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, dose res)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 5 A 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 $% the s)onsor to the >icensing !uthorit% during the course of mar/eting of the drug in India7 the full )rescri$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 contra indications7 #arnings7 )recautions7 drug interactions7 undesira$le effects7 o-erdose7 )harmacod%namic and )harmaco/inetic )ro)erties7 incom)ati$ilities7 shelf life7 )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

(-i)

!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 trial related 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) (iii)

(i')

*ponsors are re#uired to submit a status report on the clinical trial to the (icensing Authority at the prescribed periodicity$ 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 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$

at a))ro)riate inter-als.ects is gi-en in !))endi6 8' (3) R)*p '*&+&#&(&)* $ (.ect@s informed consent document as #ell as a format for the Informed Consent (orm for stud% 0u$.her legall% acce)ta$le re)resentati-e is una$le to read. armed forces personnel. (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.) E(.. 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) . 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 $% the la#(s) of India)' If the 0u$. nomads. safety and well being of all trial sub5ects$ )he ethics committee should e"ercise particular care to protect the rights.&%* C 11&(()).- (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$ .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%). 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. ethnic minority groups.her signatures to the consent form' (iii) ! chec/list of essential elements to $e included in the stud% su$. umemployed or impo'erished persons. safety and well being of all 'ulnerable sub5ects participating in the study. members of a group with hierarchical structure (e$g$ prisoners.(ii) 9here a su$.rugs with significant potential to"icity e$g$ . 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. nursing and pharmacy academic institutions). homeless persons.ect or his.or $% -isiting the stud% sites' (ii) In case an ethics committee re-o/es its a))ro-al accorded to a trial )rotocol. e$g$. patients with incurable diseases. patients in emergency situation. staff and students of medical.#rite E an im)artial #itness should $e )resent during the entire informed consent )rocess #ho must a))end his. refugees.or monitoring and internal audit re)orts furnished $% the 0)onsor and.

)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-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.. distri$ution. )harmacod%namic studies and studies relating to drug $lood le-els ()harmaco/inetic. i'e'."*) II). (i) )he primary ob5ecti'e of -hase !! trials is to e'aluate the effecti'eness of a drug for a particular indication or indications in patients with the condition under study and to determine the common short-term side-effects and risks associated with the drug$ *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$ . -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. the% should $e )erformed to su))ort formulation de-elo)ment and determine )harmaco/inetic )arameters in different age grou)s to su))ort dosing recommendations' (c) Pharmacod%namics& De)ending on the drug and the end)oints studied. characteriDation of a drugGs a$sor)tion.cytoto"ic drugs are usually studied in patients. usuall% intended to in-ol-e one or a com$ination of the follo#ing o$.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.ects or in )atients #ith the target disease' If there are a))ro)riate -alidated indicators of acti-it% and )otential efficac%.)r"p)5(&% )6p# r"( r7 (r&"#* (P. )harmacod%namic studies) ma% $e conducted in health% -olunteer 0u$. meta$olism and e6cretion' !lthough these studies continue throughout the de-elo)ment )lan.oses used in -hase !! are usually (but not always) less than the highest doses used in -hase !$ .

use of the drug in wider populations. 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$.-ost :arketing trials are studies (other than routine sur'eillance) performed after drug appro'al and related to the appro'ed indication(s)$ )hese trials go beyond the prior demonstration of the drug6s safety. in different stages of disease.."*) III).ecti-es ma% $e ser-ed $% e6)lorator% anal%ses. the number of sites and the patients as well as the 5ustification for undertaking such trials in !ndia shall be pro'ided to the (icensing Authority$ (8) T. 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$.)r"p)5(&% % '$&r1"( r7 (r&"#* (P.ecti-es of Phase II studies can include e-aluation of )otential stud% end)oints. 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. trials in-ol-ing e6tended e6)osure to the drug are ordinaril% conducted in Phase III. . >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 multi national clinical de-elo)ment of the drug.ects.(ii) !dditional o$. (i) -hase !!! studies ha'e primary ob5ecti'e of demonstration or confirmation of therapeutic benefit(s)$ *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.ustification for underta/ing such trials in India should $e )ro-ided to the >icensing !uthorit% along #ith the a))lication' (9) Post Marketing rials (Phase I!). e6amining su$sets of data and $% including multi)le end)oints in trials' (ii) !f the application is for conduct of clinical trials as a part of multi-national clinical de'elopment of the drug. drug concentration in blood and clinical response). or the safety and efficacy of the drug in combination with other drug(s)$ (ii) (or drugs intended to $e administered for long )eriods.. the num$er of sites and )atients as #ell as the .

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.s response (with regard to safety or efficacy) compared with that of the non-geriatric patient$ (2) P")2&"(r&%*.. for which there are currently no or limited therapeutic options. e-aluations should $e made in the a))ro)riate age grou)' 9hen clinical de-elo)ment is to include studies in children. )atients #ith renal or other organ s%stems failure. nursing #omen. safet% considerations.(i) ?he timing of )aediatric studies in the ne# drug de-elo)ment )rogram #ill de)end on the medicinal )roduct. at the 0)onsorGs o)tion) in meaningful num$ers. e$g$ mortality&morbidity studies. it is usuall% a))ro)riate to $egin #ith older children $efore e6tending the trial to %ounger children and then infants' (ii) !f the new drug is for diseases predominantly or e"clusi'ely affecting paediatric patients. #tu$ies in special populations : Information su))orting the use of the drug in children. epidemiological studies etc$ ". item A'3)' (1) G)r&"(r&%*. 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 use$ )hey may be of any type but should ha'e 'alid scientific ob5ecti'es$ -hase !< trials include additional drug-drug interaction(s). occurring in both adults and paediatric patients. clinical trial data should be generated in the paediatric population e"cept for initial safety and tolerability data. elderl% )atients. .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. )regnant #omen. dose-response or safety studies and trials designed to support use under the appro'ed indication(s).Beriatric )atients should $e included in Phase III clinical trials (and in Phase II trials. and the efficac% and safet% of a-aila$le treatments' (or a drug e6)ected to $e used in children. the t%)e of disease $eing treated. 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.

legal guardian' Ho#e-er.eo)ardiDed $% his or her failing to )artici)ate in the stud%' In this situation. the re-ie#ing ethics committee should include mem$ers #ho are /no#ledgea$le a$out )ediatric. and are de)endent on their )arent(s). in the o)inion of the In-estigator and )arent(s).paediatric population should be included in the clinical trials early. there ma% $e circumstances in thera)eutic studies for serious or life threatening diseases in #hich. legal guardian.ects are legall% una$le to )ro-ide #ritten informed consent. continued )arental. and this data should $e su$mitted #ith the ne# drug a))lication' (-ii) Paediatric 0u$. )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.or thera)eutic ad-ance for the )aediatric )o)ulation E the studies should $egin earl% in the drug de-elo)ment . lack of data should be 5ustified in detail$ (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 $e e6)ected after mar/eting authorisation for use in children is granted' (-) ?he )aediatric studies should include (a) clinical trials. (b) relati'e bioe#ui'alence comparisons of the paediatric formulation with the adult formulation performed in adults. following assessment of initial safety data and reasonable e'idence of potential benefit$ !n circumstances where this is not possible. legal guardian to assume res)onsi$ilit% for their )artici)ation in clinical studies' 9ritten informed consent should $e o$tained from the )arent. 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. legal guardian consent should $e sufficient to allo# )artici)ation in the stud%' (-iii)(or clinical trials conducted in the )aediatric )o)ulation. and (c) definiti'e pharmacokinetic studies for dose selection across the age ranges of paediatric patients in whom the drug is likely to be used$ )hese studies should be conducted in the paediatric patient population with the disease under study$ (-i) If the ne# drug is a ma. ethical. the #elfare of a )ediatric )atient #ould $e . clinical and )s%chosocial issues' .

