non-exploitation).
11. 4 The identity of records of human subjects of research should be kept
confidential and should not be disclosed without valid scientific and legal
reasons (Principle of Privacy and Confidentiality).
5 Due care and caution is taken to ensurethat research subjects areput to
minimum risks / no irreversiblerisks (Principleof Precautions andRisks
Minimisation).
6 The Research is conducted at all times by the competent and qualified
persons (Principle of Professional Competence).
7 The research is committed in a fair, honest, impartial and transparent
manner and records and data are maintained for a reasonableperiod (Principle of
Accountability and Transparency).
8 The research is conducted to benefit all human kind and not justsocially
better off. (Principle of Maximisationof Public Interest andof Distributive
Justice).
9 All institutional arrangements required to be made in respect of research
are made in a bonafide and transparentmanner and records are properly
maintained and preserved. (Principle of Institutional Arrangements).
10 After due experimentation and due evaluation, results arebrought into
public domain through scientific and other publications under the law in forceat
that time (Principle of Public Domain).
11 Itis the responsibility of all directly and indirectly involved with the
research to monitor, review constantly and take remedial action at all stages of
research (Principle of Totality and Responsibility).
12 All persons concerned directly and indirectly should scrupulously observe
the laid down rules, guidelines, norms, directions (Principle of Compliance).
12. SPECIFIC ETHICAL PRINCIPLES:
1. For all biomedical research involving human subjects, theinvestigator must
obtain the informed consent of the prospectivesubjector, in the case of an
individual who is not capable of giving informed consent, the proxy consent of a
properly authorized representative.
2. Before requesting an individual’s consentto participate in research, the
investigator must providethe individual with the following information, in
language that he or she is capable of understanding :
Ø That each individual is invited to participate as a subjectin research, and the
aims and methods of the research – the expected duration of the subject’s
participation – the benefits that might reasonably be expected to result to the
subjector to others as an outcome of the research
Ø Any foreseeable risks or discomfortto the subject, associated with
participation in the research
Ø Any alternative procedures or courses of treatment that might be as
advantageous to the subjectas the procedureor treatment being tested
Ø The extent of the investigator’s responsibility, if any, to providemedical
services to the subject
Ø That therapy will be provided free of chargefor specified types of research-
related injury
Ø Whether the subjector the subject’s family or departments will be
compensated for disability or death resulting fromsuch injury and
Ø That the individual is free to refuseto participate and will be free to
withdraw fromthe research at any time without penalty or loss of benefits to
which he or she would otherwisebe entitled.
3. The investigator has a duty to :
13. Ø Communicate to the prospectivesubjectal the information necessary for
adequately informed consent
Ø Give the prospectivesubjectfull opportunity and encouragement to ask
questions
Ø Exclude the possibility of unjustified deception, undue influence and
intimidation
Ø Seek consentonly after the prospectivesubjecthas adequate knowledgeof
the relevant facts and of the consequences of participation, and has had sufficient
opportunity to consider whether to participate
Ø As a general rule, obtain from each prospectivesubjecta signed form as
evidence of informed consentand
Ø Renew the informed consentof each subjectif there are material changes in
the conditions or procedures of the research
4. Subjects may be paid for inconvenience and time spent, and should be
reimbursed for expenses incurred, in connection with their participation in
research ; they may also receive free medical services. However, the payments
should not be so large or the medical services so extensive as to induce
prospectivesubjects to consentto participate in the research againsttheir better
judgement (“undue inducement”).
5. Pregnantor nursing women should in no circumstances bethe subjects of
non-clinical research unless the research carries no more than minimal risk to the
fetus or nursing infant and the object of the research is to obtain new knowledge
about pregnancy or lactation. As a general rule, pregnant or nursing women
should not be subjects of any clinical trials except such trials as are designed to
protect or advancethe health of pregnantor nursing women or fetuses or
nursing infants, and for which women who are not pregnantor nursing would not
be suitable subjects.
14. 6. Before undertaking research involving children, the investigator must ensure
that :
Ø Children will not be involved in research that might equally well be carried
out with adults
Ø The purposeof the research is to obtain knowledgerelevant to the health
needs of children
Ø A parent or legal guardian of each child has given proxy consent
Ø The consent of each child has been obtained to the extent of the child’s
capabilities
Ø The child’s refusal to participate in research mustalways be respected
unless according to the research protocolthe child would received therapy for
which there is no medially – acceptable alternative
7. Prisoners with serious illness or at risk of serious illness should not
arbitrarily be denied access to investigational drugs, vaccines or other agents that
show promiseof therapeutic or preventive benefit.
8. For severaltypes of epidemiological research individual informed consent is
either impracticable or inadvisable. In such cases, the ethical review committee
should determine whether it is ethically acceptable to proceed without
individual informed consentand whether the investigator’s plans to protect the
safety and respect the privacy of research subjects and to maintain the
confidentiality of the data are adequate
9. Individuals or communities to be invited to be subjects of research should be
selected in such a way that the burdens and benefits of the research will be
equitably distributed. Special justification is required for inviting vulnerable
individuals and, if they are selected, the means of protecting their rights and
welfare mustbe particularly strictly applied.
15. 10. The investigator mustestablish securesafeguards of the confidentiality of
research data. Subjects should be told of the limits to the investigator’s ability to
safeguard confidentiality and of the anticipated consequences of breaches of
confidentiality.
11. Research subjects who suffer physicalinjury as a result of their participation
are entitled to such financial or other assistanceas would compensate them
equitably for any temporary or permanent impairment or disability. In the case of
death, their dependants are entitled to material compensation. The right to
compensate may not be waived.
12. All proposals to conductresearch involving human subjects mustbe
submitted for review and approvalto IEC. The investigator mustobtain such
approvalof the proposal to conduct research before the research is begun.
13. An external sponsoring agency should submitthe research protocolfor
ethical and scientific review as per the guidelines for the IEC.
14. After scientific and ethical approvalin the country of the sponsoring agency,
the appropriateauthorities of the hostcountry, including a national or local
ethical review committee or its equivalent, should satisfy themselves that the
proposed research meets their own ethical requirements.
