In d Template Clinical Study Protocol

8/12/2019 In d Template Clinical Study Protocol

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IND APPLICATION TEMPLATE:

CLINICAL STUDY PROTOCOL

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Incorporate the name(s) and title(s) of individual(s) authori*ed to si!nthe +orm +" 11 submissions on behalf of the Sponsor of the IN"application.

Stu#y Monitor:

Incorporate the follo$in!, as $ritten

Education and Co!"iance #ffice for $uan Sub%ect &esearch&esearch Conduct and Co!"iance #fficeUniversity of Pittsburgh3500 Fifth Avenue, Suite 303Pittsburgh, PA 15213

Me#ical Director: (Incorporate only if applicable)

If the Sponsor of the IN" application is not a physician (or dentist, ifapplicable), incorporate the name, title, address, and telephone number ofthe /ualified physician (or dentist, if applicable) $ho is responsible for allmedical (or dental) decisions related to the clinical research study.

In%e"ti&ator'"(:

Incorporate the name(s) and title(s) of the investi!ator(s) $ho is (are)responsible for conductin! the clinical research study, and the address andtelephone number of the study site(s). +or sponsor-investi!ator IN"applications, the identity of the Investi!ator should be the same as the identityof the Sponsor.

Clinical Laoratory'ie"(+ Tec$nical De)artment'"(+ an#In"titution'"( Pro%i#in& Clinical Stu#y Ser%ice":

Incorporate the names and addresses of the clinical laboratory(ies),hospital(s), and other medical and'or technical departments or entities that$ill be utili*ed for the conduct of the clinical research study.

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C. Clinical Protocol

,. Intro#uction:

,., -ac&roun#:

Provide the name and'or identity (i.e. chemical composition) of theinvesti!ational dru! product(s) and specify the disease or condition for$hich the investi!ational dru! product(s) is (are) bein! evaluated..

"iscuss the current status of the disease or condition (i.e., clinicalindication) for $hich the investi!ational dru!(s) is (are) bein! evaluatedunder this IN" application# to include current problems or deficienciesthat $arrant an evaluation of the investi!ational dru!.

,./ Rationale:

Summari*e the reason(s) $hy it is felt that the investi!ational dru!(s) $illbe safe and effective for the clinical indication for $hich it is bein!evaluated under this IN" application# i.e.

Summari*e the safety and efficacy findin!s from non-clinical (i.e.,animal or in-vitro) studies that support the evaluation of theinvesti!ational dru!(s) in humans.

Summari*e, if applicable, the results of any prior clinical researchstudies of the investi!ational dru!(s) that are relevant to the proposedclinical evaluation of the investi!ational dru!(s) under this IN"application. +or e0ample

Summari*e any e0istin! information related to the humanpharmacoinetics of the investi!ational dru!(s).

Summari*e any e0istin! information related to the human safetyprofile (includin! no$n potential riss) of the investi!ationaldru!(s).

Summari*e any e0istin! information related to the effectiveness ofthe investi!ational dru!(s) for the clinical indication for $hich it isbein! evaluated under this IN" application.

Provide a brief description of, and ustification for, the proposed route ofadministration, dosa!e, dosa!e re!imen, and duration of dosin! of theinvesti!ational dru!(s).

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Summari*e the nature of the individuals (e.!., a!e ran!e, se0, diseasestate or underlyin! condition) $ho $ill be included in the proposed clinicalevaluation of the investi!ational dru!(s).

Specify $hether or not (i.e., to your no$led!e) the investi!ational dru!(s)has (have) been $ithdra$n from research or maretin! in any country forany reason related to its safety or effectiveness.

/. Clinical Stu#y O0ecti%e":

/., Primary o0ecti%e:

ddress the primary obective and specific aim(s) of the proposed clinicalevaluation of the investi!ational dru!(s). (Note +or Phase 1 and 2 clinicalresearch studies, the primary obective should be an evaluation of the

safety of the investi!ational dru!.)