follo# u) data ()ertaining to a )eriod a))ro)riate for that drug) on the )regnanc%.nursing infants and #here the data generated from #omen #ho are not )regnant or nursing. 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. fetus and child #ill $e re=uired' 9here a))lica$le.nursing #omen or foetuses. 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' . indications or se)arate )o)ulation need to $e gi-en' (iii) !ll rele-ant clinical and non clinical 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.(-) Pr)/'"'( r '5r*&'/ 9 1)'' (i) Pregnant or nursing #omen should $e included in clinical trials onl% #hen the drug is intended for use $% )regnant. e6cretion of the drug or its meta$olites into human mil/ should $e e6amined and the infant should $e monitored for )redicted )harmacological effects of the drug' (%) Post Marketing #ur&eillance. 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.(i) *ubse#uent to appro'al of the product. is not suita$le' (ii) (or ne# drugs intended for use during )regnanc%.

date of marketing of ($) (c) (d) (e) (f) (g) (h) ( I) (. applicant6s name. Ither information.& )<5&!"#)'%) S(52&)*. dosing. J)date of actions ta/en for safet% reasons. Conclusion. Presentation of indi-idual case histories.. period co'ered by the report.)' (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' . date of appro'al of new drug. Current #orld#ide mar/et authoriDation status. Changes to reference safet% information. )harmacolog% and other related information' (3) Sp)%&"# *(52&)*: .) (/) (l) new drug and date of reporting3 Introduction. !))endi6 )ro-iding material relating to indications. $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.(-) ! P0JR should $e structured as follo#s& (a) A title page stating: -eriodic safety update report for the product. I-erall safet% e-aluation. 0tudies.& "!"&#"+&#&(7 / . (i) (or drugs a))ro-ed else#here in the #orld and a$sor$ed s%stemicall%. A'" and A'3 of !))endi6 I. 4stimated )atient e6)osure.

)he data re#uirements stated in this *chedule are e"pected to pro'ide ade#uate information to e'aluate the efficacy.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 !nal%tical Data 4lemental anal%sis Fass s)ectrum CFR s)ectra IR s)ectra J8 s)ectra Pol%mor)hic identification Com)lete monogra)h s)ecification including Identification Identit%.'ote. 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' $ .=uantification of im)urities 4nantiomeric )urit% !ssa% "'3' "'4' .epending upon the nature of new drugs and disease(s). safety and therapeutic rationale of new drugs (as defined under rule 1 -4) prior to the permission for sale$ . IFPIR? . 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 ..

"'.' "'<' 9hen the a))lication is for clinical trials onl%.. drug categor%. "'<) are re=uired' %$ Animal -harmacology (for details refer Appendi" !<) 3'1' 3'"' 3'3' 3'4' 3'5' 0ummar% 0)ecific )harmacological actions Beneral )harmacological actions Follow-up and *upplemental *afety -harmacology *tudies Pharmaco/inetics& a$sor)tion."'5' 8alidations !ssa% method Im)urit% estimation method Residual sol-ent. dosage form and data su))orting sta$ilit% in the intended container closure s%stem for the duration of the clinical trial (information co-ered in item nos' "'1. 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 "'. distri$ution7 meta$olism7 e6cretion 4$ Animal )o"icology (for details refer Appendi" !!!) 4'1' Beneral !s)ects 4'"' 0%stemic ?o6icit% 0tudies . "'3. the international non )ro)rietar% name (ICC) or generic name.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.

in countries #here mar/eted . #ith reasons 9'"' 9'3' Restrictions on use. )aediatrics.H%)ersensiti-it% Benoto6icit% Carcinogenicit% ?$ 1uman & . if an%. if an%.4'3' 4'4' 4'5' 4'.'"' 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'"' 3io a-aila$ilit% . as a))ro)riate' 1C$ -rescribing information 1:'1' Pro)osed full )rescri$ing information 1:'"' Drafts of la$els and cartons 11$ *amples and )esting -rotocol&s . )regnant or nursing #omen B$ >egulatory status in other countries 9'1' Countries #here the drug is a' Far/eted $' !))ro-ed c' !))ro-ed as ICD d' 9ithdra#n. a$sor)tion.a))ro-ed (ree sale certificate or certificate of anal%sis. distri$ution. 3io e=ui-alence' A'3 Ither studies e'g' geriatrics.linical pharmacology (-hase !) 5'1' 0ummar% 5'"' 0)ecific Pharmacological effects 5'3' Beneral Pharmacological effects 5'4' Pharmaco/inetics.'1' 0ummar% .' 4'<' 4'A' Fale (ertilit% 0tud% (emale Re)roduction and De-elo)mental ?o6icit% 0tudies >ocal to6icit% !llergenicit%. meta$olism. e6cretion 5'5' Pharmacod%namics . earl% measurement of drug acti-it% @$ )herapeutic e"ploratory trials (-hase !!) .

s. )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% .A D!?! R4LJIR4D ?I 34 0J3FI??4D 31 !C !PP>IC!C? (IR BR!C? I( P4RFI00IIC ?I IFPIR? !CD . de-elo)ment Phase. 0ta$ilit% data 3' Far/eting information 3'1 Pro)osed )ac/age insert . the )rotocol code. structure7 )h%sico chemical )ro)erties "'" Dosage form and its com)osition "'3 ?est s)ecifications (a) acti-e ingredients ($) 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 "'. #ith testing )rotocol.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%.11'1' 0am)les of )ure drug su$stance and finished )roduct (an e=ui-alent of 5: clinical doses. refer te"t of *chedule D$ ( ) For re#uirements of data to be submitted with application for clinical trials refer te"t of this *chedule$ APPENDI= I. name of the in-estigational )roduct tested. if an%7 non )ro)rietar% or generic name. code name or num$er. IR F!CJ(!C?JR4 ! C49 DRJB !>R4!D1 !PPRI84D IC ?H4 CIJC?R1' 1' Introduction ! $rief descri)tion of the drug and the thera)eutic class "' Chemical and )harmaceutical information "'1 Chemical name. indication studied. 3ioe=ui-alence and com)arati-e dissolution studies for oral dosage forms 4'" 0u$ acute animal to6icit% studies for intra-enous infusions and in. a $rief descri)tion . if an%. or more num$er of clinical doses if )rescri$ed $% the >icensing !uthorit%). full im)urit% )rofile and release s)ecifications' CI?40& (1) All items may not be applicable to all drugs$ For e"planation.

0)onsor. $linding . allo#ed.. designates.rugs *tandard . Central la$orator% etc')' A' Introduction& ! $rief descri)tion of the )roduct de-elo)ment rationale should $e gi-en here' 9' 0tud% I$. :inistry of 1ealth.ecti-e& ! statement descri$ing the o-erall )ur)ose of the stud% and the )rimar% and secondar% o$.' >ist of !$$re-iations and Definitions ?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 $% Central Drugs 0tandard Control IrganiDation and 4thical Buidelines for 3iomedical Research on Human 0u$. the 0u$. 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.ects.linical )rials on -harmaceutical -roducts in !ndia E +.ontrol /rgani0ation. 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 .ecti-es to $e achie-ed should $e mentioned here' 1:' In-estigational Plan& ?his section should descri$e the o-erall trial design. randomiDation techni=ues if an%. the treatment )rocedures.+uidelines6 issued by the .entral . disallo#ed .ect selection criteria.of the trial design. site staff. +o'ernment of !ndia$ 4' 5' .

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' 0afet% 4-aluation ?his section should include the com)lete list 13'1 all serious ad-erse e-ents. randomised. the efficac% and safet% criteria assessed.concomitant treatment. )hone.' a' $' c' d' e' f' g' h' !))endices >ist of !))endices to the Clinical ?rial Re)ort Protocol and amendments 0)ecimen of Case Record (orm In-estigators@ name(s) #ith contact addresses. email etc' Patient data listings >ist of trial )artici)ants treated #ith in-estigational )roduct Discontinued )artici)ants Protocol de-iations CR(s of cases in-ol-ing death and life threatening ad-erse e-ent cases . #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 $rief narrati-e of all im)ortant e-ents considered related to the in-estigational )roduct' Discussion and o-erall Conclusion Discussion of the im)ortant conclusions deri-ed from the trial and sco)e for further de-elo)ment' 13' 14' 15' >ist of References 1.ects A clear accounting of all trial *ub5ects who entered the study will be gi'en here$ :ention should also be made of all cases that were dropouts or protocol de'iations$ 4numerate the patients screened. the data =ualit% assurance )rocedures and the statistical methods )lanned for the anal%sis of the data o$tained' 11' ?rial 0u$.

i' . if a-aila$le In-estigator@s certificate that he.' /' l' Pu$lications from the trial Im)ortant )u$lications referenced in the stud% !udit certificate.she has read the re)ort and that the re)ort accuratel% descri$es the conduct and the results of the stud%' .

ra# data. 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. draft re)ort. final re)ort. including its a))ro-ed )rotocol. in con.CLINICAL TO=ICITY STUDIES) 1' Beneral Princi)les ?o6icit% studies should com)l% #ith the norms of Bood >a$orator% Practice (B>P)' 3riefl%. signs and mode of death should $e re)orted. to su))ort the choice of s)ecies and treatment regimen in nonclinical to6icit% studies and to )ro-ide information #hich. reasons for the same should $e stated' . 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 non clinical to6icit% studies or in s)eciall% designed studies) should $e conducted to assess the s%stemic e6)osure achie-ed in animals and its relationshi) to dose le-el and the time course of the to6icit% stud%' Ither o$. 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.unction #ith the to6icit% findings. unless the intended route of administration in humans is onl% intra-enous. contri$utes to the design of su$se=uent non clinical to6icit% studies' 1'1 0%stemic ?o6icit% 0tudies 1'1'1 0ingle dose ?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. and minimum lethal dose (F>D) and ma6imum tolerated dose (F?D) should $e esta$lished' If )ossi$le. #ith a))ro)riate macrosco)ic and microsco)ic findings #here necessar%' >D 1: and >D5: should $e re)orted )refera$l% #ith 95 )ercent confidence limits' If >D5:s cannot $e determined. #hiche-er is higher) is recommended for oral dosing' !nimals should $e o$ser-ed for 14 da%s after the drug administration./g (or 1: times the normal dose that is intended in humans.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%.App)'2&6 III ANIMAL TO=ICOLOGY (NON. 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%.

?he dose causing se-ere to6ic manifestations or death should $e defined in the case of c%toto6ic anticancer agents.ection should $e 0u$. 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. and the )ost dosing 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%. 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%. or #here the c%toto6ic drug acts $% a no-el mechanism of action. of which one should be a non-rodent$ . or if )ermission for Phase II. antifolates).uration of the final systemic to"icity study will depend on the duration. 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'. $iochemical and microsco)ic o$ser-ations' In case of )arenteral drug administration. a control grou) of animals gi-en the -ehicle alone should $e included. $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. the sites of in. )h%siological. and should $e )laced logarithmicall% $et#een the other t#o doses' ?he )arameters to $e monitored and recorded in long term to6icit% studies should include $eha-ioral. A-.ose ranging studies should precede the 14-. is sho#n in Item 1'9' 9here-er a))lica$le. III or mar/eting is $eing sought' . item 4$ ) should be carried out in at least two mammalian species.or 1AC. F?D should $e esta$lished in non rodent s)ecies' 1$1$ >epeated-dose *ystemic )o"icity *tudies: )hese studies (see Appendi" !.day to"icity studies$ .ected to gross and microsco)ic e6amination' Initial and final electrocardiogram and fundus e6amination should $e carried out in the non rodent 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' ! non rodent s)ecies should $e added if the drug has a no-el mechanism of action. $ut not gross to6icit% or death. i'e' the minimum num$er of animals on #hich data should $e a-aila$le. BC. it should be preferred for to"icity studies$ In re)eated dose 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.

study$ .ose should be lowered appropriately when clinical or laboratory e'idence of to"icity . 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. effect on $od% #eight. to6icit% and to6ico/inetic studies' ?he studies ma% $e most a))ro)riate for com)ounds #hich ha-e an a))arentl% long half life. if an%' (ii) Dose ranging 0tud%& I$. and dose escalation in suitable steps should be done e'ery third day after drawing the samples for laboratory parameters$ .(or most com)ounds.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. (whiche'er is less). acti'ity and beha'iour etc).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 :). 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. 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. 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 :). gross )athological changes should $e re)orted' It is desira$le to include histo )atholog% of grossl% affected organs.

aily dosing by proposed clinical route at three graded dose le'els should be done$ -arameters should include signs of into"ication. acti-it% and $eha-iour etc). and a control grou) should $e ta/en' 4ach grou) should consist of . $lood $iochemistr%. $od% #eight. hematological -alues. food inta/e. organ weights.ay repeated-dose to"icity studies: /ne rodent (1?-%C&se"&group) and one non-rodent (4-@&se"&group) species are needed$ At least 4 groups. adult male animals' !nimals should $e treated #ith the test su$stance $% the intended route of clinical use . organ #eights.or clinical )athological changes E #hiche-er comes later. 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. and gross and microsco)ic studies of all -iscera and tissues' (i-) 9: Da% re)eated dose to6icit% studies& Ine rodent (15 3:. food. the highest one sho#ing minimal to6icit% in s%stemic studies. $od% #eight changes..#ater inta/e.are obser'ed$ Administration of test substance should then continue for 1C days at the well-tolerated dose le'el following which.grou)) and one non rodent (4 . urine anal%sis. autopsy and microscopic e"amination of affected tissues should be performed as in the case of rodents$ (iii) 14 "A Da% re)eated dose to6icit% studies& Ine rodent (. blood biochemistry.grou)) and one non rodent (" 3. food intake. including control.se6. samples for laboratory parameters should be taken$ *acrifice. $lood $iochemical )arameters. and e-aluated for the )arameters used for the main stud%' (') 1AC-.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$le to6icit%. hematology. and lo# dose' ?he doses should )refera$l% $e multi)les of the effecti-e dose and free from to6icit%' I$ser-ation )arameters should include cage side o$ser-ations.se6. body weight.se6. 1:. mid dose $et#een high and lo# dose. gross and microscopic e"amination of organs and tissues$ 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 "A da% to6icit% stud% in rat' ?hree dose grou)s. urine analysis. haematolog%.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 *high dose re-ersal+ grou) and its control grou) should $e also included' Parameters should include signs of into6ication (general a))earance. should be taken$ .

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. )arturition )eriods. su$se=uentl%. mating $eha-iour. #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 . )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. clinical signs of into6ication. gross e6amination.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 $e continued till the detection of -aginal )lug or 1: da%s. #hen the test article is not com)ati$le #ith the ra$$it (e'g' anti$iotics #hich are effecti-e against gram )ositi-e. )arturition. $eginning a sufficient num$er of da%s ("A da%s in males and 14 da%s in females) $efore mating' Drug treatment should continue during mating and. $od% #eight. length of gestation. gro#th )arameters. using three dose le'els as described for segment !$ )he highest dose should cause minimum maternal to"icity and the lowest one should be proportional to the proposed dose for clinical use in humans or a multiple of it$ )he route of administration should be the same as intended for human therapeutic use$ .e'elopmental )o"icity *tudies ?hese studies (see !))endi6 I. se6 #ise distri$ution in different treatment grou)s. sur-i-al. and segment II stud% should include al$ino ra$$its also as a second test s)ecies' In the occasion. )rogress of gestation. II and III studies (see $elo#) are to $e )erformed in al$ino mice or rats. food inta/e. 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. 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. during the gestation )eriod' ?hree graded doses should $e used. anaero$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.

