Clinical Research Overview

“GCP Guidelines” Syed Junaid Rehan

QA Manager e-Compliance, Novartis CRA - Norton Audits Inc, USA

IPPCR – National Institute of Health, USA M.Phil. Quality Management, Hamdard University

M.Sc. Food Science & Technology, University of Karachi

SJR/ GCP Presentation / workshop Liaquat College of Medicine & Dentistry

Overview of Clinical Research & History

Informed Consent

Human Subject’s Rights, Safety, and Welfare Protection;

Regulations

GCP - Good Clinical Practices;

Data Integrity, Misconduct and Fraud;

Adverse Event

Topics

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Patient-Oriented Research Research conducted with human subjects (or on material of human origin such as tissues, specimens and cognitive phenomena) for which an investigator (or colleague) directly interacts with human subjects…includes: Development of new technologies Mechanisms of human disease Therapeutic interventions Clinical Trials

Epidemiologic and Behavioral Studies Outcomes Research and Health Services Research

Definition of Clinical Research

*From NIH Director’s Panel on Clinical Research, 1996 SJR/ GCP / LCMD

Drug

A drug is defined as:

• (A) articles recognized in the official USP, HPUS or NF or any supplement to any of them;

• (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals;

• (C) articles (other than food) intended to affect the structure or any function of the body of man or other function of the body of man or other animals…..

“Defining a drug”

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PHASE 1 PHASE 2 PHASE 3

First in Man Safety and Tolerability Pharmacokinetics

Proof of Concept Dose Ranging Safety/PK in Special Populations and Risk Factors

Large Multi-centered Usually Placebo-Controlled Usually replicated Primary data to support marketing approval in NDA

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“Then Daniel said to the steward… Test your servants for ten days; let us be given vegetables to eat and water to drink. Then let our appearance and the appearance of the youths who eat the king’s rich food be observed by you, and according to what you see, deal with your servants. So he harkened to them in this matter; and tested them for ten days. At the end of ten days it was seen that they were better in appearance and fatter in flesh than all the youths who ate the king’s rich food. So the steward took away their rich food and the wine they were to drink, and gave them vegetables.”

History of Clinical Trials

Daniel 1:11 – 16 c. 530 BC SJR/ GCP / LCMD

History Rich in Trials and Tribulation

Ensuring Subject’s Research Protection Rights, Risks, and Welfare

Nuremberg Code Kefauver Amendments Declaration of Helsinki National Research Act Belmont Report The Common Rule

“Ethics and Research”

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Nuremberg Code - 1948

“ Voluntary Consent”

• A well-known chapter in the history of research with human subjects opened on December 9, 1946, when an American military tribunal opened criminal proceedings against 23 leading German physicians and administrators for their willing participation in war crimes and crimes against humanity.

• Among the charges were that German physicians conducted medical experiments on thousands of concentration camp prisoners without their consent. Most of the subjects of these experiments died or were permanently crippled as a result.

• As a direct result of the trial, the Nuremberg Code was established in 1948, stating that "The voluntary consent of the human subject is absolutely essential," making it clear that subjects should give consent and that the benefits of research must outweigh the risks.

• Although it did not carry the force of law, the Nuremberg Code was the first international document which advocated voluntary participation and informed consent.

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Kefauver Amendments - 1962

“Ethics become

Law”

• US History:

– Thalidomide • Late 1950s, thalidomide was approved as a sedative in Europe. • It was not approved in the United States by the FDA. • The drug was prescribed to control sleep and nausea throughout pregnancy,

but it was soon found that taking this drug during pregnancy caused severe deformities in the fetus.

• Many patients did not know they were taking a drug that was not approved for use by the FDA, nor did they give informed consent.

• Some 12,000 babies/patients were born with severe deformities due to thalidomide.

