3 In the Drugs and Cosmetics Rules, 1945 (hereinafter referred to as said rules

),
(1) in Part X!, after rule 1""D!, the follo#ing shall $e inserted, namel%&,

1""D!!' Definition of Clinical trial' (or the )ur)ose of this Part, *Clinical trial+ means
a s%stematic stud% of ne# drug(s) in human su$,ect(s) to generate data for disco-ering and .
or -erif%ing the clinical, )harmacological (including )harmacod%namic and
)harmaco/inetic) and .or ad-erse effects #ith the o$,ecti-e of determining safet% and . or
efficac% of the ne# drug' *'

(") In the said rules for 0chedule 1, the follo#ing 0chedule shall $e su$stituted, namel% &
“SCHEDULE Y
s20ee rules 1""!, 1""3, 1""D, 1""D!, 1""D!! and 1""45

REQUIREMENTS AND GUIDELINES FOR PERMISSION TO IMPORT AND / OR MANUFACTURE
OF NEW DRUGS FOR SALE OR TO UNDERTAKE CLINICAL TRIALS

1. Application for permission.- (1) Application for permission to import or manufacture new
drugs for sale or to undertake clinical trials shall be made in Form 44 accompanied with
following data in acccordance with the appendices, namely:-

(i) chemical and )harmaceutical information as )rescri$ed in item " of !))endi6 I7 (ii) animal
)harmacolog% data as )rescri$ed in item 3 of !))endi6 I and !))endi6 I87
(a) s)ecific )harmacological actions as )rescri$ed in item 3'" of !))endi6 I, and demonstrating,
thera)eutic )otential for humans shalls $e descri$ed according to the animal models and
s)ecies used' 9here-er )ossi$le, doseres)onse relationshi)s and 4D 5:s shall $e
su$mitted' 0)ecial studies conducted to elucidate mode of action shall also $e descri$ed
(!))endi6 I8)7
($) general )harmacological actions as )rescri$ed in item 3'3 of !))endi6 I and item 1'" of
!))endi6 I87
(c) )harmaco/inetic data related to the a$sor)tion, distri$ution, meta$olism and e6cretion of the
test su$stance as )rescri$ed in item 3'5 of !))endi6 I' 9here-er )ossi$le, the drug effects
shall $e corelated to the )lasma drug concentrations7
(iii) animal to6icolog% data as )rescri$ed in item 4 of !))endi6 I and !))endi6 III7
(i-) human Clinical Pharmacolog% Data as )rescri$ed in items 5,; and < of !))endi6
I and as stated $elo#&
(a) for ne# drug su$stances disco-ered in India, clinical trials are re=uired to $e carried out in
India right from Phase I and data should $e su$mitted as re=uired under items 1, ", 3, 4, 5
(data, if an%, from other countries) , and 9 of !))endi6 I7
($) for ne# drug su$stances disco-ered in countries other than India, Phase I data as re=uired
under items 1, ", 3, 4, 5 (data from other countries) and 9 of !))endi6 I should $e su$mitted
along #ith the a))lication' !fter su$mission of Phase I data generated outside India to the
>icensing !uthorit%, )ermission ma% $e granted to re)eat Phase I trials and.or to conduct
Phase II trials and su$se=uentl% Phase III trials concurrentl% #ith other glo$al trials for that
drug' Phase III trials are re=uired to $e conducted in India $efore )ermission to mar/et the
drug in India is granted7
(c) the data re=uired #ill de)end u)on the )ur)ose of the ne# drug a))lication ' ?he num$er of
stud% su$,ects and sites to $e in-ol-ed in the conduct of clinical trial #ill de)end u)on the
nature and o$,ecti-e of the stud%' Permission to carr% out these trials shall generall% $e gi-en
in stages, considering the data emerging from earlier Phase(s)7
(d) a))lication for )ermission to initiate s)ecific )hase of clinical trial should also accom)an%
In-estigator@s $rochure, )ro)osed )rotocol (!))endi6 X), case record form, stud% su$,ect@s
informed consent document(s) (!))endi6 8), in-estigator@s underta/ing (!))endi6 8II)
and ethics committee clearance, if a-aila$le, (!))endi6 8III)7
(e) re)orts of clinical studies su$mitted under items 5A of !))endi6 I should $e in consonance
#ith the format )rescri$ed in !))endi6 II of this 0chedule' ?he stud% re)ort shall $e
certified $% the Princi)al In-estigator or, if no Princi)al In-estigator is designated, then $%
each of the In-estigators )artici)ating in the stud%' ?he certification should ac/no#ledge the
contents of the re)ort, the accurate )resentation of the stud% as underta/en, and e6)ress
agreement #ith the conclusions' 4ach )age should $e num$ered7
(-) regulator% status in other countries as )rescri$ed in item 9'" of !))endi6
I, including Information in res)ect of restrictions im)osed, if an%, on the use of the
drug in other countries, e'g' dosage limits, e6clusion of certain age grou)s, #arning
a$out ad-erse drug reactions,'etc' (item 9'" of !))endi6 I)' >i/e#ise, if the drug has
$een #ithdra#n in an% countr% $% the manufacturer or $% regulator% authorities, such
information should also $e furnished along #ith the reasons and their rele-ance, if
an%, to India' ?his information must continue to $e su$mitted $% the s)onsor to the
>icensing !uthorit% during the course of mar/eting of the drug in India7
(-i) the full )rescri$ing information should $e su$mitted as )art of the ne# drug
a))lication for mar/eting as )rescri$ed in item 1: of !))endi6 I' ?he )rescri$ing
information ()ac/age insert) shall com)rise the follo#ing sections& generic name7
com)osition7 dosage form.s, indications7 dose and method of administration7 use in
s)ecial )o)ulations (such as )regnant #omen, lactating #omen, )ediatric )atients,
geriatric )atients etc') 7 contraindications7 #arnings7 )recautions7 drug interactions7
undesira$le effects7 o-erdose7 )harmacod%namic and )harmaco/inetic )ro)erties7
incom)ati$ilities7 shelflife7 )ac/aging information7 storage and handling instructions'
!ll )ac/age inserts, )romotional literature and )atient education material
su$se=uentl% )roduced are re=uired to $e consistent #ith the contents of the a))ro-ed
full )rescri$ing information' ?he drafts of la$el and carton te6ts should com)l% #ith
)ro-isions of rules 9; and 9<' !fter su$mission and a))ro-al $% the >icensing
!uthorit%, no changes in the )ac/age insert shall $e effected #ithout such changes
$eing a))ro-ed $% the >icensing !uthorit%7 and
(-ii) com)lete testing )rotocol.s for =ualit% control testing together #ith a com)lete
im)urit% )rofile and release s)ecifications for the )roduct as )rescri$ed in item 11 of
!))endi6 I should $e su$mitted as )art of ne# drug a))lication for mar/eting'
0am)les of the )ure drug su$stance and finished )roduct are to $e su$mitted #hen
desired $% the regulator% authorit%'

() !f the study drug is intended to be imported for the purposes of e"amination, test or
analysis, the application for import of small #uantities of drugs for such purpose should
also be made in Form 1$

(%) For drugs indicated in life threatening & serious diseases or diseases of special
rele'ance to the !ndian health scenario, the to"icological and clinical data re#uirements
may be abbre'iated, deferred or omitted, as deemed appropriate by the (icensing
Authority$
2. CLINICAL TRIAL

(1) Appr!"# $r %#&'&%"# (r&"#

(i) Clinical trial on a ne# drug shall $e initiated onl% after the )ermission has $een granted $%
the >icensing !uthorit% under rule "1 ($), and the a))ro-al o$tained from the res)ecti-e
ethics committee(s)' ?he >icensing !uthorit% as defined shall $e informed of the a))ro-al of
the res)ecti-e institutional ethics comittee(s) as )rescri$ed in !))endi6 8III, and the trial
initiated at each res)ecti-e site onl% after o$taining such an a))ro-al for that site' ?he trial
site(s) ma% acce)t the a))ro-al granted to the )rotocol $% the ethics committee of another
trial site or the a))ro-al granted $% an inde)endent ethics committee (constituted as )er
!))endi6 8III), )ro-ided that the a))ro-ing ethics committee(s) is.are #illing to acce)t their
res)onsi$ilities for the stud% at such trial site(s) and the trial site(s) is.are #illing to acce)t
such an arrangement and that the )rotocol -ersion is same at all trial sites'

(ii) !ll trial In-estigator(s) should )ossess a))ro)riate =ualifications, training and e6)erience
and should ha-e access to such in-estigational and treatment facilities as are rele-ant to the
)ro)osed trial )rotocol' ! =ualified )h%sician (or dentist, #hen a))ro)riate) #ho is an
in-estigator or a su$in-estigator for the trial, should $e res)onsi$le for all trialrelated
medical (or dental) decisions' >a$oratories used for generating data for clinical trials should
$e com)liant #ith Bood >a$orator% Practices' If ser-ices of a la$orator% or a facilities
outside the countr% are to $e a-ailed, its.their name(s), address(s) and s)ecific ser-ices to $e
used should $e stated in the )rotocol to a-ail >icensing !uthorit%@s )ermission to send
clinical trial related sam)les to such la$orator%(ies) and.or facilit%(ies)' In all cases,
information a$out la$orator%(ies) . facilities to $e used for the trial, if other than those at the
in-estigation site(s), should $e furnished to the >icensing !uthorit% )rior to initiation of trial
at such site(s)'

(iii) Protocol amendments if $ecome necessar% $efore initiation or during the course of a
clinical trial, all such amendments should $e notified to the >icensing !uthorit% in #riting
along #ith the a))ro-al $% the ethics committee #hich has granted the a))ro-al for the
stud%' Co de-iations from or changes to the )rotocol should $e im)lemented #ithout )rior
#ritten a))ro-al of the ethics committee and the >icensing !uthorit% e6ce)t #hen it is
necessar% to eliminate immediate haDards to the trial 0u$,ect(s) or #hen change(s)
in-ol-e(s) onl% logistic or administrati-e as)ects of the trial' !ll such e6ce)tions must $e
immediatel% notified to the ethics committee as #ell as to the >icensing
!uthorit%' !dministrati-e and.or logistic changes in the )rotocol should $e notified to the
>icensing !uthorit% #ithin 3: da%s'

(2) R)*p'*&+&#&(&)* $ Sp'*r.,
(i) )he clinical trial *ponsor is responsible for implementing and maintaining #uality
assurance systems to ensure that the clinical trial is conducted and data generated,
documented and reported in compliance with the protocol and +ood ,linical
-ractice (+,-) +uidelines issued by the ,entral .rugs *tandard ,ontrol
/rgani0ation, .irectorate +eneral of 1ealth *er'ices, +o'ernment of !ndia as well
as with all applicable statutory pro'isions$ *tandard operating procedures should
be documented to ensure compliance with +,- and applicable regulations$
(ii) *ponsors are re#uired to submit a status report on the clinical trial to the
(icensing 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 % months$ )he summary report should pro'ide a
brief description of the study, the number of patients e"posed to the drug,
dose and duration of e"posure, details of ad'erse drug reactions (Appendi"
2!), if any, and the reason for discontinuation of the study or non-pursuit of
the new drug application3
(i') Any une"pected serious ad'erse e'ent (*A4) (as defined in +,- +uidelines)
occurring during a clinical trial should be communicated promptly (within 14
calendar days) by the *ponsor to the (icensing Authority and to the other
!n'estigator(s) participating in the study (see Appendi" 2!)$

(-) R)*p'*&+&#&(&)* $ (.) I'!)*(&/"(r(*)., ?he In-estigator(s) shall $e res)onsi$le for the conduct of
the trial according to the )rotocol and the BCP Buidelines and also for com)liance as )er the
underta/ing gi-en in !))endi6 8II' *tandard operating procedures are re#uired to be
documented by the in'estigators for the tasks performed by them$ .uring and following a
sub5ect6s participation in a trial, the in'estigator should ensure that ade#uate medical care is
pro'ided to the participant for any ad'erse e'ents$ !n'estigator(s) shall report all serious and
une"pected ad'erse e'ents to the *ponsor within 4 hours and to the 4thics ,ommittee that
accorded appro'al to the study protocol within 7 working days of their occurance$

(0) I'$r1)2 C'*)'(.,
(i) !n all trials, a freely gi'en, informed, written consent is re#uired to be obtained from each
study sub5ect$ )he !n'estigator must pro'ide information about the study 'erbally as well as
using a patient information sheet, in a language that is non-technical and understandable by
the study sub5ect$ )he *ub5ect6s consent must be obtained in writing using an 8!nformed
,onsent Form6$ 9oth the patient information sheet as well as the !nformed ,onsent Form
should ha'e been appro'ed by the ethics committee and furnished to the (icensing
Authority$ Any changes in the informed consent documents should be appro'ed by the
ethics committee and submitted to the (icensing Authority before such changes are
implemented$

(ii) 9here a su$,ect is not a$le to gi-e informed consent (e'g' an unconscious )erson or a minor or
those suffering from se-ere mental illness or disa$ilit%), the same ma% $e o$tained from a legall%
acce)ta$le re)resentati-e (a legall% acce)ta$le re)resentati-e is a )erson #ho is a$le to gi-e consent
for or authoriDe an inter-ention in the )atient as )ro-ided $% the la#(s) of India)' If the 0u$,ect or
his.her legall% acce)ta$le re)resentati-e is una$le to read.#rite E an im)artial #itness should $e
)resent during the entire informed consent )rocess #ho must a))end his.her signatures to the consent
form'

(iii) ! chec/list of essential elements to $e included in the stud% su$,ect@s informed consent document
as #ell as a format for the Informed Consent (orm for stud% 0u$,ects is gi-en in !))endi6 8'



(3) R)*p'*&+&#&(&)* $ (.) E(.&%* C11&(()).,

(i) !t is the responsibility of the ethics committee that re'iews and accords its appro'al to a
trial protocol to safeguard the rights, safety and well being of all trial sub5ects$ )he ethics
committee should e"ercise particular care to protect the rights, safety and well being of all
'ulnerable sub5ects 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
impo'erished persons, patients in emergency situation, ethnic minority groups, homeless
persons, nomads, refugees, minors or others incapable of personally gi'ing consent$ 4thics
committee(s) should get document 8standard operating procedures6 and should maintain a
record of its proceedings$

(ii) 4thics Committee(s) should ma/e, at a))ro)riate inter-als, an ongoing re-ie# of the trials for
#hich the% re-ie# the )rotocol(s)' 0uch a re-ie# ma% $e $ased on the )eriodic stud% )rogress re)orts
furnished $% the in-estigators and.or monitoring and internal audit re)orts furnished $% the 0)onsor
and.or $% -isiting the stud% sites'

(ii) In case an ethics committee re-o/es its a))ro-al accorded to a trial )rotocol, it must record the
reasons for doing so and at once communicate such a decision to the In-estigator as #ell as to the
>icensing !uthorit%'

(6) Human Pharmacology (Phase I) .-

(i) )he ob5ecti'e of studies in this -hase is the estimation of safety and tolerability with the
initial administration of an in'estigational new drug into human(s)$ *tudies in this -hase of
de'elopment usually ha'e non-therapeutic ob5ecti'es and may be conducted in healthy
'olunteers sub5ects or certain types of patients$ .rugs with significant potential to"icity e$g$
cytoto"ic drugs are usually studied in patients. -hase ! trials should preferably be carried out
by !n'estigators trained in clinical pharmacology with access to the necessary facilities to
closely obser'e and monitor the *ub5ects$