$od% length. gestation. im)lantation sites. o-aries and uterine contents. general signs of into6ication. if an%' 1$%$% -erinatal *tudy (*egment !!!): )his study is specially recommended if the drug is to be gi'en to pregnant or nursing mothers for long periods or where there are indications of possible ad'erse effects on foetal de'elopment$ /ne rodent species (preferably rat) is needed$ . the total num$er. effect on food inta/e. or the drug concentration cannot $e increased $e%ond a certain le-el due to the )ro$lems of solu$ilit%. $od% #eight. food inta/e. gender. )rogress of gestation. a clear statement to this effect should $e gi-en' If the drug is a$sor$ed from the site of a))lication. the clinical signs. num$er of cor)ora lutea. and increasing grou) siDe #ith increase in duration of treatment' 9here dosing is restricted due to anatomical or humane reasons. resor)tions (if an%)7 and for the foetuses. effect on $od% #eight. e6amination of uterus.?he control and the treated grou)s should consist of at least ": )regnant rats (or mice) and 1" ra$$its. 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 $e a))lied to an a))ro)riate site (e'g'. sur-i-al and auto)s% (if needed) and #here necessar%. gro#th )arameters. se6 #ise distri$ution in dose grou)s.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%. or -ehicle control. a))ro)riate s%stemic to6icit% studies #ill also $e re=uired' . )refera$l% use of " s)ecies. 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. s/eletal a$normalities. )airing. 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. )arturition )eriods and gross )atholog% (if an%)7 and for )u)s. #eight and gross. )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. histo)atholog%' 1$4 (ocal to"icity ?hese studies (see !))endi6 I. -isceral. gross e6amination. each consisting of 1? dams should be used$ )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$ . )H or tonicit%.osing at le'els comparable to multiples of human dose should be done by the intended clinical route$ At least 4 groups (including control). on each dose le-el' !ll foetuses should to $e su$.ected to gross e6amination.

<.)atch for " hour M15 min' follo#ed $% 1: N. 0u$.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 $% e6)osure to 1: N. se'eral fold higher than the clinical dosage form should be used$ -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. 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'. a reco'ery group should be included in the subse#uent repeated-dose study$ (ocal signs (erythema. closure of introitus and histo)atholog% of -aginal #all' .4.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.cm " of J8 e6)osure' ?his should $e re)eated on da% :.cm ")' I$ser-ations recorded at "4 and 4A hours should $e used to ascertain highest nonirritant dose' Fain test should $e )erformed #ith 1: test animals and 5 controls' Induction #ith the dose selected from )retest should use :'3 ml.ect to a ma6imum of 3: da%s' I$ser-ation )arameters should include s#elling.Cotes& (i) . drugs to $e used in treatment of leucoderma)' Pretest in A animals should screen 4 concentrations ()atch a))lication for " hours M15 min') #ith and #ithout J8 e6)osure (1: N.ermal to"icity study: )he study should be done in rabbit and rat$ .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 $e done to achie-e multi)les of dail% human dose' ?he minimum duration of drug treatment is < da%s (more according to clinical use). ". oedema and eschar formation) as well as histological e"amination of sites of application should be used for e'aluation of results$ (ii) Photo allerg% or dermal )hoto to6icit%& It should $e tested $% !rmstrong.

$lood and. 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)eated dose studies' 0lit lam) e6amination should $e done to detect the changes in cornea.(i-) Rectal ?olerance ?est& (or all )re)arations meant for rectal administration this test ma% $e )erformed in ra$$its or dogs' 0i6 to ten animals )er dose grou) should $e ta/en' (ormulation in -olume com)ara$le to human dose (or the ma6imum )ossi$le -olume) should $e a))lied once or se-eral times dail%. signs of )ain. condition of anal region. re'ersibility of ad'erse effects may be determined on a case to case basis$ (-i) Icular to6icit% studies (for )roducts meant for ocular instillation)& ?hese studies should $e carried out in t#o s)ecies. ointments. iris and a=ueous humor' (luorescent d%es (sodium fluorescein. 0u$. gels or soft contact lenses (saturated #ith drug) should $e used' Initial single dose a))lication should $e done to decide the e6)osure concentrations for re)eated dose studies and the need to include a reco-er% grou)' Duration of the final stud% #ill de)end on the )ro)osed length of human e6)osure 0u$.ect to a ma6imum of 3: da%s' 0iDe of su))ositories ma% $e smaller. su$acute and chronic to6icit% studies should $e )erformed according to the intended duration of human e6)osure' 0tandard s%stemic to6icit% stud% designs (descri$ed a$o-e) should $e used' Bases and -a)ors should $e gi-en in #hole $od% e6)osure cham$ers7 aerosols are to $e gi-en $% nose onl% method' 46)osure time and . one of #hich should $e the al$ino ra$$it #hich has a sufficientl% large con.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. 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).uncti-al sacs should $e ensured' >i=uids.or mucus in faeces. gross and (if re=uired) histological e6amination of rectal mucosa' (') -arenteral .s)hincter.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. $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).uncti-a' Changes in intra ocular 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. )er rectall%.uncti-al sac' Direct deli-er% of drug onto the cornea in case of animals ha-ing small con. :'"5 to 1':O) should $e used for detecting the defects in surface e)ithelium of cornea and con.

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. the highest $eing ma6imum nonirritant dose )lus -ehicle control should $e used' ! minimum of .concentrations of test su$stance (limit dose of 5mg. findings of $ronchial la-age fluid e6amination. 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. determination of ma"imum nonirritant and minimum irritant doses.l) should $e ad. and second.ect to a ma6imum of . the main test$ )he initial study will also ha'e two components$ )o determine the intradermal induction dose.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. either onl% males or onl% females' Drug treatment is to $e gi-en on ear s/in' ?hree graded doses. 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% $e done' Cotes& (i) +uinea -ig :a"imi0ation )est: )he test is to be performed in two steps3 first. 4 dose le'els should be tested by the same route in a batch of 4 male and 4 female animals ( of each se" should be gi'en Freund6s ad5u'ant)$ )he minimum irritant dose should be used for induction$ *imilarly. 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 $e of the same se6. if needed) are re=uired' Duration of e6)osure ma% -ar% 0u$.

if such a drug is intended to $e administered for chronic illnesses or other#ise o-er a long )eriod of time tumorigenic effects' Benoto6icit% tests are in vitro and in vivo tests conducted to detect com)ounds #hich induce genetic damage directl% or indirectl%' ?hese tests should ena$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) (ii) (iii) ! test for gene mutation in $acteria' !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%' !n in vivo test for chromosomal damage using rodent hemato)oietic cells' a chronic to6icit% stud% (u) to one %ear) ma% $e necessar% to detect earl% Ither genoto6icit% tests e'g' tests for measurement of DC! adducts. 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. 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 $e em)lo%ed for technical reasons.ected to long term carcinogenicit% studies' Ho#e-er. in the a$sence of other data.. shall $e )resumed to $e trans s)ecies carcinogens. alternati-e -alidated tests can ser-e as su$stitutes )ro-ided sufficient scientific . im)l%ing a haDard to humans' 0uch com)ounds need not $e 0u$.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 . the draining auricular l%m)h nodes should $e dissected out 5 hours after i'-' 3H th%midine or $romo deo6% uridine (3rdJ)' Increase in 3H th%midine or 3rdJ incor)oration should $e used as the criterion for e-aluation of results' 1$@ +enoto"icity Benoto6ic com)ounds.

