Topic: The Trial Master File/Investigator File
Please write a 4-page (double spaced) paper (high level masters paper) answering the following two questions in detail:
1. What are the essential documents that need to be gathered and maintained?
2. Explain GDP, ALCOA-C, and source documents in the context of clinical research.
**Please utilize the following attached PDF’s & YouTube videos, which is requirement of the paper**
https://www.youtube.com/watch?v=dwwpr_ynmo8
https://www.youtube.com/watch?v=jQlk7WXno40
https://www.youtube.com/watch?v=27k5i1lqNlQ&t=2s
https://www.youtube.com/watch?v=5bLgd-ln0BY
https://www.youtube.com/watch?v=7miYVoZIemE
someTitle 2 Products,Protocols,andPretrial Preparation Pretrialpreparationsetsthestageformanagingthemanycomplexfactorsthatariseduring clinical trials. Additionally, the process of pretrial preparation offers research sites the opportunityforprocessconsistency,economiesofscale,andtechnologyintegrationacross multiplestudies.Inthischapterandthroughoutthebook,wewillbereferringtostandard operating procedures (SOPs), checklists, forms, and other tools that offer research sites opportunitiesforefficiency. Inthischapter,weinitiateourdiscussionbyreviewingdrugdevelopmentandmedical devicedevelopmentprocessesas they relate to theFoodandDrugAdministration (FDA) approval process and clinical research conducted at the site. Then, we explore sponsor researchsiteselection,confidentialdisclosureagreements(CDAs),clinicaltrialfeasibility, institutionalreviewboard(IRB)applications/submissions,andessentialdocuments. DRUGANDMEDICALDEVICEDEVELOPMENT Althoughdrugsandmedicaldeviceshavemanycommonalitiesintheirpathstoapproval, therequirementsforclinical trials tosupport theapprovalprocessvarysignificantlywith medicaldevices.Notallmedicaldevicesneedtoundergocontrolledclinicaltrialstogain regulatoryapproval.Inthefollowingpages,wewillreviewtheregulatorypathsfordrugs andmedicaldeviceswhilefocusingontheclinicaltrialaspectoftheprocess. INVESTIGATIONALNEWDRUGAPPLICATIONS Whenthesponsorofaninvestigationaldrugorbiologichasgatheredenoughdatathrough preclinical testing to determine that the investigational product exhibits pharmacological activitythatwarrantscommercialdevelopmentandthatitisreasonablysafeforinitialuse in humans, the sponsormust submit an application to the FDA to request permission to beginclinical trials.Thisapplication is referred toasanInvestigationalNewDrug(IND) application,which is technicallyanapplication to theFDAtorequestanexemptionfrom currentFederallawthatrequiresthatadrugbepartofanapprovedmarketingapplication before itcanbe transportedacrossstateboundaries.Theexemptionallowsthesponsor to shipinvestigationaldrugtoclinicalinvestigatorsinmultiplestates. Once the sponsor submits an IND application, the FDA has 30 days to review the Pfeiffer, JoAnn, and Cris Wells. A Practical Guide to Managing Clinical Trials, Taylor & Francis Group, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/wfu/detail.action?docID=5477040. Created from wfu on 2022-07-04 23:14:38. C op yr ig ht © 2 01 7. T ay lo r & F ra nc is G ro up . A ll rig ht s re se rv ed . applicationforsafetyconcernsbefore thesponsorcanbeginclinical trials. If thesponsor hasnotreceivedcommunicationfromtheFDAwithinthe30days,thesponsormaybegin clinicaltrialsasitproposedintheapplication.However,mostsponsorsconfirmthat they canmoveforwardbycontactingtheFDAiftheyhavenotreceivednoticewithinthe30-day period. Clinical trials conducted under an IND are typically categorized into phases, which impliesthattheyareconductedconsecutively.However,inpractice,thesephasesarevery fluid,theycanoverlap,andtrialsinonephasecanbeconductedwithtrialsinotherphases. Asanexample, it isnotunusual for a clinical trial tobeclassifiedas aphase1/2, study where thepurpose is todetermineefficacyand toxicity froma latephase1study intoan earlyphase2study.Thecommonphasesandtheirdescriptionsfollow: Phase0:OtherwiseknownasanExploratoryIND,phase0studiesoffersponsorsa means toexploremoreefficientdevelopmentof investigationaldrugsbyallowing testingof small amounts of an investigational drugover a very short period (less than7days) inhumansubjects.Unliketheotherphases, thereisnotherapeuticor diagnosticintentforthistypeofstudy. Phase1:Thepurposeofphase1studiesistocollectinformationonthesafetyand appropriatedosageforaninvestigationaldrug.Phase1researchersexaminehowthe investigational drug works in the body, evaluate the side effects associated with dosage escalation, and start to collect information about effectiveness. Typically, thesetypesofstudiesareshortinduration(severalmonthsinlength)andinclude20 to80healthyvolunteersassubjects,unlesstheinvestigationaldrugisintendedfor the use of cancer patients. In the cancer patient population, phase 1 studies are conductedwithin thegroupofpatients suffering from the typeofdisease, suchas liver cancer or glioblastoma. Phase 1a studies are usually single ascending dose studies,whereasphase1b studiesareusuallymultipleascendingdose studies,but thereisvariabilityinthesedescriptionsacrossresearchsitesandinvestigators. Phase2:Phase2studiesincludeseveralhundredhumanresearchsubjectswhoare sufferingfromthediseaseorconditionforwhich the investigationaldrug isbeing developed,and thestudieshaveadurationofup to2years.Thesestudiesprovide information on the safety and side effects of the investigational drug but, are not largeenough tobestatisticallysignificant in regard towhether the investigational drugwillbeeffectiveorbeneficialtothelargerintendedtherapeuticaudience. Phase3:Oftenknownaspivotalstudies,phase3studiesaredesignedtodemonstrate whether or not an investigational product offers a benefit to a specific population that has a disease or condition. These studies often run 1 to 4 years and include Pfeiffer, JoAnn, and Cris Wells. A Practical Guide to Managing Clinical Trials, Taylor & Francis Group, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/wfu/detail.action?docID=5477040. Created from wfu on 2022-07-04 23:14:38. C op yr ig ht © 2 01 7. T ay lo r & F ra nc is G ro up . A ll rig ht s re se rv ed . hundredstothousandsofparticipants.Becauseofthelargerclinicaltrialpopulation, phase3 studies provide large amounts of data on safety and efficacy, specifically relatedtothepopulationbeingstudied. Phase4:Otherwiseknownaspostmarketingstudies,thesestudiestakeplaceafteran investigational drug has been approved andmarketed.These studies are generally conductedtomonitorlong-termsafetyandefficacyunder“real-life”situationsand includethousandsofparticipants. Attheresearchsite,eachphaseofaclinicaltrialhasuniquecharacteristicsthatshould beconsideredduringpretrialpreparation.Phase0trialsareveryspecializedandtypically requireoversightbyaclinical investigatoraswellasa translationalscientist (canbeone andthesame).Additionally,theresearchsiteneedsaccesstolaboratoryandothermedical imaging or testing facilities and 24-hour care. Similarly, phase 1 studies are short in duration,areveryintense,andrequiredirectoversightbyaninvestigator.Phase1studies requirefrequenttestsandmonitoring,whichinturnrequireahighratioofstaff(research coordinators and medical professionals) to research subject. Phase 1 research sites generally have specialty (calibrated) medical equipment, temperature- and humidity- controlled drug storage, on-site blood chemistry processing, laboratories, infusion chairs, and inpatient-stylehospital beds.Although fewer subjects are required for these typesof studies, it may be difficult to recruit “healthy” research subjects, depending on the definitionof“healthy”andonthedemographicofthepopulationbeingrecruited. Unlikephase1studies,phase2studiesdonottypicallyrequireadedicatedunitthatis monitoredfull time,buttheyareusuallyconductedwithinahospitaloroutpatientsetting where subjects are (already) being treated for their condition or illness. These studies