(ii) 0tudies conducted in Phase I, usuall% intended to in-ol-e one or a com$ination of the follo#ing
o$,ecti-es&

(a) Fa6imum tolerated dose& ?o determine the tolera$ilit% of the dose range e6)ected to $e
needed for later clinical studies and to determine the nature of ad-erse reactions that can $e
e6)ected' ?hese studies include $oth single and multi)le dose administration'

($) Pharmaco/inetics, i'e', characteriDation of a drugGs a$sor)tion, distri$ution, meta$olism
and e6cretion' !lthough these studies continue throughout the de-elo)ment )lan, the% should
$e )erformed to su))ort formulation de-elo)ment and determine )harmaco/inetic )arameters
in different age grou)s to su))ort dosing recommendations'

(c) Pharmacod%namics& De)ending on the drug and the end)oints studied, )harmacod%namic
studies and studies relating to drug $lood le-els ()harmaco/inetic. )harmacod%namic studies)
ma% $e conducted in health% -olunteer 0u$,ects or in )atients #ith the target disease' If there
are a))ro)riate -alidated indicators of acti-it% and )otential efficac%, )harmacod%namic data
o$tained from )atients ma% guide the dosage and dose regimen to $e a))lied in later studies'

(d) 4arl% Feasurement of Drug !cti-it%& Preliminar% studies of acti-it% or )otential
thera)eutic $enefit ma% $e conducted in Phase I as a secondar% o$,ecti-e' 0uch studies are
generall% )erformed in later Phases $ut ma% $e a))ro)riate #hen drug acti-it% is readil%
measura$le #ith a short duration of drug e6)osure in )atients at this earl% stage'

(4) T.)r"p)5(&% )6p#r"(r7 (r&"#* (P."*) II).,

(i) )he primary ob5ecti'e of -hase !! trials is to e'aluate the effecti'eness 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$ *tudies
in -hase !! should be conducted in a group of patients who are selected by relati'ely
narrow criteria leading to a relati'ely homogeneous population$ )hese studies should be
closely monitored$ An important goal for this -hase is to determine the dose(s) and
regimen for -hase !!! trials$ .oses used in -hase !! are usually (but not always) less than
the highest doses used in -hase !$

(ii) !dditional o$,ecti-es of Phase II studies can include e-aluation of )otential stud% end)oints,
thera)eutic regimens (including concomitant medications) and target )o)ulations (e'g' mild -ersus
se-ere disease) for further studies in Phase II or III' ?hese o$,ecti-es ma% $e ser-ed $% e6)lorator%
anal%ses, e6amining su$sets of data and $% including multi)le end)oints in trials'

(ii) !f the application is for conduct of clinical trials as a part of multi-national clinical
de'elopment of the drug, the number of sites and the patients as well as the 5ustification for
undertaking such trials in !ndia shall be pro'ided to the (icensing Authority$

(8) T.)r"p)5(&% %'$&r1"(r7 (r&"#* (P."*) III).,

(i) -hase !!! studies ha'e primary ob5ecti'e of demonstration or confirmation of therapeutic
benefit(s)$ *tudies in -hase !!! are designed to confirm the preliminary e'idence
accumulated in -hase !! that a drug is safe and effecti'e for use in the intended indication
and recipient population$ )hese studies should be intended to pro'ide an ade#uate basis for
marketing appro'al$ *tudies in -hase !!! may also further e"plore 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) (or drugs intended to $e administered for long )eriods, trials in-ol-ing e6tended e6)osure to the
drug are ordinaril% conducted in Phase III, although the% ma% $e initiated in Phase II' ?hese studies
carried out in Phase III com)lete the information needed to su))ort ade=uate instructions for use of the
drug ()rescri$ing information)'

(iii) (or ne# drugs a))ro-ed outside India, Phase III studies need to $e carried out )rimaril% to
generate e-idence of efficac% and safet% of the drug in Indian )atients #hen used as recommended in
the )rescri$ing information' Prior to conduct of Phase III studies in Indian su$,ects, >icensing
!uthorit% ma% re=uire )harmaco/inetic studies to $e underta/en to -erif% that the data generated in
Indian )o)ulation is in conformit% #ith the data alread% generated a$road'

(i-) If the a))lication is for the conduct of clinical trials as a )art of multinational clinical
de-elo)ment of the drug, the num$er of sites and )atients as #ell as the ,ustification for underta/ing
such trials in India should $e )ro-ided to the >icensing !uthorit% along #ith the a))lication'

(9) Post Marketing rials (Phase I!).- -ost :arketing trials are studies (other than
routine sur'eillance) performed after drug appro'al and related to the appro'ed
indication(s)$ )hese trials go beyond the prior demonstration of the drug6s safety,
efficacy and dose definition$ )hese trials may not be considered necessary at the time
of new drug appro'al but may be re#uired by the (icensing Authority for optimi0ing the
drug;s use$ )hey may be of any type but should ha'e 'alid scientific ob5ecti'es$ -hase
!< trials include additional drug-drug interaction(s), dose-response or safety studies and
trials designed to support use under the appro'ed indication(s), e$g$ mortality&morbidity
studies, epidemiological studies etc$

". #tu$ies in special populations:
Information su))orting the use of the drug in children, )regnant #omen, nursing #omen,
elderl% )atients, )atients #ith renal or other organ s%stems failure, and those on s)ecific concomitant
medication is re=uired to $e su$mitted if rele-ant to the clinical )rofile of the drug and its antici)ated
usage )attern' !n% claim sought to $e made for the drug )roduct that is not $ased on data su$mitted
under )receding items of this 0chedule should $e su))orted $% studies included under this item of the
0chedule (!))endi6 I, item A'3)'

(1) G)r&"(r&%*.,Beriatric )atients should $e included in Phase III clinical trials (and in Phase
II trials, at the 0)onsorGs o)tion) in meaningful num$ers, if
(a) the disease intended to be treated is characteristically a disease of aging3 or
(b) the population to be treated is known to include substantial numbers of
geriatric patients3 or
(c) when there is specific reason to e"pect that conditions common in the elderly
are likely to be encountered3 or
(d) when the new drug is likely to alter the geriatric patient;s response (with
regard to safety or efficacy) compared with that of the non-geriatric patient$

(2) P")2&"(r&%*.-
(i) ?he timing of )aediatric studies in the ne# drug de-elo)ment )rogram #ill de)end on the
medicinal )roduct, the t%)e of disease $eing treated, safet% considerations, and the efficac% and safet%
of a-aila$le treatments' (or a drug e6)ected to $e used in children, e-aluations should $e made in the
a))ro)riate age grou)' 9hen clinical de-elo)ment is to include studies in children, it is usuall%
a))ro)riate to $egin #ith older children $efore e6tending the trial to %ounger children and then infants'

(ii) !f the new drug is for diseases predominantly or e"clusi'ely affecting paediatric
patients, clinical trial data should be generated in the paediatric population e"cept 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 e"pose them to inappropriate risk$

(iii) !f 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 e'idence of potential benefit$ !n circumstances where this is
not possible, lack of data should be 5ustified in detail$

(i-) If the ne# drug has a )otential for use in )aediatric )atients E )aediatric studies should $e
conducted' ?hese studies ma% $e initiated at -arious )hases of clinical de-elo)ment or after )ost
mar/eting sur-elliance in adults if a safet% concern e6ists' In cases #here there is limited )aediatric
data at the time of su$mission of a))lication E more data in )aediatric )atients #ould $e e6)ected after
mar/eting authorisation for use in children is granted'



(-) ?he )aediatric studies should include
(a) clinical trials,
(b) relati'e bioe#ui'alence comparisons of the paediatric formulation with the adult
formulation performed in adults, and
(c) definiti'e pharmacokinetic studies for dose selection across the age ranges of
paediatric patients in whom the drug is likely to be used$ )hese studies should be
conducted in the paediatric patient population with the disease under study$

(-i) If the ne# drug is a ma,or thera)eutic ad-ance for the )aediatric )o)ulation E the studies should
$egin earl% in the drug de-elo)ment , and this data should $e su$mitted #ith the ne# drug
a))lication'

(-ii) Paediatric 0u$,ects are legall% una$le to )ro-ide #ritten informed consent, and are de)endent on
their )arent(s). legal guardian to assume res)onsi$ilit% for their )artici)ation in clinical studies'
9ritten informed consent should $e o$tained from the )arent. legal guardian' Ho#e-er, all )aediatric
)artici)ants should $e informed to the fullest e6tent )ossi$le a$out the stud% in a language and in
terms that the% are a$le to understand' 9here a))ro)riate, )aediatric )artici)ants should additionall%
assent to enrol in the stud%' Fature minors and adolescents should )ersonall% sign and date a
se)aratel% designed #ritten assent form' !lthough a )artici)ant@s #ish to #ithdra# from a stud% must
$e res)ected, there ma% $e circumstances in thera)eutic studies for serious or lifethreatening diseases
in #hich, in the o)inion of the In-estigator and )arent(s). legal guardian, the #elfare of a )ediatric
)atient #ould $e ,eo)ardiDed $% his or her failing to )artici)ate in the stud%' In this situation, continued
)arental. legal guardian consent should $e sufficient to allo# )artici)ation in the stud%'

(-iii)(or clinical trials conducted in the )aediatric )o)ulation, the re-ie#ing ethics committee should
include mem$ers #ho are /no#ledgea$le a$out )ediatric, ethical, clinical and )s%chosocial issues'

(-) Pr)/'"'( r '5r*&'/ 91)''
(i) Pregnant or nursing #omen should $e included in clinical trials onl% #hen the drug is intended for
use $% )regnant.nursing #omen or foetuses.nursing infants and #here the data generated from #omen
#ho are not )regnant or nursing, is not suita$le'

(ii) (or ne# drugs intended for use during )regnanc%, follo#u) data ()ertaining to a )eriod
a))ro)riate for that drug) on the )regnanc%, fetus and child #ill $e re=uired' 9here a))lica$le,
e6cretion of the drug or its meta$olites into human mil/ should $e e6amined and the infant should $e
monitored for )redicted )harmacological effects of the drug'

(%) Post Marketing #ur&eillance.-
(i) *ubse#uent to appro'al of the product, new drugs should be closely monitored for their
clinical safety once they are marketed$ )he applicants shall furnish -eriodic *afety =pdate
>eports (-*=>s) in order to-
(a) re)ort all the rele-ant ne# information from a))ro)riate sources7
(b) relate these data to patient e"posure 3
(c) summariDe the mar/et authoriDation status in different countries and an% significant
-ariations related to safet%7 and
(d) indicate #hether changes should $e made to )roduct information in
order to o)timiDe the use of the )roduct'

(ii) Irdinaril% all dosage forms and formulations as #ell as indications for ne# drugs should $e
co-ered in one P0JR' 9ithin the single P0JR se)arate )resentations of data for different dosage
forms, indications or se)arate )o)ulation need to $e gi-en'

(iii) !ll rele-ant clinical and nonclinical safet% data should co-er onl% the )eriod of the re)ort
(inter-al data)' ?he P0JRs shall $e su$mitted e-er% si6 months for the first t#o %ears after a))ro-al of
the drug is granted to the a))licant' (or su$se=uent t#o %ears E the P0JRs need to $e su$mitted
annuall%' >icensing authorit% ma% e6tend the total duration of su$mission of P0JRs if it is considered
necessar% in the interest of )u$lic health' P0JRs due for a )eriod must $e su$mitted #ithin 3:
calendar da%s of the last da% of the re)orting )eriod' Ho#e-er, all cases in-ol-ing serious une6)ected
ad-erse reactions must $e re)orted to the licensing authorit% #ithin 15 da%s of initial recei)t of the
information $% the a))licant' If mar/eting of the ne# drug is dela%ed $% the a))licant after o$taining
a))ro-al to mar/et, such data #ill ha-e to $e )ro-ided on the deferred $asis $eginning from the time
the ne# drug is mar/eted'

(i-) Ce# studies s)ecificall% )lanned or conducted to e6amine a safet% issue should $e descri$ed in
the P0JRs'

(-) ! P0JR should $e structured as follo#s&
(a) A title page stating: -eriodic safety update report for the product, applicant6s name,
period co'ered by the report, date of appro'al of new drug, date of marketing of
new drug and date of reporting3
($) Introduction,
(c) Current #orld#ide mar/et authoriDation status,
(d) J)date of actions ta/en for safet% reasons,
(e) Changes to reference safet% information,
(f) 4stimated )atient e6)osure,
(g) Presentation of indi-idual case histories,
(h) 0tudies,
( I) Ither information,
(,) I-erall safet% e-aluation,
(/) Conclusion,
(l) !))endi6 )ro-iding material relating to indications, dosing, )harmacolog% and other related
information'

(3) Sp)%&"# *(52&)*: ;&"!"&#"+&#&(7 / ;&)<5&!"#)'%) S(52&)*.,
(i) (or drugs a))ro-ed else#here in the #orld and a$sor$ed s%stemicall%, $ioe=ui-alence #ith the reference
formulation should $e carried out #here-er a))lica$le' ?hese studies should $e conducted under the
la$eled conditions of administration' Data on the e6tent of s%stemic a$sor)tion ma% $e re=uired for
formulations other than those designed for s%stemic a$sor)tion'

(ii) 4-aluation of the effect of food on a$sor)tion follo#ing oral administration should $e carried out' Data
from dissolution studies should also $e su$mitted for all solid oral dosage forms'

(iii) Dissolution and $ioa-aila$ilit% data su$mitted #ith the ne# drug a))lication must )ro-ide information
that assures $ioe=ui-alence or esta$lishes $ioa-aila$ilit% and dosage correlations $et#een the
formulation(s) sought to $e mar/eted and those used




for clinical trials during clinical de-elo)ment of the )roduct' (0ee items A'1, A'" and A'3 of
!))endi6 I,)'

(i-) !ll $ioa-aila$ilit% and $ioe=ui-alence studies should $e conducted according to the Buidelines
for 3ioa-aila$ilit% and 3ioe=ui-ance studies as )rescri$ed'

'ote.- )he data re#uirements stated in this *chedule are e"pected to pro'ide ade#uate
information to e'aluate the efficacy, safety and therapeutic rationale of new drugs (as defined
under rule 1-4) prior to the permission for sale$ .epending upon the nature of new drugs
and disease(s), additional information may be re#uired by the (icensing Authority$ )he
applicant shall certify the authencity of the data and documents submitted in support of an
application for new drug$ )he (icensing Authority reser'es the right to re5ect any data or any
document(s) if such data or contents of such documents are found to be of doubtful integrity$


APP(')I* I

D!?! ?I 34 0J3FI??4D !>ICB 9I?H ?H4 !PP>IC!?IIC ?I CICDJC? C>ICIC!>
?RI!>0 . IFPIR? . F!CJ(!C?JR4 I( C49 DRJB0 (IR F!RK4?ICB IC ?H4 CIJC?R1'

1$ !ntroduction
! $rief descri)tion of the drug and the thera)eutic class to #hich it $elongs'

$ ,hemical and pharmaceutical information
"'1' Information on acti-e ingredients
Drug information (Beneric Came, Chemical Came or ICC)

"'"' Ph%sicochemical Data
a' Chemical name and 0tructure
4m)irical formula
Folecular #eight
$' Ph%sical )ro)erties
Descri)tion
0olu$ilit%
Rotation
Partition coefficient
Dissociation constant

"'3' !nal%tical Data
4lemental anal%sis
Fass s)ectrum
CFR s)ectra
IR s)ectra
J8 s)ectra
Pol%mor)hic identification

