MODULE B:

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MODULE B:Overview of the Clinical Trial &

Protocol

Jane FendlMarch 31, 2010

Version: Final 31- Mar-2010

Version: Final 31- Mar-2010 2

Phases of the Clinical Trial Phase 1 – “human pharmacology trials”First time tested in man Healthy normal volunteersTo gather information about the drug’s safety and the

effect of the drug on the human bodyPharmacokinetic evaluation – how the drug is absorbed

the way it is absorbed, distributed in the body, metabolized and excreted

Dose is progressively increased until a tolerable toxicity level is achieved

Measures AEs Determine maximum tolerable dose

21 CFR 312.21


Phase 2 – “therapeutic exploratory trials”

Volunteers with targeted disease stateTesting for safety and efficacyTo determine the potential effectiveness Identify common adverse events Ensure the drug has suitable risk to benefit ratioTo determine the optimal effective doseTo prove efficacy by evaluating an objective or

comparative measurement such as:Positive change in the disease processImprovement in quality of lifeReduction in mortalityImprovement in symptomatology

21 CFR 312.21


Phase 3a – “therapeutic confirmatory trials”To evaluate safety and efficacy in a large number of subjectsEmphasis on assessing the tolerance to the drugAdditional gathering of information about drug interactions and addiction potentialPotential effectiveness of the productIdentify common adverse events within a heterogeneous populationExpanded number of subjects with specific problem or indication

21 CFR 312.21


Phase 3b – “therapeutic use trials”Further safety and efficacy as well as new

indicationsMore subjectsLonger period of timeTested for long-term effectsUnderstand how the product is prescribedMay include thousands of subjects Subjects with different stratifying characteristics such as age, race & concomitant medicationsGather information such as:

Response to productSafety in general populationSafety for subjects with certain characteristicsSafety in association with other drugAffect on Subject’s quality of life

21 CFR 312.21


Phase 4 – “post-marketing trials”May be at the request of regulatory authorities

as a condition of approvalSponsor may wish to compare the drug with

other active agents for:

Marketing reasonsCost-benefit ratio for insurance/managed health care

purposesInvestigate new indications or formulationsInterested in surveying safety data in large populations


Phases of Drug Development1 2 3a & 3b 4

Average Time

1 week to 1 month

Several months to 2 years

Several months to 4 years

Several months to several years

Average # of Subjects

20 – 100 Several hundred

Several hundred to several thousands

50 to several thousand

Types of Subjects

Healthy volunteers

Subjects with disease



Main Purpose

Determine safe dose in man

Determine effectiveness at safe dose

Determine safety & effectiveness in varied large population of a long time period

As a condition for approval or approval for new indication


What is a protocol?Recipe or overall master plan for the trialGuide or road map for the Investigator, site staff, and the IRB to follow

What is the purpose?Provides consistency of processes across

all sites involvedHelps ensure consistent collection of data


What is the trial purpose?What will be proven?How and why the trial is being conducted?How many subjects?Who will be the subjects?What is the qualifying criteria?How long will it last?

ICH GCP 1.44

What questions does it answer?


General informationBackground informationTrial objectives and

purposeTrial designSelection and

withdrawal of subjectsTreatment of subjectsAssessment of efficacy

Assessment of safetyStatisticsDirect access to source

data and documentsEthicsData handling and

record keeping Financing and insurancePublication policySupplements

ICH GCP 6.0

What should be included in the protocol?

What is not included in the protocol can be referenced in the Investigators Brochure


Sections of the ProtocolGeneral InformationBackground

InformationTrial Objectives &

PurposeTrial DesignSelection and

Withdrawal of SubjectsInclusion CriteriaExclusion CriteriaWithdrawal CriteriaTreatment

EfficacySafetyAnalysis & StatisticsDirect Access to Source

Data & DocumentsEthicsData Handling & Record

KeepingFinancing & InsurancePublication PolicyAppendices/

SupplementsSignature & Agreement


General Information Protocol title, number & dateSponsor informationName & title of the person authorized to sign the protocol & amendmentsName, title, address & telephone numbers of Sponsor’s medical experts


Background InformationDescribe the investigational productMechanism of ActionSummaries of findings from previous studiesRisks and benefits of investigational productPopulation to be studiedDescription of the justification for the route of administration, dosage, & regimen

Trial Objectives & PurposeObjectives should describe what the trial is trying to proveObjectives should correlate with the trial design and what data will measure


Trial DesignPrimary endpoints –

focus of the trialSecondary endpoints –

any other items that the trial may measure

Description of design and measures to minimize bias

Randomization – how maintained & procedures for breaking the code

Trial treatments & dose, the form, regimen, packaging & labeling

Length of subject participation, description of sequence & duration of all trial periods (visits)

Drug accountabilityRules for discontinuing

the investigational product and withdrawing the subject

Criteria for stopping parts of the trial or ending the trial

What is considered source data


Inclusion Criteria

Exclusion Criteria

Statements which describe the qualification or conditions that a subject must meet to participate in the trial

Specific conditions that disqualify a subject from participating


Withdrawal CriteriaWhen & how the investigational product must be stopped & subjects withdrawn from the trial

Product may be taperedThe conditions under which the Investigator should terminate a subject

Missed visitsHow the data is to be collected

Have the subject return, complete which visitThe type of information that is to be collected

Reason discontinuedInformation regarding replacement of subjects

Number of subjects needed to complete


TreatmentName of all productsDose – milligrams, grams, ounces, etcDosing schedule – BID, TID, QID, PRNRoute or mode of administration – IV, oral, inhalerTreatment periods – length of time on productMedications or treatments permitted and those that are not permitted – treatments known to interfere with the action of the productProcedures for monitoring compliance – site staff is to count used and unused product to determine if subject took the product as directed


EfficacyMethods and

measures to determine if the investigational product is effective

Example - Blood pressure decreases as predicted

How the efficacy measures will be recorded and analyzed

SafetyHow and when to

measure for the safety of the investigational product

How to capture, record and report adverse events, serious adverse events and concurrent illness

Type and duration of follow-up for subjects who experience AEs or SAEs


Statistical methods used to analyze the information that is gathered from the dataNumber of subjects to be enrolledIf multi-center study may include # of subjects/siteJustification of sample sizeStatistical level of significanceCriteria for termination of the trial Procedures for accounting for missing, unused & false dataProcedures for reporting deviations from the

original SAPSelection of subject to included in the analysesAny planned interim analyses

Analysis & Statistics


Source Documents & DocumentsSpecifies that the Sponsor or delegates should be permitted access to all documents relating to the trial for the purpose of monitoring, auditing, IRB review and regulatory inspections

EthicsDescribes any ethical considerations relating to the trial


Methods used to collect, monitor, and maintain

source documents and filesInvestigators’ responsibility for ensuring

confidentiality and rules for disclosure of dataHow long data and records should be retainedRules for the accessibility of trial information for

Sponsor, IRB or inspectorsHow data is maintained in the source documents

and Case Report Forms

Data Handling & Record Keeping


Publication PolicyMay be included – deals with the requirement of Sponsor permission and approval to disclosure data collected by the site and Investigator. Appendices/SupplementsIncludes documents that are referenced in the protocol.Signature & AgreementInvestigator signs and dates the “Signature Page” or “Investigator’s Statement” signifying he/she will conduct the trial according to the protocol and will not deviate from the protocol.

MODULE B:

Documents

Transcript of MODULE B: