GOOD CLINICAL PRACTICES

DR. KARUN KUMAR

JUNIOR RESIDENT – I

DEPT. OF PHARMACOLOGY

What is Clinical Research ?

•Research conducted on•Human subjects or •Material of human origin •Tissues, •Specimens, and •Cognitive phenomena

http://keck.usc.edu/Research/Clinical_Research/Definition.aspx

What is Clinical Trial ?

•Scientific studies

•Test the effectiveness of •Treatment, •Device, or•Drug

•Find new & better wayshttp://keck.usc.edu/en/Research/Clinical_Research/Clinical_Trials.aspx

Phases of Clinical Trial

Phase Primary goal Dose Patient monitorNumber of

participants

Preclinical

Testing of drug in non-human subjects

UnrestrictedA graduate level researcher-Ph.D.

In vitro & in vivo animal models

Phase 0Oral bioavailability & half-life of drug

SubtherapeuticClinical researcher

10 people

Phase ITesting of drug on healthy volunteers (safety)

Subtherapeuticwith asc. Doses

Clinical researcher

20-100

Phase IITesting of drug on patients (efficacy & tolerability)

Therapeutic doseClinical researcher

100-300

Phase IIITesting of drug on pts.(confirm efficacy)

Therapeutic doseClinical research.& Physician

1000-2000

Phase IVPost-marketing surveillance (A/E, D-D I)

Therapeutic dose PhysicianAnyone seeking treatment

Phase V Translational research No dosing None All reported use

DeMets D., Friedman, L., and Furberg, C.,(2010).Fundamentals of Clinical Trials.Springer 4th EditionGoodman and Gilman's The Pharmacological Basis of Therapeutics, (2011) 12th Edition

What are Good Clinical Practices ?

•More than any one document •Collective compilation of many • thoughts, • ideas and• learning moments

spanning the globe over

•International ethical and scientific quality standard for •Design,•Conduct, •Performance, •Monitoring, •Auditing, •Recording, •Analysis, and •Reporting

of clinical trials

Historical BackgroundYear Event

460 B.C. Oath of Hippocrates

1930's U.S. Food, Drugs and Cosmetic Act

1947 Nuremberg Code

Dec. 10th 1948 Declaration of Human Rights

1962 Kefauver-Harris Amendment

1964 Declaration of Helsinki

1979 The Belmont Report

1982 International Guidelines for Biomedical Research Involving Human Subjects (WHO & CIOMS)

1996 ICH-GCP guidelines issued

1997 ICH-GCP guidelines implemented

Vijayananthan A, Nawawi O.The importance of Good Clinical Practice guidelines and its role in clinical trials.Biomed Imaging Interv J. 2008 Jan-Mar; 4(1).

The death sentences imposed in October 1946 were carried out by Master Sergeant John C. Woods (1903-50), who told a reporter from Time magazine that he was proud of his work. "The way I look at this hanging job, somebody has to do it . . . ten men in 103 minutes. That's fast work."

http://www.history.com/topics/world-war-ii/nuremberg-trials

Brigadier General Telford Taylor, Chief of Counsel, during the Doctors Trial, which was held in Nuremberg, Germany, from December 9, 1946, to August 20, 1947.

During testimony at the Doctors Trial, American medical expert Dr. Leo Alexander points to scars on Jadwiga Dzido’s leg. Dzido, a member of the Polish underground, was a victim of medical experiments at the Ravensbrüeck concentration camp. Nuremberg, Germany, December 22, 1946.

Nazi physician Carl Clauberg who performed medical experiments on prisoners in Block 10 of the Auschwitz camp. Poland, between 1941 and 1944.

A prisoner in a compression chamber loses consciousness (and later dies) during an experiment to determine altitudes at which aircraft crews could survive without oxygen. Dachau, Germany, 1942.

Victim of a medical experiment immersed in freezing water at the Dachau concentration camp. Dachau, Germany, between August 1942 and May 1943.

A Romani (Gypsy) victim of Nazi medical experiments to make seawater potable. Dachau concentration camp, Germany, 1944.