"'4' Com)lete monogra)h s)ecification including
Identification
Identit%.=uantification of im)urities
4nantiomeric )urit%
!ssa%

"'5' 8alidations
!ssa% method
Im)urit% estimation method
Residual sol-ent.other -olatile im)urities (I8I) estimation method

"';' 0ta$ilit% 0tudies (for details refer !))endi6 IX)
(inal release s)ecification
Reference standard characteriDation
Faterial safet% data sheet

"'<' Data on (ormulation
Dosage form
Com)osition
Faster manufacturing formula
Details of the formulation (including inacti-e ingredients)
In )rocess =ualit% control chec/
(inished )roduct s)ecification
46ci)ient com)ati$ilit% stud%
8alidation of the anal%tical method
Com)arati-e e-aluation #ith international $rand(s) or a))ro-ed Indian $rands, if a))lica$le
Pac/ )resentation
Dissolution
!ssa%
Im)urities
Content uniformit%
)H
(orce degradation stud%
0ta$ilit% e-aluation in mar/et intended )ac/ at )ro)osed storage conditions
Pac/ing s)ecifications
Process -alidation

9hen the a))lication is for clinical trials onl%, the international non)ro)rietar% name (ICC) or generic
name, drug categor%, dosage form and data su))orting sta$ilit% in the intended containerclosure
s%stem for the duration of the clinical trial (information co-ered in item nos' "'1, "'3, "';, "'<) are
re=uired'

%$ Animal -harmacology (for details refer Appendi" !<)

3'1' 0ummar%
3'"' 0)ecific )harmacological actions
3'3' Beneral )harmacological actions
3'4' Follow-up and *upplemental *afety -harmacology *tudies
3'5' Pharmaco/inetics& a$sor)tion, distri$ution7 meta$olism7 e6cretion

4$ Animal )o"icology (for details refer Appendi" !!!)
4'1' Beneral !s)ects
4'"' 0%stemic ?o6icit% 0tudies
4'3' Fale (ertilit% 0tud%
4'4' (emale Re)roduction and De-elo)mental ?o6icit% 0tudies
4'5' >ocal to6icit%
4';' !llergenicit%.H%)ersensiti-it%
4'<' Benoto6icit%
4'A' Carcinogenicit%

?$ 1uman & ,linical pharmacology (-hase !)
5'1' 0ummar%
5'"' 0)ecific Pharmacological effects
5'3' Beneral Pharmacological effects
5'4' Pharmaco/inetics, a$sor)tion, distri$ution, meta$olism, e6cretion
5'5' Pharmacod%namics . earl% measurement of drug acti-it%

@$ )herapeutic e"ploratory trials (-hase !!)
;'1' 0ummar%
;'"' 0tud% re)ort(s) as gi-en in !))endi6 II

7$ )herapeutic confirmatory trials (-hase !!!)
<'1' 0ummar%
<'"' Indi-idual stud% re)orts #ith listing of sites and In-estigators'

A$ *pecial studies
A'1' 0ummar%
A'"' 3ioa-aila$ilit% . 3ioe=ui-alence'
A'3 Ither studies e'g' geriatrics, )aediatrics, )regnant or nursing #omen


B$ >egulatory status in other countries
9'1' Countries #here the drug is
a' Far/eted
$' !))ro-ed
c' !))ro-ed as ICD
d' 9ithdra#n, if an%, #ith reasons

9'"' Restrictions on use, if an%, in countries #here mar/eted .a))ro-ed
9'3' (ree sale certificate or certificate of anal%sis, as a))ro)riate'

1C$ -rescribing information
1:'1' Pro)osed full )rescri$ing information
1:'"' Drafts of la$els and cartons

11$ *amples and )esting -rotocol&s

11'1' 0am)les of )ure drug su$stance and finished )roduct (an e=ui-alent of 5: clinical doses, or
more num$er of clinical doses if )rescri$ed $% the >icensing !uthorit%), #ith testing
)rotocol.s, full im)urit% )rofile and release s)ecifications'

CI?40&
(1) All items may not be applicable to all drugs$ For e"planation, refer te"t of
*chedule D$
() For re#uirements of data to be submitted with application for clinical trials
refer te"t of this *chedule$

APPENDI= I,A

D!?! R4LJIR4D ?I 34 0J3FI??4D 31 !C !PP>IC!C? (IR BR!C? I( P4RFI00IIC ?I
IFPIR? !CD . IR F!CJ(!C?JR4 ! C49 DRJB !>R4!D1 !PPRI84D IC ?H4
CIJC?R1'

1' Introduction
! $rief descri)tion of the drug and the thera)eutic class

"' Chemical and )harmaceutical information
"'1 Chemical name, code name or num$er, if an%7 non)ro)rietar% or generic name, if an%,
structure7 )h%sicochemical )ro)erties
"'" Dosage form and its com)osition
"'3 ?est s)ecifications
(a) acti-e ingredients
($) inacti-e ingredients
"'4 ?ests for identification of the acti-e ingredients and method of tis assa%
"'5 Iutline of the method of manufacture of acti-e ingredients
"'; 0ta$ilit% data

3' Far/eting information
3'1 Pro)osed )ac/age insert . )romotional literature
3'" Draft s)ecimen of the la$el and carton

4' 0)ecial studies conducted #ith a))ro-al of >icensing !uthorit%
4'1 3ioa-aila$ilit% . 3ioe=ui-alence and com)arati-e dissolution studies for
oral dosage forms
4'" 0u$acute animal to6icit% studies for intra-enous infusions and in,ecta$les

App)'2&6 II

STRUCTURE> CONTENTS AND FORMAT FOR CLINICAL STUDY REPORTS

1' ?itle Page&
?his )age should contain information a$out the title of the stud%, the )rotocol code, name of
the in-estigational )roduct tested, de-elo)ment Phase, indication studied, a $rief descri)tion
of the trial design, the start and end date of )atient accrual and the names of the 0)onsor and
the )artici)ating Institutes (In-estigators)'

"' 0tud% 0%no)sis (1 to " )ages)& ! $rief o-er-ie# of the stud% from the )rotocol de-elo)ment to
the trial closure should $e gi-en here' ?his section #ill onl% summariDe the im)ortant
conclusions deri-ed from the stud%'

%$ *tatement of compliance with the 8+uidelines for ,linical )rials on -harmaceutical
-roducts in !ndia E +,- +uidelines6 issued by the ,entral .rugs *tandard ,ontrol
/rgani0ation, :inistry of 1ealth, +o'ernment of !ndia$

4' >ist of !$$re-iations and Definitions

5' ?a$le of contents

;' 4thics Committee&
?his section should document that the stud% #as conducted in accordance #ith the ethical
)rinci)les of Declaration of Helsin/i' ! detailed descri)tion of the 4thics Committee
constitution and date(s) of a))ro-als of trial documents for each of the )artici)ating sites
should $e )ro-ided' ! declaration should state that 4C notifications as )er Bood Clinical
Practice Buidelines issued $% Central Drugs 0tandard Control IrganiDation and 4thical
Buidelines for 3iomedical Research on Human 0u$,ects, issued $% Indian Council of Fedical
Research ha-e $een follo#ed'

<' 0tud% ?eam&
3riefl% descri$e the administrati-e structure of the stud% (In-estigators, site staff, 0)onsor.
designates, Central la$orator% etc')'

A' Introduction&
! $rief descri)tion of the )roduct de-elo)ment rationale should $e gi-en here'

9' 0tud% I$,ecti-e&
! statement descri$ing the o-erall )ur)ose of the stud% and the )rimar% and secondar%
o$,ecti-es to $e achie-ed should $e mentioned here'

1:' In-estigational Plan&
?his section should descri$e the o-erall trial design, the 0u$,ect selection criteria, the
treatment )rocedures, $linding . randomiDation techni=ues if an%, allo#ed. disallo#ed
concomitant treatment, the efficac% and safet% criteria assessed, the data =ualit% assurance
)rocedures and the statistical methods )lanned for the anal%sis of the data o$tained'

11' ?rial 0u$,ects
A clear accounting of all trial *ub5ects who entered the study will be gi'en here$
:ention should also be made of all cases that were dropouts or protocol
de'iations$ 4numerate the patients screened, randomised, and prematurely discontinued$
*tate reasons for premature discontinuation of therapy in each applicable case$

1"' 4fficac% e-aluation
?he results of e-aluation of all the efficac% -aria$les #ill $e descri$ed in this section #ith
a))ro)riate ta$ular and gra)hical re)resentation' ! $rief descri)tion of the demogra)hic
characteristics of the trial )atients should also $e )ro-ided along #ith a listing of )atients and
o$ser-ations e6cluded from efficac% anal%sis'

13' 0afet% 4-aluation
?his section should include the com)lete list
13'1 all serious ad-erse e-ents, #hether e6)ected or une6)ected and
13'" une6)ected ad-ese e-ents #hether serious or not (com)liled from data recei-ed as )er
!))endi6 XI)'
?he com)arison of ad-erse e-ents across stud% grou)s ma% $e )resented in a ta$ular or
gra)hical form' ?his section should also gi-e a $rief narrati-e of all im)ortant e-ents
considered related to the in-estigational )roduct'

14' Discussion and o-erall Conclusion
Discussion of the im)ortant conclusions deri-ed from the trial and sco)e for further
de-elo)ment'

15' >ist of References

1;' !))endices
>ist of !))endices to the Clinical ?rial Re)ort
a' Protocol and amendments
$' 0)ecimen of Case Record (orm
c' In-estigators@ name(s) #ith contact addresses, )hone, email etc'
d' Patient data listings
e' >ist of trial )artici)ants treated #ith in-estigational )roduct
f' Discontinued )artici)ants
g' Protocol de-iations
h' CR(s of cases in-ol-ing death and life threatening ad-erse e-ent cases
i' Pu$lications from the trial
,' Im)ortant )u$lications referenced in the stud%
/' !udit certificate, if a-aila$le
l' In-estigator@s certificate that he.she has read the re)ort and that the re)ort
accuratel% descri$es the conduct and the results of the stud%'
App)'2&6 III

ANIMAL TO=ICOLOGY (NON,CLINICAL TO=ICITY STUDIES)

1' Beneral Princi)les

?o6icit% studies should com)l% #ith the norms of Bood >a$orator% Practice (B>P)' 3riefl%, these
studies should $e )erformed $% suita$l% trained and =ualified staff em)lo%ing )ro)erl% cali$rated and
standardiDed e=ui)ment of ade=uate siDe and ca)acit%' 0tudies should $e done as )er #ritten )rotocols
#ith modifications (if an%) -erifia$le retros)ecti-el%' 0tandard o)erating )rocedures (0IPs) should $e
follo#ed for all managerial and la$orator% tas/s related to these studies' ?est su$stances and test
s%stems (in-itro or in-i-o) should $e )ro)erl% characteriDed and standardiDed' !ll documents
$elonging to each stud%, including its a))ro-ed )rotocol, ra# data, draft re)ort, final re)ort, and
histolog% slides and )araffin tissue $loc/s should $e )reser-ed for a minimum of 5 %ears after
mar/eting of the drug'

?o6ico/inetic studies (generation of )harmaco/inetic data either as an integral com)onent of the
conduct of nonclinical to6icit% studies or in s)eciall% designed studies) should $e conducted to assess
the s%stemic e6)osure achie-ed in animals and its relationshi) to dose le-el and the time course of the
to6icit% stud%' Ither o$,ecti-es of to6ico/inetic studies include o$taining data to relate the e6)osure
achie-ed in to6icit% studies to to6icological findings and contri$ute to the assessment of the rele-ance
of these findings to clinical safet%, to su))ort the choice of s)ecies and treatment regimen in
nonclinical to6icit% studies and to )ro-ide information #hich, in con,unction #ith the to6icit%
findings, contri$utes to the design of su$se=uent nonclinical to6icit% studies'

1'1 0%stemic ?o6icit% 0tudies

1'1'1 0ingledose ?o6icit% 0tudies& ?hese studies (see !))endi6 I item 4'") should $e carried out in "
rodent s)ecies (mice and rats) using the same route as intended for humans' In addition,
unless the intended route of administration in humans is onl% intra-enous, at least one
more route should $e used in one of the s)ecies to ensure s%stemic a$sor)tion of the
drug' ?his route should de)end on the nature of the drug' ! limit of "g./g (or 1: times
the normal dose that is intended in humans, #hiche-er is higher) is recommended for oral
dosing' !nimals should $e o$ser-ed for 14 da%s after the drug administration, and
minimum lethal dose (F>D) and ma6imum tolerated dose (F?D) should $e
esta$lished' If )ossi$le, the target organ of to6icit% should also $e determined' Fortalit%
should $e o$ser-ed for u) to < da%s after )arenteral administration and u) to 14 da%s after
oral administration' 0%m)toms, signs and mode of death should $e re)orted, #ith
a))ro)riate macrosco)ic and microsco)ic findings #here necessar%' >D1: and >D5: should
$e re)orted )refera$l% #ith 95 )ercent confidence limits' If >D5:s cannot $e determined,
reasons for the same should $e stated'

?he dose causing se-ere to6ic manifestations or death should $e defined in the case of
c%toto6ic anticancer agents, and the )ostdosing o$ser-ation )eriod should $e to 14
da%s' Fice should first $e used for determination of F?D' (indings should then $e
confirmed in rat for esta$lishing linear relationshi) $et#een to6icit% and $od% surface area' In
case of nonlinearit%, data of the more sensiti-e s)ecies should $e used to determine the Phase I
starting dose' 9here rodents are /no#n to $e )oor )redictors of human to6icit% (e'g',
antifolates), or #here the c%toto6ic drug acts $% a no-el mechanism of action, F?D should $e
esta$lished in nonrodent s)ecies'

1$1$ >epeated-dose *ystemic )o"icity *tudies: )hese studies (see Appendi" !, item 4$)
should be carried out in at least two mammalian species, of which one should be a
non-rodent$ .ose ranging studies should precede the 14-, A-, BC- or 1AC- day to"icity
studies$ .uration of the final systemic to"icity study will depend on the duration,
therapeutic indication and scale of the proposed clinical trial$ (see !tem 1$A)$ !f a
species is known to metaboli0e the drug in the same way as humans, it should be
preferred for to"icity studies$

In re)eateddose to6icit% studies the drug should $e administered < da%s a #ee/ $% the route
intended for clinical use' ?he num$er of animals re=uired for these studies, i'e' the minimum
num$er of animals on #hich data should $e a-aila$le, is sho#n in Item 1'9'

9here-er a))lica$le, a control grou) of animals gi-en the -ehicle alone should $e included,
and three other grou)s should $e gi-en graded doses of the drug' ?he highest dose should
)roduce o$ser-a$le to6icit%7 the lo#est dose should not cause o$ser-a$le to6icit%, $ut should
$e com)ara$le to the intended thera)eutic dose in humans or a multi)le of it ' ?o ma/e
allo#ance for the sensiti-it% of the s)ecies the intermediate dose should cause some
s%m)toms, $ut not gross to6icit% or death, and should $e )laced logarithmicall% $et#een the
other t#o doses'

?he )arameters to $e monitored and recorded in longterm to6icit% studies should include
$eha-ioral, )h%siological, $iochemical and microsco)ic o$ser-ations' In case of )arenteral
drug administration, the sites of in,ection should $e 0u$,ected to gross and microsco)ic
e6amination' Initial and final electrocardiogram and fundus e6amination should $e carried out
in the nonrodent s)ecies'