15. In the treatment of the sick person, the physician mustbe free to sueto a
new diagnostic and therapeutic measure, if in his or her judgement it offers hope
of saving life, re-establishing health or alleviating suffering.
16. The potential benefits, hazards and discomfortof a new method should be
weighted against the advantages of the best current diagnostic and therapeutic
methods.
17. In any medical study, every patient – including those of a control group, if
any – should be assured of the best proven diagnostic and therapeutic method.
18. The refusal of the patient to participate in a study mustnever interfere with
the physician-patientrelationship.
16. 19. If the physician considers it essential not to obtain informed consent, the
specific reasons for this proposalshould be stated in the experimental protocol
for transmission to IEC.
20. The physician can combine medical research with professionalcare, the
objective being the acquisition of new medical knowledge, only to the extent that
medical research is justified by its potential diagnostic or therapeutic value for the
patient.
21. In the purely scientific application of medical research carried out on a human
being, it is the duty of the physician to remain the protector of the life and health
that person on whombiomedical research is being carried out.
22. The subjects should bevolunteers – either healthy persons or patients for
whomthe experimental design is not related to the patient’s illness.
23. The investigator or the investigating team should discontinue the research if
in his / her or their judgment it may, if continued, be harmfulto the individual.
24. In research on man, the interest of science and society should never take
precedence over considerations related to the well-being of the subject.
25. Safeguarding confidentiality –The investigator mustsafeguard the
confidentiality of research data, which might lead to the identification of the
individual subjects. Data of individual subjects can be disclosed only in the court
of law under the orders of the presiding judgeor in somecases may be required
to communicate to drug registration authority or to health authority.
26. Obligationof the sponsor topay – The sponsor whether a pharmaceutical
company, a government, or an institution, should agree, before the research
begins, to providecompensation for any physicalor mental injury for which
subjects areentitled to compensation or agree to provide insurancecoveragefor
an unforeseen injury whenever possible.
27. ResearchandPublication– The results of the experimental research may be
reported in such a way that it would seem that human application is of main
concern. Premature reports and publicity stunts should be avoided. Researchers
17. should take care to avoid talking to journalists or reporters about preliminary
feelings of seemingly promising research.
SUBMISSION OF APPLICATION:
The researcher should submitan appropriate application in a prescribed
formatalong with the study protocolat least three weeks in advance. The
protocol should include the following :
1. Clear research objectives and rationale for undertaking the investigation in
human subjects in the light of existing knowledge.
2. Recent curriculumvitae of the Investigators indicating qualification and
experience.
3. Subjectrecruitment procedures
4. Inclusion and exclusion criteria for entry of subjects in the study
5. Precisedescription of methodology of the proposed research, including
intended dosages of drugs, planned duration of treatment and details of invasive
procedures if any.
6. A description of plans to withdraw or withhold standard therapies in the
courseof research
7. The plans for statistical analysis of the study
8. Procedurefor seeking and obtaining informed consent in English and / or
vernacular language.
9. Safety of proposed intervention and any drug or vaccine to be tested
including results of relevant laboratory and animal research.
10. An account of plans to providemedical therapy for research carrying more
than minimal injury, toxicity due to over dosages
18. 11. Proposed compensation and reimbursementof incidental expenses
12. Details of storageand maintenance of data collected during the trial
13. Plan for publication of results – positive or negative – while maintaining the
privacy and confidentiality of the study participants.
14. A statement on probableethical issues and steps taken to tackle the same
15. All other relevant documents related to the study protocol including
regulatory clearances.
16. Agreement to comply with institutional ethical guidelines for clinical trials.
17. Details of Funding agency / Sponsors and fund allocation for the proposed
work.
18. New proposals willbe received every quarter as per following
schedule. Emergency meeting canbe calledby the Chairman anytime.
S.No. ApplicationSubmissionDates ReviewDates
1 2nd
Week March 1st
Week April
2 2nd
Week June 1st
Week July
3 2nd
Week September 1st
Week October
4. 2nd
Week December 1st
Week January
19. CHECK-LIST FOR PROTOCOL :
Title of study
Summary of proposed research
Statement of justification of study
Summary of previous studies on the topic including the nature, extent and
relevance of animal studies and other pre-clinical studies
An account of the previous submissions of theprotocol for ethical review, if
any, and its outcome.
Brief description of the site where the research is to be conducted
Relevant demographic and epidemiological information
Name and address of the sponsor
Name, address and qualification of the Principal Investigator
The objectives of the trial
The design of the trial
The number of the research subjects with justification
Inclusion and exclusion criteria
Description and explanation of all interventions including the method of
treatment, route of administration, dose, dose interval treatment period, and
other details of the investigational productin case of drug trials
Any other treatment that may be given / permitted / contraindicated during
the study
Clinical and laboratory tests to be carried out during the study
Samples of case reportforms to be used
Methods to determine the compliance with the treatment and its recording
Definitive criteria for removing the subjects fromthe study or trial.
Methods of recording and reporting adverseevents / reactions
Methods of dealing with complications
The known side effects of trial drug / vaccine / productused, if relevant
20. The potential benefit of the research to the subjects and to others.
The informed consentformformatted in English and Hindi.
An account of any economic or incentives to prospectivesubjects such as cash
payment / gifts / free medical services etc.
Description of plans for statistical analysis of the study including plans for
interim analysis, if any, and criteria for pre-maturely terminating the study as a
whole, if necessary
A list of references in the protocol.
The sourceand amount of funding of the research : the
organization that is sponsoring .
A detailed account of the sponsor’s financial
commitments to the research institution, the
investigators, the research subjects, and, when relevant,
the community.
The time schedule for completion of the study.
Date: ________________
Name __________________________
Signature _______________________
21. DECISION MAKING
The IECprovides complete and adequate review of the research proposals
submitted to them. Itmeets periodically at frequentintervals to review new
proposals, evaluateannual progress of ongoing ones and assess finalreports of all
research activities involving human beings through a previously scheduled
agenda, amended wherever appropriate. The following guidelines are followed
for decision making.
