IINVESTIGATOR'S brochure and its articles

An IB is a comprehensive document that summarizes the clinical and non clinical details about an investigational product obtained during a drug trial

1. PRESENTED BY:- NAIBEDYA KUMAR
BRANCH:- M.PHARM, PHARMACEUTICS
REG. NO:- 2361611009
SUBJECT:-REGULATORY AFFAIRS
SUBJECT CODE:- MPH 104T
DATE OF PRESENTATION:-18/01/24
SCHOOL OF PHARMACEUTICAL SCIENCES
SHIKSHA ‘O’ ANUSANDHAN DEEMED TO BE UNIVERSITY
A Deemed to be University declared U/S 3 of the UGC Act, 1956
Khandagiri Square, Bhubaneswar 751030, Odisha, India
www.soauniversity.ac.in
INVESTIGATOR’S BROCHURE

2. INTRODUCTION:-
1.Investigatorbrochureisacollectionoftheclinicalandnon-clinicaldataonthe
investigationalproductsthatarerelevanttothestudyoftheproductinhuman
subjects.
2.IBisacomprehensivedocumentsummarizingtheinformationaboutthe
investigationalproductsobtainedduringclinicaltrials.
3.Theinformationshouldbepresentedinashort,simple,objective.
4.IBispreparedbythesponsorwhoalsocontrolsthedistributionofthe
document.
5.Thesponsorisresponsibleforensuringthatanup-to-dateIBismadeavailableto
theinvestigatorandinvestigatorsareresponsibleforprovidingtheup-to-dateIB
totheresponsibleIRB/IEC(InstitutionalReviewBoard/InstitutionalEthicsCommittee).

3. PURPOSE OF I.B:-
➢ItspurposeistoprovideinformationtotheInvestigatorsandothersinvolvedinthetrialsuchas
thedose,dosefrequency/interval,methodsofadministration:andsafetymonitoringprocedures.
IB contains Summary of Data and Guidance for the Investigator:
1.Providetheinvestigatorwithaclearunderstandingofthepossiblerisksandadversereactions,
detailsoftests,observations,andprecautionsthatmaybeneededforaclinicaltrial.
2.Theinformationshouldbebasedontheavailablephysical,chemical,pharmaceutical,
pharmacological,toxicological,andclinicalinformationontheinvestigationalproduct.
3.Itshouldalsoprovidetreatmentforpossibleoverdoseandadversedrugreactions.
4.TheIBshouldbereviewedannually.

4. GENERAL CONSIDERATION: -
1.Titlepage
➢Sponsor'sname:
➢Product:
➢ResearchNumber:
➢Name(s):Chemical,Generic(ifapproved)&TradeName(s).
➢EditionNumber:
➢ReleaseDate:
➢ReplacesPreviousEditionNumber:
➢Date
2.Confidentialitystatement:
➢ThesponsormayincludeastatementinstructingtheinvestigatortotreattheIBasaconfidentialdocumentforthe
soleinformationanduseoftheinvestigator’steamandtheIRB/IEC(InstitutionalReviewBoard/InstitutionalEthics
Committee).

6. Contents of IB:-
I.TableofContents
II.Summary
III.Introduction
IV.Physical,chemicalandpharmaceuticalproperties&andformulation
V.Nonclinicalstudies
VI.Effectonhumans
VII.SummaryofDataandGuidancefortheInvestigator