In the case of c%toto6ic anticancer agents dosing and stud% design should $e in accordance
#ith the )ro)osed clinical schedule in terms of da%s of e6)osure and num$er of c%cles' ?#o
rodent s)ecies ma% $e tested for initiating Phase I trials' ! nonrodent s)ecies should $e
added if the drug has a no-el mechanism of action, or if )ermission for Phase II, III or
mar/eting is $eing sought'

(or most com)ounds, it is e6)ected that single dose tissue distri$ution studies #ith sufficient
sensiti-it% and s)ecificit% #ill )ro-ide an ade=uate assessment of tissue distri$ution and the
)otential for accumulation' ?hus, re)eated dose tissue distri$ution studies should not $e
re=uired uniforml% for all com)ounds and should onl% $e conducted #hen a))ro)riate data
cannot $e deri-ed from other sources' Re)eated dose studies ma% $e a))ro)riate under certain
circumstances $ased on the data from single dose tissue distri$ution studies, to6icit% and
to6ico/inetic studies' ?he studies ma% $e most a))ro)riate for com)ounds #hich ha-e an
a))arentl% long half life, incom)lete elimination or unantici)ated organ to6icit%'


Cotes&

(i) 0ingle Dose ?o6icit% 0tud%& 4ach grou) should contain at least 5 animals of either se6' !t
least four graded doses should $e gi-en' !nimals should $e e6)osed to the test su$stance in a
single $olus or $% continuous infusion or se-eral doses #ithin "4 hours' !nimals should $e
o$ser-ed for 14 da%s' 0igns of into6ication, effect on $od% #eight, gross )athological changes
should $e re)orted' It is desira$le to include histo)atholog% of grossl% affected organs, if an%'

(ii) Doseranging 0tud%& I$,ecti-es of this stud% include the identification of
target organ of to6icit% and esta$lishment of F?D for su$se=uent studies'

(a) >odents: *tudy should be performed in one rodent species (preferably rat) by
the proposed clinical route of administration$ At least four graded doses including
control should be gi'en, and each dose group as well as the 'ehicle control
should consist of a minimum of ? animals of each se"$ Animals should be
e"posed to the test substance daily for 1C consecuti'e days$ 1ighest dose
should be the ma"imum tolerated dose of single-dose study$ Animals should be
obser'ed daily for signs of into"ication (general appearance, acti'ity and
beha'iour etc), and periodically for the body weight and laboratory
parameters$ +ross e"amination of 'iscera and microscopic e"amination of
affected organs should be done$

(b) Fon-rodents: /ne male and one female are to be taken for ascending -hase
:). study$ .osing should start after initial recording of cage-side and laboratory
parameters$ *tarting dose may be % to ? times the e"trapolated effecti'e dose or
:). (whiche'er is less), and dose escalation in suitable steps should be done
e'ery third day after drawing the samples for laboratory parameters$ .ose
should be lowered appropriately when clinical or laboratory e'idence of to"icity
are obser'ed$ Administration of test substance should then continue for 1C days
at the well-tolerated dose le'el following which, samples for laboratory
parameters should be taken$ *acrifice, autopsy and microscopic e"amination of
affected tissues should be performed as in the case of rodents$

(iii) 14"A Da% re)eateddose to6icit% studies& Ine rodent (;1:.se6.grou)) and one non
rodent ("3.se6.grou)) s)ecies are needed' Dail% dosing $% )ro)osed clinical route at
three dose le-els should $e done #ith highest dose ha-ing o$ser-a$le to6icit%, middose
$et#een high and lo# dose, and lo# dose' ?he doses should )refera$l% $e multi)les of
the effecti-e dose and free from to6icit%' I$ser-ation )arameters should include cage
side o$ser-ations, $od% #eight changes, food.#ater inta/e, $lood $iochemistr%,
haematolog%, and gross and microsco)ic studies of all -iscera and tissues'

(i-) 9:Da% re)eateddose to6icit% studies& Ine rodent (153:.se6.grou)) and one non
rodent (4;.se6.grou)) s)ecies are needed' Dail% dosing $% )ro)osed clinical route at
three graded dose le-els should $e done' In addition to the control a *highdose
re-ersal+ grou) and its control grou) should $e also included' Parameters should
include signs of into6ication (general a))earance, acti-it% and $eha-iour etc), $od%
#eight, food inta/e, $lood $iochemical )arameters, hematological -alues, urine
anal%sis, organ #eights, gross and microsco)ic stud% of -iscera and tissues' Half the
animals in *re-ersal+ grou)s (treated and control) should $e sacrificed after 14 da%s of
sto))ing the treatment' ?he remaining animals should $e sacrificed after "A da%s of
sto))ing the treatment or after the reco-er% of signs and.or clinical )athological changes
E #hiche-er comes later, and e-aluated for the )arameters used for the main stud%'

(') 1AC-.ay repeated-dose to"icity studies: /ne rodent (1?-%C&se"&group) and one
non-rodent (4-@&se"&group) species are needed$ At least 4 groups, including
control, should be taken$ .aily dosing by proposed clinical route at three graded
dose le'els should be done$ -arameters should include signs of into"ication,
body weight, food intake, blood biochemistry, hematology, urine analysis, organ
weights, gross and microscopic e"amination of organs and tissues$


1$ :ale Fertility *tudy

Ine rodent s)ecies ()refera$l% rat) should $e used' Dose selection should $e done from the results of
the )re-ious 14 or "Ada% to6icit% stud% in rat' ?hree dose grou)s, the highest one sho#ing minimal
to6icit% in s%stemic studies, and a control grou) should $e ta/en' 4ach grou) should consist of ; adult
male animals' !nimals should $e treated #ith the test su$stance $% the intended route of clinical use
for minimum "A da%s and ma6imum <: da%s $efore the% are )aired #ith female animals of )ro-en
fertilit% in a ratio of 1&" for mating'

Drug treatment of the male animals should continue during )airing' Pairing should $e continued till
the detection of -aginal )lug or 1: da%s, #hiche-er is earlier' (emales getting thus )regnant should $e
e6amined for their fertilit% inde6 after da% 13 of gestation' !ll the male animals should $e sacrificed
at the end of the stud%' 9eights of each testis and e)idid%mis should $e se)aratel% recorded' 0)erms
from one e)idid%mis should $e e6amined for their motilit% and mor)holog%' ?he other e)idid%mis
and $oth testes should $e e6amined for their histolog%'

1$% Female >eproduction and .e'elopmental )o"icity *tudies

?hese studies (see !))endi6 I, item 4'4) need to $e carried out for all drugs )ro)osed to $e studied or
used in #omen of child $earing age' 0egment I, II and III studies (see $elo#) are to $e )erformed in
al$ino mice or rats, and segment II stud% should include al$ino ra$$its also as a second test s)ecies'
In the occasion, #hen the test article is not com)ati$le #ith the ra$$it (e'g' anti$iotics #hich are
effecti-e against gram )ositi-e, anaero$ic organisms and )rotoDoas) the 0egment II data in the mouse
ma% $e su$stituted'

1'3'1 (emale (ertilit% 0tud% (0egment I)& ?he stud% should $e done in one rodent s)ecies (rat
)referred)' ?he drug should $e administered to $oth males and females, $eginning a sufficient
num$er of da%s ("A da%s in males and 14 da%s in females) $efore mating' Drug treatment
should continue during mating and, su$se=uentl%, during the gestation )eriod' ?hree graded
doses should $e used, the highest dose (usuall% the F?D o$tained from )re-ious s%stemic
to6icit% studies) should not affect general health of the )arent animals' !t least 15 males and 15
females should $e used )er dose grou)' Control and the treated grou)s should $e of similar
siDe' ?he route of administration should $e the same as intended for thera)eutic use'

Dams should $e allo#ed to litter and their medication should $e continued till the #eaning of
)u)s' I$ser-ations on $od% #eight, food inta/e, clinical signs of into6ication, mating $eha-iour,
)rogress of gestation. )arturition )eriods, length of gestation, )arturition, )ost)artum health and gross
)atholog% (and histo)atholog% of affected organs) of dams should $e recorded' ?he )u)s from $oth
treated and control grou)s should $e o$ser-ed for general signs of into6ication, se6#ise distri$ution
in different treatment grou)s, $od% #eight, gro#th )arameters, sur-i-al, gross e6amination, and
auto)s%' Histo)atholog% of affected organs should $e done'

1$%$ )eratogenicity *tudy (*egment !!): /ne rodent (preferably rat) and one non-rodent
(rabbit) species are to be used$ )he drug should be administered throughout the
period of organogenesis, using three dose le'els as described for segment !$ )he
highest dose should cause minimum maternal to"icity and the lowest one should be
proportional to the proposed dose for clinical use in humans or a multiple of it$ )he
route of administration should be the same as intended for human therapeutic use$

?he control and the treated grou)s should consist of at least ": )regnant rats (or mice) and 1" ra$$its,
on each dose le-el' !ll foetuses should to $e su$,ected to gross e6amination, one of the foetuses
should $e e6amined for s/eletal a$normalities and the other half for -isceral
a$normalities' I$ser-ation )arameters should include& (Dams) signs of into6ication, effect on $od%
#eight, effect on food inta/e, e6amination of uterus, o-aries and uterine contents, num$er of cor)ora
lutea, im)lantation sites, resor)tions (if an%)7 and for the foetuses, the total num$er, gender, $od%
length, #eight and gross. -isceral. s/eletal a$normalities, if an%'

1$%$% -erinatal *tudy (*egment !!!): )his study is specially recommended if the drug is to
be gi'en to pregnant or nursing mothers for long periods or where there are
indications of possible ad'erse effects on foetal de'elopment$ /ne rodent species
(preferably rat) is needed$ .osing at le'els comparable to multiples of human dose
should be done by the intended clinical route$ At least 4 groups (including control),
each consisting of 1? dams should be used$ )he drug should be administered
throughout the last trimester of pregnancy (from day 1? of gestation) and then the
dose that causes low foetal loss should be continued throughout lactation and
weaning$ .ams should then be sacrificed and e"amined as described below$

Ine male and one female from each litter of (1 generation (total 15 males and 15 females in each
grou)) should $e selected at #eaning and treated #ith -ehicle or test su$stance (at the dose le-els
descri$ed a$o-e) throughout their )eriods of gro#th to se6ual maturit%, )airing, gestation, )arturition
and lactation' Fating )erformance and fertilit% of (1 generation should thus $e e-aluated to o$tain the
(" generation #hose gro#th )arameters should $e monitored till #eaning' ?he criteria of e-aluation
should $e the same as descri$ed earlier (3'4'1)'

!nimals should $e sacrificed at the end of the stud% and the o$ser-ation )arameters should include
(Dams) $od% #eight, food inta/e, general signs of into6ication, )rogress of gestation. )arturition
)eriods and gross )atholog% (if an%)7 and for )u)s, the clinical signs, se6#ise distri$ution in dose
grou)s, $od% #eight, gro#th )arameters, gross e6amination, sur-i-al and auto)s% (if needed) and
#here necessar%, histo)atholog%'

1$4 (ocal to"icity

?hese studies (see !))endi6 I, item 4'5) are re=uired #hen the ne# drug is )ro)osed to $e used $%
some s)ecial route (other than oral) in humans' ?he drug should $e a))lied to an a))ro)riate site (e'g',
s/in or -aginal mucous mem$rane) to determine local effects in a suita$le s)ecies' ?%)ical stud%
designs for these studies should include three dose le-els and untreated and. or -ehicle control,
)refera$l% use of " s)ecies, and increasing grou) siDe #ith increase in duration of treatment' 9here
dosing is restricted due to anatomical or humane reasons, or the drug concentration cannot $e
increased $e%ond a certain le-el due to the )ro$lems of solu$ilit%, )H or tonicit%, a clear statement to
this effect should $e gi-en' If the drug is a$sor$ed from the site of a))lication, a))ro)riate s%stemic
to6icit% studies #ill also $e re=uired'


Cotes&

(i) .ermal to"icity study: )he study should be done in rabbit and rat$ .aily topical
(dermal) application of test substance in its clinical dosage form should be done$ )est
material should be applied on sha'ed skin co'ering not less than 1CG of the total
body surface area$ -orous gau0e dressing should be used to hold li#uid material in
place$ Formulations with different concentrations (at least %) of test substance,
se'eral fold higher than the clinical dosage form should be used$ -eriod of
application may 'ary from 7 to BC days depending on the clinical duration of
use$ Hhere skin irritation is grossly 'isible in the initial studies, a reco'ery group
should be included in the subse#uent repeated-dose study$ (ocal signs (erythema,
oedema and eschar formation) as well as histological e"amination of sites of
application should be used for e'aluation of results$

(ii) Photoallerg% or dermal )hototo6icit%& It should $e tested $% !rmstrong. Har$er ?est in
guinea )ig' ?his test should $e done if the drug or a meta$olite is related to an agent causing
)hotosensiti-it% or the nature of action suggests such a )otential (e'g', drugs to $e used in
treatment of leucoderma)' Pretest in A animals should screen 4 concentrations ()atch
a))lication for " hours M15 min') #ith and #ithout J8 e6)osure (1: N.cm
"
)' I$ser-ations
recorded at "4 and 4A hours should $e used to ascertain highest nonirritant dose' Fain test
should $e )erformed #ith 1: test animals and 5 controls' Induction #ith the dose selected
from )retest should use :'3 ml.)atch for " hour M15 min' follo#ed $% 1: N.cm
"
of J8
e6)osure' ?his should $e re)eated on da% :, ",4,<,9 and 11 of the test' !nimals should $e
challenged #ith the same concentration of test su$stance $et#een da% ": to "4 of the test #ith
a similar "hour a))lication follo#ed $% e6)osure to 1: N.cm
"
of J8 light' 46amination and
grading of er%thema and oedema formation at the challenge sites should $e done "4 and 4A
hours after the challenge' ! )ositi-e control li/e mus/ am$rett or )soralin should $e used'

(iii) 8aginal ?o6icit% ?est& 0tud% is to $e done in ra$$it or dog' ?est su$stance should $e
a))lied to)icall% (-aginal mucosa) in the form of )essar%, cream or ointment' 0i6 to ten
animals )er dose grou) should $e ta/en' Higher concentrations or se-eral dail% a))lications
of test su$stance should $e done to achie-e multi)les of dail% human dose' ?he minimum
duration of drug treatment is < da%s (more according to clinical use), 0u$,ect to a ma6imum of
3: da%s' I$ser-ation )arameters should include s#elling, closure of introitus and
histo)atholog% of -aginal #all'

(i-) Rectal ?olerance ?est& (or all )re)arations meant for rectal administration this test ma% $e
)erformed in ra$$its or dogs' 0i6 to ten animals )er dose grou) should $e ta/en' (ormulation
in -olume com)ara$le to human dose (or the ma6imum )ossi$le -olume) should $e a))lied
once or se-eral times dail%, )er rectall%, to achie-e administration of multi)les of dail% human
dose' ?he minimum duration of a))lication is < da%s (more according to clinical use), 0u$,ect
to a ma6imum of 3: da%s' 0iDe of su))ositories ma% $e smaller, $ut the drug content should
$e se-eral fold higher than the )ro)osed human dose' I$ser-ation )arameters should include
clinical signs (sliding on $ac/side), signs of )ain, $lood and.or mucus in faeces, condition of
anal region.s)hincter, gross and (if re=uired) histological e6amination of rectal mucosa'

(') -arenteral .rugs: For products meant for intra'enous or intramuscular or
subcutaneous or intradermal in5ection the sites of in5ection in systemic to"icity studies
should be specially e"amined grossly and microscopically$ !f needed, re'ersibility of
ad'erse effects may be determined on a case to case basis$

