Good Clinical Practice (GCP)
Guidelines
Pete Manspeaker, M.H.Sc.; CIP

What’s the Difference?
VS

What is a Clinical Research
Study?
• Members of a clinical research team are scientists performing wellplanned experiments in search of unknown data.
• A clinical research study is a scientific experiment and all activities are held to a higher standard than routine clinical practice.

Conducting a Clinical Research
Study
• All clinical experiments must be conducted with the highest level of truth, honesty, and integrity.
• And to insure this level of conduct, there is often constant and independent oversight at every step of the process.

Guidelines vs. Regulation
•
•

Guidelines vs. Regulation
• FDA provides Guidances and Information Sheets on
Good Clinical Practice in clinical trials involving
FDA-regulated products
• FDA regulated products for Dx and Rx of diseases –
– Drugs, Biologics, & Medical Devices

Guidelines vs. Regulation
• These guidances and information sheets, first put forth in 1977 and updated regularly, represent the
Agency's current thinking on good clinical practice and the conduct of clinical trials.
– An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both.
However, in many places throughout these documents, specific regulations are cited and the requirements of the regulations are reiterated.
• The regulations are laws and are binding and enforceable.

Good Clinical Practice (GCP)
• GCPs provide an ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve human subjects.
• Compliance with GCPs seeks to assure that the rights, safety, and well-being of trial subjects are protected and that the clinical trial data are credible.

ICH Good Clinical Practice (GCP)
• The International Conference on Harmonization
(ICH) guidance provides companies and researchers with a unified standard for the
European Union, Japan, and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in those jurisdictions.
• Published in 1996
• Prior to this, companies often had to conduct separate clinical studies and reports for each market.

Conducting a Clinical Research
Study

come
• Every law and guidance that we live with every day, in all facets of our lives, came about because somebody didn’t do the right thing and serious consequences resulted.

History
• From the beginnings of civilization people have been concerned about the quality and safety of foods and remedies for their illnesses.
• In 1202, King John of England proclaimed the first English food law, the “Azzize of Bread", which prohibited adulteration of bread with ingredients such as beans and ground peas.

History
• US Colonial, State and National Efforts
– Public health and safety was a concern
– Regulation was a state or local issue, no Federal control or oversight
– Population was raked by disease
– Unsanitary, adulterated, and spoiled food
– No good science
– Strong protectionist bias, as many felt the Federal government had no business in local matters
– Only after Civil War, the coming of the railroads, and the industrial revolution did interstate commerce grow significantly

History
Early Food and Drug “Regulation” at the
Federal Level - 1862 –1960
• 1862 –1890 Chemical Division
• 1890- 1901 Division of Chemistry
• 1901 – 1927 Food, Drug, and Insecticide
Administration
• 1927- 1930 Food and Drug Administration
• USDA → HEW → DHHS

History
• Upton Sinclair published The Jungle in 1906
• Nauseating story of the plight of workers in the food processing industry around Chicago
• Public was horrified by the food processing, not the workers
• Need for regulation at the Federal level, as each state had its own laws
• Led to the 1906, Pure Food and
Drug Act

History
• 1937 Congress publishes Code of Federal
Regulations (CFR) which establishes the laws under which some 50 different government agencies operate and exert their influence.
– 21 CFR is the FDA
– 45 CFR is the DHHS
– 14 CFR is NASA
– 12 CFR is Banking
– 6 CFR is Homeland Security

History
• Continuing problems with dangerous drugs that fell outside the parameters of the Pure Food and Drugs Act, finally received national attention with the Elixir
Sulfanilamide disaster in 1937.
• Massengill distributed this preparation without testing for safety (which was not required by law).
• It contained diethylene glycol as a vehicle, a chemical analogue of antifreeze,
• Over 100 people died, many of whom were children.