8. 2. Summary:-
▪Abriefsummary(preferablynotexceedingtwopages)shouldbegiven,highlightingthesignificantphysical,
chemical,pharmaceutical,pharmacological,toxicological,pharmacokinetic,metabolic,andclinicalinformation
availablethatisrelevanttothestageofclinicaldevelopmentoftheinvestigationalproduct.
3.Introduction:-
▪Containsthechemicalname(genericandtradenamewhenapproved),allAPIs,pharmacologicalclass,therationale
forperformingresearchoftheinvestigationalproducts,andtheanticipatedprophylactic,therapeutic,ordiagnostic
indication(s).
▪Finally,theintroductorystatementshouldprovidethegeneralapproachtobefollowedinevaluatingthe
investigationalproduct.
4.Physical,Chemical,andPharmaceuticalPropertiesandFormulation:-
▪Adescriptionshouldbeprovidedoftheinvestigationalproductsubstance(thechemicaland/orstructuralformula(e)),
andbriefsummaryshouldbegivenofthephysical,chemical,andpharmaceuticalproperties.Topermitappropriate
safetymeasurestobetakeninthecourseofthetrial,adescriptionoftheformulation(s)used.
▪Instructionsforthestorageandhandlingofthedosageform(s)shouldalsobegiven.
▪Anystructuralsimilaritiestootherknowncompoundsshouldbementioned.

9. 5. Nonclinical studies:-
Theinformationprovidedmayincludethe
following,asappropriate,ifknown/available:
▪Speciestested
▪Numberandsexofanimalsineachgroup
▪Unitdose
▪Doseinterval
▪Routeofadministration
▪Durationofdosing
▪Informationonsystemicdistribution
▪Durationofpost-exposurefollow-up
Results, including the following aspects:
▪Natureandfrequencyofpharmacologicalor
toxiceffects
▪Severityorintensityofpharmacologicalor
toxiceffects
▪Timetoonsetofeffects
▪Reversibilityofeffects
▪Durationofeffects
▪DoseresponseNonclinicalPharmacology
•The results of all relevant nonclinical pharmacology, toxicology, pharmacokinetic, and investigational product
metabolism studies should be provided in summary form.
•This summary should address the methodology used, the results, and a discussion of the relevance of the findings
to the investigated therapeutic and the possible unfavourable and unintended effects on humans

10. 5.1NonclinicalPharmacology:-
➢Asummaryofthepharmacologicalaspectsoftheinvestigationalproductand,itssignificant
metabolitesstudiedinanimals,shouldbeincluded.
➢Suchasummaryshouldincorporatestudiesthatassesspotentialtherapeuticactivity(e.g.,
efficacymodels,receptorbinding,andspecificity)aswellasthosethatassesssafety(e.g.,special
studiestoassesspharmacologicalactionsotherthantheintendedtherapeuticeffect).
5.2PharmacokineticsandProductMetabolisminAnimals:-
➢Asummaryofthepharmacokineticsandbiologicaltransformationanddisposition(gettinga
drugintoitsappropriatepositioninthebodyandinanappropriateconcentration)ofthe
investigationalproductinallspeciesstudiedshouldbegiven.
➢Absorptionandthelocalandsystemicbioavailabilityoftheinvestigationalproductandits
metabolites,andtheirrelationshiptothepharmacologicalandtoxicologicaleffectsinanimal
species.

11. 5.3Toxicology:-
➢Thestudyoftheadverseeffectsofchemicalsonanimalsisdescribedunderthefollowingheadingswhere
appropriate:-
➢Singledose
➢Repeateddose
➢Carcinogenicity
➢Special studies (e.g. irritancy and sensitization)
➢Reproductivetoxicity
➢Genotoxicity(mutagenicity)
➢6.EffectsonHumans:-
➢Athoroughdiscussionoftheknowneffectsoftheinvestigationalproduct(s)inhumansshouldbeprovided,
includinginformationon:-
▪Pharmacokinetics,metabolism,pharmacodynamics,dose-response,safety,efficacy,andotherpharmacological
activities.Wherepossible,asummaryofeachcompletedclinicaltrialshouldbeprovided.