/./ Secon#ary o0ecti%e":

ddress, if applicable, secondary obective(s) and specific aim(s) of theproposed clinical evaluation of the investi!ational dru!(s).

1. Stu#y De"i&n:

"escribe the type'desi!n (e.!., double-blind, placebo-controlled, parallel

desi!n) of the proposed clinical evaluation of the investi!ational dru!(s)# toinclude

a !eneral description of the measures (e.!., randomi*ation, blindin!) that

$ill be taen to minimi*e'avoid bias on the part of the study participants,,investi!ators, and analysts# and

the e0pected total duration of subect participation and a !eneral

description of the se/uence and duration of individual study periods orsta!es (includin! follo$-up, if any)#

1., Stu#y #e"i&n "c$ematic

Provide a schematic dia!ram of the study desi!n and sta!es.

3.2 Allocation to treatment (Incorporate only if the proposed clinicalstudy involves multiple treatment arms)

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"escribe the plan and procedures for allocatin! the study participants tothe various cohorts or arms of the proposed clinical investi!ation of theinvesti!ational dru!(s).

3.3 -reain& t$e lin# (Incorporate only if the proposed clinical study

is blinded)

"escribe the procedures for breain! the blind should a !iven studyparticipant suffer a serious adverse event $herein no$led!e of theidentity of the study dru! received by the subect is necessary for effectiveemer!ency treatment of the event.

2. Su0ect Selection:

Specify the 3niversity'3P45 location $here the proposed clinical evaluationof the investi!ational dru!(s) $ill be conducted, and the estimated total

number of individuals to be enrolled into this clinical research study. Indicatethat %enrollment into the study& is defined as providin! informed consent forstudy participation (i.e., as per 3niversity of Pittsbur!h I67 policies).

2., Su0ect inclu"ion criteria

8ist the specific subect inclusion criteria.

2./ Su0ect e3clu"ion criteria

8ist the specific subect e0clusion criteria

4. Stu#y Dru&'"(:

"escribe, in detail, the study dru!s that $ill be administered to each cohort orarm of the proposed clinical evaluation of the investi!ational dru!(s)# toinclude, for each dru! product, its identity (i.e., proprietary and !enericname), +"-approval status, dose (includin! ma0imum dose), dosin!schedule, route'mode of administration, and duration of administration.

"escribe, if applicable, the procedures for dose reductions or increasesbased on the outcome of safety or efficacy assessments# or, if applicable, the

procedures for the taperin! of doses upon subect $ithdra$al from, orcompletion of, the clinical research study.

4., Stu#y #ru& com)liance5a#$erence

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"escribe the procedures that $ill be used to assess research subectcompliance'adherence $ith the assi!ned study dru! dosa!e re!imen.

4.,., 6it$#ra7al of "u0ect" #ue to non8com)liance5a#$erence

Specify the criteria and procedures for $ithdra$in! research subectsfrom study participation due to non-compliance'adherence $ith theassi!ned study dosa!e re!imen, the clinical research study

procedures, or the instructions of the investi!ator or members of theinvesti!ators research staff.

Specify if subects $ithdra$n from study participation due tononcompliance'adherence $ill be replaced and, if so, thecorrespondin! procedures for their replacement.

4./ Stu#y #ru& "u))lie"

4./., 9ormulation an# )aca&in&

"escribe the source and formulation of each of the study dru!s (e.!.,investi!ational dru!, placebo, comparator dru!9s:) and ho$ they $ill be

paca!ed and labeled for use in the clinical research study.

4././ Pre)arin& an# #i")en"in&

"escribe the procedures for the on-site preparation, if applicable, anddispensin! of the study dru!(s).

4./.1 Dru& a#mini"tration

"escribe the procedures (e.!., investi!ator-directed, research subect-directed) for the administration of each of the study dru!s# to include, ifapplicable, the specific instructions that $ill be provided to theresearch subects.