(-i) Icular to6icit% studies (for )roducts meant for ocular instillation)& ?hese studies should
$e carried out in t#o s)ecies, one of #hich should $e the al$ino ra$$it #hich has a sufficientl%
large con,uncti-al sac' Direct deli-er% of drug onto the cornea in case of animals ha-ing small
con,uncti-al sacs should $e ensured' >i=uids, ointments, gels or soft contact lenses (saturated
#ith drug) should $e used' Initial single dose a))lication should $e done to decide the
e6)osure concentrations for re)eateddose studies and the need to include a reco-er%
grou)' Duration of the final stud% #ill de)end on the )ro)osed length of human e6)osure
0u$,ect to a ma6imum of 9: da%s' !t least t#o different concentrations e6ceeding the human
dose should $e used for demonstrating the margin of safet%' In acute studies, one e%e should
$e used for drug administration and the other /e)t as control' ! se)arate control grou) should
$e included in re)eateddose studies'

0litlam) e6amination should $e done to detect the changes in cornea, iris and a=ueous
humor' (luorescent d%es (sodium fluorescein, :'"5 to 1':O) should $e used for detecting the
defects in surface e)ithelium of cornea and con,uncti-a' Changes in intraocular tension
should $e monitored $% a tonometer' Histological e6amination of e%es should $e done at the
end of the stud% after fi6ation in Da-idson@s or Pen/er@s fluid'

(-ii) Inhalation to6icit% studies& ?he studies are to $e underta/en in one rodent and one non
rodent s)ecies using the formulation that is to $e e-entuall% )ro)osed to $e
mar/eted' !cute, su$acute and chronic to6icit% studies should $e )erformed according to
the intended duration of human e6)osure' 0tandard s%stemic to6icit% stud% designs
(descri$ed a$o-e) should $e used' Bases and -a)ors should $e gi-en in #hole $od%
e6)osure cham$ers7 aerosols are to $e gi-en $% noseonl% method' 46)osure time and
concentrations of test su$stance (limit dose of 5mg.l) should $e ad,usted to ensure e6)osure
at le-els com)ara$le to multi)les of intended human e6)osure' ?hree dose grou)s and a
control ()lus -ehicle control, if needed) are re=uired' Duration of e6)osure ma% -ar%
0u$,ect to a ma6imum of ; hours )er da% and fi-e da%s a #ee/' (ood and #ater should $e
#ithdra#n during the )eriod of e6)osure to test su$stance'

?em)erature, humidit% and flo# rate of e6)osure cham$er should $e recorded and
re)orted' 4-idence of e6)osure #ith test su$stance of )article siDe of 4 micron (es)eciall% for
aerosols) #ith not less that "5O $eing 1 micron should $e )ro-ided' 4ffects on res)irator%
rate, findings of $ronchial la-age fluid e6amination, histological e6amination of res)irator%
)assages and lung tissue should $e included along #ith the regular )arameters of s%stemic
to6icit% studies or assessment of margin of safet%'




1$? Allergenicity& 1ypersensiti'ity:

0tandard tests include guinea )ig ma6imiDation test (BPF?) and local l%m)h node assa% (>>C!) in
mouse' !n% one of the t#o ma% $e done'

Cotes&
(i) +uinea -ig :a"imi0ation )est: )he test is to be performed in two steps3 first,
determination of ma"imum nonirritant and minimum irritant doses, and second, the
main test$ )he initial study will also ha'e two components$ )o determine the
intradermal induction dose, 4 dose le'els should be tested by the same route in a
batch of 4 male and 4 female animals ( of each se" should be gi'en Freund6s
ad5u'ant)$ )he minimum irritant dose should be used for induction$ *imilarly, a
topical minimum irritant dose should be determined for challenge$ )his should be
established in males and females$ A minimum of @ male and @ female animals
per group should be used in the main study$ /ne test and one control group should
be used$ !t is preferable to ha'e one more positi'e control group$ !ntradermal
induction (day 1) coupled with topical challenge (day 1) should be done$ !f there is
no response, re-challenge should be done 7-%C days after the primary
challenge$ 4rythema and oedema (indi'idual animal scores as well as ma"imi0ation
grading) should be used as e'aluation criteria$

(ii) >ocal >%m)h Code !ssa%& Fice used in this test should $e of the same se6, either onl%
males or onl% females' Drug treatment is to $e gi-en on ear s/in' ?hree graded doses, the
highest $eing ma6imum nonirritant dose )lus -ehicle control should $e used' ! minimum of ;
mice )er grou) should $e used' ?est material should $e a))lied on ear s/in on three
consecuti-e da%s and on da% 5, the draining auricular l%m)h nodes should $e dissected out 5
hours after i'-'
3
Hth%midine or $romodeo6%uridine (3rdJ)' Increase in
3
Hth%midine or
3rdJ incor)oration should $e used as the criterion for e-aluation of results'







1$@ +enoto"icity

Benoto6ic com)ounds, in the a$sence of other data, shall $e )resumed to $e transs)ecies carcinogens,
im)l%ing a haDard to humans' 0uch com)ounds need not $e 0u$,ected to longterm carcinogenicit%
studies' Ho#e-er, if such a drug is intended to $e administered for chronic illnesses or other#ise o-er
a long )eriod of time a chronic to6icit% stud% (u) to one %ear) ma% $e necessar% to detect earl%
tumorigenic effects'

Benoto6icit% tests are in vitro and in vivo tests conducted to detect com)ounds #hich induce genetic
damage directl% or indirectl%' ?hese tests should ena$le a haDard identification #ith res)ect to damage
to DC! and its fi6ation'

?he follo#ing standard test $atter% is generall% e6)ected to $e conducted&

(i) ! test for gene mutation in $acteria'
(ii) !n in vitro test #ith c%togenetic e-aluation of chromosomal damage #ith mammalian cells or
an in vitro mouse l%m)homa t/ assa%'
(iii) !n in vivo test for chromosomal damage using rodent hemato)oietic cells'

Ither genoto6icit% tests e'g' tests for measurement of DC! adducts, DC! strand $rea/s, DC! re)air
or recom$ination ser-e as o)tions in addition to the standard $atter% for further in-estigation of
genoto6icit% test results o$tained in the standard $atter%' Inl% under e6treme conditions in #hich one
or more tests com)rising the standard $atter% cannot $e em)lo%ed for technical reasons, alternati-e
-alidated tests can ser-e as su$stitutes )ro-ided sufficient scientific ,ustification should $e )ro-ided to
su))ort the argument that a gi-en standard $atter% test is not a))ro)riate'

3oth in-itro and in-i-o studies should $e done' In-itro studies should include !mes@ 0almonella
assa% and chromosomal a$errations (C!) in cultured cells' In-i-o studies should include
micronucleus assa% (FC!) or C! in rodent $one marro#' Data anal%sis of C! should include
anal%sis of Qga)s'@

C%toto6ic anticancer agents& Benoto6icit% data are not re=uired $efore Phase I and II trials' 3ut these
studies should $e com)leted $efore a))l%ing for Phase III trials'

Cotes&

!mes@ ?est (Re-erse mutation assa% in 0almonella)& 0' t%)himurium tester strains such as ?!9A,
?!1::, ?!1:", ?!1535, ?!9< or Escherichia coli 9P" uvrA or Escherichia
coli 9P" uvrA ()KF1:1) should $e used'
(i) !n-'itro e"posure (with and without metabolic acti'ation, *B mi") should be done at a
minimum of ? log dose le'els$ I*ol'entJ and Ipositi'eJ control should be
used$ -ositi'e control may include B-amino-acridine, -nitrofluorine, sodium a0ide
and mitomycin ,, respecti'ely, in the tester strains mentioned abo'e$ 4ach set
should consist of at least three replicates$ A $? fold (or more) increase in number of
re'ertants in comparison to spontaneous re'ertants would be considered positi'e$
(ii) In-itro c%togenetic assa% & ?he desired le-el of to6icit% for in vitro c%togenetic tests using
cell lines should $e greater than 5:O reduction in cell num$er or culture confluenc%' (or
l%m)hoc%te cultures, an inhi$ition of mitotic inde6 $% greater than 5:O is considered
sufficient' It should $e )erformed in CHI cells or on human l%m)hoc%te in culture' In-itro
e6)osure (#ith and #ithout meta$olic acti-ation, 09 mi6) should $e done using a minimum of
3 log doses' *0ol-ent+ and *)ositi-e+ control should $e included' ! )ositi-e control li/e
C%clo)hos)hamide #ith meta$olic acti-ation and Fitom%cin C for #ithout meta$olic
acti-ation should $e used to gi-e a re)roduci$le and detecta$le increase clastogenic effect o-er
the $ac/ground #hich demonstrates the sensiti-it% of the test s%stem' 4ach set should consist
of at least three re)licates' Increased num$er of a$errations in metaPhase chromosomes
should $e used as the criteria for e-aluation'
(iii) In-i-o micronucleus assa%& Ine rodent s)ecies ()refera$l% mouse) is needed' Route of
administration of test su$stance should $e the same as intended for humans' (i-e animals )er
se6 )er dose grou)s should $e used' !t least three dose le-els, )lus *sol-ent+ and *)ositi-e+
control should $e tested' ! )ositi-e control li/e mitom%cin C or c%clo)hos)hamide should $e
used' Dosing should $e done on da% 1 and " of stud% follo#ed $% sacrifice of animals ; hours
after the last in,ection' 3one marro# from $oth the femora should $e ta/en out, flushed #ith
fetal $o-ine serum (": min'), )elletted and smeared on glass slides' BiemsaFa%Bruen#ald
staining should $e done and increased num$er of micronuclei in )ol%chromatic er%throc%tes
(minimum 1:::) should $e used as the e-aluation criteria'
(i-) In-i-o c%togenetic assa%& Ine rodent s)ecies ()refera$l% rat) is to $e used' Route of
administration of test su$stance should $e the same as intended for humans' (i-e
animals.se6.dose grou)s should $e used' !t least three dose le-els, )lus *sol-ent+ and
*)ositi-e+ control should $e tested' Positi-e control ma% include c%clo)hos)hamide' Dosing
should $e done on da% 1 follo#ed $% intra)eritoneal colchicine administration at ""
hours' !nimals should $e sacrificed " hours after colchicine administration' 3one marro#
from $oth the femora should $e ta/en out, flushed #ith h%)otonic saline (": min'), )elletted
and resus)ended in Carno%@s fluid' Ince again the cells should $e )elletted and dro))ed on
clean glass slides #ith a Pasteur )i)ette' Biemsa staining should $e done and increased
num$er of a$errations in metaPhase chromosomes (minimum 1::) should $e used as the
e-aluation criteria'

1$7 ,arcinogenicity (see Appendi" !, item 4$A)
Carcinogenicit% studies should $e )erformed for all drugs that are e6)ected to $e clinicall% used
for more than ; months as #ell as for drugs used fre=uentl% in an intermittent manner in the
treatment of chronic or recurrent conditions' Carcinogenicit% studies are also to $e )erformed
for drugs if there is concern a$out their carcinogenic )otential emanating from )re-ious
demonstration of carcinogenic )otential in the )roduct class that is considered rele-ant to
humans or #here structureacti-it% relationshi) suggests carcinogenic ris/ or #hen there is
e-idence of )reneo)lastic lesions in re)eated dose to6icit% studies or #hen longterm tissue
retention of )arent com)ound or meta$olite(s) results in local tissue reactions or other
)atho)h%siological res)onses' (or )harmaceuticals de-elo)ed to treat certain serious diseases,
>icensing !uthorit% ma% allo# carcinogenicit% testing to $e conducted after mar/eting
)ermission has $een granted'

In instances #here the lifee6)ectanc% in the indicated )o)ulation is short (i'e', less than " 3
%ears) no longterm carcinogenicit% studies ma% $e re=uired' In cases #here the thera)eutic
agent for cancer is generall% successful and life is significantl% )rolonged there ma% $e later
concerns regarding secondar% cancers' 9hen such drugs are intended for ad,u-ant thera)% in
tumour free )atients or for )rolonged use in noncancer indications, carcinogenicit% studies ma%
$e . are needed' Com)leted rodent carcinogenicit% studies are not needed in ad-ance of the
conduct of large scale clinical trials, unless there is s)ecial concern for the )atient )o)ulation'

Carcinogenicit% studies should $e done in a rodent s)ecies ()refera$l% rat)' Fouse ma% $e
em)lo%ed onl% #ith )ro)er scientific ,ustification' ?he selected strain of animals should not
ha-e a -er% high or -er% lo# incidence of s)ontaneous tumors'

!t least three dose le-els should $e used' ?he highest dose should $e su$lethal, and it should
not reduce the life s)an of animals $% more than 1:O of e6)ected normal' ?he lo#est dose
should $e com)ara$le to the intended human thera)eutic dose or a multi)le of it, e'g' "'567 to
ma/e allo#ance for the sensiti-it% of the s)ecies' ?he intermediate dose to $e )laced
logarithmicall% $et#een the other t#o doses' !n untreated control and (if indicated) a -ehicle
control grou) should $e included' ?he drug should $e administered < da%s a #ee/ for a fraction
of the life s)an com)ara$le to the fraction of human life s)an o-er #hich the drug is li/el% to $e
used thera)euticall%' Benerall%, the )eriod of dosing should $e "4 months for rats and 1A
months for mice'

I$ser-ations should include macrosco)ic changes o$ser-ed at auto)s% and detailed
histo)atholog% of organs and tissues' !dditional tests for carcinogenicit% (shortterm $ioassa%s,
neonatal mouse assa% or tests em)lo%ing transgenic animals) ma% also $e done de)ending on
their a))lica$ilit% on a case to case $asis'

Cote&
4ach dose grou) and concurrent control grou) not intended to $e sacrificed earl% should contain
atleast 5: animals of each se6' ! high dose sattelite grou) for e-aluation of )atholog% other
than neo)lasia should contain ": animals of each se6 #hile the sattelite control grou) should
contain 1: animals of each se6' I$ser-ation )arameters should include signs of into6ication,
effect on $od% #eight, food inta/e, clinical chemistr% )arameters, hematolog% )arameters, urine
anal%sis, organ #eights, gross )atholog% and detailed histo)atholog%' Com)rehensi-e
descri)tions of $enign and malignant tumour de-elo)ment, time of their detection, site,
dimensions, histological t%)ing etc' should $e gi-en'

1$A Animal to"icity re#uirements for clinical trials and marketing of a new drug$


0%stemic ?o6icit% 0tudies

Route of
administration
Duration of )ro)osed
human administration
Human
Phase(s) for
#hich stud%
is )ro)osed to
$e conducted
>ong term to6icit% re=uirements
Iral or Parenteral or
?ransdermal
0ingle dose or se-eral
doses in one da%, J)to
1#/
I,II,III "s),"#/
R 1 #/ $ut u)to "#/ I,II,III "s)74#/
R " #/ $ut u)to 4#/ I,II,III "s)71"#/
I-er 1mo I,II,III "s)7"4#/
Inhalation (general
anaesthetics,
aerosols)
J)to " #/ I,II,III "s)71mo7 (46)osure time 3h.d,
5d.#/)
J)to 4#/ I,II,III "s)71"#/, (46)osure time ;h.d,
5d.#/)
R 1 4#/ I,II,III "s)7"4#/, (46)osure time ;h.d,
5d.#/)