?!1535. ?!1::. (i) ?!1:". -nitrofluorine. hours after the last in. 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. *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. respecti'ely.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. 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 . )elletted and smeared on glass slides' Biemsa Fa%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 .. flushed #ith fetal $o-ine serum (": min'). ?!9< or Escherichia coli 9P" uvrA or Escherichia coli 9P" uvrA ()KF1:1) should $e used' !n-'itro e"posure (with and without metabolic acti'ation. an inhi$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. sodium a0ide and mitomycin .ection' 3one marro# from $oth the femora should $e ta/en out.

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.dose grou)s should $e used' !t least three dose le-els. 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 structure acti-it% relationshi) suggests carcinogenic ris/ or #hen there is e-idence of )reneo)lastic lesions in re)eated dose to6icit% studies or #hen long term 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.animals. )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 $e ta/en out. flushed #ith h%)otonic saline (": min').se6.arcinogenicity (see Appendi" !. item 4$A) Carcinogenicit% studies should $e )erformed for all drugs that are e6)ected to $e clinicall% used for more than . are needed' Com)leted rodent carcinogenicit% studies are not needed in ad-ance of the conduct of large scale clinical trials. carcinogenicit% studies ma% $e . )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 . 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 . >icensing !uthorit% ma% allo# carcinogenicit% testing to $e conducted after mar/eting )ermission has $een granted' In instances #here the life e6)ectanc% in the indicated )o)ulation is short (i'e'.u-ant thera)% in tumour free )atients or for )rolonged use in non cancer indications. e'g' "'567 to ma/e allo#ance for the sensiti-it% of the s)ecies' ?he intermediate dose to $e )laced . 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. less than " %ears) 3 no long term 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.

II. 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% (short term $ioassa%s.#/) "s)7"4#/. clinical chemistr% )arameters.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%. organ #eights.III I. effect on $od% #eight. site.II.III "s)74#/ "s)71"#/ "s)7"4#/ "s)71mo7 (46)osure time 3h.III .II.III >ong term to6icit% re=uirements Iral or Parenteral or ?ransdermal Inhalation (general anaesthetics. 5d. gross )atholog% and detailed histo)atholog%' Com)rehensi-e descri)tions of $enign and malignant tumour de-elo)ment.III I.d. hematolog% )arameters.II. 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 I.#/) "s)71"#/.h.II.II. dimensions. urine anal%sis.II. food inta/e. (46)osure time . aerosols) 0ingle dose or se-eral doses in one da%. 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."#/ I.#/) J)to 4#/ R 1 4#/ I.d.h. 5d. J)to 1#/ R 1 #/ $ut u)to "#/ R " #/ $ut u)to 4#/ I-er 1mo J)to " #/ "s).III I.d. time of their detection. 5d. (46)osure time .III I.

II.II III I.II.when there is a cause for concern. !!! .II. !!.when there is a cause of concern or for parenteral drugs (including dermal application) Photo allerg% or dermal )hoto to6icit%& • -hase !.II III I. !!! in male 'olunteers&patients (emale Re)roduction and De-elo)mental ?o6icit% 0tudies& • *egment !! studies in species3 -hase !!.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' .III I. !!.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 . or when the drug is to be used for more than @ months$ !$$re-iations& s) s)ecies7 mo month7 #/ #ee/7 d da%7 h hour7 I.II III I. 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 $e re)eated. !!! . II.H%)ersensiti-it%& • -hase !.>ocal ?o6icit% 0tudies Dermal J)to " #/ R " #/ J)to " #/ I. !!! in'ol'ing female patients of child-bearing age$ • *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%.III 1s)74#/ "s)74#/ "s)71"#/ 1s)74#/ "s)74#/ "s)71"#/ 1s)74#/ "s)74#/ "s)71"#/ Icular or Itic or Casal 8aginal or Rectal R " #/ J)to " #/ R " #/ 0)ecial ?o6icit% 0tudies Fale (ertilit% 0tud%& • -hase !. !!! arcinogenicit%& • -hase !!! .-hase ! • 9oth in-'itro and in-'i'o .III I. !!.-hase !!.

1: .olour • (p1) 9ile • =robilinogen • /ccult pigments 9lood • :icroscopic e"amination of urinary sediment$ 3lood 3iochemical Parameters • +lucose • • >eaction )otal >9. .oagulation )ime. 15 3: 15 3: 4. 1: "3 "3 .1'9 Cum$er of animals re=uired for re)eated dose to6icit% studies Brou) Control >o# dose Intermediate dose High dose 14 "A da%s Rodent (Rat) Con rodent (Dog or Fon/e%) F ( F ( . 1: "3 "3 . 15 3: 15 3: 4.ount • • 1aematocrit -latelet . . 1: . 4.holesterol • )riglycerides • 1.ount )erminal 9one :arrow 4"amination • 4*> (Fon• +eneral 9lood -icture: A special mention of abnormal and rodents only) immature cells should be made$ • .oagulation -arameters (Fon-rodents only): 9leeding )ime.ifferential H9. 1: .ount • . . "': >a$orator% )arameters to $e included in to6icit% studies' Haematological )arameters • 1aemoglobin • • )otal H9. 1: "3 "3 . 1: "3 "3 A4 1A" da%s Rodent (Rat) Con rodent (Dog or Fon/e%) F ( F ( 15 3: 15 3: 4. . -rothrombin )ime. 4. Acti'ated -artial )hromboplastin )ime Jrinal%sis Parameters • . 4. 15 3: 15 3: 4. 1: . 4.ount • • • Appearance Albumin • *pecific +ra'ity • *ugar • 4-hour urinary output • Acetone .( .

erebru • m.holesterol (Fon-rodents only) • Alkaline -hosphatase (A(-) • )otal -roteins • -otassium • 9ilirubin • *+-) (A()) .reatinine • • • +lobulin (. cerebellum.• (.alcium • *odium Bross and Ficrosco)ic Patholog% • 9rainK: .alculated 'alues) • .holesterol (Fonrodents only) • *+/) (A*)) • ++) (Fonrodents only) Albumin -hosphorus • 9lood =rea Fitrogen • .ord) • 4ye • 4ar) (:iddle (-arathyroid) (-ancreas) Aorta Le5unum (i'erK )estisK :ammary • • • • ileum • • • *pleenK ()rachea) /esophagus )erminal MidneyK /'ary :esenteric lymph node • • • • • )hymus (ungK *tomach .( .uodenum • • • • (>ectum) 4pididymis *kin • • • gland (*pinal . :idbrain • )hyroid • • AdrenalK • • 1eartK • • .olon =rinary bladder • =terusK • *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' Con clinical 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 non clinical to6icit% studies listed $elo#' .

F r P."*) III C#&'&%"# Tr&"#* Pro-ide a summar% of all the non clinical safet% data (listed a$o-e) alread% su$mitted #hile o$taining the )ermissions for Phase I and II trials. #ith a))ro)riate references' com)lete details of the non clinical safet% data needed for o$taining the )ermission for Phase I trial.de-elo)mental to6icit% stud% (if female )atients of child $earing age are going to $e in-ol-ed) F r P. #ith a))ro)riate references' In case of an a))lication for directl% starting a Phase II trial must $e su$mitted' Re)eat dose 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. as )er the list )ro-ided a$o-e ."*) II C#&'&%"# Tr&"#* Pro-ide a summar% of all the non clinical safet% data (listed a$o-e) alread% su$mitted #hile o$taining the )ermissions for Phase I trial.H%)ersensiti-it% tests (#hen there is a cause for concern or for )arenteral drugs. including dermal a))lication) Photo allerg% or dermal )hoto to6icit% 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) F r P."*) I C#&'&%"# Tr&"#* 0%stemic ?o6icit% studies i' 0ingle dose to6icit% studies ii' Dose Ranging 0tudies iii' Re)eat dose 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%.