4.2 Stu#y #ru& "tora&e an# accountaility

"escribe the re/uirements (e.!., temperature, protection from li!ht) forappropriate stora!e of each of the study dru!s so as to ensure theirstability throu!hout the assi!ned e0piration period.

"escribe the procedures for ensurin! proper accountability of each of thestudy dru!s# to include the procedures for destruction or other disposition

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of the study dru!s upon completion or termination of the clinical researchstudy.

4.4 Concomitant Me#ication"

"escribe or list the concomitant medications that $ill be permitted and'ornot permitted prior to and'or durin! the subects participation in the clinicalresearch study.

"escribe ho$ the subects use of concomitant medications $ill beassessed and accounted for durin! clinical study participation.

4.4./ Re"cue Me#ication

Identify, if applicable, acceptable rescue medications that may be usedby the subects durin! their participation in the clinical study.

. Re"earc$ Stu#y Proce#ure":

(Note that Investi!ators are not permitted to deviate from proceduresdescribed in an I67- or +"-accepted clinical research protocol. ;ence, theclinical research protocol should be desi!ned in such a $ay so as to minimi*ethe potential for protocol deviations. +or e0ample, information related to themanufacture of the investi!ational dru! should not appear in the clinical

protocol# nor should the clinical protocol include a detailed description of theprocedures associated $ith any in-vitro analyses that $ill be performed oncollected biolo!ical specimens.


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"escribe, in detail, or list the follo$-up procedures that $ill be performedafter the subect completes the study dru! administration procedures..

.2 Sc$e#ule of acti%itie" 'Stu#y Tale(

Provide a table that summari*es the clinical protocol procedures# toinclude the procedures that $ill be performed at screenin!, durin! thestudy dru! administration, and at follo$-up (if applicable) to the study dru!administration.

;. Safety an# Effecti%ene"" A""e""ment":

;./ Safety a""e""ment"

Specify the parameters (i.e., procedures, laboratory tests, or other

measures) that $ill be used to evaluate the safety of the studytreatment(s)# to include the methods and timin! for assessin!, recordin!,and analy*in! these parameters

;./ Effecti%ene"" a""e""ment"

Specify the parameters (i.e., observations and'or measurements) that $illbe used to evaluate the effectiveness of the study dru!(s)# to include themethods and timin! for assessin!, recordin!, and analy*in! these

parameters.


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6easonable possibility. For the !ur!ose of +- safety re!orting,

)reasonab"e !ossibi"ity* eans there is evidence to suggest a causa"re"ationshi! bet'een the drug and the adverse event(

8ife-threatenin!, suspected adverse reaction. A sus!ected adverse

reaction is considered )"ife.threatening* if, in the vie' of either the+nvestigator /i(e(, the study site !rinci!a" investigator or S!onsor, itsoccurrence !"aces the !atient or research sub%ect at iediate ris ofdeath( +t does not inc"ude a sus!ected adverse reaction that had itoccurred in a ore severe for, ight have caused death(

Serious, suspected adverse reaction( A sus!ected adverse reaction isconsidered )serious* if, in the vie' of the +nvestigator /i(e(, the study site!rinci!a" investigator or S!onsor, it resu"ts in any of the fo""o'ingoutcoes death, a "ife.threatening adverse reaction, in!atienthos!ita"iation or !ro"ongation of e4isting hos!ita"iation, a !ersistent or

significant inca!acity or substantia" disru!tion of the abi"ity to conductnora" "ife functions, or a congenita" anoa"ybirth defect(

+!ortant drug.re"ated edica" events that ay not resu"t in death, be

"ife.threatening, or re6uire hos!ita"iation ay be considered )serious*'hen, based u!on a!!ro!riate edica" %udgent, they ay %eo!ardiethe research sub%ect and ay re6uire edica" or surgica" interventionto !revent one of the outcoes "isted in this definition( E4a!"es ofsuch edica" events inc"ude a""ergic bronchos!as re6uiring intensivetreatent in the eergency roo or at hoe, b"ood dyscrasias orconvu"sions that do not resu"t in in!atient hos!ita"iation, or the

deve"o!ent of drug de!endency or drug abuse(

3ne0pected, suspected adverse reaction( A sus!ected adversereaction is considered )une4!ected* if it is not "isted in the genera"investigationa" !"an, c"inica" !rotoco", or e"se'here in the current +-a!!"ication7 or is not "isted at the s!ecificity or severity that has been!revious"y observed andor s!ecified(