– Tuskegee Syphilis Study (1932-1972) • Conducted by the U.S. Public Health Service. • Six hundred low-income African-American males, 400 of whom were

infected with syphilis, were monitored for 40 years. • Free medical examinations were given; however, subjects were not told

about their disease. • Even though a proven cure (penicillin) became available in the 1950s, the

study continued until 1972 with participants being denied treatment. • In some cases, when subjects were diagnosed as having syphilis by other

physicians, researchers intervened to prevent treatment. • Many subjects died of syphilis during the study.

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Declaration of Helsinki - 1964

“A call for Independence”

• Issues outlined in the Declaration of Helsinki include:

– Research with humans should be based on the results from laboratory and animal experimentation

– Research protocols should be reviewed by an independent

committee prior to initiation – Informed consent from research participants is necessary – Research should be conducted by medically/scientifically

qualified individuals – Risks should not exceed benefits

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National Research Act - 1974

• In Summary:

– Nazi atrocities in World War II drew attention to the lack of international standards on research with human subjects and led to the formulation of the Nuremberg Code.

– The thalidomide disaster led to the adoption of the "Kefauver Amendments" to the Food, Drug and Cosmetic Act, requiring drug manufacturers to prove to the FDA the effectiveness of their products before marketing them.

– The Declaration of Helsinki is the basis for Good Clinical Practices used today.

– The Tuskegee Syphilis Study is probably the worst case of unethical human subjects research in the history of the United States.

– The National Research Act codified the requirement that human

subjects in research must be protected and set the stage for the issuance of the Belmont Report.

“Human Subject’s Protection”

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The Belmont Report - 1979

“Foundation for Regulations”

• Beneficence:

– Human subjects should not be harmed

– Research should maximize possible benefits and minimize possible harms.

• Justice:

– The benefits and risks of research must be distributed fairly.

• Respect for persons:

– Individuals should be treated as autonomous agents

– Persons with diminished autonomy are entitled to

protection. SJR/ GCP / LCMD

The Common Rule - 1981

• The Main Elements of the Common Rule include :

– requirements for assuring compliance by research institutions;

– requirements for researchers obtaining and documenting informed consent;

– requirements for Institutional Review Board (IRB) membership, function, operations, review of research, and record keeping;

– additional protections for certain vulnerable research subjects-- pregnant women, prisoners, and children

“Additional Protections”

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1898: William Osler

“To deliberately inject a poison of known

high degree of virulency into a human being,

unless you obtain a man’s sanction…is criminal.”

(In response to an oral presentation by Giuseppe Sanarelli on discovery of

the etiologic agent of yellow fever)

History of Informed Consent

1849-1919

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“…how to provide each patient with a reasonable understanding of his role in a study project and the means for obtaining evidence of such understanding and consent.”

1962:

Kefauver-Harris amendment to Food and Drug Act stipulating subjects must be told whether a drug is being used for investigational purposes

Surgeon General requires peer review (IRBs) for all PHS grants.

1967:

FDA required all new drug sponsors obtain informed consent for use of investigational drugs in humans.

Informed Consent

Minutes of Medical Board MEDICAL BOARD

Tuesday, June 9, 1953, 3:00 p.m. Chairman: Dr. Luther Terry

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The study involves research of an unproven drug, the purpose of the research

How long the participant will be expected to participate in the study

What will happen in the study

Possible risks/benefits to the participant

Participation is voluntary and that participants can quit the study at any time without penalty or loss of benefits to which they are otherwise entitled.