History
• In June 1938 President Roosevelt signed the Federal Food, Drug and
Cosmetic Act into law.
• Among other things, this law required new drugs to be tested for safety before marketing, the results of which would be submitted to FDA in a new drug application (NDA).
• The law also required that drugs have adequate labeling for safe use.
• All drug advertising now had to be reviewed.

History
• 1947 - Nuremberg Code of ethics guidelines
• 1962 Kefauver-Harris Amendment
– Tightened safety and efficacy testing
– Informed consent required
– Reporting of adverse events
• 1964 Declaration of Helsinki
• 1972 - Discovery of the 1940s Tuskegee studies
• 1974 - National Research Act - Established IRBs
• 1977 - Proposed FDA GCP Guidelines published
• 1979 - Belmont Report on ethical guidelines
• 1996 ICH GCP Guidelines published

Research Ethics
• The first century physician Celsus justified experiments on condemned criminals in
Egypt using wording that became a classic defense for hazardous experimentation:
– "It is not cruel to inflict on a few criminals sufferings which may benefit multitudes of innocent people through all centuries.".
• Both the ethics and regulation of human subjects research have changed considerably since Celsus’ time.
• This evolution of ethical principles, and how they have influenced research involving human subjects laid the cornerstone for GCP.

Research Ethics
• What has led us to the establishment of GCPs?:
– Ethics is important when conducting research involving human subjects.
– Historical events have influenced how research involving human subjects is conducted today, because they violated ethical standards.
– Publication of the Belmont Principles in 1979.
– IRB review plays a role in ensuring the ethical design and conduct of research.
– Regulations and oversight play an important role in preserving the public trust in human research.

The Public Health Service Syphilis Study (1932-1971)
• Unethical study involving 400 poor black men in rural Alabama initially designed to study syphilis.
• The study continued to track these men until 1972 when the first public accounts of the study appeared in the national press.
• Public was outraged.
• The study resulted in 28 deaths, 100 cases of disability, 40 wives had been infected, and 19 cases of congenital syphilis.
• In 1973, Fred Gray filed a $1.8 billion lawsuit against the
Government
• Government settled out of court for $10 million
• 1994 President Clinton formally apologized to the survivors and the families

The Public Health Service Syphilis Study (1932-1971)
• What were some of the ethical problems?
:
– lack of informed consent,
– deception,
– withholding of information,
– withholding of available treatment,
– putting men and their families at risk,
– coercion and undue influence
– exploitation of a vulnerable group of subjects who would not benefit from participation.

• Public was so outraged that Congress commissioned the National Research Council
• NRC created The Belmont Report which identifies three basic ethical principles that must underlie all human subject research, and are commonly called the Belmont Principles:
• respect for persons
• beneficence
• justice

• All individuals involved in the conduct of human research should read the Belmont Report .
• The conduct of ethical research is not intuitive –
– Just as one must know and understand the basic principles science and know how to apply them to the design and conduct of research in order to do good science;
– So too, must one know and understand the basic ethical principles from the Belmont Report and know how to apply them in order to conduct ethical research.

Review by an Institutional Review Board (IRB)
• In addition to providing ethical guidance for the conduct of research, the Belmont Principles form the basis for many of the requirements found in the federal regulations.
• The specific criteria for IRB approval spelled out in 45 CFR 46.111 and 21 CFR 56.111 of the regulations are drawn directly from the three basic Belmont Principles.
• Therefore, the Belmont Principles also serve as a guide to compliance with the current federal regulations and GCP guidelines.

Ethics in Biomedical Research
• Why we need IRB review?
• Why not just obtain a commitment from the researchers that they will follow the ethical principles spelled out in the Belmont Report in the conduct of their research?
• Surely, by now we are aware of the issues such ethical lapses can cause, and the regulations have provided sufficient safeguards that such events are a thing of the past.

Can’t we simply trust our researchers to do the right thing?