"*) I? C#&'&%"# Tr&"#* Pro-ide a summar% of all the non clinical safet% data (listed a$o-e) alread% su$mitted #hile o$taining the )ermissions for Phase I. months) F r P. II and III trials. 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 $e used for more than . as )er the list )ro-ided a$o-e must $e )ro-ided' Re)eat dose s%stemic to6icit% studies of a))ro)riate duration to su))ort the duration of )ro)osed human e6)osure Re)roducti-e. complete details of the nonclinical safety data needed for obtaining the permissions for -hase !. these studies should also $e conducted in an accredited la$orator%' App)'2&6 I? !CIF!> PH!RF!CI>IB1 1$ +eneral Principles .de-elo)mental to6icit% studies 0egment I (if female )atients of child $earing age are going to $e in-ol-ed). #ith a))ro)riate references' !n case an application is made for initiating the -hase !< trial. as per the list pro'ided abo'e must be submitted$ 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. !! and !!! trials.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.

or ex vivo methods including electro)h%siolog% should also $e considered' . the e6clusion of certain test(s) or e6)loration(s) of certain organs. a general approach to safety pharmacology studies can be applied$ *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$stance that ma% ha-e rele-ance to its human safet%7 to e-aluate ad-erse )harmacod%namic and. in vivo and.ustified' 1$ $1$1 .ardio'ascular *ystem 4ffects of the in-estigational drug should $e studied on $lood )ressure.or sus)ected' ?he aim of the essential safet% )harmacolog% is to stud% the effects of the test drug on -ital functions' 8ital organ s%stems such as cardio-ascular.or )atho)h%siological effects o$ser-ed in to6icolog% and. and the electrocardiogram' If )ossi$le in vitro. s%stems or functions should $e scientificall% .or clinical studies7 and to in-estigate the mechanism of the ad-erse )harmacod%namic effects o$ser-ed and. heart rate. res)irator% and central ner-ous s%stems should $e studied' 4ssential safet% )harmacolog% studies ma% $e e6cluded or su))lemented $ased on scientific rationale' !lso.*pecific and general pharmacological studies should be conducted to support use of therapeutics in humans$ !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.

)H. com)liance. learning and memor%. coordination. c%tolog% and $lood urea nitrogen.1$ $1$ . osmolalit%. 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.entral Fer'ous *ystem ?hese include $eha-ioral studies . 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$1 . electro)h%siolog% studies . their agonists and antagonists on the cardio-ascular s%stem' 1$%$1$ .ardio'ascular *ystem ?hese include -entricular contractilit%. $eha-ioral changes. )harmaco-igilance. )ulmonar% arterial )ressure. -ascular resistance and the effects of chemical mediators. 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. e6)erimental in vitro or in vivostudies. neurochemistr% and ligand $inding studies' 1$%$1$% >espiratory *ystem ?hese include air#a% resistance. clinical trials. and the data generated from safet% )harmacolog% studies. creatinine and )lasma )roteins estimation' 1$%$ $ Autonomic Fer'ous *ystem .entral Fer'ous *ystem 4ffects of the in-estigational drug should $e studied on motor acti-it%. $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. )roteins. s)ecific gra-it%.

$ile secretion. should $e conducted if necessar%.?hese include $inding to rece)tors rele-ant for the autonomic ner-ous s%stem. 1$%$ $4 /ther /rgan *ystems 4ffects of the in-estigational drug on organ s%stems not in-estigated else#here should $e assessed #hen there is a cause for concern' (or e6am)le de)endenc% )otential. in the case of a ne# deri-ati-e ha-ing similar )harmaco/inetics and )harmacod%namics' 1$? )iming /f *afety -harmacology *tudies !n >elation )o . $ased on a cause for concern' 1$?$ . in #hich case this should $e . and.uring . and effects of direct stimulation of autonomic ner-es and their effects on cardio-ascular res)onses' 1$%$ $% +astrointestinal *ystem ?hese include studies on gastric secretion.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. immune and endocrine functions ma% $e in-estigated' 1$4 . s/eletal muscle.linical . in cases #hen the )harmacolog% of the in-estigational drug is #ell /no#n. and functional res)onse to agonist or antagonist res)onses in vivo or in vitro. gastric )H measurement.or #hen s%stemic a$sor)tion from the site of a))lication is lo#' 0afet% )harmacolog% testing is also not necessar%. gastric mucosal e6amination.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.ustified' !-aila$le .e'elopment 1$?$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. gastric em)t%ing time in vivo and ileocaecal contraction in vitro.

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%' .

ectGs )artici)ation ma% $e terminated $% the In-estigator #ithout the 0u$.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$ @$ . if any.ect that ma% result from )artici)ation in the stud%' . #hich ma% $e re=uired a' 0tatement of foreseea$le circumstances under #hich the 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.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.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$ . 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.escription of any reasonably foreseeable risks or discomforts to the *ub5ect ?$ .App)'2&6 ? IC(IRF4D CIC04C? 1' Chec/list for stud% 0u$. rights of *ub5ects and in the e'ent of any in5ury 11$ )he anticipated prorated payment. to the *ub5ect for participating in the trial 1 $ *ub5ect.ectGs consent' $' !dditional costs to the 0u$.s participation 3' Descri)tion of the )rocedures to $e follo#ed.s responsibilities on participation in the trial 1%$ *tatement that participation is 'oluntary. including all in-asi-e )rocedures and 4$ .

ectGs re)resentati-e #ill $e notified in a timel% manner if significant ne# findings de-elo) during the course of the research #hich ma% affect the 0u$. others #or/ing on the 0)onsor@s $ehalf. if the 0u$.ect) I confirm that I ha-e read and understood the information sheet dated 2 5 TTT for the a$o-e stud% and ha-e had the o))ortunit% to as/ =uestions' ( I understand that m% )artici)ation in the stud% is -oluntar% and that I am free to #ithdra# at an% time. 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.ect@s decision to #ithdra# from the research and )rocedures for orderl% termination of )artici)ation $% 0u$.ect' d' 0tatement that the 0u$. #ithout gi-ing an% reason.c' ?he conse=uences of a 0u$. I understand that m% identit% #ill not 2 5 ii) (iii) 2 5 .ect or 0u$. !ge& TTTTTTTTTTTTTTTTT 0u$.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 Came&TTTTTTTTTTTTTTT (i) Please initial $o6 (0u$. e-en if I #ithdra# from the trial' I agree to this access' Ho#e-er.ect is or ma% $ecome )regnant). #hich are currentl% unforeseea$le f' !))ro6imate num$er of 0u$.ect (or to the em$r%o or fetus.ect@s Initials& TTTTTTTTTTTTTTT Date of 3irth . #ithout m% medical care or legal rights $eing affected' I understand that the 0)onsor of the clinical trial.ectGs #illingness to continue )artici)ation #ill $e )ro-ided' e' ! statement that the )articular treatment or )rocedure ma% in-ol-e ris/s to the 0u$.

TTTTTT 0ignator%@s Came& TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT 0ignature of the TTTTT.TTTTT.TTTTTT In-estigator& TTTTTTTTTTTTTTTTTTTTTTTTTTTT Date& 0tud% In-estigator@s Came& TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT 0ignature of the 9itness TTTTTTTTTTTTTTTTTTTTTT Date&TTTTT.$e re-ealed in an% information released to third )arties or )u$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) I agree to ta/e )art in the a$o-e stud%' 2 2 5 5 0ignature (or ?hum$ im)ression) Re)resentati-e&TTTTTTTTTTTTT of the 0u$.mar/eted indi-iduall% are com$ined for the first time.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 $e similar to data re=uired for an% ne# drug (including clinical trials) 2see rule 1""4.TTTTT. for a )articular claim and #here the ingredients are li/el% to ha-e significant interaction of a )harmacod%namic or ($) .TTTTT. item (a)5' (i) ?he second grou) (DCs includes those in #hich acti-e ingredients alread% a))ro-ed.ect.>egall% !cce)ta$le Date& TTTTT.