1. The decision must be taken by a broad consensus after the quorum
requirements are fulfilled to recommend / reject / suggestmodification for a
repeat review or advice appropriatesteps.
2. A member must voluntarily withdraw fromthe IECwhile making a
decision on an application, which evokes a conflict of interest, which should be
indicated in writing to the chairperson prior to the review and should be recorded
so in the minutes.
3. A negative decision should always be supported by clearly defined
reasons.
4. An IECmay decide to reverseits positive decision on a study in the
event of receiving information that may adversely affect the benefit / risk ratio.
5. The discontinuation of a trial should be ordered if the IECfinds that
the goals of the trials have already been achieved midway or unequivocal results
are obtained
6. In case of premature termination of study, notification should include
the reasons for termination along with the summary of results conducted till date.
7. If necessary, theapplicant / investigator may be invited to presentthe
protocol or offer clarifications in the meeting.
22. 8. Subject experts may be invited to offer their views, butshould not
take part in the decision making process. However, her / his opinion mustbe
recorded.
9. The following circumstances required the matter to be broughtto the
attention of IEC:
a. Any amendment to the protocolfromthe originally approved protocolwith
proper justification
b. Serious and unexpected adverseevents and remedial steps taken to tackle
them
c. Any new information that may influence the conductof the study.
10. Minutes of the Meeting should be approved and signed by the
Chairperson.
RECORD KEEPING:
All documentation and communication of the IECaredated, filed and preserved
according to written procedure. Strict confidentiality is to be maintained during
access and retrieval procedures.
The following records aremaintained
i.. The Constitution and composition of the IEC
ii. The curriculumvitae of all IECmembers
iii. Standing operating procedures of the IEC
iv. National and Internationalguidelines
v. Copies of protocols submitted for review
23. vi. All correspondence, with IECmembers and investigators regarding
application, decision and follow up
vii. Agenda of all IECmeetings
viii. Minutes of all IECmeetings with signatureof the Chairperson
ix. Copies of decisions communicated to the applicants
x. Record of all notification issued for premature termination of a study
with a summary of the reasons
xi. Final reportof the study including microfilms, CDs and Video-
recordings etc.
* It is recommendedthat all records must be safely maintainedafter the
completion/ terminationof the study for at least aperiodof 15 years, it is not
possible tomaintainthe same permanently.
QUALITY ASSURANCE:
1. The sponsor is responsiblefor the implementation of a systemof
quality assurancein order to ensurethat the study is performed and data is
generated, recorded and reported in compliance with the protocol, GCP and
other requirements. Documented standard operating procedures are a
prerequisite for quality assurance.
2. All observations & findings should be verified for credibility of the
data.
3. Statistically controlled sampling may be an acceptable method of data
verification in each study.
4. Quality control must be applied to each step of data handling
24. 5. Audit should be conducted by persons independent of those
responsiblefor study.
6. All data and documentation should be available for inspection of
audit.
GUIDELINES FOR DRUG TRIALS:
The Ethical Committee while reviewing proposals on Drug Trials will ensurethat
following guidelines in this regard are strictly followed.
· Clinical trial of drugs is a randomized single or double blind controlled
study in human subjects, designed to evaluate prospectively the safety and
effectiveness of new drugs.
· The proposed drug trials should be carried out, only after approvalof
the Drugs Controller General of India (DCGI), as is necessary under The Schedule Y
of Drugs and Cosmetics Act, 1940.
· The investigator should also get the approvalof Ethical Committee of
the Institution beforesubmitting the proposalto DCGI.
· All the guiding principles should be followed irrespectiveof whether
the drug has been developed in this country or abroad or whether clinical trials
have been carried out outside India or not.
· The new drug as defined under the Drugs and cosmetic Rules 1945
(DCR), and subsequentamendments include.
i. A new chemical entity (NCE)
ii. A drug which has been approved for a certain
indication, by a certain route, in a certain dosage regimen, but which is now
proposed to be used for another indication, by another route, or in another
dosageregimen
25. iii. A combination of two or more drugs which, although
approved individually, are proposed to be combined for the firsttime in a Fixed
DoseCombination (FDC).
PHASES OF CLINICAL TRIALS:
The firstthree of the following four phases require ethical clearance :-
Phase I (Human / Clinical Pharmacology trial) :
· The objective of phase 1 of clinical trial is to determine the safety of the
maximum tolerated dosein healthy adults of both sexes.
· At least two subjects should be administered each dose to establish the safe
doserange, pharmacokinetic, pharmacodynamic effect, and adverse reaction, if
any, with their intensity and nature.
· Investigator trained in clinical pharrmacology should preferably carry out
these studies.
· The duration of time lapsing between two trails in the same volunteer
should be a minimum of 3 months.
· The volunteers should preferably be covered under some insurancescheme.
Phase II (Exploratory trial) :
· These arecontrolled studies conducted in a limited number of patients of
both sexes to determine therapeutic uses, effective doserange and further
evaluation of safety and pharmacokinetics.
· Usually, 20 –25 patients should be studied for each dose.
· Studies are limited to 3 – 4 centres
26. Phase III (Confirmatory trial) :
· The purposeof these trials is to obtain adequate data about the efficacy and
safety of drugs in a larger number of patients fromboth sexes at multiple
centers.
· Only after successfulcompletion of phaseIII trials, permission is granted for
marketing the drug.
Phase IV (Post Marketing Surveillance) :
· It is undertaken to obtain additional information about the drug’s risks,
benefits and optimal use
· Long term effects and adversedrug reaction if any should be broughtto the
notice of Ethics Committee.
** Trials of drugs without the approvalof the appropriate authority should be
dealt according to the law of the land and the Guidelines formulated by the
country’s regulatory agencies.
*** After the trial is over, if need be, it should be made mandatory that the
sponsoring agency should providethe drug to the patient till it is marketed in the
country.
**** The criteria for termination of a trial must be defined as a priority in the
proposalof the trial and plan of interim analysis mustbe clearly presented. This
is important when on interim analysis the test drug is found to be clearly more
effective or less effective than the standard drugs. The trial can be discontinued
thereafter and better drug should be given to patient receiving less effective drug.