Ethics in Biomedical Research
• Because of human nature….
• First, researchers are highly motivated people who tend to focus on their scientific goals.
– As a result, they may overlook the ethical implications of what they are doing.
– IRB review provides a system that requires researchers to take ethics into account when designing and conducting their research.

Ethics in Biomedical Research
• Secondly, no one can be totally objective about their own work.
– Researchers tend to underestimate the risks of their own research, not because they are callous, but because the procedures are so familiar to them.

Ethics in Biomedical Research
• Thirdly, researchers have an inherent conflict of interest when judging their own research.
– They have a stake in getting the research done as quickly and efficiently as possible.
• Oversight by an independent panel, such as an IRB is therefore necessary to ensure that ethical concerns are not overlooked.

Ethics in Biomedical Research

Ethics in Biomedical Research
Unfortunately, ethical problems associated with human research continue…..
• 1953 – Wichita Jury Case
• 1963 – Milgram Obedience to
Authority Study
• 1970 – Humphrey “Tea Room
Trade Study”
• 1973 Zimbardo “Simulated Prison
Study”
• 1996 -Death of normal volunteer at
University of Rochester in a physiology experiment
• 1997 Robert Fiddes Lab
Fraud case
• 1999 – Death of subject in a
Gene Therapy Trial at
University of Pennsylvania
• 2001 – Death of normal volunteer at Johns Hopkins
University in a pulmonary experiment
• 2001 Restaurant Letter Study
• ??????

Ethics in Biomedical Research
Public Trust
• The regulations also reflect the need to maintain the public trust in research.
– Researchers do not simply have the right to conduct research involving human subjects.
– Society grants researchers the privilege of conducting such research.
– The granting of that privilege is based on the public’s trust that research will be conducted responsibly.
– Erosion of that trust can result in the withdrawal of this privilege.
• The federal regulations evolved as a response to the erosion of public trust that resulted from the scandals that have occurred.
• These events caused the public to question on a number of occasions the ethics of researchers conducting experiments using human subjects.

Ethics in Biomedical Research
• Congress, responding to public concern, directed that federal agencies adopt regulations for research funded or conducted with federal funds and for research using products regulated by the FDA.
• Universities and institutions that receive federal funding for research involving human subjects, must have a Federalwide Assurance (FWA) in place with the Office of Human Research Protection (OHRP), a
Division of DHHS.
• This FWA states the level and type of oversight that research conducted at that University or Institution has agreed to with the
Federal government.

Ethics in Biomedical Research
• Public trust is maintained through accountability
– the ability of researchers to demonstrate to others that they are conducting research responsibly.
– Accountability is accomplished through documentation.
– The federal regulations include requirements for the necessary documentation of ethical conduct.

Ethical Guidelines
– Perform adequate and well-controlled clinical investigations
– Based on pre-clinical evidence of potential for a safe and efficacious product
– Conducted by qualified scientific experts
– Oversight by a local independent review board.

Roles and Responsibilities of the Research Team
FDA
SPONSOR INVESTIGATIVE
SITE
IRB
SMO /
CRO
SUBJECT

GCP: FDA Regulations
• All products:
– 21 CFR 50 (IC)
– 21 CFR 56 (IRB)
– 21 CFR 54
(financial disclosure)
• Devices:
– 21 CFR 812, 813 (IDE)
– 21 CFR 814 (PMA)
• Drugs:
– 21 CFR 312 (IND)
– 21 CFR 314 (NDA)
• Biologics:
– 21 CFR 600
– 21 CFR 601

Roles and Responsibilities of the Research Team

Investigator Responsibilities:
Must complete and sign FDA Form 1572 , which is a contract between the investigator and the FDA that states that the investigator will:
– Conduct study according to Protocol
– Personally supervise or conduct the study
– Inform Subjects of investigational status and comply with 21 CFR 50 & 21 CFR
56
– Report adverse experiences to Sponsor
– Read and understand the Investigator’s
Brochure