requiresafetyandeffectivenessoversight,butthestaff/clinicaltrialsubjectratioisnotas highasinphase1studies.Subjectsarerecruitedthroughphysicianreferral,throughpatient advocacy or support groups, and through foundations such as the Susan G. Komen Foundation. Phase3studiesareoftenconductedinoutpatientsettingsandincludelargerandmore diverse populations than phase 2 studies. Because phase 3 studies are randomized and blinded(meaningthatsubjectsareassignedtodifferentarmsofastudybychanceanddo notknowwhethertheyareassignedtoaninvestigationalproduct),theyrequireadedicated clinical trial coordinator who works with the research pharmacist to ensure accurate distribution and documentation of the investigational product. Additionally, recruitment andscreeningofsubjectscanbeparticularlyonerous,requiringphysicianreferralnetworks, dedicatedrecruitmentspecialists,andadvertisingfunds. Phase 4 studies are postmarketing studies. It is important to remember that they are Pfeiffer, JoAnn, and Cris Wells. A Practical Guide to Managing Clinical Trials, Taylor & Francis Group, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/wfu/detail.action?docID=5477040. Created from wfu on 2022-07-04 23:14:38. C op yr ig ht © 2 01 7. T ay lo r & F ra nc is G ro up . A ll rig ht s re se rv ed . conducted after the FDA has approved a drug or biologic to be sold for an indicated treatment in a specifiedpopulation.Thismeans that theNewDrugApplicationhas been approvedbytheCenterforDrugEvaluationandResearchforinvestigationaldrugsorthata biologic has been approved through theBiologics LicenseApplication by theCenter for BiologicsEvaluationandResearch.Becausethesetypesofstudieshaveabroaderarrayof clinical trial designs and have different goals from premarketing studies, there may be confusionontheactualpurposesofaphase4clinicaltrial.Dependingontheinvestigator’s interestandpreference,thesestudiesmaynotbedesirableforsomeresearchsites. INVESTIGATIONALDEVICEEXEMPTIONS Medicaldevicesaredividedintothreecategoriesbasedonthelevelofrisktousers.They arethengroupedaccordingtothemedicalareaofuse.ClassIdevicesofferminimalriskto auserandfallunderGeneralControls,thebaselinerequirementsthatapplytoallmedical devices.AnexampleofaClassIdeviceisatonguedepressor.ClassIIandClassIIIdevices aremorecomplexdevicesandincludemoderateandhighrisk,respectively. Class II devices, such as infusion pumps,must followSpecialControls and labeling, mandatory performance standards, and postmarketing surveillance. Class III devices support or sustain human lives and have the strictest guidelines because they pose the greatestrisk.BesidesfollowingtheClassIandClassIIguidelines,ClassIIIdevicesmust alsobepremarketapprovedbytheFDA. Dependingonan initialassessmentof risk to theuserby themedicaldevicesponsor, devices are classified as significant risk (SR) or nonsignificant risk (NSR) devices. If a deviceiscategorizedasSR(mostClassIIIdevices), it issubject toclinical investigation underInvestigationalDeviceExemption(IDE)regulations,andifitisanNSRdevice,itis subjecttoabbreviatedIDEregulations. AnIDEissimilartoanINDinthatitallowsaninvestigationaldevicetobeusedina clinicaltrialinordertocollectsafetyandeffectivenessdata.Ifadeviceisclassifiedasan SRdevice,clinical studiescannotbeginuntil the IDE isapprovedby theFDAandbyan IRB. The clinical trial sponsor and investigator must comply with the full list of IDE requirementsin21C.F.R.Part812. IfadeviceisclassifiedasanNSRdevice,thesponsordoesnotneedtosubmitanIDEto theFDA;however,thesponsormustfollowtheabbreviatedrequirementsofanIDErelating to labeling, IRB approval, informed consent, monitoring, records and reports, and promotion.Rather thanFDAapproval, the IRBservesas theFDA’sproxy for initial and continuingreviewoftheNSRmedicaldevices. Manymedicaldevicecompaniesaresmallcompanieswithlimitedfundingtoconduct Pfeiffer, JoAnn, and Cris Wells. A Practical Guide to Managing Clinical Trials, Taylor & Francis Group, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/wfu/detail.action?docID=5477040. Created from wfu on 2022-07-04 23:14:38. C op yr ig ht © 2 01 7. T ay lo r & F ra nc is G ro up . A ll rig ht s re se rv ed . clinical research. However, this fact may or may not be a consideration for particular researchsitesthatutilizedevicetrialstomeettheneedsoftheirpatientsorclients. Like drug trials,medical device studies are conducted to demonstrate the safety and effectivenessof thedevicebeforemarketing,validatingpreviousbenchoranimal testing. Pilotstudiesareusuallyconductedatsingleresearchsiteswithlimitednumbersofsubjects toallow thesponsor tocollectdataonaseriesofpatientoutcomes thatcontribute to the selectionof endpoints forpivotal trials.Conversely,pivotal trials aremulticenter studies that focus on the safety and effectiveness of a device, whichwill eventually be used in supportof thefinishedproduct’s label.Thestudiesareusuallyshort indurationandmay requirededicatedspace,especiallyiftheinvestigationaldeviceistobeimplanted. SPONSORSELECTIONOFTHERESEARCHSITES Thecostofconductingclinicaltrialsisamajorpartofthedrugdevelopmentprocessand budget, influencing sponsors to seek investigators and research sites that can recruit participants and conduct studies in an efficient, economical, ethical, and timelymanner. Sponsors seek research sites that have adequate and qualified staff and have the facility/spaceandequipment resourcesnecessary toproperlyconduct theclinical trial. In addition,sponsorsconsiderthefollowing: Theresearchsite’shistoryofmeetingrecruitmentgoalsinsimilarstudies. Compliance with applicable Codes of Federal Regulations and International ConferenceonHarmonisation(ICH)GoodClinicalPractices(GCPs). Investigator’sinterestintheclinicaltrial. Ahistoryoftheresearchsitebeingabletomeetclinicaltrialdeadlines. Itisalsoimportanttothesponsorthataresearchsiteisabletoinitiateaclinicaltrialin a timely manner. A research site that is not able to start a clinical trial quickly (IRB processes, contracting, and recruitment) delays the clinical trial, ultimately costing the sponsortimeandmoney. Financialmotivesarenottheonlyconsiderationinasponsor’sselectionofasite.Two key sponsor responsibilities according to 21 C.F.R. Part 312.50 (FDA IND General ResponsibilitiesofSponsors,2015)areselectingqualifiedinvestigatorstoconductclinical trials and ensuring that the clinical trial(s) are conducted in accordancewith the general protocolandprotocolscontainedintheINDapplication.Thesetworesponsibilitiesarealso found in 21 C.F.R. Part 812.40 (FDA IDE General Responsibilities of sponsors, 2015). Additionally, the ICHE6GCPGuidelinesnote that “investigators shouldbequalifiedby Pfeiffer, JoAnn, and Cris Wells. A Practical Guide to Managing Clinical Trials, Taylor & Francis Group, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/wfu/detail.action?docID=5477040. Created from wfu on 2022-07-04 23:14:38. C op yr ig ht © 2 01 7. T ay lo r & F ra nc is G ro up . A ll rig ht s re se rv ed . trainingandexperienceandshouldhaveadequateresourcestoproperlyconductthetrialfor which the investigator is selected” (ICH,1996,Section5.6.1).Because thesponsor is the author/initiator of a clinical trial, it has the discretion to determine what qualifications, training,education,andexperiencearerequiredofaninvestigator, theresearchteam,and facility(U.S.DepartmentofHealthandHumanServices,FDA,2010,p.6). As part of its due diligence, sponsors examine multiple research site metrics to determinewhetherornottoselectaresearchsite.Thesemetricsmayincludethefollowing: 1. Adequateandqualifiedstaff:Doestheresearchsitehaveadequateandqualifiedstaff to conduct the clinical trial? This includes the principal investigator, clinical trial coordinator(s),andsupportstaffneededforthetrial(forexample,labtechniciansto analyzeurine samples, a researchpharmacist tomix investigationaldrug,oradata entryperson).Iftheclinicaltrialincludesproceduressuchasx-raysorbiopsies,the