12. 6.1PharmacokineticsandProductMetabolisminHumans:-
➢Asummaryofinformationonthepharmacokineticsoftheinvestigationalproductshouldbepresented,including
thefollowing:
▪Pharmacokinetics(includingmetabolism,asappropriate,andabsorption,plasmaproteinbinding,distribution,and
elimination).
▪Bioavailabilityoftheinvestigationalproductusingareferencedosageform.
▪Populationsubgroups(e.g.,gender,age,andimpairedorganfunction).
▪Interactions(e.g.,product-productinteractionsandeffectsoffood).
▪Otherpharmacokineticdata(e.g.,resultsofpopulationstudiesperformedwithinaclinicaltrial(s).
6.2SafetyandEfficacy:-
➢Asummaryofinformationshouldbeprovidedabouttheinvestigationalproduct'ssafety,pharmacodynamics,
efficacy,anddoseresponsethatwereobtainedfromprecedingtrialsinhumansubjects.
➢Importantdifferencesinadversedrugreactionpatterns/incidencesacrossindicationsorsubgroupsshouldbe
discussed.
➢TheIBshouldprovideadescriptionofthepossiblerisksandadversedrugreactionstobeanticipatedonthebasis
ofpriorexperienceswiththeproductunderinvestigationandwithrelatedproducts.

13. 6.3MarketingExperience:-
➢TheIBshouldidentifycountrieswheretheinvestigationalproducthasbeenmarketedorapproved.
➢Anysignificantinformationarisingfromthemarketeduseshouldbesummarized(e.g.,formulations,
dosages,routesofadministration,andadverseproductreactions).
➢TheIBshouldalsoidentifyallthecountrieswheretheinvestigationalproductdidnotreceive
approval/registrationformarketingorwaswithdrawnfrommarketing/registration.
7.SummaryofDataandGuidancefortheInvestigator:-
➢Thissectionshouldprovideanoveralldiscussionofthenonclinicalandclinicaldataandshould
summarizetheinformationfromvarioussourcesondifferentaspectsoftheinvestigationalproduct,
whereverpossible.
➢Inthisway,theinvestigatorcanbeprovidedwiththemostinformativeinterpretationoftheavailable
dataandwithanassessmentoftheimplicationsoftheinformationforfutureclinicaltrials.
➢Whereappropriate,thepublishedreportsonrelatedproductsshouldbediscussed.
➢Thiscouldhelptheinvestigatortoanticipateadversedrugreactionsorotherproblemsinclinicaltrials

15. ARTICLE1
Preclinicalefficacystudiesininvestigatorbrochures:Dotheyenablerisk-benefitassessment?:-
WieschowskiS.etal.,intheyear2019Preparedameta-researcharticleonPreclinicalefficacystudiesininvestigatorbrochures.
Tomakeaclinicaltrialethical,regulatoryagenciesandinstitutionalreviewboardshavetojudgewhetherthetrial-relatedbenefits
(theknowledgegain)outweighthetrial-inherentrisks.Forearly-phasehumanresearch,theserisk–benefitassessmentsareoften
basedonevidencefrompreclinicalanimalstudiesreportedinso-called“investigatorbrochures.”
➢Objective:
Thisanalysisaimstoinvestigatewhetherpreclinicalefficacystudiesreportedininvestigatorbrochuresprovidesufficient
informationtoenableacomprehensiverisk-benefitassessmentforearly-phaseclinicaltrials.
➢Methods:
▪Datasource:Analyzearepresentativesampleofinvestigatorbrochuresforinvestigationalnewdrugs(INDs)submittedto
regulatoryagencies.
▪Studydesign:Thedesignisrobustandrelevanttotheclinicaltrial(e.g.,blinding,randomization,appropriatecontrols)
▪Methodology:Themethodsareclearlydescribedandreproducible(e.g.,samplesize,outcomemeasures,statistical
analysis)
▪Results:Theresultswerepresentedcomprehensivelyandtransparently(e.g.,dataavailability,effectsize,reportingof
negativefindings)

16. ▪Analysis:
Quantitatively:Calculatingtheproportionofbrochuresmeetingspecificcriteria.
Qualitatively:Analyzingthenatureandseverityofreportingdeficiencies.
➢Results:
▪Preliminaryfindings:Existingresearchsuggests:-
▪Amajorityofbrochureslacksufficientinformationforproperrisk-benefitassessment.
▪Reportingoftenlackscrucialdetailsaboutstudydesign,methodology,andresults.
▪Negativefindingsandlimitationsarerarelyreportedsystematically.
▪Expectedoutcomes:Thisanalysiswillfurtherquantifythesefindingsandidentifyspecificareasforimprovement
➢Conclusion:
▪Preclinical efficacy studies in investigator brochures currently fall short of enabling a comprehensive risk-benefit
assessment for early-phase clinical trials. Addressing these shortcomings through improved reporting, training, and
regulatory oversight is crucial to ensure the ethical and efficient development of new drugs.