Investigator Responsibilities:
• FDA Form 1572
– Inform all personnel of study requirements
– Maintain adequate records and make them available
– Assure IRB is in compliance with regulations
– Assume responsibility for initial and ongoing IRB review

Investigator Responsibilities:
• FDA Form 1572
– Report any changes in the study to the IRB for approval prior to implementation
– Report any unanticipated risks to IRB
– Comply with Investigator responsibilities in 21 CFR 312
– Delegate study responsibilities to team based on education and experience

Coordinator Responsibilities
• Conduct study activities delegated by Investigator
– Prepare IRB documents
– Recruit patients
– Obtain informed consent
– Complete accurate regulatory documentation
– Conduct study activities with subject
– Maintain accurate drug accountability

Coordinator Responsibilities
• Conduct study activities delegated by Investigator
– Collect and report adverse events
– Collect and prepare lab specimens
– Subject education
– Train staff
– Maintain IRB compliance
– Administrative duties

Coordinator Responsibilities
• Conduct study activities delegated by Investigator
– Host Monitor visits
– Attend Investigator meetings
– Maintain current credentials for staff
– Comply with all regulations and GCP guidelines

Research Staff Responsibilities
• Conduct study activities delegated by Investigator
– Pharmacist
– Lab tech
– Diagnostic tech
– Phlebotomist
– Administrator
– Nurse

Sponsor Responsibilities:
• Select qualified Investigators
• Provide information to conduct study
• Ensure proper monitoring
• Ensure compliance with general investigational plan and protocols in IND
• Maintain an effective IND
• Ensure FDA and Investigators are notified of significant new adverse events or risks

IRB Responsibilities
• Protect the rights, welfare and safety of the research
Subject
• Oversight of research activities at the site

21 CFR 50 and 45 CFR 46

Informed Consent Regulations
• Provide time for Subject to consider consent
• No coercion or undue influence
• Lay language
– (7 th to 8 th grade)
• Native language

Informed Consent Regulations
• Consent Form
Requirements under 21
CFR 50
– Must be IRB-approved
– Must contain required elements
– Must be signed and dated by Subject
– Copy given to Subject

Informed Consent Regulations
• Record verifying information of consent in source document that the subject is enrolled in a research study
• Ensure the consent is legal
• IRBs or Sponsors may require additional signatures
• IRBs determine children’s participation and assent requirement

Informed Consent Regulations
Required Elements of Consent
•
•
•
• Statement that the study is research, purpose of study, expected duration of involvement, procedures to be followed, and identification of procedures which are experimental.
Description of risks or discomforts
Description of benefits
Disclosure of appropriate alternative procedures

Informed Consent Regulations
•
•
•
•
Required Elements of Consent (Cont)
Privacy and confidentiality of records, and who has access
Compensation for injury or medical care description and accessibility of more information
Contact person information for questions about research, subject rights, and research-related injury
Statement that participation is voluntary, they may discontinue at any time, and such decisions will involve no penalty or loss of benefits to which they would normally be entitled

Informed Consent Regulations
• Additional Optional Elements of Consent
 Statement that a treatment or procedure may involve risks to subject (embryo or fetus) which are currently unknown
 Circumstances in which participation may be terminated
 Costs to the subject for participating (time and/or financial).
 Consequences and procedures if withdrawing from study
 Any significant new findings that may impact subject’s willingness to continue in the study will be provided
 Approximate number of subjects in study

21 CFR 56 and 45 CFR 46

IRB Regulations
• Purpose of IRB:
– To protect the rights and ensure the welfare of subjects who participate in research
– Both initially and throughout the course of the research
• IRB review actions:
– Approve
– Disapprove
– Require modifications
• Full review vs. Expedited review vs. Exempt
• Research projects must be reviewed at least annually

