CLINICAL STUDY AND BASIC CONCEPT

GOOD CLINICAL PRACTICE

CLINICAL STUDY AND BASIC CONCEPTWhat is a Clinical Trial?

A clinical trial (clinical research) is a research study in human volunteers (preclinical trail – in animals) to answer specific health questions.

Carefully conducted clinical trials are the fastest and safest way to find treatments that work in people and ways to improve health.

CLINICAL STUDY AND BASIC CONCEPTTypes of clinical trials

Treatment trialsPrevention trials Diagnostic trialsScreening trialsQuality of Life trials

CLINICAL STUDY AND BASIC CONCEPT

Clinical trials, FDA approval

Before a company initiates clinical trials (i.e. testing in humans), it must conduct extensive experiments in animal and human cells and in live animals (Preclinical Trial)

If this stage of testing is successful, the company files an Investigational New Drug (IND) application with the Food and Drug Administration (FDA) to request permission to conduct clinical trials.

CLINICAL STUDY AND BASIC CONCEPT

Clinical Trials

Preclinical testing

F

I

L

E

IND

at

FDA

Phase I Phase II Phase III F

I

L

E

NDA

at

FDA

FDA Phase IV

Years 3.5 1 2 3 2.5 12 Total

Additional post marketing testing

Test population

Lab and Animal Studies

20 to 80 healthy volunteers

100 to 300 patient volunteers

1000 to 3000 patient volunteers

Review process/ Approval

Success rate

5000 compounds evaluated

5 enter trials 1 approved

CLINICAL STUDY AND BASIC CONCEPT

Preclinical trialsTrial carried out on to the animal species Objective: To evaluate safety, toxicity and

tolerance data (by applying the factor for conversion of animal data to human data)

StudyDrug metabolism pathwayPK of the drugPK-PD relationProtein bindingTissue distributionDevelopment of methodology for quantification

of drug and metabolite in biological fluidLong term toxicity Placental transfer kinetic

CLINICAL STUDY AND BASIC CONCEPTPhase 1Trial carried out on healthy volunteers except

AIDS or Cancer.StudyDose-concentration (in plasma)-response-

toxicity studyIV, single dose study (for checking

bioavailability)Radioactive tracer study (for evaluation of first

pass metabolism)Evaluation of suitability of preclinical animal

model (to predict pharmacological effect in human)

Effect of food

CLINICAL STUDY AND BASIC CONCEPTPhase 2First time trial on patient and conducted in

OPEN mannerStudyEvaluation of difference in PK and PD

between the healthy volunteer and patientTo search new therapeutic effect of the

drug

CLINICAL STUDY AND BASIC CONCEPTPhase 3StudySearch less common side effect of drug

(which is conc. independent)Comparison with the marketed drugDrug-drug interactionStudy in special population like age, sex

race etc.Develop the dosage form

CLINICAL STUDY AND BASIC CONCEPTPhase 4Post marketing surveillanceNot well planned study but random studySome rare side effect or toxicity may come

out

GOOD CLINICAL PRACTICEGood Clinical Practice (GCP) is an international

ethical and scientific quality standard for designing, recording and reporting trials that involve the participation of human subjects.

Compliance with this standard provides public assurance that the rights, safety and well being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.

Regulations tell you what you are required to do by law. Guidelines tell you the best way to do it

GOOD CLINICAL PRACTICEFDA GCP Regulations Regulations contained in 21 CFR Part 50, 56, and 312 Part 50 (applies to consenting of subjects), Part 56 (applies to IRB responsibilities) and Part 312 (applies to IND submissions, sponsor responsibility,

and investigator responsibility)

GCP Guidelines- International Conference on Harmonization

The objective of ICH GCP Guidelines is to provide a unified standard for European Union, Japan and United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in the jurisdiction.