sponsor must be assured that the research site has access to vendors qualified to performtheproceduresandtheabilitytodotheproceduresinatimelymanner.The sponsorisresponsibleforensuringthattheresearchstaffarequalifiedandhavenot been barred by the FDA from conducting clinical trials as discussed inChapter 1. This information assists the sponsor in avoiding the use of unqualified or barred investigatorsthatcouldimpactthereliabilityandvalidityoftheclinicaltrialdata.It alsoensuresthattheinvestigatorhasstaffthatsheorhecandedicatetotheclinical trialtoensurethattheclinicaltrialisgiventheattentionneededtoassuresuccessful completionoftheclinicaltrial.TheICH(1996)statesthat“Theinvestigatorshould haveavailableanadequatenumberofqualifiedstaffandadequate facilities for the foreseendurationofthetrialtoconductthetrialproperlyandsafely”(Section4.2.3). 2. Adequate spaceand facilities:Does the research sitehaveadequate space, required facilities, andequipment toproperly conduct the clinical trial?Space includes safe and secure storage for the investigational product and clinical trial binders, a laboratory for tests such as urinalysis, appropriate exam rooms, waiting area, and appropriate office space. The research site must have the necessary general equipment,suchasstethoscopes,electrocardiogrammachines,andscales,toconduct theclinicaltrialproceduresandappropriateofficeequipmentsuchascomputers,fax machines, and telephones. In some cases, the sponsor will require equipment calibration recordsandequipmentmaintenance records.Some trials require special facilities/equipment such as an area for IV infusions, beds, and the ability to accommodateasubjectovernightorforothertimeframes.Sponsorsgenerallysupply anyspecializedequipmentrequiredforaclinicaltrial,forexample, infusionpumps orelectronicclinicaltrialsmanagementsoftware.Inaddition,thesponsorevaluates Pfeiffer, JoAnn, and Cris Wells. A Practical Guide to Managing Clinical Trials, Taylor & Francis Group, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/wfu/detail.action?docID=5477040. Created from wfu on 2022-07-04 23:14:38. C op yr ig ht © 2 01 7. T ay lo r & F ra nc is G ro up . A ll rig ht s re se rv ed . sharedspaces(examrooms,lab,etc.)andthenumberofstudies,subjects,andvisits that occur in the space to determine that the space is not overused and will be availableasneededforclinicaltrialvisits. 3. Clinical trial population: Does the investigator/research site have access to the clinicaltrialpopulation?Itdoesnotmatterhowgoodorefficientaresearchsiteisif theresearchteamcannotrecruitsubjectsfortheclinicaltrial.Theresearchteammust demonstrate its ability to recruit the required population in a timely fashion by havingasolid recruitmentplan.Thisplanmight targetpatientdatabases, referring physiciansandclinics,orrecruitmentmaterialstargetingthegeneralpopulation. 4. Support: Organization/department support is critical to the success of the investigator/researchsiteandtheclinicaltrial.Thesponsorneedsassurancethatthe key stakeholders, including upper management within the organization, are supportive of research and that the institution embraces a culture that includes clinical research. Without support, resources needed for research may not be available or limited, and recruitment of subjects may not be an organizational priority. 5. Currentresearchsiteobligations:Researchsitesthatconductmultiplestudiesrunthe riskofhavingcompetitivestudiesthatrequirethesameclinicaltrialpopulation.The sponsor needs assurance that the research team (including the investigator) can effectively manage its current work load as well as add another clinical trial. A sponsorwill be hesitant to place a clinical trial at a research site that has current activestudies thatare recruiting thesamepopulationas thenewclinical trial—this placesthetrialinacompetitivepositionagainstothertrials.Theresearchteammay overcome this obstacle if it has