21 CFR 54

Financial Disclosure
Regulations
• Purpose:
– Concern that if CoI exists, data may be biased
– FDA may consider clinical studies or data to be inadequate if steps are not taken to minimize bias
– Require an Applicant to disclose certain financial arrangements between Sponsors and Investigators to assess adequacy of studies
– CoI does not rule out an Investigator, it just means it must be disclosed and assessed

Financial Disclosure Regulations
• Regulatory Scope:
– Must report any significant equity interest in the
Sponsor
• Any equity interest in a publicly traded company that exceeds $50,000
• Any interest must be reported if the company is privately owned
• Institutions may be even more restrictive in their reporting requirements
– Proprietary interest in the tested product
• A patent, trademark, copyright or licensing agreement
– Significant payments of other sorts
• Monetary value of more than $25,000 for items such as open ended grants, equipment purchases, consulting arrangement, or honoraria
– Clinical studies impacted

• Personnel affected:
– Principal Investigators
– Sub-Investigators directly involved in the treatment or evaluation of research subjects
– Spouse and dependent child of an Investigator
• Duration of Disclosure:
– During the time of the trial and for 1 year following completion of the study
• Sponsor reports to FDA
• FDA Evaluation of Financial Interests:
– Review of each disclosure statement to assess impact
– Review what steps were taken to minimize potential bias due to CoI, such as blinding, objective endpoints, or use of independent evaluators of efficacy
– May initiate audit of data in question, ask Sponsor to evaluate data without questionable data to assess impact, or do additional studies
– May refuse to review data as being adequate if they suspect or demonstrate bias

21 CFR 312 & 812

Test Article Accountability
• Investigator ’s Responsibilities
– Maintain control of the test articles under investigation.
21 CFR 812.100
– Administer the test article only to Subjects under the
Investigator ’s supervision and shall not supply the test article to any unauthorized person.
21 CFR 812.110.c.

Test Article Accountability
• Keep records of disposition, dates of administration, quantity and use by Subjects.
21 CFR 312.62(a)
• Administer the test article only to
Subjects under the Investigator’s personal supervision or the supervision of a Sub-Investigator responsible to the Principal
Investigator.
21 CFR 321.61 & 21 CFR 812.110

Test Article Accountability
• Return unused supplies to the
Sponsor from an investigator whose participation is discontinued or terminated.
• Sponsor may arrange for documented destruction of test article in a manner that does not endanger the safety of humans .
21 CFR 312.59 & 21 CFR 812.110(e)
• Sponsor shall maintain written records of any disposition of drug
21 CFR 312.57

Test Article Accountability
• Obtain IRB written approval prior to administration of an investigational test article.
21 CFR 312.66 & 21 CFR 812.110(a)

Test Article Accountability
• Investigator must properly train all associates involved in the study of their responsibilities and the associated risks and benefits of the test article
• Store in substantially constructed enclosure that is secured with controlled access
• Storage conditions for test article according to Sponsor instructions

Test Article Accountability
• Sponsor’s Responsibilities:
– Maintain records of receipt, shipment and disposition of IND drugs, batch number, and date, quantity and batch code for each shipment to investigational sites and allow for FDA inspection of records and reports .
21 CFR 312.57, 312.58, & 312.59

Test Article Accountability
• Sponsor’s Responsibilities:
– Properly label each unit of test article supplied to investigational sites
– Ship the test article only to qualified Investigators participating in the study.
21 CFR 812.43(b)

Test Article Accountability
• Provide written instructions to the Principal
Investigator for storage conditions and
Subject administration.
21 CFR 312.23
• Monitor the Investigator ’s compliance with regulations and make compliant or terminate if study non-compliance continues.
21 CFR 312.56
• Report to the FDA any Investigator terminated for non-compliance.
21 CFR 312.56

21 CFR 312 & 812

Adverse Event Reporting
• Investigator’s Responsibilities:
– Report to the Sponsor adverse experiences that occur in the course of the investigation 21 CFR
312.64(b)
– AEs that “may reasonably be regarded as caused by, or probably caused by the test article, require prompt notice to the Sponsor.”
21 CFR 312.64(b)
– AEs that are alarming need to be reported to the Sponsor immediately
21 CFR 312.64(b)