>ocal ?o6icit% 0tudies

Dermal J)to " #/ I,II 1s)74#/
III "s)74#/
R " #/ I,II,III "s)71"#/
Icular or Itic or
Casal
J)to " #/ I,II 1s)74#/
III "s)74#/
R " #/ I,II,III "s)71"#/
8aginal or Rectal J)to " #/ I,II 1s)74#/
III "s)74#/
R " #/ I,II,III "s)71"#/

0)ecial ?o6icit% 0tudies


Fale (ertilit% 0tud%&
• -hase !, !!, !!! in male 'olunteers&patients

(emale Re)roduction and De-elo)mental ?o6icit% 0tudies&
• *egment !! studies in species3 -hase !!, !!! in'ol'ing female patients of child-bearing
age$
• *egment ! study3 -hase !!! in'ol'ing female patients of child-bearing age$
• *egment !!! study3 -hase !!! for drugs to be gi'en to pregnant or nursing mothers for
long periods or where there are indications of possible ad'erse effects on foetal
de'elopment$

!llergenicit%.H%)ersensiti-it%&
• -hase !, !!, !!! - when there is a cause of concern or for parenteral drugs (including
dermal application)
Photoallerg% or dermal )hototo6icit%&
• -hase !, !!, !!! - if the drug or a metabolite is related to an agent causing
photosensiti'ity or the nature of action suggests such a potential$
Benoto6icit%&
• !n-'itro studies - -hase !
• 9oth in-'itro and in-'i'o - -hase !!, !!!
arcinogenicit%&
• -hase !!! - when there is a cause for concern, or when the drug is to be used for more
than @ months$
!$$re-iations& s)s)ecies7 momonth7 #/#ee/7 d da%7 hhour7 I, II, III Phases of clinical trial7
Cote& 1'!nimal to6icit% data generated in other countries ma% $e acce)ted and ma% not $e
as/ed to $e re)eated.du)licated in India on a case to case $asis de)ending u)on the
=ualit% of data and the credentials of the la$orator% (ies) #here such data has $een
generated'
"' Re=uirements for fi6ed dose com$inations are gi-en in !))endi6 8I'

1'9 Cum$er of animals re=uired for re)eateddose to6icit% studies


14"A da%s A41A" da%s
Brou) Rodent (Rat) Conrodent
(Dog or Fon/e%)
Rodent (Rat) Conrodent
(Dog or Fon/e%)
F ( F ( F ( F (
Control ;1: ;1: "3 "3 153: 153: 4; 4;
>o# dose ;1: ;1: "3 "3 153: 153: 4; 4;
Intermediate
dose
;1: ;1: "3 "3 153: 153: 4; 4;
High dose ;1: ;1: "3 "3 153: 153: 4; 4;






"': >a$orator% )arameters to $e included in to6icit% studies'

Haematological )arameters
• 1aemoglobin • )otal >9,
,ount
• 1aematocrit
• )otal H9,
,ount
• .ifferential
H9, ,ount
• -latelet ,ount • )erminal
9one :arrow
4"amination
• 4*> (Fon-
rodents only)
• +eneral 9lood -icture: A special mention of abnormal and
immature cells should be made$
• ,oagulation -arameters (Fon-rodents only): 9leeding )ime, ,oagulation )ime,
-rothrombin )ime, Acti'ated -artial
)hromboplastin )ime

Jrinal%sis Parameters
• ,olour • Appearance • *pecific
+ra'ity
• 4-hour urinary
output
• >eaction
(p1)
• Albumin • *ugar • Acetone
• 9ile
pigments
• =robilinogen • /ccult
9lood

• :icroscopic e"amination of urinary sediment$

3lood 3iochemical Parameters
• +lucose • ,holesterol • )riglycerides • 1.(
,holesterol (Fon-
rodents only)
• (.(
,holesterol
(Fon-rodents
only)
• 9ilirubin • *+-) (A()) • *+/) (A*))
• Alkaline
-hosphatase
(A(-)
• ++) (Fon-
rodents only)
• 9lood =rea
Fitrogen
• ,reatinine
• )otal
-roteins
• Albumin • +lobulin
(,alculated 'alues)
• *odium
• -otassium • -hosphorus • ,alcium

Bross and Ficrosco)ic Patholog%
• 9rainK: ,erebru
m, cerebellum,
:idbrain
• (*pinal ,ord) • 4ye • (:iddle
4ar)
• )hyroid • (-arathyroid) • *pleenK • )hymus
• AdrenalK • (-ancreas) • ()rachea) • (ungK
• 1eartK • Aorta • /esophagus • *tomach
• .uodenum • Le5unum • )erminal
ileum
• ,olon
• (>ectum) • (i'erK • MidneyK • =rinary
bladder
• 4pididymis • )estisK • /'ary • =terusK
• *kin • :ammary
gland
• :esenteric
lymph node
• *keletal
muscle
S Irgans mar/ed #ith an asteris/ should $e #eighed'
() Irgans listed in )arenthesis should $e e6amined if indicated $% the nature of the drug or o$ser-ed
effects'
Conclinical to6icit% testing and safet% e-aluation data of an ICD needed for the conduct of different
)hases of clinical trials

Cote& Refer !))endi6 III (Points 1'1 through 1'< and ta$les 1'A and 1'9) for essential features of stud%
designs of the nonclinical to6icit% studies listed $elo#'

Fr P."*) I C#&'&%"# Tr&"#*
0%stemic ?o6icit% studies
i' 0ingle dose to6icit% studies
ii' Dose Ranging 0tudies
iii' Re)eatdose s%stemic to6icit% studies of a))ro)riate duration to su))ort the duration to su))ort
the duration of )ro)osed human e6)osure'

Fale fertilit% stud%
In-itro genoto6icit% tests
Rele-ant local to6icit% studies #ith )ro)osed route of clinical a))lication (duration de)ending
on )ro)osed length of clinical e6)osure)

!llergenicit%.H%)ersensiti-it% tests (#hen there is a cause for concern or for )arenteral drugs,
including dermal a))lication)

Photoallerg% or dermal )hototo6icit% test (if the drug or a meta$olite is related to an agent
causing )hotosensiti-it% or the nature of action suggests such a )otential)

Fr P."*) II C#&'&%"# Tr&"#*

Pro-ide a summar% of all the nonclinical safet% data (listed a$o-e) alread% su$mitted #hile
o$taining the )ermissions for Phase I trial, #ith a))ro)riate references'

In case of an a))lication for directl% starting a Phase II trial com)lete details of the non
clinical safet% data needed for o$taining the )ermission for Phase I trial, as )er the list )ro-ided a$o-e
must $e su$mitted'

Re)eatdose s%stemic to6icit% studies of a))ro)riate duration to su))ort the duration of
)ro)osed human e6)osure

In-i-o genoto6icit% tests

0egment II re)roducti-e.de-elo)mental to6icit% stud% (if female )atients of child $earing age
are going to $e in-ol-ed)

Fr P."*) III C#&'&%"# Tr&"#*

Pro-ide a summar% of all the nonclinical safet% data (listed a$o-e) alread% su$mitted #hile
o$taining the )ermissions for Phase I and II trials, #ith a))ro)riate references'

In case of an a))lication for directl% initiating a Phase III trial com)lete details of the non
clinical safet% data needed for o$taining the )ermissions for Phase I and II trials, as )er the list
)ro-ided a$o-e must $e )ro-ided'

Re)eatdose s%stemic to6icit% studies of a))ro)riate duration to su))ort the duration of
)ro)osed human e6)osure

Re)roducti-e.de-elo)mental to6icit% studies
0egment I (if female )atients of child $earing age are going to $e in-ol-ed), and
0egment III (for drugs to $e gi-en to )regnant or nursing mothers or #here there are indications of
)ossi$le ad-erse effects on foetal de-elo)ment)

Carcinogenicit% studies (#hen there is a cause for concern or #hen the drug is to $e used for
more than ; months)

Fr P."*) I? C#&'&%"# Tr&"#*

Pro-ide a summar% of all the nonclinical safet% data (listed a$o-e) alread% su$mitted #hile
o$taining the )ermissions for Phase I, II and III trials, #ith a))ro)riate references'

!n case an application is made for initiating the -hase !< trial, complete details of the non-
clinical safety data needed for obtaining the permissions for -hase !, !! and !!! trials, as per
the list pro'ided abo'e must be submitted$
Application /f +ood (aboratory -ractices (+(-)
?he animal studies $e conducted in an accredited la$orator%' 9here the safet% )harmacolog% studies
are )art of to6icolog% studies, these studies should also $e conducted in an accredited la$orator%'

App)'2&6 I?

!CIF!> PH!RF!CI>IB1
1$ +eneral Principles
*pecific and general pharmacological studies should be conducted to support use of
therapeutics in humans$ !n the early stages of drug de'elopment enough information may not
be a'ailable to rationally select study design for safety assessment$ !n such a situation, a
general approach to safety pharmacology studies can be applied$ *afety pharmacology
studies are studies that in'estigate potential undesirable pharmacodynamic effects of a
substance on physiological functions in relation to e"posure within the therapeutic range or
abo'e$

1'1 0)ecific Pharmacological !ctions

0)ecific )harmacological actions are those #hich demonstrate the thera)eutic )otential for
humans'
?he s)ecific studies that should $e conducted and their design #ill $e different $ased on the
indi-idual )ro)erties and intended uses of in-estigational drug' 0cientificall% -alidated
methods should $e used' ?he use of ne# technologies and methodologies in accordance #ith
sound scientific )rinci)les should $e )referred'

1'" Beneral Pharmacological !ctions

1'"'1 4ssential 0afet% Pharmacolog%

0afet% )harmacolog% studies need to $e conducted to in-estigate the )otential undesira$le
)harmacod%namic effects of a su$stance on )h%siological functions in relation to e6)osure #ithin the
thera)eutic range and a$o-e' ?hese studies should $e designed to identif% undesira$le
)harmacod%namic )ro)erties of a su$stance that ma% ha-e rele-ance to its human safet%7 to e-aluate
ad-erse )harmacod%namic and.or )atho)h%siological effects o$ser-ed in to6icolog% and.or clinical
studies7 and to in-estigate the mechanism of the ad-erse )harmacod%namic effects o$ser-ed and.or
sus)ected'

?he aim of the essential safet% )harmacolog% is to stud% the effects of the test drug on -ital functions'
8ital organ s%stems such as cardio-ascular, res)irator% and central ner-ous s%stems should $e studied'
4ssential safet% )harmacolog% studies ma% $e e6cluded or su))lemented $ased on scientific
rationale' !lso, the e6clusion of certain test(s) or e6)loration(s) of certain organs, s%stems or
functions should $e scientificall% ,ustified'

1$$1$1 ,ardio'ascular *ystem
4ffects of the in-estigational drug should $e studied on $lood )ressure, heart rate, and the
electrocardiogram' If )ossi$le in vitro, in vivo and.or ex vivo methods including
electro)h%siolog% should also $e considered'

1$$1$ ,entral Fer'ous *ystem
4ffects of the in-estigational drug should $e studied on motor acti-it%, $eha-ioral
changes, coordination, sensor% and motor refle6 res)onses and $od% tem)erature'

1$$1$% >espiratory *ystem
4ffects of the in-estigational drug on res)irator% rate and other functions such as tidal
-olume and hemoglo$in o6%gen saturation should $e studied'

1'3 (ollo#u) and 0u))lemental 0afet% Pharmacolog% 0tudies
In addition to the essential safet% )harmacological studies, additional su))lemental
and follo#u) safet% )harmacolog% studies ma% need to $e conducted as a))ro)riate'
?hese de)end on the )harmacological )ro)erties or chemical class of the test
su$stance, and the data generated from safet% )harmacolog% studies, clinical trials,
)harmaco-igilance, e6)erimental in vitro or in vivostudies, or from literature re)orts'

1'3'1 (ollo#u) 0tudies (or 4ssential 0afet% Pharmacolog%
(ollo#u) studies )ro-ide additional information or a $etter understanding than that
)ro-ided $% the essential safet% )harmacolog%'

1$%$1$1 ,ardio'ascular *ystem
?hese include -entricular contractilit%, -ascular resistance and the effects of chemical
mediators, their agonists and antagonists on the cardio-ascular s%stem'
1$%$1$ ,entral Fer'ous *ystem
?hese include $eha-ioral studies , learning and memor%, electro)h%siolog% studies ,
neurochemistr% and ligand $inding studies'
1$%$1$% >espiratory *ystem
?hese include air#a% resistance, com)liance, )ulmonar% arterial )ressure, $lood gases
and $lood )H'

1$%$ *upplemental *afety -harmacology *tudies
?hese studies are re=uired to in-estigate the )ossi$le ad-erse )harmacological effects
that are not assessed in the essential safet% )harmacological studies and are a cause
for concern'
1$%$$1 =rinary *ystem
?hese include urine -olume, s)ecific gra-it%, osmolalit%, )H, )roteins, c%tolog% and
$lood urea nitrogen, creatinine and )lasma )roteins estimation'
1$%$$ Autonomic Fer'ous *ystem
?hese include $inding to rece)tors rele-ant for the autonomic ner-ous s%stem, and
functional res)onse to agonist or antagonist res)onses in vivo or in vitro, and effects of
direct stimulation of autonomic ner-es and their effects on cardio-ascular res)onses'
1$%$$% +astrointestinal *ystem
?hese include studies on gastric secretion, gastric )H measurement, gastric mucosal
e6amination, $ile secretion, gastric em)t%ing time in vivo and ileocaecal
contraction in vitro.
1$%$$4 /ther /rgan *ystems
4ffects of the in-estigational drug on organ s%stems not in-estigated else#here should
$e assessed #hen there is a cause for concern' (or e6am)le de)endenc% )otential,
s/eletal muscle, immune and endocrine functions ma% $e in-estigated'

1$4 ,onditions =nder Hhich *afety -harmacology *tudies Are Fot Fecessary

0afet% )harmacolog% studies are usuall% not re=uired for locall% a))lied agents e'g'
dermal or ocular, in cases #hen the )harmacolog% of the in-estigational drug is #ell
/no#n, and.or #hen s%stemic a$sor)tion from the site of a))lication is lo#' 0afet%
)harmacolog% testing is also not necessar%, in the case of a ne# deri-ati-e ha-ing
similar )harmaco/inetics and )harmacod%namics'

1$? )iming /f *afety -harmacology *tudies !n >elation )o ,linical
.e'elopment

1$?$1 -rior )o First Administration !n 1umans

?he effects of an in-estigational drug on the -ital functions listed in the essential
safet% )harmacolog% should $e studied )rior to first administration in humans' !n%
follo#u) or su))lemental studies identified, should $e conducted if necessar%, $ased
on a cause for concern'

1$?$ .uring ,linical .e'elopment

!dditional in-estigations ma% $e #arranted to clarif% o$ser-ed or sus)ected ad-erse
effects in animals and humans during clinical de-elo)ment
'
1$?$% 9efore applying for marketing Appro'al
(ollo#u) and su))lemental safet% )harmacolog% studies should $e assessed )rior to
a))ro-al unless not re=uired, in #hich case this should $e ,ustified' !-aila$le
information from to6icolog% studies addressing safet% )harmacolog% end)oints or
information from clinical studies can re)lace such studies'

1$@ Application /f +ood (aboratory -ractices (+(-)

?he animal studies $e conducted in an accredited la$orator%' 9here the safet% )harmacolog%
studies are )art of to6icolog% studies, these studies should also $e conducted in an accredited
la$orator%'
App)'2&6 ?

IC(IRF4D CIC04C?