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A"" observed or vo"unteered adverse events /serious or non.seriousand abnora" test findings, regard"ess of study grou! or sus!ectedcausa" re"ationshi! to the study drug/s 'i"" be recorded in the sub%ects8

case histories( For a"" adverse events, sufficient inforation 'i"" be!ursued andor obtained so as to !erit 1 an ade6uate deterinationof the outcoe of the event /i(e(, 'hether the event shou"d bec"assified as a serious adverse event and7 2 an assessent of thecasua" re"ationshi! bet'een the adverse event and the study drug/s(

Adverse events or abnora" test findings fe"t to be associated 'ith thestudy drug/s 'i"" be fo""o'ed unti" the event /or its se6ue"ae or theabnora" test finding reso"ves or stabi"ies at a "eve" acce!tab"e to theS!onsor.+nvestigator(


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9he S!onsor.+nvestigator of the +- a!!"ication'i"" !ro!t"yrevie' docuented adverse events and abnora" test findings todeterine 1 if the abnora" test finding shou"d be c"assified as anadverse event7 2 if there is a reasonab"e !ossibi"ity that theadverse event 'as caused by the study drug/s7 and 3 if the

adverse event eets the criteria for a serious adverse event(

+f the S!onsor.+nvestigator8s fina" deterination of causa"ity is)unno'n and of 6uestionab"e re"ationshi! to the study drug/s*, theadverse event 'i"" be c"assified as associated $ith the use of thestudy dru!(s)for re!orting !ur!oses( +f the S!onsor.+nvestigator8sfina" deterination of causa"ity is )unno'n but not re"ated to thestudy drug/s*, this deterination and the rationa"e for thedeterination 'i"" be docuented in the res!ective sub%ect8s casehistory(


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&e"evant fo""o'.u! inforation to an +- Safety &e!ort 'i"" besubitted to the a!!"icab"e revie' division of the F-A as soon asthe inforation is avai"ab"e and 'i"" be identified as such /i(e(,)Fo""o'.u! +- Safety &e!ort*(

+f the resu"ts of the S!onsor.+nvestigator8s fo""o'.u! investigationsho' that an adverse event that 'as initia""y deterined to notre6uire a 'ritten +- Safety &e!ort does, in fact, eet there6uireents for re!orting7 the S!onsor.+nvestigator 'i"" subit a'ritten +- Safety &e!ort as soon as !ossib"e, but in no event "aterthan 15 ca"endar days, after the deterination 'as ade(


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Fo""o'.u! inforation to a re!orted adverse event 'i"" be subitted tothe +&< as soon as the re"evant inforation is avai"ab"e( +f the resu"tsof the S!onsor.+nvestigator8s fo""o'.u! investigation sho' that anadverse event that 'as initia""y deterined to not re6uire re!orting tothe +&< does, in fact, eet the re6uireents for re!orting7 the

S!onsor.+nvestigator 'i"" re!ort the adverse event to the +&< as soonas !ossib"e, but in no event "ater than 10 ca"endar days, after thedeterination 'as ade(


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reflections on, or calculations of, the po$er of the study and clinicalustification.

9.3 Definition'"(: Analy"i" )o)ulation'"(

"efine the various terminolo!ies (e.!., Safety Population, Intent to


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Any deviations fro the !revious"y described statistica" !"ans based on theresu"ts of the interi ana"ysis 'i"" be described and %ustified in a !rotoco"aendent andor in the fina" re!ort subitted to the +- a!!"ication(

9.7 Data an# Safety Monitorin& Committee (Incorporate only if a

"ata and Safety 4onitorin! 5ommittee $ill be utili*ed)

"escribe the composition and operations of the "ata and Safety4onitorin! 5ommittee that $ill provide oversi!ht of the clinical study.

ddress the process for communication of "ata and Safety 4onitorin!5ommittee determinations to the Sponsor-Investi!ator.