Adverse Event Reporting
• Investigator’s
Responsibilities
– The IRB must also be notified in the event of:
• subject deaths,
• serious adverse events, or
• any unanticipated problems involving risk to human subjects
21 CFR 312.66

Adverse Event Reporting
• Sponsor ’s Responsibilities ( 21 CFR 312.32
)
– Timely reporting of associated adverse events that are both serious and unexpected to the FDA and to all investigators, who will then notify their
IRBs
– For Medical Devices, all unanticipated device adverse effects must be reported to the Sponsor and the IRB as soon as possible, but no later than 10 working days after learning of an event.
– For drugs and biologics, Sponsors must report certain adverse events to the FDA in a timely manner:
• 7-day Reports - All unexpected, fatal, or life-threatening experiences associated with the use of the drug. Telephone, followed by written report, within 7 calendar days.
• 15-day Reports – A written report of any adverse experience, both serious and unexpected, and associated with use of the drug, must be reported with in 15 calendar days.

Study Documentation
“In God we trust”
“All others must show documentation.”
Dr. Antoine El Hage, FDA
1999 ACRP Annual Meeting

Study Documentation

Study Documentation
Source document
• The first place data is recorded.
• Subject’s medical chart, laboratory report, nurses’ notes, or any official case history record documenting original observations or activities are examples of source documentation.
• In some cases the CRF may be the source document for certain pieces of data.
• Source documents are used for verification of the data entered on the CRF
Case-report form (CRF)
• Reporting form usually provided by the Sponsor for the collection of data and other protocol required information of each Subject enrolled in a trial.
• The form is used to provide protocol specific data to the trial Sponsor.
• CRF Records may be printed on paper or electronic media (such as magnetic or optical disks).

Study Documentation
Investigator Responsibilities:
• FDA regulations 21 CFR 312 require that an Investigator:
– maintain adequate and accurate case histories
– record all observations and pertinent data to reflect a
Subject’s condition prior to, during, and following participation in a clinical study
– Maintain complete study records that contain a Subject’s:
• definitive diagnosis,
• Test article treatment information
• concomitant or concurrent therapies,
• adverse experiences and related information,
• hospitalization and surgery information - even if the surgery is elective
• any factor that might alter the test article’s effect.

Study Documentation
• Regulatory Documents needed to start study:
– Final protocol, with signature page signed by
Investigator
– Investigator Brochure
– Investigator and staff CVs
– Copy of current Investigator’s medical license
– Signed FDA Form 1572 or Investigator
Agreement
– Financial disclosure
– Written IRB approval of study
– IRB Approved consent form
– IRB membership or assurance statement
– Laboratory certification and Director’s CV
– Lab’s normal reference ranges

Study Documentation
• Document all Sponsor interactions:
– Site evaluation visit report
– Initiation visit report
– Routine monitoring visit reports
– Telephone reports
– Adverse Event reporting
– Patient tracking (screening and enrollment) logs
– Test article accountability
– Regulatory documentation updates
– Close-out visit report

Study Documentation
• Document all IRB interactions after initial approval:
– SAE reports
– IND safety reports
– Protocol amendments
– Consent Form changes
– Location / Staff changes
– Periodic (Continuing Review) reports
– Final report to IRB
– Resolved IRB questions
• Archive with study records in the “Regulatory File”

Study Documentation
• Standard Regulatory Documentation -
Regulatory documents are necessary to demonstrate the study was conducted in compliance with FDA Regulations and ICH and
FDA Good Clinical Practice (GCP) Guidelines.
• The regulatory documentation file is maintained in addition to all source documentation and case report form data.