1' Chec/list for stud% 0u$,ect@s informed consent documents
1'1 4ssential 4lements&
1$ *tatement that the study in'ol'es research and e"planation of the purpose of
the research
$ 4"pected duration of the *ub5ect;s participation
3' Descri)tion of the )rocedures to $e follo#ed, including all in-asi-e )rocedures and
4$ .escription of any reasonably foreseeable risks or discomforts to the *ub5ect
?$ .escription of any benefits to the *ub5ect or others reasonably e"pected from
research$ !f no benefit is e"pected *ub5ect should be made aware of this$
@$ .isclosure of specific appropriate alternati'e procedures or therapies a'ailable
to the *ub5ect$
7$ *tatement describing the e"tent to which confidentiality of records identifying
the *ub5ect will be maintained and who will ha'e access to *ub5ect6s medical
records
A$ )rial treatment schedule(s) and the probability for random assignment to each
treatment (for randomi0ed trials)
B$ ,ompensation and&or treatment(s) a'ailable to the *ub5ect in the e'ent of a
trial-related in5ury
1C$ An e"planation about whom to contact for trial related #ueries, rights of
*ub5ects and in the e'ent of any in5ury
11$ )he anticipated prorated payment, if any, to the *ub5ect for participating in the
trial
1$ *ub5ect;s responsibilities on participation in the trial
1%$ *tatement that participation is 'oluntary, that the sub5ect can withdraw from
the study at any time and that refusal to participate will not in'ol'e any penalty
or loss of benefits to which the *ub5ect is otherwise entitled
14$ Any other pertinent information

1'" !dditional elements, #hich ma% $e re=uired
a' 0tatement of foreseea$le circumstances under #hich the 0u$,ectGs
)artici)ation ma% $e terminated $% the In-estigator #ithout the 0u$,ectGs consent'

$' !dditional costs to the 0u$,ect that ma% result from )artici)ation in the
stud%'

c' ?he conse=uences of a 0u$,ect@s decision to #ithdra# from the research and
)rocedures for orderl% termination of )artici)ation $% 0u$,ect'

d' 0tatement that the 0u$,ect or 0u$,ectGs re)resentati-e #ill $e notified in
a timel% manner if significant ne# findings de-elo) during the course of the research
#hich ma% affect the 0u$,ectGs #illingness to continue )artici)ation #ill $e )ro-ided'

e' ! statement that the )articular treatment or )rocedure ma% in-ol-e ris/s to the 0u$,ect
(or to the em$r%o or fetus, if the 0u$,ect is or ma% $ecome )regnant), #hich are
currentl% unforeseea$le

f' !))ro6imate num$er of 0u$,ects enrolled in the stud%

"' (ormat of informed consent form for 0u$,ects )artici)ating in a clinical trial

Informed Consent form to )artici)ate in a clinical trial
0tud% ?itle&
0tud% Cum$er&

0u$,ect@s Initials& TTTTTTTTTTTTTTT 0u$,ect@s Came&TTTTTTTTTTTTTTT

Date of 3irth . !ge& TTTTTTTTTTTTTTTTT

Please initial
$o6 (0u$,ect)
(i) I confirm that I ha-e read and understood the information sheet dated
TTT for the a$o-e stud% and ha-e had the o))ortunit% to as/
=uestions'

2 5
(
ii)
I understand that m% )artici)ation in the stud% is -oluntar% and that I
am free to #ithdra# at an% time, #ithout gi-ing an% reason, #ithout
m% medical care or legal rights $eing affected'

2 5
(iii) I understand that the 0)onsor of the clinical trial, others #or/ing on
the 0)onsor@s $ehalf, the 4thics Committee and the regulator%
authorities #ill not need m% )ermission to loo/ at m% health records
$oth in res)ect of the current stud% and an% further research that ma%
$e conducted in relation to it, e-en if I #ithdra# from the trial' I
agree to this access' Ho#e-er, I understand that m% identit% #ill not
2 5
$e re-ealed in an% information released to third )arties or )u$lished'

(i-) I agree not to restrict the use of an% data or results that arise from this
stud% )ro-ided such a use is onl% for scientific )ur)ose(s)
2 5

(-) I agree to ta/e )art in the a$o-e stud%'

2 5

0ignature (or ?hum$ im)ression) of the 0u$,ect.>egall% !cce)ta$le
Re)resentati-e&TTTTTTTTTTTTT


Date& TTTTT.TTTTT.TTTTTT

0ignator%@s Came& TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

0ignature of the In-estigator& TTTTTTTTTTTTTTTTTTTTTTTTTTTT Date&
TTTTT.TTTTT.TTTTTT

0tud% In-estigator@s Came& TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

0ignature of the 9itness TTTTTTTTTTTTTTTTTTTTTT Date&TTTTT.TTTTT.TTTTTTT

Came of the 9itness& TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT


App)'2&6 ?I

(IX4D DI04 CIF3IC!?IIC0 ((DCs)

(i6ed Dose Com$inations refer to )roducts containing one or more acti-e ingredients used for a
)articular indication(s)' (DCs can $e di-ided into the follo#ing grou)s and data re=uired for a))ro-al
for mar/eting is descri$ed $elo#&

(a) ?he first grou) of (DCs includes those in #hich one or more of the acti-e ingredients is a ne#
drug' (or such (DCs to $e a))ro-ed for mar/eting data to $e su$mitted #ill $e similar to data
re=uired for an% ne# drug (including clinical trials) 2see rule 1""4, item (a)5'

($) (i) ?he second grou) (DCs includes those in #hich acti-e ingredients alread%
a))ro-ed.mar/eted indi-iduall% are com$ined for the first time, for a )articular claim and
#here the ingredients are li/el% to ha-e significant interaction of a )harmacod%namic or
)harmaco/inetic nature 2see rule 1""4, item (c)5' If clinical trials ha-e $een carried out #ith
the (DC in other countries, re)orts of such trials should $e su$mitted' If the (DC is mar/eted
a$road, the regulator% status in other countries should $e stated' (see !))endi6 I, item 9)'

(ii) (or mar/eting )ermission, a))ro)riate chemical and )harmaceutical data #ill $e
su$mitted' In case such a com$ination is not mar/eted an%#here in the #orld $ut these drugs
are alread% in use concomitantl% (not as an (DC $ut indi-iduall%) for the said claim,
mar/eting )ermission ma% $e granted $ased on chemical and )harmaceutical data' Data
sho#ing the sta$ilit% of the )ro)osed dosage form #ill also ha-e to $e su$mitted'

(iii) (or an% other such (DCs, clinical trials ma% $e re=uired' (or o$taining )ermission to
carr% out clinical trials #ith such (DCs a summar% of a-aila$le )harmacological, to6icological
and clinical data on the indi-idual ingredients should $e su$mitted, along #ith the rationale
for com$ining them in the )ro)osed ratio' In addition, acute to6icit% data (>D 5:) and
)harmacological data should $e su$mitted on the indi-idual ingredients as #ell as their
com$ination in the )ro)osed ratio'

(c) ?he third grou) of (DCs includes those #hich are alread% mar/eted, $ut in #hich it is
)ro)osed either to change the ratio of acti-e ingredients or to ma/e a ne# thera)eutic
claim' (or such (DCs, the a))ro)riate rationale including )u$lished re)orts (if an%) should $e
su$mitted to o$tain mar/eting )ermission' Permission #ill $e granted de)ending u)on the
nature of the claim and data su$mitted'

(d) ?he fourth grou) of (DC includes those #hose indi-idual acti-e ingredients (or drugs from the
same class) ha-e $een #idel% used in a )articular indication(s) for %ears, their concomitant use
is often necessar% and no claim is )ro)osed to $e made other than con-enience' It #ill ha-e to
$e demonstrated that the )ro)osed dosage form is sta$le and the ingredients are unli/el% to
ha-e significant interaction of a )harmacod%namic or )harmaco/inetic nature'

Fo additional animal or human data are generally re#uired for these F.,s, and marketing
permission may be granted if the F., has an acceptable rationale$
Appen$i, !II

JCD4R?!KICB 31 ?H4 IC840?IB!?IR

1' (ull name, address and title of the Princi)al In-estigator (or In-estigator(s) #hen there
is no Princi)al In-estigator)

"' Came and address of the medical college, hos)ital or other facilit% #here the clinical
trial #ill $e conducted& 4ducation, training U e6)erience that =ualif% the In-estigator
for the clinical trial (!ttach details including Fedical Council registration num$er, and
. or an% other statement(s) of =ualification(s))

3' Came and address of all clinical la$orator% facilities to $e used in the stud%'

4' Came and address of the 4thics Committee that is res)onsi$le for a))ro-al and
continuing re-ie# of the stud%'

5' Cames of the other mem$ers of the research team (Co or su$In-estigators) #ho #ill
$e assisting the In-estigator in the conduct of the in-estigation (s)'

;' Protocol ?itle and 0tud% num$er (if an%) of the clinical trial to $e conducted $% the
In-estigator'

<' Commitments&

(i) I ha-e re-ie#ed the clinical )rotocol and agree that it contains all the necessar%
information to conduct the stud%' I #ill not $egin the stud% until all necessar% 4thics
Committee and regulator% a))ro-als ha-e $een o$tained'

(ii) I agree to conduct the stud% in accordance #ith the current )rotocol' I #ill not
im)lement an% de-iation from or changes of the )rotocol #ithout agreement $% the
0)onsor and )rior re-ie# and documented a))ro-al . fa-ora$le o)inion from the
4thics Committee of the amendment, e6ce)t #here necessar% to eliminate an
immediate haDard(s) to the trial 0u$,ects or #hen the change(s) in-ol-ed are onl%
logistical or administrati-e in nature'

(iii) I agree to )ersonall% conduct and.or su)er-ise the clinical trial at m% site'

(i-) I agree to inform all 0u$,ects, that the drugs are $eing used for in-estigational
)ur)oses and I #ill ensure that the re=uirements relating to o$taining informed consent
and ethics committee re-ie# and a))ro-al s)ecified in the BCP guidelines are met'

(-) I agree to re)ort to the 0)onsor all ad-erse e6)eriences that occur in the course of
the in-estigation(s) in accordance #ith the regulator% and BCP guidelines'

(-i) I ha-e read and understood the information in the In-estigatorGs $rochure,
including the )otential ris/s and side effects of the drug'

(-ii) I agree to ensure that all associates, colleagues and em)lo%ees assisting in the
conduct of the stud% are suita$l% =ualified and e6)erienced and the% ha-e $een
informed a$out their o$ligations in meeting their commitments in the trial'

(-iii) I agree to maintain ade=uate and accurate records and to ma/e those records
a-aila$le for audit . ins)ection $% the 0)onsor, 4thics Committee, >icensing !uthorit%
or their authoriDed re)resentati-es, in accordance #ith regulator% and BCP
)ro-isions' I #ill full% coo)erate #ith an% stud% related audit conducted $% regulator%
officials or authoriDed re)resentati-es of the 0)onsor'

(i6) I agree to )rom)tl% re)ort to the 4thics Committee all changes in the clinical trial
acti-ities and all unantici)ated )ro$lems in-ol-ing ris/s to human 0u$,ects or others'

(6) I agree to inform all une6)ected serious ad-erse e-ents to the 0)onsor as #ell as
the 4thics Committee #ithin se-en da%s of their occurance'

(6i) I #ill maintain confidentialit% of the identification of all )artici)ating stud%
)atients and assure securit% and confidentialit% of stud% data'

(6ii) I agree to com)l% #ith all other re=uirements, guidelines and statutor% o$ligations
as a))lica$le to clinical In-estigators )artici)ating in clinical trials

A' 0ignature of In-estigator #ith Date
Appendix VIII

ETHICS COMMITTEE

1' ?he num$er of )ersons in an 4thcis Committee should ha-e atleast se-en mem$ers' 4thics
Committee should a))oint, from among its mem$ers, a Chair)erson (#ho is from outside the
institution) and a Fem$er 0ecretar%' Ither mem$ers should $e a mi6 of medical.non
medical, scientific and nonscientific )ersons, including la% )u$lic, to reflect the different
-ie#)oints'

(or re-ie# of each )rotocol the =uorum of 4thics Committee should $e atleast 5 mem$ers
#ith the follo#ing re)resentations&
(a) basic medical scientists (preferably one pharmacologist)$
(b) clinicians
(c) legal e"pert
(d) social scientist & representati'e of non-go'ernmental 'oluntary agency &
)hiloso)her . ethicist . theologian or a similar )erson
(e) lay person from the community$

In an% case, the ethics committee must include at least one mem$er #hose )rimar% area of
interest . s)ecialiDation is nonscientific and at least one mem$er #ho is inde)endent of the
institution . trial site' 3esides, there should $e a))ro)riate gender re)resentation on the
4thics Committee' If re=uired, 0u$,ect e6)erts ma% $e in-ited to offer their
-ie#s' (urther, $ased on the re=uirement of research area, e'g' HI8 !ID0, genetic
disorders etc' s)ecific )atient grou)s ma% also $e re)resented in the 4thics Committee as
far as )ossi$le'

Inl% those 4thics Committee mem$ers #ho are inde)endent of the clinical trial and the
0)onsor of the trial should -ote . )ro-ide o)inion in matters related to the stud%'

2. Format for Approval of Ethics Committee

?o

Dr'


Dear Dr' TTTTTTTT

?he Institutional 4thics Committee . Inde)endent 4thics Committee (state name of the
committee, as a))ro)riate) re-ie#ed and discussed %our a))lication to conduct the clinical
trial entitled *VV+ on VV'(date)'

?he follo#ing documents #ere re-ie#ed&

a' ?rial Protocol( including )rotocol amendments), datedTTTTTTTTTTTT 8ersion
no (s)'TTTTTTTTTT
$' Patient Information 0heet and Informed Consent (orm (including u)dates if
an%) in 4nglish and.or -ernacular language'
c' In-estigator@s 3rochure, datedTTTTTTTTT, 8ersion no'TTTTTTTT
d' Pro)osed methods for )atient accrual including ad-ertisement (s) etc' )ro)osed
to $e used for the )ur)ose'
e' Princi)al In-estigator@s current C8'
f' Insurance Polic% . Com)ensation for )artici)ation and for serious ad-erse
e-ents occurring during the stud% )artici)ation'
g' In-estigator@s !greement #ith the 0)onsor'
h' In-estigator@s Jnderta/ing (!))endi6 8II)'

?he follo#ing mem$ers of the ethics committee #ere )resent at the meeting held on (date,
time, )lace)'

TTTTTTTTTT Chairman of the 4thics Committee
TTTTTTTTTT Fem$er secretar% of the 4thics Committee
TTTTTTTTTT Came of each mem$er #ith designation

9e a))ro-e the trial to $e conducted in its )resented form'

?he Institutional 4thics Committee . Inde)endent 4thics Committee e6)ects to $e informed
a$out the )rogress of the stud%, an% 0!4 occurring in the course of the stud%, an% changes in
the )rotocol and )atient information.informed consent and as/s to $e )ro-ided a co)% of the
final re)ort'

1ours sincerel%,

Fem$er 0ecretar%, 4thics Committee'

App)'2&6 I=

0?!3I>I?1 ?40?ICB I( C49 DRJB0

0ta$ilit% testing is to $e )erformed to )ro-ide e-idence on ho# the =ualit% of a drug su$stance
or formulation -aries #ith time under the influence of -arious en-ironmental factors such as
tem)erature, humidit% and light, and to esta$lish shelf life for the formulation and
recommended storage conditions'