***** GCP provide operative guidelinesfor ethical andscientific standards for
the designing of a trial protocol including conduct, recording andreporting
procedures andshould be strictly adheredtowhile carrying out a trial. Till such
time that the SOP for Indian GCP are formulated, the international guidelines
issuedby WHO and ICH should be followed.
27. GUIDELINES FOR VACCINE TRIALS:
The Ethical Committee while reviewing proposals on vaccine trials will ensure that
the guidelines in this regard are strictly followed. The phases of these trials differ
fromdrug trials as given below :
Phase I :
· This refers to the firstintroduction of a vaccine into a human population for
determination of its safety and biological effects including immunogenicity.
· This phase includes study of doseand route of administration and should
involve Low risk subjects. For example, immunogenicity to hepatitis B vaccine
should not be determined in high risk subjects.
Phase II :
· This refers to the initial trial examining, effectiveness (immunogenicity) in a
limited number of volunteers.
· Vaccines can be prophylactic and therapeutic in nature.
· Prophylactic vaccines are given to normalsubjects, therapeutic or curative
vaccines may be given to patients suffering fromparticular disease.
Phase III :
· This focuses on assessmentof safety and effectiveness in the prevention of
disease, involving controlled study on a larger number of volunteers (in
thousands) in multi-centres.
Ø Vaccines that contain active or live – attenuated micro-organisms can
possibly posses a small risk of producing that particular infection. The subjectto
be vaccinated should be informed of the same.
28. Ø The subjects in control groups or when subjected to ineffective vaccines run
a risk of contracting the disease
Ø The risks associated with vaccines produced by recombinant DNA techniques
are not completely known. However, for allthe recombinant vaccines / products
the Guidelines issued by the Department of Biotechnology should be strictly
followed.
PRINCIPLES FOR HUMAN GENETICS RESEARCH
In the area of biomedical research, therehas been concern for ethical issues in
the field of human genetics. In recent years this concern has grown even further
because of the possibility of commercial eugenics. The advent of recombinant
DNA technology has provided one of the mostpowerfultools in the hands of
mankind to unravelthe mysteries of the human genome.
Serious issues related to participation of human subjects in genetic research are
raised particularly when the intervention involves rights of human embryo and
subjects who are not competent to give informed consent. Besides Human Rights,
issues of dignity, autonomy and justice, the Human Genome Project(HGP) has
also precipitated an unprecedented concern for Intellectual Property Rights.
Clinical research in fields of human genetics and human genome, including gene
therapy, besides being subjectto general ethical considerations of protection
fromharm and voluntariness of participation has following additional
considerations :-
Ø The harmmay not only be physical, but also psychosocial.
Psychologically, the genetic information may produce anxiety and depression or
damage familial relationship, which should be safeguarded.
29. Ø Written explanation understandableto layman about presentation
and natural courseof the diseases, interventions available and their outcome, as
also implication of the information for progeny and family, has special place in
clinical research in this field.
Ø Genetic manipulations haveconsequences for the future, some of
which are unknown. Hence, greater care towards potential dangers is necessary.
Ø Careful guidelines need to be evolved by peers in the profession to
tackle such situation. The professionalsocieties should actively participate in
these activities.
Ø The science of Medical Genetics is progressing very rapidly.
Therefore, there is a need for frequent updating of any guidelines for research in
this field. To meet this challenge not only the guidelines should be flexible, but
there should also be a built-in mechanismto review the guidelines fromtime to
time.
Ø The InstitutionalEthical Committees reviewing research proposals
related to research on human genetics should have necessary expertise, which
includes knowledgeof latest developments in the field of human genetics. In
areas of doubt, open discussion should be encouraged. This has to be the
responsibility of National agencies e.g. Central Ethical Committee (ICMR) and / or
National Bioethics Committee to organizenational debates on such issues to
evolve consensus on them.
Ø Concerned with the misuseof genetic tests, particularly for the pre-
selection of sex, the Government India has enacted a law known as “The Prenatal
Diagnostic Techniques (Regulation and Prevention of Misuse) Act 1994”. All
researchers in this area shall follow the provisions of this act (and such other acts
which may be passed in future).
30. APPENDIX– I
THE NUREMBERG CODE – 1949
Beginning with the outbreak of World War – II, CriminalMedical
experiments on non-German Nationals, both prisoners of war civilians were
carried out on large scaleby the NaziPhysicians. Evidence given during these
trials revealed unprecedented suffering, pain and disfigurement. In responseto
these findings, the judges proposed 10 principles “moral, ethical and legal”
human experimentation, which collectively came to be known as The Nuremberg
Code. Today, it is the basis of GCP in scientific research and is the fundamental
document in the history of bioethics.
1. The voluntary consentof the human subjectis absolutely essential.
2. The experimentshould be such as to yield fruitfulresults for the good
of society, unprocurable by other methodsor meansof study, and notrandom and
unnecessary in nature.
3. The experimentshould be designed and based on the results of animal
experimentation and a knowledge of the naturalhistory of the disease or other
problem under study thatthe anticipated results will justify the performance of
the experiment.
4. The experimentshould be so conducted asto avoid all unnecessary
physicaland mental suffering and injury.
5. No experimentshould be conducted where there isan a priority
reason to believe that death or disabling injury willoccur except, perhaps, in those
experimentswhere the experimentalphysiciansalso service as subjects.
6. The degree of risk to be taken should never exceed that determined
by the humanitarian importance of the problem to be solved by the experiment.
31. 7. Proper preparationsshould be made and adequate facilities provide to
protectthe experimentalsubjectagainsteven remote possibilities of injury,
disability, or death.
8. The experimentshould be conducted only by scientifically qualified
persons. The highest degree of skill and care should be required through allstages
of the experimentof those who conductor engage in the experiment.
9. During the course for the experimentthe human subjectshould be at
liberty to bring the experimentto an end if he has reached the physicalor mental
state where continuation of the experimentseems to him to be impossible.
