RegulatoryRegulatory

Clinical TrialsClinical Trials

Clinical TrialsClinical Trials

Definition: research studies to find ways to Definition: research studies to find ways to improve healthimprove health

Each trial tries to answer scientific questionsEach trial tries to answer scientific questions Types of trialsTypes of trials

– Treatment trialsTreatment trials: test new treatments (new : test new treatments (new drug)drug)

– Prevention trialsPrevention trials: test new approaches to : test new approaches to prevent illness (vaccines)prevent illness (vaccines)

– Screening trialsScreening trials: test new methods (new test : test new methods (new test method)method)

– Quality of Life trialsQuality of Life trials: (supportive care) test for : (supportive care) test for ways to improve comfort and quality of lifeways to improve comfort and quality of life

Pre Clinical TrialsPre Clinical Trials

Performed on Performed on animalsanimals– Try to use animal model which most Try to use animal model which most

closely relates to human subjectclosely relates to human subject i.e. pigs may be used to study effects on skini.e. pigs may be used to study effects on skin

Performed to Performed to predict potential predict potential toxic effects on humanstoxic effects on humans– Minimize the risk of harm during clinical Minimize the risk of harm during clinical

trialtrial

Clinical InvestigationClinical Investigation

Definition: any experiment that Definition: any experiment that involves a test article and one or involves a test article and one or more human subjects and that is more human subjects and that is either subject to requirements for either subject to requirements for submission to FDA or is not submission to FDA or is not subject for submission but results subject for submission but results are intended to be submitted are intended to be submitted later.later.

Clinical Trial: why do Clinical Trial: why do it?it? To understand if the drug or To understand if the drug or

device does what it claims to do device does what it claims to do (efficacy)(efficacy)

To ensure safety to publicTo ensure safety to public To ensure safety to participantsTo ensure safety to participants

Clinical Trial: Who Clinical Trial: Who oversees?oversees? FDA establishes guidelines for FDA establishes guidelines for

clinical trialsclinical trials– 21CFR50: Title 21 Section 50 of 21CFR50: Title 21 Section 50 of

Code of Federal RegulationsCode of Federal Regulations

Regulatory DepartmentRegulatory Department– Within any organization this group Within any organization this group

oversees the actual clinical trialoversees the actual clinical trial

Why did the FDA need Why did the FDA need to establish to establish guidelines?guidelines? To ensure To ensure patients knew they were patients knew they were

participatingparticipating– Informed consent: Informed consent: was not always was not always

obtainedobtained– HIPAA came on board to protect the patient’s HIPAA came on board to protect the patient’s

privacyprivacy To ensure To ensure guidelines were in place for guidelines were in place for

controllingcontrolling the drug which was being the drug which was being investigatedinvestigated– Accountability; prevent abuses of drugs and Accountability; prevent abuses of drugs and

devicesdevices

Informed ConsentInformed Consent

Written documentWritten document Outlines the following:Outlines the following:

– Purpose and method of the studyPurpose and method of the study– Alternative methods of treatmentAlternative methods of treatment– Benefits and Risks of participationBenefits and Risks of participation– Right to refuse or withdraw from studyRight to refuse or withdraw from study

Does Does notnot include the right to see the include the right to see the results of the studyresults of the study

International International GuidelinesGuidelines ICH: International Conference on ICH: International Conference on

Harmonization….Harmonization….– Regulatory authorities in Europe, Japan, Regulatory authorities in Europe, Japan,

and US got together to establish and US got together to establish guidelines for clinical trials and product guidelines for clinical trials and product registrationregistration

Declaration of HelsinkiDeclaration of Helsinki– World Medical AssociationWorld Medical Association– 11stst adopted in 1964 adopted in 1964

Phases of Clinical Phases of Clinical TrialsTrials

Phase 1Phase 1: small number of patients, : small number of patients, (10-20)(10-20)

– Can take 9-18 months to completeCan take 9-18 months to complete– May continue with animal studies for long term dataMay continue with animal studies for long term data

Phase 2Phase 2: continues to test safety and evaluates how well : continues to test safety and evaluates how well the new drug is working. More patients enrolled the new drug is working. More patients enrolled (100-300)(100-300)

– May take 1-2 years to completeMay take 1-2 years to complete Phase 3Phase 3: most extensive study,1-3 years: most extensive study,1-3 years

– Fully assess safety and effectiveness of drugFully assess safety and effectiveness of drug– 100-1000 patients involved, diverse group, multiple sites100-1000 patients involved, diverse group, multiple sites– May compare old and new drug treatmentsMay compare old and new drug treatments– Evaluating side effects Evaluating side effects

Phase 4Phase 4: long term side effects and effectiveness: long term side effects and effectiveness