,@. uality Control an# uality A""urance:

Incorporate the first t$o para!raphs, as $ritten

+nde!endent onitoring of the c"inica" study for !rotoco" and >CP co!"iance'i"" be conducted !eriodica""y /i(e(, at a iniu of annua""y by 6ua"ified staffof the Education and Co!"iance #ffice ? $uan Sub%ect &esearch,&esearch Conduct and Co!"iance #ffice, University of Pittsburgh(

9he S!onsor.+nvestigator and the University of Pittsburgh and UP@C 'i""!erit direct access of the study onitors and a!!ro!riate regu"atoryauthorities to the study data and to the corres!onding source data anddocuents to verify the accuracy of this data(

"escribe the nature and timin! of the /uality control'/uality assurancerevie$s (i.e., independent of the previously described monitorin! activities)that $ill be undertaen by the Sponsor-Investi!ator to ensure appropriateconduct of the clinical research study and /uality and completeness of theaccrued study data. I.e., describe the data and safety monitorin! plan for the

proposed clinical research study.

,,.Data Ban#lin& an# Recor#8ee)in&:

,,., Data recor#in&5Ca"e Re)ort 9orm"

Incorporate para!raphs 1 and 2, as $ritten

A Case &e!ort For /C&F, see A!!endi4 1 'i"" be co!"eted for eachsub%ect enro""ed into the c"inica" study( 9he S!onsor.+nvestigator 'i""revie', a!!rove and signdate each co!"eted C&F7 the S!onsor.+nvestigator8s signature serving as attestation of the S!onsor.

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+nvestigator8s res!onsibi"ity for ensuring that a"" c"inica" and "aboratory dataentered on the C&F are co!"ete, accurate and authentic(

Source "ataare the c"inica" findings and observations, "aboratory and testdata, and other inforation contained in Source "ocuments( Source

"ocuments are the origina" records /and certified co!ies of origina"records7 inc"uding, but not "iited to, hos!ita" edica" records, !hysicianor office charts, !hysician or nursing notes, sub%ect diaries or eva"uationchec"ists, !haracy dis!ensing records, recorded data fro autoatedinstruents, 4.rays, etc( :hen a!!"icab"e, inforation recorded on theC&F sha"" atch the Source "atarecorded on the Source "ocuments(

Identify, if applicable, any clinical study data that $ill be recorded directlyon the 56+, $hereupon the 56+ data is to be considered the Source"ata.

"escribe the procedures for accountin! for any missed, unused, and'orspurious data.

"escribe ho$ the subect-specific data and 5ase 6eport +orms $ill becoded and ho$ these materials, and the subect identification code list,$ill be stored so as to protect the subects confidentiality. Specify thatsubect names or other directly identifiable information $ill not appear onany reports, publications, or other disclosures of clinical study outcomes.

If an electronic system $ill be used as the sole instrument for therecordin! and analysis of clinical and laboratory data related to the safetyand'or effectiveness of the study dru!(s), address compliance $ith the+"s electronic records and electronic si!natures re!ulations at 21 5+6Part 11. Note that in the absence of any /ualifyin! statement, the +" $illassume that the electronic data recordin! system is compliant $ith these+" re!ulations. ;ence, if the electronic data system bein! used has notbeen certified to be in compliance $ith the 21 5+6 Part 11, incorporate astatement specifyin! such# e.!. %


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F-A corres!ondence re"ated to the +- and c"inica" !rotoco", inc"uding

co!ies of subitted Safety &e!orts and Annua" &e!orts

+&< corres!ondence /inc"uding a!!rova" notifications re"ated to the

c"inica" !rotoco"7 inc"uding co!ies of adverse event re!orts and annua"or interi re!orts

Current and !ast versions of the +&


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(Incorporate the follo$in! into the above list, but only if they are applicableto this clinical research study)

-ecoding !rocedures for b"inded tria"s

@aster randoiation "ist

&etained bio"ogica" s!ecien "og +nteri data ana"ysis re!ort/s

(Incorporate the follo$in! into the above list, but only if the clinicalresearch study $ill be conducted at e0ternal study sites)

Signed F-A For 15;2 Stateents of +nvestigator /i(e( for

+nvestigators res!onsib"e for the conduct of the c"inica" research studyat e4terna" study sites(

Financia" disc"osure inforation /i(e(, for +nvestigators res!onsib"e for

the conduct of the c"inica" research study at e4terna" study sites7 a"sofor a"" study site sub.investigators 'ho 'i"" be invo"ved in theadinistration of the study drugs andor the eva"uation of researchsub%ects i(e(, 'ho 'i"" contribute significant"y to the study dataB

Curricu"u vitae /i(e(, for +nvestigators res!onsib"e for the conduct of

the c"inica" research study at e4terna" study sites

Certificates of re6uired training7 e(g(, huan sub%ect !rotections, >ood

C"inica" Practice, etc( /i(e(, for +nvestigators res!onsib"e for the conductof the c"inica" research study at e4terna" study sites7 a"so for a"" studysite sub.investigators 'ho 'i"" be invo"ved in the adinistration of thestudy drugs andor the eva"uation of research sub%ects i(e(, 'ho 'i""

contribute significant"y to the study dataB isting of !rinted naessignatures /i(e(, for +nvestigators res!onsib"e

for the conduct of the c"inica" research study at e4terna" study sites7a"so for a"" study site sub.investigators 'ho 'i"" be invo"ved in theadinistration of the study drugs andor the eva"uation of researchsub%ects i(e(, 'ho 'i"" contribute significant"y to the study dataB

Co!ies of initia" and continuing +&< a!!rova" notifications /i(e(, for each

of the e4terna" study sites

ora" va"ue/srange/s for edica""aboratorytechnica" !rocedures

or tests inc"uded in the c"inica" !rotoco" /i(e(, for each of the e4terna"study sites

aboratory certification inforation /i(e(, for each of the e4terna" studysites

@onitoring visit re!orts /i(e(, for a"" e4terna" study sites

Co!ies of S!onsor.+nvestigator corres!ondence /inc"uding notifications

of safety inforation to +nvestigators res!onsib"e for the conduct of thec"inica" research study at e4terna" study sites


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9he S!onsor.+nvestigator 'i"" retain the s!ecified records and re!orts foru! to 2 years after the areting a!!"ication is a!!roved for theinvestigationa" drug7 or, if a areting a!!"ication is not subitted ora!!roved for the investigationa" drug, unti" 2 years after investigations

under the +- have been discontinued and the F-A so notified(

,/.Et$ic":

12.1 In"titutional Re%ie7 -oar# 'IR-( a))ro%al


9he S!onsor.+nvestigator 'i"" obtain, fro the University of Pittsburgh+nstitutiona" &evie' uide"ines on>ood C"inica" Practice /C>P(

+n the event that the University of Pittsburgh +&< re6uires, as a conditionof a!!rova", substantia" changes to a c"inica" !rotoco" subitted under anF-A.acce!ted +- a!!"ication, or in the event of the S!onsor.+nvestigator8s decision to odify the !revious"y acce!ted c"inica" !rotoco"

for a Phase 1 c"inica" study 9he S!onsor.+nvestigator 'i"" subit /i(e(,

in advance of i!"eenting the change a Protoco" Aendent to the+- describing any change to the Phase 1 c"inica" !rotoco" thatsignificant"y affects the safety of the sub%ects( For changes that do notaffect critica" safety assessents, the revisions to the c"inica" !rotoco"'i"" be addressed in the Annua" &e!ort to the +-(

for Phase 2 and 3 c"inica" studies 9he S!onsor.+nvestigator 'i""

subit /i(e(, in advance of i!"eenting the change a Protoco"