Study Documentation
• Standard Regulatory Documentation
– Final, signed protocol and amendments
– Signed FDA Form 1572 or Investigator
Agreement and all amended forms
– Financial disclosure documentation
– CVs of Principal Investigator, Sub-Investigator and research staff
– Copy of current state medical license/credentials

Study Documentation
• Standard Regulatory Documentation
– GCP & study training documentation for all staff members
– Responsibility/Delegation-of-authority list
– Copy of IRB-approved informed consent form
– Copy of IRB submissions for protocol, Subject recruitment materials, and consent form(s)
– Copies of IRB approvals for all documents and all amendments
– HIPAA authorization to access PHI

Study Documentation
• Standard Regulatory Documentation
– Copies of IRB correspondence, progress reports, and close-out letter
– IRB membership list or letter describing IRB compliance to 21 CFR 56 regulations, including membership
– All internal and external communications relating to the study: letters, memos, phone contacts, etc.
– Log of monitoring visits and any reports from monitoring visits
– Laboratory certification and laboratory reference ranges for each lab used, and laboratory director’s CV

• Standard Regulatory Documentation
– Original or copy of test article dispensing log for investigational product, and equipment, as appropriate
– Copies of test article shipment documents from Sponsor
– Copy of test article return-shipment documents to Sponsor
– Copies of any information relating to products used in this study

Study Documentation
• Standard Regulatory Documentation
– Copy of the test article randomization code (if available at end of study)
– Information on all AEs, including IRB notification as required
– Original, signed informed consent form(s) for each
Subject (may be more than one per subject)
– Investigator’s Brochure, updates, and IND Safety reports from Sponsor
– Interim and Final Study Reports to IRB

Study Documentation
• RECORD MAINTENANCE AND RETENTION
– FDA 21 CFR 312.62 (c)
An Investigator shall retain records required to be maintained under this part for a period of two (2) years following the date an NDA is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notified.
– ICH 4.9.5
All study-related records are kept for at least two (2) years after a marketing application is approved for the test article in an ICH region, and until there is no pending or contemplated marketing application in an ICH region , or at least 2 years have elapsed since the formal discontinuation of the clinical development of the investigational product. These documents should be retained for a longer period, however, if required by the applicable regulatory requirement or by an agreement with the
Sponsor.

Study Execution Activities
• Because of the huge product development expense ($800MM), drug companies go to extreme measures to assure that the data generated to demonstrate safety and efficacy is the best and most accurate that it can be.
• No other industry both imposes, and has imposed upon it, such oversight at every step of the process.
• There is too much at stake to not be sure it is done correctly….

Study Execution Activities
• For even after all of that, there is no guarantee that the data will demonstrate that a drug is both safe or effective…. as very few drugs that enter the clinic, actually make it to market.
• But it would be unacceptable to have a drug be rejected or need to have studies repeated because of inaccurate data, or the use of data obtained by fraudulent or unethical means.

FDA Audits
• Purpose:
– Ensure compliance
– Ensure data intregrity
• Study-directed audits
• Investigator-directed audits

FDA Audit
• FDA Expects data to be:
– Adequate
– Accurate
– Consistent
– Check compliance:
• FDA regulations
• Protocol
• SOPs

What FDA Looks For
• Who did what
• Degree of delegation
• Where study was performed
• How & where data were recorded
• Drug accountability
• Monitor contact
• Data audit

So, after all of this…..
Who is responsible for ensuring adherence to GCPs?
Regulatory
Agencies
Investigator
Sponsor
You
Institutional
Review
Board (IRB)

ETHICS
PROTECTION
OF HUMAN
RIGHTS
SCIENCE
INTEGRITY AND
REPRODUCIBILITY
OF DATA
COMPLIANCE
Adherence to FDA
Regulations and FDA and ICH
Guidelines
QUALITY STUDY