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. and marketing permission may be granted if the F. to6icological and clinical data on the indi-idual ingredients should $e su$mitted.. 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' (d) Fo additional animal or human data are generally re#uired for these F. has an acceptable rationale$ .. 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.s. item (c)5' If clinical trials ha-e $een carried out #ith the (DC in other countries. 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. item 9)' (ii) (or mar/eting )ermission. 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. re)orts of such trials should $e su$mitted' If the (DC is mar/eted a$road. $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 regulator% status in other countries should $e stated' (see !))endi6 I. the a))ro)riate rationale including )u$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' ?he fourth grou) of (DC includes those #hose indi-idual acti-e ingredients (or drugs from the same class) ha-e $een #idel% used in a )articular indication(s) for %ears. along #ith the rationale for com$ining them in the )ro)osed ratio' In addition.)harmaco/inetic nature 2see rule 1""4.

and . hos)ital or other facilit% #here the clinical trial #ill $e conducted& 4ducation.ects or #hen the change(s) in-ol-ed are onl% logistical or administrati-e in nature' (iii) I agree to )ersonall% conduct and. e6ce)t #here necessar% to eliminate an immediate haDard(s) to the trial 0u$. training U e6)erience that =ualif% the In-estigator for the clinical trial (!ttach details including Fedical Council registration num$er. !II JCD4R?!KICB 31 ?H4 IC840?IB!?IR 1' (ull name.or su)er-ise the clinical trial at m% site' "' 3' 4' 5' . fa-ora$le o)inion from the 4thics Committee of the amendment. or an% other statement(s) of =ualification(s)) Came and address of all clinical la$orator% facilities to $e used in the stud%' Came and address of the 4thics Committee that is res)onsi$le for a))ro-al and continuing re-ie# of the stud%' 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 $% the 0)onsor and )rior re-ie# and documented a))ro-al .' <' . address and title of the Princi)al In-estigator (or In-estigator(s) #hen there is no Princi)al In-estigator) Came and address of the medical college.Appen$i.

>icensing !uthorit% or their authoriDed re)resentati-es.ects. 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 .(i-) I agree to inform all 0u$. ins)ection $% the 0)onsor. including the )otential ris/s and side effects of the drug' (-ii) I agree to ensure that all associates. 4thics Committee.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. 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. 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$. colleagues and em)lo%ees assisting in the conduct of the stud% are suita$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 .

there should $e a))ro)riate gender re)resentation on the 4thics Committee' If re=uired. trial site' 3esides. ethicist . )ro-ide o)inion in matters related to the stud%' 2. including la% )u$lic. theologian or a similar )erson (e) lay person from the community$ In an% case. 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$ers #ho are inde)endent of the clinical trial and the 0)onsor of the trial should -ote . a Chair)erson (#ho is from outside the institution) and a Fem$er 0ecretar%' Ither mem$ers should $e a mi6 of medical. the ethics committee must include at least one mem$er #hose )rimar% area of interest . s)ecialiDation is nonscientific and at least one mem$er #ho is inde)endent of the institution .ect e6)erts ma% $e in-ited to offer their -ie#s' (urther.Appendix VIII ETHICS COMMITTEE 1' ?he num$er of )ersons in an 4thcis Committee should ha-e atleast se-en mem$ers' 4thics Committee should a))oint. Format for Approval of Ethics Committee ?o Dr' Dear Dr' TTTTTTTT . 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 . from among its mem$ers. $ased on the re=uirement of research area. 0u$.non medical. scientific and non scientific )ersons.

an% 0!4 occurring in the course of the stud%. 8ersion no'TTTTTTTT Pro)osed methods for )atient accrual including ad-ertisement (s) etc' )ro)osed to $e used for the )ur)ose' Princi)al In-estigator@s current C8' Insurance Polic% . )lace)' TTTTTTTTTT Chairman of the 4thics Committee TTTTTTTTTT Fem$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%. Com)ensation for )artici)ation and for serious ad-erse e-ents occurring during the stud% )artici)ation' In-estigator@s !greement #ith the 0)onsor' In-estigator@s Jnderta/ing (!))endi6 8II)' ?he follo#ing mem$ers of the ethics committee #ere )resent at the meeting held on (date. Fem$er 0ecretar%.?he Institutional 4thics Committee .informed consent and as/s to $e )ro-ided a co)% of the final re)ort' 1ours sincerel%. datedTTTTTTTTTTTT 8ersion no (s)'TTTTTTTTTT Patient Information 0heet and Informed Consent (orm (including u)dates if an%) in 4nglish and.or -ernacular language' In-estigator@s 3rochure. datedTTTTTTTTT. time. 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' $' c' d' e' f' g' h' ?rial Protocol( including )rotocol amendments). an% changes in the )rotocol and )atient information. 4thics Committee' .

and functionalit% tests (e'g'. as a))ro)riate. o6idation. )reser-ati-e content (e'g'. the )h%sical. humidit% and light. and micro$iological attri$utes. 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 ).or efficac%' In case of formulations the testing should co-er. #hich in turn esta$lish the degradation )ath#a%s. 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' >ong term 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 . its sensiti-it% to moisture' ?he storage conditions and the length of studies chosen should $e sufficient to co-er storage. $iological. for a dose deli-er% s%stem)' 8alidated sta$ilit% indicating anal%tical )rocedures should $e a))lied' (or long term studies.App)'2&6 I= 0?!3I>I?1 ?40?ICB I( C49 DRJB0 0ta$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. and. antimicro$ial )reser-ati-e). chemical. a drug su$stance should $e e-aluated under storage conditions that test its thermal sta$ilit% and. if a))lica$le. and )hotol%sis on the drug su$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. 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%. humidit% #here a))ro)riate. safet%. fre=uenc% of testing should $e sufficient to esta$lish the sta$ilit% )rofile of the drug su$stance' In general. antio6idant. shi)ment and su$se=uent use' 0tress testing of the drug su$stance should $e conducted to identif% the li/el% degradation )roducts.

<5O RH M 5O RH Duration of stud% 1" months . months@ testing under the accelerated storage condition..:O RH M 5O RH . months duration at the time of su$mission' In case of drug su$stances.. 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.5O RH M 5O RH 4:WC M "WC. 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 $e stored in a refrigerator 0tud% >ong term !ccelerated 0tud% conditions Duration of stud% 5WC M 3WC 1" months "5WC M "WC.continued for a )eriod of time sufficient to co-er the )ro)osed shelf life' !ccelerated testing should co-er a minimum of . such changes occur that cause the )roduct to fail in com)l%ing #ith the )rescri$ed standards. 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% >ong term !ccelerated 0tud% conditions 3:WC M "WC. months If at an% time during . months . 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.

"%@/r 5'2 "'2 I'(r 25%(& ' a$ -reclinical e"perience b$ . 0tud% num$er. storage condition. should $e conducted to )ro-ide information for the la$eling on the )re)aration.num$er of the in-estigational drug d' Com)lete name and address of the 0)onsor and contract research organiDation if an% e' >ist of the In-estigators #ho are conducting the stud%. if a))lica$le. T"+#) $ C '()'(* ! com)lete ?a$le of Contents including a list of all !))endices' .(iii) 0tud% conditions for drug su$stances and formulations intended to $e stored in a free0er 0tud% >ong term 0tud% conditions ":WC M 5WC Duration of stud% 1" months (i-) Drug su$stances intended for storage $elo# ":WC shall $e treated on a case $% case $asis' 0ta$ilit% testing of the formulation after constitution or dilution. 1. their res)ecti-e institutional affiliations and site locations f' Came(s) of clinical la$oratories and other de)artments and. $' Protocol . and in use )eriod of the constituted or diluted )roduct' ?his testing should $e )erformed on the constituted or diluted )roduct through the )ro)osed in use )eriod' (-) App)'2&6 = CONTENTS OF THE PROPOSED PROTOCOL FOR CONDUCTING CLINICAL TRIALS 1' ?itle Page a' (ull title of the clinical stud%.linical e"perience .or facilities )artici)ating in the stud%' 2. and )rotocol -ersion num$er #ith date c' ?he ICD name.

to6icological and other $iological )ro)erties of the drug. and the t%)e. dis)ensation and retrie-al of medication.ects in each grou) and in-estigati-e site. 0tud% Po)ulation& the num$er of 0u$. $lood or urine testing. -.ect cohort assignment. S(527 R"(& '"#) ?his section should descri$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 $e )ro-ided' -.ect )o)ulation re=uired is also mentioned. multicentre. 0tud% I$. )rocedures and methods to $e descri$ed in detail 0tud% Conduct stating the t%)es of stud% acti-ities that #ould $e included in this section #ould $e& medical histor%. ad-erse e-ent re-ie#.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.ects re=uired to $e enrolled in the stud% at the in-estigati-e site and $% all sites along #ith a $rief descri)tion of the nature of the 0u$. electrocardiogram (4CB). 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. and )re-ious efficac% and safet% e6)erience should $e a' I-er-ie# of the 0tud% Design& Including a descri)tion of the t%)e of stud% (i'e'. s%m)tom measurement. 0u$. diagnostic testing such as )ulmonar% function tests. )lace$o controlled. ho# this drug #as considered for this should $e discussed' Rele-ant information regarding descri$ed' 2. 0u$.' a' $' <' A' 0u$. etc'). dou$le $lind. .ect 4ligi$ilit% Inclusion Criteria 46clusion Criteria 0tud% !ssessments E )lan.medical de-ice. t%)e of )h%sical e6amination.ecti-e(s) ()rimar% as #ell as secondra%) and their logical relation to the stud% design' S(527 D)*&/' )harmacological. etc' . a detail of the s)ecific treatment grou)s and num$er of stud% 0u$.$iologic.ect num$er assignment.

or dumm% medications if the% are )art of the treatment )lan' If a))lica$le. 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. 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%.4ach -isit should $e descri$ed se)aratel% as 8isit 1. and duration of the e6)erimental treatment) Descri$e the administration of )lace$os and.$enefit assessment& 4thics Committee re-ie# and communications . fre=uenc%. or other reasons for discontinuation of 0u$. fre=uenc%.ects& Descri$es the circumstances for 0u$. their doses.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. including conditions #here the stud% #ill $e terminated for non com)liance #ith the )rotocol' 9' a' 0tud% ?reatment Dosing schedule ( dose. dro)outs. storage re=uirements and dis)ensing re=uirements should $e )ro-ided' c' d' e' Dose modification for stud% drug to6icit%& Rules for changing the dose or sto))ing the stud% drug should $e )ro-ided' Possi$le drug interactions 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$.ect #ithdra#al.ect Jn$linding )rocedures& If the stud% is $linded. etc' Discontinued 0u$. concomitant drug(s). 8isit ". these should $e descri$ed here' f' g' 3linding )rocedures& ! detailed descri)tion of the $linding )rocedure if the stud% em)lo%s a $lind on the In-estigator and.or the 0u$. 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' a' $' 4thical Considerations& Bi-e the summar% of& Ris/.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.

dis)ensation. and return of the in-estigational )roducts to ensure a com)lete accounting of all in-estigational )roducts recei-ed. dis)ensed. including #hat needs to $e stored follo#ing stud% com)letion should $e descri$ed' 1-.ect #ithdra#als7 rationale and conditions for an% interim anal%sis if )lanned' . and $linding of stud% su$stances Fethod of assigning treatments to 0u$. statistical tests to $e used. non com)liance. storage. and 0u$.ect confidentialit% including o#nershi) of data and coding )rocedures 0tud% Fonitoring and 0u)er-ision& ! descri)tion of stud% monitoring )olicies and )rocedures should $e )ro-ided along #ith the )ro)osed fre=uenc% of site monitoring -isits. and the methods used for missing data7 method of e-aluation of the data for treatment failures. Descri$e )olic% and )rocedure for handling unused in-estigational )roducts' D"(" A'"#7*&*: Pro-ide details of the statistical a))roach to $e follo#ed including sam)le siDe. la$eling. ho# the sam)le siDe #as determined. including #ho gets #hich co)ies of the forms and an% s)ecifics re=uired in filling out the forms CR( correction re=uirements.destro%ed' g' 10. and returned.ect identification code num$ering s%stem 0torage conditions for stud% su$stances In-estigational )roduct accounta$ilit%& Descri$e instructions for the recei)t.c' d' 1"' Informed consent )rocess 0tatement of 0u$.ects and the 0u$. 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$e the le-el of significance. and #ho is e6)ected to )erform monitoring' Case Record (orm (CR() com)letion re=uirements. In-estigational Product Fanagement a' Bi-e In-estigational )roduct descri)tion and )ac/aging (stating all Ingredients and the formulation of the in-estigational drug and an% )lace$os used in the stud%) $' ?he )recise dosing re=uired during the stud% c' d' e' f' Fethod of )ac/aging. authoriDed to ma/e corrections on the CR( and ho# =ueries a$out stud% data including #ho is are handled and ho# errors. if an%. are to $e corrected should $e stated' In-estigator stud% files.

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'. co)ies of the informed consent documents ()atient information sheet.' Jnderta/ing $% the In-estigator (see !))endi6 8II) !))endices& Pro-ide a stud% s%no)sis.IPD record num$er etc')S Bender !ge and.Descri$e statistical considerations for Pharmaco/inetic (PK) anal%sis. informed consent form etc')7 CR( and other data collection forms7 a summar% of rele-ant )re clinical safet% information and an% other documents referenced in the clinical )rotocol' App)'2&6 =I Data 4lements for re)orting serious ad-erse e-ents occuring in a clinical trial 1' Patient Details Initials U other rele-ant identifier (hos)ital. mg. ml. if a))lica$le 15' 1. as for the sus)ected drug(s)' 4' Details of 0us)ected !d-erse Drug Reaction(s) .I?C drugs) and non drug thera)ies. 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.

"::3 DF0 U P(!) .or treatment that ma% ha-e $een conducted (or a fatal outcome. out )atient clinic. cause of death and a comment on its )ossi$le relationshi) to the sus)ected reaction7 !n% )ost mortem findings' Ither information& an%thing rele-ant to facilitate assessment of the case. hos)ital. #hene-er )ossi$le. drug or alcohol a$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 $e )ro-ided'+ (('Co' X 11:14. such as medical histor% including allerg%.1. descri$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'.(ull descri)tion of reaction(s) including $od% site and se-erit%. nursing home) 5' Iutcome Information on reco-er% and an% se=uelae7 results of s)ecific tests and. home. 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.

NIIC? 04CR4?!R1. dated the "1st Decem$er.45 H(I). 1945 and last amended -ide dated the . BI84RCF4C? I( ICDI! (oot Cote & "A B'0'R' (4) ?he Prinici)al Rules #ere )u$lished in the Ifficial BaDette -ide notification Co' (' 1:.(RI?! ?4I?I!).

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