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Under GCP, the FDA Requires That People be Informed

Federal Regulations

TITLE 21 – Food and Drug

CHAPTER I – Food and Drug

Administration

Department of Health and Human Services

SUBCHAPTER D – Drugs for Human Use

Investigational New Drug Application

21Code of Federal Regulations

Part 312

FDA’s Compliance Policy

Programs

7348.811 CHAPTER 48

Bioresearch Monitoring

Clinical Investigators

OCTOBER 1, 1997

Guidance for Industry

Good Clinical Practices:

Consolidated Guidance

(ICH-E6)

International Conference on

Harmonization

April 1996

Regulations & Guidelines

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Clinical Trial Oversight

“Safety Nets”

Clinical Investigator

Sponsor

CRO

IRB

FDA Sponsor/ CRO

IRB Clinical Investigator

Subject & Consumer Protection

“Umbrella of Protection SJR/ GCP / LCMD

Clinical Trial Oversight

Understanding the roles defined in the FD&C Act

The Sponsor The CRO

“The Sponsor”

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Clinical Trial Oversight

• Understanding the roles defined in the FD&C Act

– The Institutional Review Board

– Synonym: Ethics Committee

“IRB”

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Clinical Trial Oversight

Understanding the roles defined in the FD&C Act

The Clinical Investigator Synonym: Principal Investigator or Researcher

The Study Coordinator

“Clinical Investigator”

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Monitoring Clinical Trials

Medical Monitor

Clinical Research Team

Clinical Investigator or

Researcher

Monitor or

Clinical Research Associate

• Assessing protocol adherence at the Clinical Investigator

• Assessing regulation adherence

• Reports on progress and findings

• Ensures immediate and prompt corrective actions on the behalf of the sponsor

• Ensuring proper reporting and accuracy of clinical data results

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Goal of Monitoring

Clinical Investigator’s

Data

Sponsor/CRO Database

Monitor’s Role

Monitor: ◘Source verify clinical data ◘Request clarifications ◘Submit paper case report forms or ◘Approve electronic submissions

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Inspection Procedures

The inspections conducted should be sufficient in scope to determine the clinical investigator's practices for each point identified:

– Authority and Administration

– Protocol

– Subjects’ records

– Other study records

– Consent of human subjects

– Institutional review board (IRB)

– Sponsor

– Test article accountability

– Records retention

– Electronic records and signatures

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Monitoring / Auditing Skills

Global Skills Presented

– Communication Skills

– Interviewing Skills

– Observation Skills

– Data Techniques

– Writing Skills

– Organizational Skills

– Legal Expertise

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ICH-GCP Guideline – E6 Good Clinical Practice

A given standard for the:

– Design

– Conduct

– Performance

– Monitoring

– Auditing

– Recording

– Analysis

– Reporting of clinical trials

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Provides....

assurance that the data and reported results are credible and accurate, and that the rights, integrity and confidentiality of trial subjects are Protected.

What it Does ?

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WHY???

• Increase protection of human research subjects

• Ensure the integrity of the clinical investigation

• Ensure the approval of safe and effective products

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Are mainly focused on the protection of human rights in clinical trial.

Provide assurance of the safety of the newly developed compounds.

Provide standards on how clinical trials should be conducted.

Define the roles and responsibilities of

Clinical sponsors,

Clinical research investigators,

Clinical Research Associates, and

Monitors.

Good Clinical Practice Guidelines

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Good Clinical Practice Guidelines

Data Integrity

Protection of Subject’s

Rights

Compliance with GCPs provide public assurance that the rights and safety of participants in human subject research are protected and that the data that arises from the study is credible

They are defined as an international ethical and scientific standard for designing, conducting, recording and reporting trials that involve the participation of human subjects

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Composition of ICH

ICH Co-Sponsors

United States

Japan

European Union

ICH Observers

Canada

WHO

European Free Trade Area

IFPMA

International Federation of

Pharmaceutical

Manufacturers Ass.

(represents 56 countries) * Pharmaceutical Research & Manufacturers of America

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1 Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirements 2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks 3 The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society 4 The available non clinical and clinical information on an investigational product should be adequate to support the proposed clinical trial

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Thirteen core principles of GCP Guidance

5 Clinical trials should be scientifically sound, and described in a clear, detailed protocol 6 A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favorable opinion 7 The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified medical health practitioner. 8 Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective tasks 9 Freely given informed consent should be obtained from every subject prior to clinical trial participation

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Thirteen core principles of GCP Guidance

10 All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification 11 The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirements 12 Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol 13 Systems with procedures that assure the quality of every aspect of the trial should be implemented

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Thirteen core principles of GCP Guidance

Data Integrity

The integrity of these data touches every part of business and operations we are constantly creating and processing data throughout the entire product life cycle which often more than 10 years. It is relevant during preclinical in research, clinical trial, registration, manufacturing, testing, release & distribution.