Photo of wounds left by a medical experiment. The victim had been burned with phosphorous so that medicaments could be tested

Nuremberg Code (1947)

•Voluntary consent of the human subject is absolutely essential

•Favorable risk/benefit ratio

•Research must help society

•Research should be based on previous knowledge

•Participant must be free to stop at any time

•Research should not cause mental & physical suffering

•Research should avoid risk of injury & death

Declaration of Helsinki (1964)

•Well being of subject > interest of science & society

•Consent should be in writing

•Limited use of placebo

•Greater access to benefit

(April, 1979)

Respect for persons

•Protecting autonomy of subjects

•Treating subjects with courtesy and respect

•Allowing for informed consent

Beneficence

•The philosophy of "Do no harm”

•Maximize benefits for the research project

•Minimize risks to the research subjects

Justice

•Ensure considered procedures are administered fairly

•Fair distribution between•Burden of research (Costs)•Benefit of research

Common Rule (1981)

•Describes the types of research subject(s)

•Defines key terms such as •Research, •Human subject, and •Minimal risk

•Sets forth requirements for •IRB membership•Review procedures•Criteria for approval

•Lists requirements for informed consent

Overview of Clinical research process

Development of the trial protocol

Development of standard operating procedures (SOPs)

Development of support systems and tools

Selection of trial sites and the selection of properly qualified, trained, and experienced investigators and study personnel

Ethics committee review & approval of the protocol

Enrollment of subjects into the study:-

Recruitment,

Eligibility, &

Informed consent

Review by regulatory authorities

Safety management and reporting

Trial data acquisition: conducting the trial

The investigational product(s): quality, handling and accounting

Monitoring the trial

Quality assurance of the trial performance and data

Managing trial data

Reporting the trial

WHO principles for GCP

Principle 1 – Ethical Conduct

•Research involving humans Scientifically sound

In accordance with Declaration of Helsinki

Principle 2: Protocol

•Research

To be described in a •Clear,•Detailed, and•“Scientifically justified” protocol

Principle 3: Risk Identification

•Foreseeable risks and discomforts and any anticipated benefit(s)

To be identified

Principle 4: Benefit-Risk Assessment

•Research initiated only if anticipated benefit(s) outweigh the risks

•Most important considerations•Rights,•Safety, and•Well-being of trial subjects

Principle 5: Review by IEC/IRB

•Research should receive independent (IEC/IRB) approval prior to initiation

Principle 6: Protocol Compliance

•Research Conducted in compliance with the approved protocol

Principle 7: Informed Consent

•To be obtained •From every subject •Prior to research participation •In accordance with national culture(s) and requirements

Principle 8: Continuing review / ongoing benefit-risk assessment

•Research Continued only if the benefit-risk profile remains favorable

Principle 9: Investigator Qualifications

•Qualified and duly licensedmedical personnel Responsible for the

medical care of trial subjects

Principle 10: Staff Qualifications

•Each individual involved should be qualified by•Education, •Training, and•Experience

Principle 11: Records

•Clinical trial information should be •Recorded,•Handled, and •Stored

•In a way that allows its accurate

•Reporting,

•Interpretation, and

•Verification

Principle 12: Confidentiality / Privacy

•Confidentiality of records should be protected

•In accordance with the applicable regulatory requirement(s)

Principle 13: Good Manufacturing Practice(s)

•Investigational products should be •Manufactured, •Handled, and •Stored

in accordance with applicable GMP

Principle 14: Quality Systems

•Systems with procedures that assure the quality of every aspect of the trial should be implemented •Quality control (QC)•Quality assurance (QA)•Quality improvement (QI)

Code of Federal Regulations, Title 21

21 CFR 11: Electronic records and signatures

21 CFR 50: Protection of human subjects

21 CFR 54: Financial disclosure by clinical investigators

21 CFR 56: IRB that oversee clinical trials

21 CFR 312: Investigational New Drug Application

21 CFR 812: Investigational Device Exemptions

ICH-GCP guidelines

•“Bible” of clinical trials

•Global law which safeguards humanity

•13 core principles

Who is responsible for GCP ?

•Each & every person involved in the research process.

•This includes

1.Sponsors

2.Investigators and research staff

3. Contract Research Organizations

4. IRB/EC

5. FDA

6. Research Subject

Never ending debate

•Whether the "greater good" trumps the rights of the individual?

•Are individual’s rights what make up the greater good?

•Is it the greater good that allows for individual’s rights?

Take Home Message

•"If it wasn't documented, it wasn't done.”

•GCP is more than a piece of paper or a set of rules

•A mind-set of dedication that ensures a high level of ethics & quality in research

THANK YOU