18. ARTICLE2
InvestigatorbrochuresforphaseI/IItrialsthatlackinformationontherobustnessofpreclinicalsafety
studies:-
SorenSievers.etal.,intheyear2020preparedanarticleoninvestigatorbrochuresforphaseI/IItrialsthatlackinformationonthe
robustnessofpreclinicalsafetystudies.Thisrelieslargelyonpreclinicalanimalstudiesaddressingthesafetyandefficacyoftreatments.
ThesestudiesarereportedinanInvestigator’sBrochure(IB)toinformethicsreviewboardsandregulatoryauthorities.Thestudy
investigatedtheextent,reportingqualityandaccessibilityofpreclinicalsafetystudies(PCSSs)compiledinIBs.
➢Objective:
ThisanalysisaimstoinvestigatetheextenttowhichinvestigatorbrochuresforphaseI/IIclinicaltrialslackinformationonthe
robustnessofpreclinicalsafetystudies.
➢Methods:
▪Datasource:AnalyzingarepresentativesampleofinvestigatorbrochuresforphaseI/IItrialsapprovedbyaspecificregulatory
agencyorobtainedfromaresearchinstitution.
▪Studydesign:Thedesignappropriatetoassessthespecificsafetyconcernsofthedrug(e.g.,adequatespeciesselection,dose
range,relevantendpoints).
▪Methodology:ThemethodssoundandadherenttoGoodLaboratoryPractice(GLP)guidelines(e.g.,randomization,blinding,
qualitycontrol).
▪Reporting:Thebrochureprovidessufficientdetailsaboutthestudyconduct,analysis,andresults(e.g.,samplesizes,statistical
methods,adverseeventreporting).

19. ▪Analysis:
Quantitatively:Calculatingtheproportionofbrochuresmeetingspecificrobustnesscriteria.
Qualitatively:Analyzingthenatureandfrequencyofmissingorinadequatelyreportedinformation.
➢Results:
Preliminaryfindings:Existingresearchsuggests:
▪Asignificantproportionofbrochureslackkeyinformationabouttherobustnessofpreclinicalsafetystudies.
▪Missingdetailsoftenpertaintostudydesign,methodology,andreportingoflimitations.
▪Inadequateinformationlimitstheabilitytofullyassesspotentialsafetyrisksforparticipantsinclinicaltrials.
▪Expectedoutcomes:Thisanalysiswillfurtherquantifytheextentofmissinginformationandidentifyspecificareaswhere
robustnessreportingislacking.
➢Conclusion:
▪Investigator brochures for phase I/II trials often lack critical information about the robustness of preclinical safety
studies. This gap in reporting hinders the ability to make informed decisions about the safety of new drugs and the
ethics of conducting early-phase trials. Addressing this issue through improved reporting standards, training, and
regulatory oversight is crucial to ensure the safety of participants and the responsible development of new drug

20. REFERENCE:-
➢Wieschowski S, Chin WW, Federico C, Sievers S, Kimmelman J, Stretch D. Preclinical
efficacy studies in investigator brochures: do they enable risk–benefit assessment?. PLoS
biology. 2018 Apr 5;16(4):e2004879.
➢Sievers S, Wieschowski S, Strech D. Investigator brochures for phase I/II trials lack
information on the robustness of preclinical safety studies. British Journal of Clinical
Pharmacology. 2021 Jul;87(7):2723-31.