0ta$ilit% studies should include testing of those attri$utes of the drug su$stance that are
susce)ti$le to change during storage and are li/el% to influence =ualit%, safet%, and.or efficac%'
In case of formulations the testing should co-er, as a))ro)riate, the )h%sical, chemical,
$iological, and micro$iological attri$utes, )reser-ati-e content (e'g', antio6idant,
antimicro$ial )reser-ati-e), and functionalit% tests (e'g', for a dose deli-er% s%stem)'

8alidated sta$ilit%indicating anal%tical )rocedures should $e a))lied' (or long term studies,
fre=uenc% of testing should $e sufficient to esta$lish the sta$ilit% )rofile of the drug su$stance'

In general, a drug su$stance should $e e-aluated under storage conditions that test its thermal
sta$ilit% and, if a))lica$le, its sensiti-it% to moisture' ?he storage conditions and the length of
studies chosen should $e sufficient to co-er storage, shi)ment and su$se=uent use'


0tress testing of the drug su$stance should $e conducted to identif% the li/el% degradation
)roducts, #hich in turn esta$lish the degradation )ath#a%s, e-aluate the intrinsic sta$ilit% of
the molecule and -alidate the sta$ilit% indicating )o#er of the anal%tical )rocedures used' ?he
nature of the stress testing #ill de)end on the indi-idual drug su$stance and the t%)e of
formulation in-ol-ed'

0tress testing ma% generall% $e carried out on a single $atch of the drug su$stance' It should
include the effect of tem)eratures ), humidit% #here a))ro)riate, o6idation, and )hotol%sis on
the drug su$stance'

Data should $e )ro-ided for (a) Photosta$ilit% on at least one )rimar% $atch of the drug
su$stance as #ell as the formulation, as the case ma% $e and ($) the susce)ti$ilit% of the drug
su$stance to h%drol%sis across a #ide range of )H -alues #hen in solution or sus)ension'

>ongterm testing should co-er a minimum of 1" months@ duration on at least three )rimar%
$atches of the drug su$stance or the formulation at the time of su$mission and should $e
continued for a )eriod of time sufficient to co-er the )ro)osed shelf life' !ccelerated testing
should co-er a minimum of ; months duration at the time of su$mission'

In case of drug su$stances, the $atches should $e manufactured to a minimum of )ilot scale
$% the same s%nthetic route and using a method of manufacture that simulates the final
)rocess to $e used for )roduction $atches' In case of formulations, t#o of the three $atches
should $e at least )ilot scale and the third one ma% $e smaller' ?he manufacturing )rocess(es)
used for )rimar% $atches should simulate that to $e a))lied to )roduction $atches and should
)ro-ide )roducts of the same =ualit% and meeting the same s)ecifications as that intended for
mar/eting'

?he sta$ilit% studies for drug su$stances should $e conducted either in the same container
closure s%stem as )ro)osed for storage and distri$ution or in a container closure s%stem that
simulates the )ro)osed final )ac/aging' In case of formulations, the sta$ilit% studies should
$e conducted in the final container closure s%stem )ro)osed for mar/eting'

0ta$ilit% ?esting of ne# drug su$stances and formulations&

(i) 0tud% conditions for drug su$stances and formulations intended to $e
stored under general conditions

0tud% 0tud% conditions Duration of stud%

>ong term 3:WC M "WC.;5O RH M 5O RH 1" months
!ccelerated 4:WC M "WC.<5O RH M 5O RH ; months

If at an% time during ; months@ testing under the accelerated storage condition, such changes
occur that cause the )roduct to fail in com)l%ing #ith the )rescri$ed standards, additional
testing under an intermediate storage condition should $e conducted and e-aluated against
significant change criteria'

(ii) 0tud% conditions for drug su$stances and formulations intended to $e
stored in a refrigerator

0tud% 0tud% conditions Duration of stud%

>ong term 5WC M 3WC 1" months
!ccelerated "5WC M "WC.;:O RH M 5O RH ; months


(iii) 0tud% conditions for drug su$stances and formulations intended to $e
stored in a free0er

0tud% 0tud% conditions Duration of stud%

>ong term ":WC M 5WC 1" months



(i-) Drug su$stances intended for storage $elo# ":WC shall $e treated on a
case$%case $asis'

(-) 0ta$ilit% testing of the formulation after constitution or dilution, if a))lica$le, should
$e conducted to )ro-ide information for the la$eling on the )re)aration, storage
condition, and inuse )eriod of the constituted or diluted )roduct' ?his testing should
$e )erformed on the constituted or diluted )roduct through the )ro)osed inuse )eriod'

App)'2&6 =

CONTENTS OF THE PROPOSED PROTOCOL FOR CONDUCTING CLINICAL
TRIALS

1' ?itle Page
a' (ull title of the clinical stud%,
$' Protocol . 0tud% num$er, and )rotocol -ersion num$er #ith date
c' ?he ICD name.num$er of the in-estigational drug
d' Com)lete name and address of the 0)onsor and contract research organiDation if an%
e' >ist of the In-estigators #ho are conducting the stud%, their res)ecti-e institutional
affiliations and site locations
f' Came(s) of clinical la$oratories and other de)artments and.or facilities )artici)ating in
the stud%'

2. T"+#) $ C'()'(*
! com)lete ?a$le of Contents including a list of all !))endices'
1. ;"%@/r5'2 "'2 I'(r25%(&'
a$ -reclinical e"perience
b$ ,linical e"perience

Pre-ious clinical #or/ #ith the ne# drug should $e re-ie#ed here and a descri)tion of ho#
the current )rotocol e6tends e6isting data should $e )ro-ided' If this is an entirel% ne#
indication, ho# this drug #as considered for this should $e discussed' Rele-ant information
regarding )harmacological, to6icological and other $iological )ro)erties of the
drug.$iologic.medical de-ice, and )re-ious efficac% and safet% e6)erience should $e
descri$ed'

2. S(527 R"(&'"#)

?his section should descri$e a $rief summar% of the $ac/ground information rele-ant to the
stud% design and )rotocol methodolog%' ?he reasons for )erforming this stud% in the
)articular )o)ulation included $% the )rotocol should $e )ro-ided'

-. 0tud% I$,ecti-e(s) ()rimar% as #ell as secondra%) and their logical relation to the stud% design'

-. S(527 D)*&/'

a' I-er-ie# of the 0tud% Design& Including a descri)tion of the t%)e of stud% (i'e',
dou$le$lind, multicentre, )lace$o controlled, etc'), a detail of the s)ecific treatment
grou)s and num$er of stud% 0u$,ects in each grou) and in-estigati-e site, 0u$,ect
num$er assignment, and the t%)e, se=uence and duration of stud% )eriods'
$' (lo# chart of the stud%
c' ! $rief descri)tion of the methods and )rocedures to $e used during the stud%'
d' Discussion of 0tud% Design& ?his discussion details the rationale for the design
chosen for this stud%'

3. 0tud% Po)ulation& the num$er of 0u$,ects re=uired to $e enrolled in the stud% at the in-estigati-e
site and $% all sites along #ith a $rief descri)tion of the nature of the 0u$,ect )o)ulation re=uired
is also mentioned.

;' 0u$,ect 4ligi$ilit%
a' Inclusion Criteria
$' 46clusion Criteria

<' 0tud% !ssessments E )lan, )rocedures and methods to $e descri$ed in detail

A' 0tud% Conduct stating the t%)es of stud% acti-ities that #ould $e included in this section #ould
$e& medical histor%, t%)e of )h%sical e6amination, $lood or urine testing, electrocardiogram
(4CB), diagnostic testing such as )ulmonar% function tests, s%m)tom measurement,
dis)ensation and retrie-al of medication, 0u$,ect cohort assignment, ad-erse e-ent re-ie#, etc'

4ach -isit should $e descri$ed se)aratel% as 8isit 1, 8isit ", etc'

Discontinued 0u$,ects& Descri$es the circumstances for 0u$,ect #ithdra#al, dro)outs, or other
reasons for discontinuation of 0u$,ects ' 0tate ho# dro) outs #ould $e managed and if the%
#ould $e re)laced
Descri$e the method of handling of )rotocol #ai-ers, if an%' ?he )erson(s) #ho a))ro-es all
such #ai-ers should $e identified and the criteria used for s)ecific #ai-ers should $e
)ro-ided'

Descri$es ho# )rotocol -iolations #ill $e treated, including conditions #here the stud% #ill $e
terminated for noncom)liance #ith the )rotocol'

9' 0tud% ?reatment
a' Dosing schedule ( dose, fre=uenc%, and duration of the e6)erimental treatment) Descri$e the
administration of )lace$os and.or dumm% medications if the% are )art of the treatment )lan' If
a))lica$le, concomitant drug(s), their doses, fre=uenc%, and duration of concomitant treatment
should $e stated'
$' 0tud% drug su))lies and administration& ! statement a$out #ho is going to )ro-ide the stud%
medication and that the in-estigational drug formulation has $een manufactured follo#ing all
regulations Details of the )roduct sta$ilit%, storage re=uirements and dis)ensing re=uirements
should $e )ro-ided'
c' Dose modification for stud% drug to6icit%& Rules for changing the dose or sto))ing the stud%
drug should $e )ro-ided'
d' Possi$le drug interactions
e' Concomitant thera)%& ?he drugs that are )ermitted during the stud% and the conditions under
#hich the% ma% $e used are detailed here' Descri$e the drugs that a 0u$,ect is not allo#ed to
use during )arts of or the entire stud%' If an% #ashout )eriods for )rohi$ited medications are
needed )rior to enrollment, these should $e descri$ed here'
f' 3linding )rocedures& ! detailed descri)tion of the $linding )rocedure if the stud% em)lo%s a
$lind on the In-estigator and.or the 0u$,ect
g' Jn$linding )rocedures& If the stud% is $linded, the circumstances in #hich un$linding ma%
$e done and the mechanism to $e used for un$linding should $e gi-en

1:' !d-erse 4-ents (0ee !))endi6 XI)& Descri)tion of e6)ected ad-erse e-ents should $e gi-en'
Procedures used to e-aluate an ad-erse e-ent should $e descri$ed'
11' 4thical Considerations& Bi-e the summar% of&
a' Ris/.$enefit assessment&
$' 4thics Committee re-ie# and communications
c' Informed consent )rocess
d' 0tatement of 0u$,ect confidentialit% including o#nershi) of data and coding )rocedures
1"' 0tud% Fonitoring and 0u)er-ision& ! descri)tion of stud% monitoring )olicies and )rocedures
should $e )ro-ided along #ith the )ro)osed


fre=uenc% of site monitoring -isits, and #ho is e6)ected to )erform monitoring'

Case Record (orm (CR() com)letion re=uirements, including #ho gets #hich co)ies of the
forms and an% s)ecifics re=uired in filling out the forms CR( correction re=uirements,
including #ho is authoriDed to ma/e corrections on the CR( and ho# =ueries a$out stud% data
are handled and ho# errors, if an%, are to $e corrected should $e stated'
In-estigator stud% files, including #hat needs to $e stored follo#ing stud% com)letion should
$e descri$ed'

1-. In-estigational Product Fanagement
a' Bi-e In-estigational )roduct descri)tion and )ac/aging (stating all Ingredients and the
formulation of the in-estigational drug and an% )lace$os used in the stud%)
$' ?he )recise dosing re=uired during the stud%
c' Fethod of )ac/aging, la$eling, and $linding of stud% su$stances
d' Fethod of assigning treatments to 0u$,ects and the 0u$,ect identification code num$ering
s%stem
e' 0torage conditions for stud% su$stances
f' In-estigational )roduct accounta$ilit%& Descri$e instructions for the recei)t, storage,
dis)ensation, and return of the in-estigational )roducts to ensure a com)lete accounting of all
in-estigational )roducts recei-ed, dis)ensed, and returned.destro%ed'
g' Descri$e )olic% and )rocedure for handling unused in-estigational )roducts'

10. D"(" A'"#7*&*:
Pro-ide details of the statistical a))roach to $e follo#ed including sam)le siDe, ho# the
sam)le siDe #as determined, including assum)tions made in ma/ing this determination,
efficac% end)oints ()rimar% as #ell as secondar%) and safet% end)oints'

0tatistical anal%sis& Bi-e com)lete details of ho# the results #ill $e anal%Ded and re)orted
along #ith the descri)tion of statistical tests to $e used to anal%De the )rimar% and
secondar% end)oints defined a$o-e' Descri$e the le-el of significance, statistical tests to
$e used, and the methods used for missing data7 method of e-aluation of the data for
treatment failures, noncom)liance, and 0u$,ect #ithdra#als7 rationale and conditions for
an% interim anal%sis if )lanned'
Descri$e statistical considerations for Pharmaco/inetic (PK) anal%sis, if a))lica$le

15' Jnderta/ing $% the In-estigator (see !))endi6 8II)

1;' !))endices& Pro-ide a stud% s%no)sis, co)ies of the informed consent documents ()atient
information sheet, informed consent form etc')7 CR( and other data collection forms7 a
summar% of rele-ant )reclinical safet% information and an% other documents referenced in the
clinical )rotocol'

App)'2&6 =I

Data 4lements for re)orting serious ad-erse e-ents occuring in a clinical trial

1' Patient Details

Initials U other rele-ant identifier (hos)ital.IPD record num$er etc')S
Bender
!ge and.or date of $irth
9eight
Height

"' 0us)ected Drug(s)

Beneric name of the drugS
Indication(s) for #hich sus)ect drug #as )rescri$ed or tested
Dosage form and strength
Dail% dose and regimen (s)ecif% units e'g', mg, ml, mg./g)
Route of administration
0tarting date and time of da%
0to))ing date and time, or duration of treatment

3' Ither ?reatment(s)

Pro-ide the same information for concomitant drugs (including non )rescri)tion.I?C drugs) and non
drug thera)ies, as for the sus)ected drug(s)'

4' Details of 0us)ected !d-erse Drug Reaction(s)

(ull descri)tion of reaction(s) including $od% site and se-erit%, as #ell as the criterion (or criteria) for
regarding the re)ort as serious' In addition to a descri)tion of the re)orted signs and s%m)toms,
#hene-er )ossi$le, descri$e a s)ecific diagnosis for the reaction'S

0tart date (and time) of onset of reaction
0to) date (and time) or duration of reaction
Dechallenge and rechallenge information
0etting (e'g', hos)ital, out)atient clinic, home, nursing home)

5' Iutcome
Information on reco-er% and an% se=uelae7 results of s)ecific tests and.or treatment that ma% ha-e
$een conducted
(or a fatal outcome, cause of death and a comment on its )ossi$le relationshi) to the sus)ected
reaction7 !n% )ostmortem findings'






Ither information& an%thing rele-ant to facilitate assessment of the case, such as medical histor%
including allerg%, drug or alcohol a$use7 famil% histor%7 findings from s)ecial in-estigations etc'

;' Details a$out the In-estigatorS
Came
!ddress
?ele)hone num$er
Profession (s)ecialt%)

Date of re)orting the e-ent to >icensing !uthorit%&
Date of re)orting the e-ent to 4thics Committee o-erseeing the site&

0ignature of the In-estigator
Cote& Information mar/ed S must $e )ro-ided'+



(('Co' X11:14.1."::3DF0 U P(!)



(RI?! ?4I?I!),
NIIC? 04CR4?!R1, BI84RCF4C? I( ICDI!

(oot Cote & ?he Prinici)al Rules #ere )u$lished in the Ifficial BaDette -ide notification Co' ('
"A 1:.45H(I), dated the "1
st
Decem$er, 1945 and last amended -ide
B'0'R' (4) dated the


























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