GCP Guidelines
Guidances
• FDA Information Sheet Guidances for Institutional Review Boards, Clinical
Investigators, and Sponsors
• Financial Relationships and Interests in Research Involving Human
Subjects: Guidance for Human Subject Protection
• Guidance for Clinical Investigators, Institutional Review Boards and
Sponsors Process for Handling Referrals to FDA under 21 CFR 50.54
• Guidance for Clinical Trial Sponsors: Establishment and Operation of
Clinical Trial Data Monitoring Committees
• Guidance for Industry: Acceptance of Foreign Clinical Studies
• Guidance for Industry: Available Therapy
• Guidance for Industry: Collection of Race and Ethnicity Data in Clinical
Trials
• Guidance for Industry: Computerized Systems Used in Clinical Trials
• Guidance for Industry: Development and Use of Risk Minimization Action
Plans
• Guidance for Industry Exploratory IND Studies
• Guidance for Industry: Financial Disclosure by Clinical Investigators
•
Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence
Studies

GCP Guidelines
Guidances
• Guidance for Industry: Good Pharmacovigilance Practices and
Pharmacoepidemiologic Assessment
• Guidance for Industry: Guideline for the Monitoring of Clinical
Investigators
• Guidance for Industry: Guideline for the Study and Evaluation of
Gender Differences in the Clinical Evaluation of Drugs
• Guidance for Industry on Handling and Retention of Bioavailability and Bioequivalence Testing Samples; Availability
• Guidance for Industry : IND Exemptions for Studies of Lawfully
Marketed Drug or Biologicial Products for the Treatment of Cancer
• Guidance for Industry: Information Program on Clinical Trials for
Serious or Life-Threatening Diseases and Conditions Text version of draft guidance
• Guidance for Industry: IRB Review of Stand-Alone HIPAA
Authorizations Under FDA Regulations

GCP Guidelines
Guidances
• Guidance for Industry: Financial Disclosure by Clinical Investigators
• Guidance for Industry: Food-Effect Bioavailability and Fed
Bioequivalence Studies
• Guidance for Industry: Good Pharmacovigilance Practices and
Pharmacoepidemiologic Assessment
• Guidance for Industry: Guideline for the Monitoring of Clinical
Investigators
• Guidance for Industry: Guideline for the Study and Evaluation of
Gender Differences in the Clinical Evaluation of Drugs
• Guidance for Industry on Handling and Retention of Bioavailability and Bioequivalence Testing Samples; Availability
• Guidance for Industry : IND Exemptions for Studies of Lawfully
Marketed Drug or Biologicial Products for the Treatment of Cancer
• Guidance for Industry: Information Program on Clinical Trials for
Serious or Life-Threatening Diseases and Conditions Text version of draft guidance

GCP Guidelines
Guidances
• Guidance for Industry on Part 11, Electronic Records; Electronic Signatures-
-Scope and Application
• Guidance for Industry and FDA Staff: General Principles of Software
Validation
• Guidance for Industry: Pharmacogenomic Data Submissions
• Guidance for Industry: Premarketing Risk Assessment
• Guidance for Industry: Providing Regulatory Submissions in Electronic
Format- Human Pharmaceutical Product Applications and Related
Submissions Using the eCTD Specifications
• Guidance for Industry and Clinical Investigators on the Use of Clinical Holds
Following Clinical Investigator Misconduct [PDF]
• Guidance for Industry on Using a Centralized IRB Process in Multicenter
Clinical Trial
• Guidance for Sponsors, Institutional Review Boards, Clinical Investigators and FDA Staff on Informed Consent for In Vitro Diagnostic Device Studies
Using Leftover Human Specimens that are Not Individually Identifiable

GCP Guidelines
ICH Guidances
• ICH E3: Guideline for Industry Structure and Content of
Clinical Study Reports
• ICH E5: Ethnic Factors in the Acceptability of Foreign
Clinical Data
• ICH E6: Good Clinical Practice: Consolidated Guidance
• ICH E10: Choice of Control Group and Related Issues in
Clinical Trials