10. During the course of the experimentthe scientific in charge mustbe
prepared to terminate the experimentat any stage, if he has probable cause to
believe, in the exercise of the good faith, superior skill and carefuljudgment
required of him that a continuation of the experimentis likely to resultin injury,
disability, or death to the experimentalsubject.
APPENDIX– II
THE DECLARATION OF HELSINKI – 1964
Unlike the Nuremberg Code the declaration of Helsinki focused on the integrity
and the experience of scientific investigators, in the protection of human subjects.
According to the declaration of Helsinkiissued by World Medical Assembly each
potential subjectinvolved in a clinical investigation mustbe adequately informed
of the aims, methods, anticipated benefits and the potential hazards of the study
and the discomfortit may entail. The declaration of Helsinki forms the basis of
ICH GCP 6.0. Thereforeit is a more universally used document than the
Nuremberg code. Ithas the following principals.
1. The World Medical Association has developed the declaration of Helsinki as a
statement of ethical principle to provide guidance to physiciansand other
32. participantsin medicalresearch involving human subjects. MedicalResearch
involving human subjectsincludesresearch on identifiable human materialor
identifiable data.
2. It is the duty of physician to promote and safeguard the health of the people.
The physiciansknowledge and conscience are dedicated to the fulfillment of this
duty.
3. The Declaration of Geneva of World MedicalAssociation bindsthe physician
with the words, “The health of my patient will be my first consideration”, and the
Internationalcode of medicalethics declaresthat, “A physician shall at only in the
patients interest when providing medicalcare which mighthave the effectof
weakening the physicaland mentalcondition of the patient”.
4. Medicalprogressis based on research, which ultimately mustrest in parton
experimentation involving human subjects.
5. In medical research on humn subjects, considerationsrelated to the well-
being of the human subjectshould take precedence over the interest of science
and society.
6. The Primary purpose of medicalresearch involving human subjectis to
improve prophylactic, diagnostic and therapeutic proceduresand the
understanding of the aetiology and pathogenesisof disease. Even the best proven
prophylactic, diagnostic, and therapeutic mustcontinuously be challenged
through research for their effectiveness, efficiency, accessibility and quality.
7. In currentmedicalpractice and in medicalresearch, mostprophylactic,
diagnostic and therapeutic proceduresinvolved risks and burdens.
8. Medicalresearch is subjectto ethical standardsthat promote respectfor all
human beingsand protecttheir health and rights. Some research populationsare
vulnerable and need special protection. The particular needsof the economically
and medically disadvantaged mustbe recognized. Specialattention is also
required for those who cannotgive a refuse consent for themselves, for those who
33. may be subjectto giving consentunder duress, for those who will not benefit
personally from the research and for those whom the research is combined with
care.
9. Research investigatorsshould be aware of ethical, legal, and regulatory
requirementsfor research on human subjectin their own countriesas well as
applicable internationalrequirements. No nationalethical, legal or regulatory
requirementshould be allowed to reduce or eliminate any of the protectionsfor
human subjectsset-forth in this Declaration.
WHO GUIDELINES FOR ETHICS IN HUMAN RESEARCH:
2. Whento Submit an ApplicationtoConduct a Clinical Trial:
An application for approvalto conducta clinical trial is required for the
following categories of medicines:
a. Unregistered medicines
b. Registered medicines where the proposed clinical trials are outside of
the conditions of approval. Thesemay include changes to:
i. indication(s) and clinical use
ii. target patient population(s)
iii. route(s) of administration
iv. dosageregimen(s)
An application for authorization to conduct a clinical trial described in
Aboveparagraph mustbe made on a formand accompanied by an
application fee as determined by the Regulatory Authority.
No person may conduct a clinical trial using investigational products
included in above
paragraph abovewithout prior authorisation fromthe
Regulatory Authority.
A clinical trial authorised by the Regulatory Authority must be conducted in
accordancewith guidelines for Good Clinical Practice (GCP) as may from
time to time be determined by the Authority.
A clinical trial authorised by the regulatory Authority may only proceed at a
clinical trial site once clearance has been obtained froma recognised
Research Ethics Committee.
Approvalby the Regulatory Authority to conductpost-marketing clinical
trials of a registered medicine within the approved conditions of
34. registration of such a medicine is not required. However, approvalby a
recognised Research Ethics Committee is required prior to initiation of
such studies.
of an individual patient by a medical practitioner with an
unregistered medicine or with a registered medicine outside of the
approved conditions of registration of such a medicine is not considered to
be a clinical trial and would usually require special approvalby the
Regulatory Authority on a named patient basis.
3. Responsibilities Relating toClinical Trials:
An application to conducta clinical trial may be made by a pharmaceutical
company (sponsor), clinicalresearch organisation (CRO), or in the case of
investigator-initiated academic research studies, by the research
institution or principle investigator.
A statement by the applicant mustbe provided indicating that all
information contained in, or referenced by, the application is complete and
accurate and is not falseor misleading.
applicant and all investigators mustsign declarations that they are
familiar with and understand the clinical trial protocol and will comply with
Good Clinical Practice standards, as determined by the Regulatory
Authority, in the conductof the trial.
In the case of multicentre trials, the coordinating investigator must also
sign the application form.
Upon signing the application, all parties accept responsibility that all
applicable regulations and requirements will be adhered to. Furthermore,
all parties are responsiblefor ensuring that the trial is based on and
implemented according to well-founded ethical and scientific principles,
which are expressed in the Helsinki Declaration and its current revisions
as well as in international guidelines for Good Clinical Practice (GCP).
The principle investigator mustbe an appropriately qualified and
competent person having practical experience within the relevant
professionalarea, who is a resident in the country and who is responsible
for the conductof the clinical trial at a clinical trial site. A principle
investigator must havehad previous experience as a co-investigator in at
least two trials in the relevant professionalarea.
investigators in a clinical trial as well as the trial monitor musthave had
formaltraining in Good Clinical Practice (GCP) within the last three years.
Multi-centre trials must have a coordinating investigator who will be
35. responsiblefor coordinating all local clinical trial sites. This person does
not necessarily haveto be involved with any direct treatment of subjects
involved in the trial.