Data Generates at every Step. SJR/ GCP / LCMD

Actual – complete – factual – concise – precise

Proper storage & accessibility

Mishandling of data – however intentional can result in misleading interpretation of Clinical trial results, wrong dosage of medicine, malfunction of medical products, Drug Shortages or interruption of therapists for patients and reputation damage to organization.

Data Integrity

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Misconduct

deliberate or repeated noncompliance

does not include honest error or honest differences of opinion.

Generally has elements of safety concerns.

• Mismanagement of responsibilities

• Intentional wrongdoing; specifically :

– deliberate violation of a law or standard

• Improper professional behavior

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Fraud Can be combined with misconduct charges

• Intentional perversion of truth in order to induce another to part with something of value or to surrender a legal right

– An act of deceiving or misrepresenting

• A person who is not what he or she pretends to be

FALSIFICATION OF DATA!!

PHS - PLAGIARISM!!!

FDA’s Definition of Research Fraud

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Acts of Fraud

– Fabrication and Manufactured data

– Falsification (False Information)

– Forgery

– False statements

– Altered data

– Omitted data

– Plagiarism

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Adverse Event (AE):

Any untoward medical occurrence in a patient, consumer, or clinical trial subject administered a product, which does not necessarily have a causal relationship

with this treatment.

An adverse event can therefore be any unfavorable and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally associated with the use of a product, whether or not considered related to the product.

Adverse Event

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In addition, all cases of drug-drug interaction, pregnancy (with or without outcome), exposure during breastfeeding, paternal exposure, LOE, overdose, drug abuse and misuse, drug maladministration or accidental exposure and dispensing errors are collected and databased even if no adverse event has been reported.

Adverse Event

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Serious Adverse Event

An adverse event is any undesirable experience associated with the use of a medical product in a patient. The event is serious and should be reported to FDA when the patient outcome is:

• Death • Life-threatening • Hospitalization (initial or prolonged) • Disability or Permanent Damage • Congenital Anomaly/Birth Defect • Required Intervention to Prevent Permanent Impairment or Damage

(Devices)

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Other Serious (Important Medical Events) Report when the event does not fit the other outcomes, but the event may jeopardize the patient and may require medical or surgical intervention (treatment) to prevent one of the other outcomes. Examples include allergic bronchospasm (a serious problem with breathing) requiring treatment in an emergency room, serious blood dyscrasias (blood disorders) or seizures/convulsions that do not result in hospitalization. The development of drug dependence or drug abuse would also be examples of important medical events.

Serious Adverse Event

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It is estimated that only 5 in 5,000 compounds that enter preclinical testing make it to human testing, and only 1 of those 5 may be safe and effective enough to reach pharmacy shelves.

Tools for Understanding Legal Requirements

• International Conference on Harmonization (ICH- GCP) – E6 • FD&C Act of 1938 • Code of Federal Regulations (CFR) • Guidance and Information Documents:

– Good Clinical Practice in FDA-Regulated Clinical Trials: http://www.fda.gov/oc/gcp/default.htm

– Information Sheets: http://www.fda.gov/oc/gcp/guidance.html

– Dear Doctor Letters – Educational Outreach

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References:-

• http://www.fda.gov/

• http://en.wikipedia.org/wiki/ICH-GCP

• NIH • www.NIDCR.nih.gov

• www.NIAID.nih.gov

• NIH IPPCR Training Modules

• NAI Training Modules for CRA

• University/research institute sites

UTHSC – www.uth.tmc.edu

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Thanks...

Q&A

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