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Aendent to the +- describing any change to a Phase 2 or Phase 3!rotoco" that significant"y affects the safety of sub%ects, the sco!e ofthe investigation, or the scientific 6ua"ity of the study( E4a!"es ofPhase 2 and 3 c"inica" !rotoco" changes re6uiring the subission of aProtoco" Aendent inc"ude

o Any increase in drug dosage or duration of e4!osure of individua"

sub%ects to the investigationa" drug beyond that described in thecurrent !rotoco", or any significant increase in the nuber ofsub%ects under study(

o Any significant change in the design of the !rotoco" /such as the

addition or de"etion of a contro" grou!(

o 9he addition of a ne' test or !rocedure that is intended to i!rove

onitoring for, or reduce the ris of, a side effect or adverse event7

or the dro!!ing of a test intended to onitor the safety of theinvestigationa" drug(

12.2 Et$ical an# "cientific con#uct of t$e clinical re"earc$"tu#y


9he c"inica" research study 'i"" be conducted in accordance 'ith thecurrent +&


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consent !rocess 'i"" be docuented in the sub%ect8s case history( 9heS!onsor.+nvestigator 'i"" retain the origina" co!y of the signed inforedconsent for, and a co!y 'i"" be !rovided to the sub%ect, or to thesub%ect8s authoried re!resentative(

9he S!onsor.+nvestigator 'i"" ae certain that a!!ro!riate !rocesses and!rocedures are in !"ace to ensure that ongoing 6uestions and concerns ofenro""ed sub%ects are ade6uate"y addressed and that the sub%ects areinfored of any ne' inforation that ay affect their decision to continue!artici!ation in the c"inica" study( +n the event of substantia" changes tothe c"inica" study or the ris.to.benefit ratio of study !artici!ation, theS!onsor.+nvestigator 'i"" obtain the infored consent of enro""ed sub%ectsfor continued !artici!ation in the c"inica" study

,1.Stu#y Di"continuation Criteria:

,1., Di"continuation of in#i%i#ual re"earc$ "u0ect" 'referal"o to "ection" 4.,., an# ithdra$al of subects due to non-compliance'adherence) or section ?.@(>ithdra$al of subects due to adverse events) of the clinical protocol.

ddress the nature and timin! of any data that $ill continue to becollected from the $ithdra$n subects.

Specify if subects $ithdra$n from study participation due to thesecriteria $ill be replaced and, if so, the correspondin! procedures fortheir replacement.

,1./ S)on"or8In%e"ti&ator #i"continuation of t$e clinicalre"earc$ "tu#y

"escribe the discontinuation criteria or %stoppin! rules& for parts of theclinical research study, if applicable, or for the entire clinical researchstudy.

Specify, if applicable, that respective protocol modifications $ill besubmitted prospectively to the 3niversity of Pittsbur!h I67 and to the+" for discontinuation of parts of the clinical study.

Specify that the 3niversity of Pittsbur!h Institutional 6evie$ 7oard(I67) and the +" $ill be notified promptly of discontinuation of theentire clinical study.

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ddress, if applicable, the procedures for notifyin! enrolled subects andsub-investi!ators (and, if applicable, e0ternal study site Investi!ators) ofdiscontinuation of parts of the clinical research study# and for obtainin! theinformed consent of the subects for continued participation in this study.

ddress the procedures for notifyin! enrolled research subects and sub-investi!ators (and, if applicable, e0ternal site Investi!ators) ofdiscontinuation of the clinical research study# to include the types andtimin! of data that $ill be subse/uently collected from the enrolledsubects to ensure their safety

,2.Reference":

Provide references to the literature and data that are cited in the 7ac!round,6ationale, and other applicable sections of the clinical protocol.

In d Template Clinical Study Protocol

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