Published by the FDA in Federal Register in May, 1997 Adopted by all parties as GCP standard (considered law in

European Union; considered “final guidance” in the US) Based on the Declaration of Helsinki

GOOD CLINICAL PRACTICESome important terms (Glossary)InvestigatorSponsorSubject /Trial SubjectInvestigator’s BrochureNon Clinical StudyProtocolBlinding (Masking)Institutional Review Board (IRB)Adverse Event (AE)Serious Adverse Event (SAE)

GOOD CLINICAL PRACTICEElements of GCPIRBInvestigatorSponsorClinical trial protocol and protocol

amendmentsInvestigator BrochureEssential documents

GOOD CLINICAL PRACTICEInstitutional review board (IRB) or

Independent Ethics Committee (IEC)It consists of reasonable number of members,

who collectively have qualifications and experience to review and evaluate the science and medical aspects as well as ethics of proposed trials.

It should perform the functions in accordance with written procedures, maintain written records of its activities and minutes of its meetings and should comply with GCP.

Acts as a safe guard to the rights of the trial subject

Should consider the qualification of the investigator for the proposed trial

Should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk.

GOOD CLINICAL PRACTICEInvestigator Qualified to perform study should have

Appropriate education, training and experience to assume responsibility and should provide evidence of such qualifications.

Sufficient time to devote to study timelines. Personally conduct or supervise study. Adequate and qualified staff and facilities. Awareness of and compliance with GCP. Familiar with the investigational product and

inventory. Adherence to protocol requirements. Inform subject’s primary physician Ensure adequate medical care for SAEs. Maintained records should be accurate, complete,

legible and timely.

GOOD CLINICAL PRACTICEInvestigator-Communication with IRB

Obtaining written and dated IRB approved consent form

Submission of Investigational BrochureOngoing communication

Report of SAEsIND Safety ReportsSignificant protocol deviations

The investigator should submit written summaries of the status of the trial to the IRB annually or more frequently, if requested by the IRB

GOOD CLINICAL PRACTICEInvestigator- Communication with the

Sponsor/CRO

Reporting of any AEs or SAEsNotification of changes in staff and addressRetention of all pertinent study information

and records until notified in writing that records are no longer required

Coordination of publication plansIf trial is blinded, the investigator should

promptly document and explain to the sponsor any:

Premature unblindingAccidental unblinidingUnblinding due to serious adverse

events

GOOD CLINICAL PRACTICEInvestigator-Communication with Study Subjects

Obtaining valid written informed consent The information language should be non-technical and

understandable to the subject/LAR/impartial Provide subject a copy of a fully executed consent Provide subject with any new information Answer questions at any time The investigator must inform the subject when medical

care is needed for inter-current illness(es) of which investigator becomes aware.

It is recommended that the investigator inform subject’s primary physician about subject’s participation in study.

If subject wishes to withdraw from the study, the investigator should make reasonable effort to ascertain the reasons – while fully respecting the subject’s rights.

GOOD CLINICAL PRACTICEInvestigator- Investigator – Compliance with Protocol

The investigator should conduct the trial in compliance with: The protocol agreed to by the sponsor If required, protocol agreed to by the regulatory authority(ies) Ultimately given approval by the IRB

The investigator should not implement any deviation from, or changes of the protocol without: Agreement by the sponsor Prior review and documented approval from the IRB of an

amendment Exception: where necessary to eliminate an immediate hazard

(s) to trial subjects or when the changes involve only logistical or administrative aspects of the trial. However, as soon as possible, the implemented deviation or change, the reason for it, and, if appropriate, the proposed protocol amendment(s) should be submitted to:

The IRB for review and approval To the sponsor for agreement If required, to the regulatory authorities

GOOD CLINICAL PRACTICEInvestigator – Investigational Products

It is the investigator’s responsibility for investigational product(s) accountability at the trial site

The investigator or person who is designated by the investigator should maintain records of:

o The product(s) delivery to the siteo The inventory at the siteo The use by each subjecto The return to the sponsor or disposition of unused

products The records should include:

Date, quantities, batch/serial numbers, expiration dates and the unique code numbers assigned to the product(s) and subjects

Products should be stored as specified by the sponsor and in accordance with applicable regulatory requirements

Should explain to the subject: Correct use of the product Should check at appropriate intervals that the subject is following

the instructions properly to use the product

GOOD CLINICAL PRACTICEInvestigator – Records and Reports

Records should be accurate, complete, legible and timely pertinent to the data reported to the sponsor in the CRFs (Case Report Forms) and other required reports

All corrections to a CRF should be dated, explained and should not obscure the original entry whether the entry is written or electronic changes or corrections.

The investigator should retain records of the changes and corrections.

GOOD CLINICAL PRACTICEInvestigator’s Brochure

For investigational (not FDA-approved) drug trials

Summary of significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic, and clinical information that is relevant to the investigational product

Relevant animal and clinical studies, adverse events, etc.

GOOD CLINICAL PRACTICEFDA Form 1572 – to initiate clinical trials

Investigator agrees to comply with conditions required by FDA for use of investigational articles

“Contract” that the investigator signs/dates “Warning: A willing false statement is a criminal

offense”

Content of Form 1572

Principal Investigator name/address Name/address of site(s) of study conduct Name/address clinical labs (local/central) Name/address IRB Names of key personnel with study participant contact Submit CVs of key personnel (signed/dated) listed in

form

GOOD CLINICAL PRACTICEProgress Reports

The investigator should submit written summaries (where required by applicable regulatory requirements) of the trial’s status to the institution.

The investigator should submit written summaries of the status of the trial to the IRB annually or more frequently, if requested by the IRB

The investigator should promptly provide written reports to the sponsor and the IRB and where required by the regulatory authorities, the institution on any changes significantly affecting the trial and/or increasing the risk to subjects.

GOOD CLINICAL PRACTICESafety Reporting

All serious adverse events (SAE) should be reported immediately to the sponsor except for those SAEs that the protocol or other document identifies as not needing immediate reporting

The immediate and follow up reports should identify Subjects by unique code numbers assigned to trial, but not with identifiers (name, address, identification numbers)

The immediate reports should be followed promptly by detailed, written reports

Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be reported to the sponsor within the time periods specified by the sponsor in the protocol

For reported deaths, the investigator should supply the sponsor and the IRB with any additional requested information (e.g., autopsy reports and terminal medical reports)

GOOD CLINICAL PRACTICEPremature Termination or Suspension of a Trial

If the trial is suspended or prematurely terminated for any reason the investigator should promptly Inform the trial subjects, should assure appropriate therapy and follow-up and where required, should inform the regulatory authorities and the IRB

If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator should inform the institution, regulatory authorities(if required), the sponsor and the IRB with detailed written explanation of the termination or suspension

If the sponsor terminates/suspends a trial, the investigator should promptly inform the institution (per applicable regulatory requirements) and the IRB and provide written explanation of the termination/suspension

If the IRB terminates/suspends its approval, the investigator should inform the institution and the investigator should promptly notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension

GOOD CLINICAL PRACTICEFinal ReportUpon the completion of the trial, the

investigator should inform and provide the IRB and the sponsor:All required reportsSummary of the trial’s outcomeReports to regulatory authorities if applicable

GOOD CLINICAL PRACTICERecords Retention Requirements

Essential documents should be retained until at least two (2) years after the last approval of a marketing application in an ICH region.

These documents should be retained, however, if required by the applicable regulatory requirements (state or federal) or by an agreement with the sponsor.

It is the responsibility of the sponsor to inform the investigator as to when these documents no longer need to be retained.

Upon request of the monitor, auditor, IRB or regulatory authority, the investigator/institution should make available for direct access all requested trial-related records.

Referenceswww.fda.govwww.google.comEMEA, InspectionsStanford school of medicine;

FACILITATING TRANSLATIONAL RESEARCH AND MEDICINE

CLINICAL RESEARCH