If the trial is a partof an international study, information regarding the
other participating countries must be provided including how large a part
of the trial will be carried out locally.
4. Ethical Assessment:
clinical trial that has received approvalfromthe Regulatory Authority
may only proceed once clearance has also been obtained froma
recognized Research Ethics Committee for a particular trial site.
Ethical evaluations of clinical trials of drugs musttake place in accordance
with the principles of Good Clinical Practice as well as the Declaration of
Helsinki and its current revisions.
5. Insurance of Trial Subjects:
All subjects mustbe satisfactorily insured againstpossibleinjuries that
might arise during the conductof the clinical trial.
For all sponsor-initiated trials, a valid insurancecertificate for the duration
of the study must be provided prior to study initiation.
For investigator-initiated research trials, proof of current malpractice
insurancethat covers clinical trials mustbe provided.
6. Good Clinical Practice (GCP):
Applicants must be able to demonstrate that clinical trials are conducted
according to generally accepted principles of good clinical practice.
Trials mustbe conducted in accordance with the applicable regulatory
requirement(s)
Before a trial is initiated, foreseeablerisks and inconveniences mustbe
weighed againstthe anticipated benefit for the individual trial subjectand
society. A trial should be initiated and continued only if the anticipated
benefits justify the risks.
The rights, safety, and well being of the trial subjects are the most
important considerations and must prevailover interests of science and
society.
The available non-clinical and clinical information on an investigational
drug must be adequate to supportthe proposed clinical trial.
Clinical trials mustbe scientifically sound, and described in a clear,
detailed protocol.
A trial mustbe conducted in compliance with a protocolthat has received
36. regulatory and ethics approvalprior to initiation.
The medical care given to, and medical decisions made on behalf of,
subjects mustalways be the responsibility of a qualified physician or,
when appropriate, of a qualified dentist.
Each individual involved in conducting a trial should be qualified by
education, training, and experience to performhis or her respective
task(s).
Freely given informed consentmust be obtained from every subjectprior
to clinical trial participation.
All clinical trial information must be recorded, handled, and stored in a way
that enables its accuratereporting, interpretation and verification.
The confidentiality of records that could identify subjects mustbe
protected, respecting the privacy and confidentiality rules in accordance
with the applicable regulatory requirement(s).
Investigationaldrugs mustbe manufactured, handled, and stored in
accordancewith applicable good manufacturing practices (GMP) and
must be used in accordancewith the approved protocol.
Systems with procedures that assurethe quality of every aspect of the trial
must be implemented.
7. The Clinical Trial Application:
The Regulatory Authority will undertakean assessmentof a clinical trial
only upon receiving fully completed applications.
The following are the requirements when submitting an application to
conduct a clinical trial (6 copies of each of the following are to be
submitted):
Covering letter
Completed Application form(CTF1)
Cover sheet
Checklist
Final version of the Clinical Trial Protocol
Patient Information leaflet and Informed Consentform
Investigators Brochureand/or PackageInsert
Signed investigator(s) CV(s) in required format
Signed declaration by Principalinvestigator(s)
Signed joint declaration by Sponsor/NationalPrincipal
investigator
Signed declaration by Co- or Sub-investigators
37. Signed declaration by regional monitor and/or study coordinator
Indemnity and InsuranceCertificate and/or
Proof of Malpractice insuranceof trialist(s)
Ethics Committee(s) approvalor
Copy of letter submitted to Ethics Committee(s)
Electronic copies to be submitted in MicrosoftWord format
Financial declaration by Sponsor and Principleinvestigator
Documentation mustbe arranged in separate folders. The extent of the
documentation requirements will generally depend on the development
phaseof the investigational product.
8. The Clinical Trial Protocol:
The clinical trial protocolmust contain at least the following information,
consistentwith the requirements of internationally accepted GCP
guidelines:
Background and purposeof the trial
Details of the study population;
Design and type of trial
Criteria for selection of trial subjects
Trial treatments
Control groups and control treatments whereapplicable
Choice of method and statistical justification for the number of trial
Subjects
Monitoring, assessmentand reporting of effects, adversedrug
reactions and adverseevents
Clinical and laboratory safety test
Assessmentof results
Quality assuranceof data and procedures
Drug accountability
Ethical assessment
To facilitate evaluation as well as provideguidance on the relevance of the
study, the protocol should clearly indicate the complete development plan
for the trial and the investigational product. This should include the
following:
A plan for the possiblediscontinuation of previous treatment
The rationale for the use of placebo products
38. Follow-up of trial subjects after the conclusion of the trial
A plan for involvement of other personnel
The state of readiness in caseof complications
A plan for the publication of the results (publishing plan)
A description of how special lists of the trial subjects and forms
relating to the trial subjects will be kept for each trial subject
included in the trial
9. The Investigator’s Brochure:
The investigator's brochuremustcontain at least following information:
The physical, chemical and pharmaceutical properties of the drug
The pharmacologicalaspects of the drug, including its metabolites
in all animal species tested
The pharmacokinetics and metabolism of the drug, including the
biological transformation of the drug in all animal species tested
Toxicological effects in any animal species tested under a single
dosestudy, a repeated dosestudy or a special study in respect of
the drug
Results of carcinogenicity studies in any animal species tested in
respect of the drug
Results of clinical pharmacokinetic studies of the drug
Information regarding drug safety, pharmacodynamics, efficacy and
doseresponses of the drug that were obtained fromprevious
clinical trials in humans.
10. Labelling and Dispensing of Trial Medications:
Investigational, comparator and /or placebo products used in a clinical trial
must be properly labelled and contain the following information:
A statement indicating that the drug is an investigational drug to be
used only by a qualified investigator
The name, number or identifying mark of the drug
The expiration date of the drug
The recommended storageconditions for the drug
The lot number of the drug
The name and address of the sponsor
The protocol code or identification
The name and address of the premises wherethe clinical trial is to
be carried out.
39. Registered products that are incorporated in the trial mustalso be labelled
in accordancewith 10.1 above.
Trial medications must be stored and dispensed by the pharmacy or the
pharmaceutical department at the trial site in accordancewith good
dispensing practices. The general principle is that investigational products
used in clinical trials should be handled in the sameway as registered
medicines.
11. Chemistry andManufacturing:
Clinical trial investigational medicinal products mustbe manufactured in
accordancewith the code of Good Manufacturing Practice (GMP)
including Good Manufacturing Practice for InvestigationalMedicinal
Products. This implies that the manufactureof the investigational product
may be subjectto control and inspection in the same way as in the case of
marketed medicinal products.
Certificates of analysis (COAs) mustbeprovided for all investigational and
comparator products.
Chemistry and manufacturing information provided in the clinical trial
application should be presented in a concisemanner and should include
the following:
a. Drug Substance:
_ Names and Source
_ Method of Manufacture
_ PhysicochemicalProperties and StructureElucidation
_ Impurities
_ Specifications and Test Methods and Batch Analyses
_ Stability and Packaging
b. DosageForm:
_ Source
_ Developmental Pharmaceutics
_ Formulation and Method of Manufactureand Packaging
_ Specifications and Test Methods and Batch Analyses
_ Stability
If the pharmaceutical or chemical properties of the investigational product
have been altered compared to those in use during animal testing or
previous clinical trials, such alterations mustbe described and justified.
This, for instance, applies to impurities and degradation products.
Pharmaceutical and/or chemical alterations in an investigational product
40. that is used in an ongoing clinical trial, and that may affect the quality,
safety and/or efficacy of the medicinal product must immediately be
reported to the Regulatory Authority.
If the composition of the medicinal productis altered, additional
bioavailability or bioequivalence studies may be required.
Based on stability data, all investigation)In cases wherean extension of
the shelf life for the finished medicinal productis desired, an application
for this must be submitted to the Regulatory Authority. In such cases
stability data or certificates of analysis (COAs) fromreanalysis of the
relevant batches mustbe submitted.
The re-labelling of any remaining packages frompreviously manufactured
batches mustbe performed in accordancewith established written
procedures and Good Manufacturing Practices (GMP).
12. RequirementsConcerning InformedConsent:
Itis an important principle that subjects contemplating participation in a
clinical trial have access to certain basic information regarding the clinical
trial.
A copy of the written information intended for trial subjects, as it will be
setout in the informed consent form, that includes a statement of the risks
and anticipated benefits arising to the health of trial subjects as a resultof
their participation in the clinical trial, mustbe submitted to the Regulatory
Authority.
The following list of items (not exhaustive), should be included in the
patient information leaflet:
An introduction including information on participation in the
study
The aims, objectives and goals of the study
The methods to be employed and what this will involve for
the trial subject
Criteria for selection that apply to the subject
Whether the trial has any direct benefit for the trial subject
Which medicines are included in the trial; whether the
preparations are available on the market and if inactive
substances (placebo) will be used. The patient mustbe
informed of the fact that allocation to a specific treatment
group will occur at random
Other medicines that may/may not be taken at the same
41. time as the trial medication. Non-prescription medications
and complementary products should be mentioned
specifically
Pregnantand breast-feeding subjects mustbe excluded
fromparticipation in the study and safecontraceptives must
be used by women of a childbearing age. Information
concerning safe useof contraceptives for men, if this is
relevant, mustbe provided
Practical consequences of participating (type of involvement,
time required)
Risks, adversedrug reactions and any possiblediscomfort
should be detailed
If the person does not consentto participate, details of
alternative treatments available must be provided
Discontinuing currenttreatment as a condition of
participating
Follow-up treatment, if applicable
Confidentiality
Emphasis that participation is voluntary and that consent can
be withdrawn at any time and without having to provide
reasons. Subjects mustbeinformed that refusing to
participate will have no effect on further treatment or the
relationship to the treating physician or to the institute
Information thatRegulatory Authorities and Research Ethics
Committees may require access to subjectidentifying data.
Consent for this access mustbe a condition for participation
in the study
Information aboutwho the trial subjectcan contact. This
should include details of the investigator, Research Ethics
Committee and Regulatory Authority
Information aboutindemnity, insuranceand compensation in
the event of trial-related injury
Information if biological fluids will be used and/or stored for
pharmacogenetic sub-studies. Participation in this part of
the study should be voluntary and a separate informed
consentmust be obtained
Additionally, the following issues, whereapplicable, mustbe addressed in
42. the process of obtaining informed consent:
Trials on under-aged subjects and subjects with reduced
competence to consent
Withdrawalof consent
Provision of new information to subjects as these become
available
13. Clinical Trial Amendments:
Applications for amendments to clinical trial protocols must be submitted
to the Regulatory authority for approvalprior to their implementation.
The applicant mustsubmit the original wording, revised wording, and
rationale for the change including a copy of a complete protocol
incorporating all amendments.
These amendments mustalso be presented to the Research Ethics
Committee for approvalprior to implementation.
Approvalmustbe obtained for the following amendments to the clinical
trial protocol:
Changes that affect patient selection and monitoring
Changes that affect clinical efficacy and safety requirements
(e.g. dosage adjustments, study procedures, etc)
Changes that affect patient discontinuation
Changes that resultin the extension of the duration of the
clinical trial
Changes that resultto the chemistry and manufacturing
information that may affect drug safety and quality (For
example: specifications for the drug wherethe limits of the
test are relaxed or deleted; wherea new impurity or
degradation producthas been identified; and, the addition of
new raw materials, solvents, reagents, catalysts or any other
material used in the manufactureof the drug substance.)
14. Clinical Trial Records:
The sponsor mustrecord, handle and store all information in respect of a
clinical trial in order to ensure that the clinical trial is conducted in
accordancewith good clinical practices and in a way that allows its
complete and accuratereporting as well as its interpretation and
verification.
The sponsor mustkeep all records related to the conduct of a clinical trial
in a format that facilitates verification for the purposeof an inspection.
43. The sponsor mustsubmitrequested records within 48 hours if safety
concerns arise.
Additionally, the Regulatory Authority can request the submission of
additional information within seven days to facilitate an inspection of a site.