Participants in clinical Participants in clinical trialstrials InvestigatorInvestigator SponsorSponsor Sponsor InvestigatorSponsor Investigator Human SubjectHuman Subject InstitutionInstitution Institution Review BoardInstitution Review Board

InvestigatorInvestigator

Individual who actually Individual who actually conducts the conducts the clinical investigationclinical investigation or is the or is the leader of the team conducting the trialleader of the team conducting the trial

Main person Main person responsible for the responsible for the safety of the human subjectsafety of the human subject participating in the studyparticipating in the study– however, all healthcare workers are however, all healthcare workers are

responsible for protecting the human responsible for protecting the human subjectssubjects Nurse, investigator, IRB, etc.Nurse, investigator, IRB, etc.

Sponsor and Sponsor Sponsor and Sponsor InvestigatorInvestigator

SponsorSponsor: person who : person who initiates a initiates a clinical investigationclinical investigation, but does , but does not actually conduct the not actually conduct the investigationinvestigation

Sponsor Investigator: person who Sponsor Investigator: person who both initiates AND actually both initiates AND actually conducts the clinical investigationconducts the clinical investigation

Human Subject and Human Subject and InstitutionInstitution Human participating in the clinical Human participating in the clinical

investigationinvestigation

InstitutionInstitution: any public or private : any public or private entity or facility. Typically the entity or facility. Typically the facility where the clinical facility where the clinical investigation is being conductedinvestigation is being conducted

Institutional Review Institutional Review BoardBoard

Definition: any board, committee or Definition: any board, committee or group formally designated by an group formally designated by an institution to review biomedical institution to review biomedical research involving human subjectsresearch involving human subjects

IRB approval MUST be obtained IRB approval MUST be obtained before an investigator can begin a before an investigator can begin a studystudy

Institutional Review Institutional Review BoardBoard Usually comprised of medical and Usually comprised of medical and

lay persons lay persons (at least 5 members, (at least 5 members, no conflict no conflict of interestof interest))

Established to Established to protectprotect the human the human subjects and ensure fair enrollmentsubjects and ensure fair enrollment

Review and Review and Approve Informed Approve Informed ConsentConsent

Conduct periodic reviews to ensure Conduct periodic reviews to ensure integrityintegrity of the study of the study

When is IRB not When is IRB not required?required? Studies for cosmeticsStudies for cosmetics Studies for taste of foodsStudies for taste of foods Studies for veterinary useStudies for veterinary use

New devices (drugs, reagents or New devices (drugs, reagents or hardware such as pacemakers, hardware such as pacemakers, artificial joints) artificial joints) requirerequire IRB IRB

Clinical Trial Data Clinical Trial Data AnalysisAnalysis

Data analyzed by Statistics or Data analyzed by Statistics or Biostatistics groupBiostatistics group

Use well defined, accepted and pre-Use well defined, accepted and pre-determined data analysis formulas and determined data analysis formulas and methods.methods.– Looking for levels of significance 99% still Looking for levels of significance 99% still

means 1% error possible of 1/100 (0.01).means 1% error possible of 1/100 (0.01). Is that good enough?Is that good enough? How do you balance the data with the delay in How do you balance the data with the delay in

releasing a product?releasing a product? OutlierOutlier: data point outside of the average : data point outside of the average

range and is usually larger or smaller than range and is usually larger or smaller than the rest of the pointsthe rest of the points

Clinical Trial Data Clinical Trial Data AnalysisAnalysis INCLUSION/EXCLUSION CRITERIA: INCLUSION/EXCLUSION CRITERIA: The The

medical or social standards determining medical or social standards determining whether a person may or may not be whether a person may or may not be allowed to enter a clinical trial. allowed to enter a clinical trial. These These criteria are based on such factors as age, criteria are based on such factors as age, gender, the type and stage of a disease, gender, the type and stage of a disease, previous treatment history, and other previous treatment history, and other medical conditionsmedical conditions. It is important to note . It is important to note that that inclusion and exclusion criteria are not inclusion and exclusion criteria are not used to reject people personally, but rather used to reject people personally, but rather to identify appropriate participants and to identify appropriate participants and keep them safekeep them safe..

Single and Double Single and Double Blinded StudyBlinded Study Single-Blind studySingle-Blind study: clinical trial : clinical trial

study in which the study in which the human subjects human subjects do not know if they are receiving do not know if they are receiving the active product or a placebo.the active product or a placebo.

Double-Blind studyDouble-Blind study: study in which : study in which neither the subject nor the neither the subject nor the investigator knows the investigator knows the treatment assignedtreatment assigned. . (usually subjects, (usually subjects, investigators, monitors and data analysts are investigators, monitors and data analysts are unaware) unaware)