The sponsor mustmaintain complete and accuraterecords in respect of
the useof a drug in a clinical trial, including:
A copy of all versions of the investigator's brochurefor the
drug;
Records respecting each changemade to the investigator's
brochure, including the rationale for each change and
documentation that supports each change;
Records respecting all adverseevents in respect of the drug
that have occurred locally or internationally, including
information that specifies the indication for useand the
dosageformof the drug at the time of the adverseevent;
Records in respect of the enrolment of clinical trial subjects,
including information sufficient to enable all clinical trial
subjects to be identified and contacted in the event that the
use of the drug may endanger the health of the clinical trial
subjects or other persons;
Records in respect of the shipment, receipt, disposition,
return and destruction of the drug;
For each clinical trial site, an undertaking fromthe principle
investigator that is signed and dated by the principle
investigator prior to the commencement of his or her
responsibilities in respectof the clinical trial, that states that
the principle investigator will conduct the clinical trial in
accordancewith good clinical practices;
For each clinical trial site, a copy of the protocol, informed
consentform and any amendment to the protocol or
informed consent formthat havebeen approved by the
Research Ethics Committee and Regulatory Authority for
that clinical trial site.
15. Discontinuance of a Clinical Trial by a Sponsor:
If a clinical trial is discontinued by the sponsor in its entirety or at a clinical
trial site, the sponsor mustinformthe Regulatory Authority no later than 15
days after the date of the discontinuance; and must:
44. Providethe Regulatory Authority with the reason/s for the
discontinuanceand its impact on the proposed or ongoing
clinical trials in respect of the drug conducted by the
sponsor;
As soon as possible, informall investigators of the
discontinuanceand of the reasons for the discontinuance,
and advisethem in writing of any potential risks to the health
of clinical trial subjects or other persons;
16. Reporting of Adverse Drug Reactions andAdverseEvents:
The term adversedrug reactions is understood as adverseevents where
the connection to the trial medication cannotbe excluded (possibleor
probable connection).
The sponsor mustreportserious adversedrug reactions that emerge
during trials as individual reports (onereport per patient).
During the courseof a clinical trial, the sponsor mustinformthe
Regulatory Authority and the Research Ethics Committee of any serious
unexpected adversedrug reaction in respect of the drug that has occurred
locally or internationally as follows:
If it is fatal or life threatening, immediately but no later than
seven days after becoming awareof the information
If it is neither fatal nor life threatening, within 15 days after
becoming awareof the information.
The potential connection to the study drug must be clarified, and updated
reports sent to the Regulatory Authority as soon as these are available.
With regard to adversedrug reaction that are serious and already known
(described in Investigator’s Brochureor the Summary of Product
characteristics (SPC)) thereare no fixed time limits. These cases mustbe
reported as soon as the necessary information is available.
17. Submissionof Progress Reports:
The applicant conducting the clinical trial must submitprogress reports to
the Regulatory Authority on a six monthly basis fromthe date of initiation
of the clinical trial and within 30 days of the completion or termination of
the clinical trial
18. Inspectionof Clinical Trials:
The Regulatory Authority may inspect clinical trial sites and trial sponsors
to ensure that the generally accepted principles of good clinical practice
are met.
45. The objectives of the inspection will be to ensurethat participants in
clinical trials are not subjected to undue risks, to validate the quality of the
data generated or to investigate complaints.
The Regulatory Authority may usethe information collected as a result of
these inspections to ensurecompliance with the regulatory framework and
may take enforcement action, when deemed necessary.
19. Withdrawal of AuthorisationtoConduct a Clinical Trial
The Regulatory Authority may requestadditional information on a clinical
trial or withdraw the authorisation to conducta clinical trial if the Authority
is of the opinion that the safety of the subjects in the trial is compromised,
or that the scientific reasons for conducting the trial have changed.
SCHEDULEY :
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 accordance 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 shall 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;
46. (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
trails are required to be conducted in India before permission to
market the drug in India is granted;
(c) the data required will depend upon the purpose of the new drug
application. The number of study subjects and sites to be involved in
the conduct of clinical trial will depend upon the nature and objective
of the study. Permission to carry out these trials shall generally be
given in stages, considering the data emerging from earlier Phase(s);
(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;
47. (v) regulatory status in other countries as prescribed in item 9.2 of AppendixI,
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 aboutadversedrug 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
3
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.
48. (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 approvalgranted by an independent ethics committees (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
49. Licensing Authority in writing along with the approval by the ethics
committee which has granted the approval for the study. No deviations
from the charges 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
4
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
50. 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 approvalto 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) Itis the responsibility of the ethics committees 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
51. particular care to protect the rights, safety and well being of all
vlunerable 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, ethic minority groups,
homeless persons, nomads, refugees, minors or others incapable of
personally giving consent. Ethics committee(s) should get
5
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.
52. (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.
6
53. 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 benefits(s). Studies in Phase III are designed to confirm
the preliminary evidence accumulated in PhaseII 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 needs 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
54. 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).
(1) Geriatrics.-Geriatric patients should be included in Phase III clinical trials (and
in Phase II trials, at the Sponsor’s option) in meaningful numbers, if-
(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
7
(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.
(2) Paediatrics.-
(i) The timing of paediatric studies in the new drug development program will
depend on the medicinal product, the type of disease being treated,
safety considerations, and the efficacy and safety of available
treatments. For a drug expected to be used in children, evaluations
should be made in the appropriate age group. When clinical
development is to include studies in children, it is usually appropriate to
begin with older children before extending the trial to younger children
and then infants.
55. (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 wherethis 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 pharmacokenetic 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)/legalguardian 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
56. 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 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 conduced in the paediatric population, the reviewing
ethics committee should include members who are knowledgeable
about pediatric, ethical, clinical and psychosocial issues.
8
(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,
foetus 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
57. (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 reason,
(e) Changes to reference safety information,
(f) Estimated patient exposure,
(g) Presentation of individual case histories,
(h) Studies,
(i) Other information,
58. (j) Overall safety evaluation,
(k) Conclusion,
9
(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 bioaviliability 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 Bioequivalance
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 authenticity 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
