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Temple University Office of Clinical Trials Good Clinical Research Practices


Good Clinical Practices and the Clinical Research Process ... 2. Research should yield fruitful results for the good of society. ... – PowerPoint PPT presentation

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Title: Temple University Office of Clinical Trials Good Clinical Research Practices

Temple University Office of Clinical Trials Good
Clinical Research Practices
  • Objectives
  • To reinforce many of the GCPs, principles and
    practices for developing new pharmaceuticals
    through an exploration of the WHYS to underscore
    the HOWS.
  • For everyone to further understand and appreciate
    the significant role each of you play in
    developing new forms of therapy in improving

Why is this important?
1. To refresh your state of awareness regarding
recent regulatory initiatives and concerns,
important contemporary issues and recent FDA
enforcement activities. 2. To provide ample
opportunity to share experiences and gain a
practical perspective on what works and what
needs fine tuning to improve the quality of
clinical research. 3. To sharpen your ability
to identify site performance drivers while
effectively and efficiently managing your
clinical trial.
Principles of Clinical Research The Good
Clinical Practices (GCPs)
  • Good Science
  • Sound Ethical Conduct
  • Good Statistical Design
  • Integrity and Quality
  • Good Business Practices Approval of a new

Good Clinical Practices and the Clinical Research
  • GCPs are standards developed by industry
    addressing how clinical trails are designed,
    implemented and reported to ensure that data are
    credible, complete, correct and accurate.
  • GCPs also address the rights, integrity,
    protection and confidentiality of human research
  • GCPs are responsibilities shared by all
    participants in the evaluation of new products
    for the healthcare marketplace.

Good Clinical Practices
Shared Responsibilities
  • FDA
  • Sponsor
  • Investigator
  • IRB
  • Research subject/patient

Why are there Laws and Regulations?
  • To ensure the welfare and protection of human
    research subjects.
  • To ensure the integrity and reliability of data
    submitted in support of a marketing application.
  • To ensure that clinical research is conducted in
    a consistent and uniform manner.
  • To never forget that history has a tendency to
    repeat itself and laws are too frequently enacted
    as a result of a catastrophe.

What do we need to prove to the FDA about a new
Safety………………………………..Are the side effects
acceptable? Tolerability……………………………Will it be
taken? Efficacy……………………………….Can it
work? Efficiency……………………………...Does it provide
sufficient value to the healthcare
consumer? The FDA relies on the integrity of the
clinical trial and the quality of the data on
which to base its decision to approve the new
drug for use. The pharmaceutical manufacturer
must provide those assurances.
Good Clinical Practices What are they?
  • No single document
  • Collection of guidelines and regulations each
    addressing specific aspects of clinical research
    and human subject protection.
  • GCPs are industry-created standards by which
    clinical trials are designed, implemented,
    conducted, monitored and reported so that there
    is assurance that the data are complete,
    correct and accurate and that the rights,
    welfare and confidentiality of the research
    subjects are adequately protected.

What are the GCPs?
  • Industry initiated-
  • Elements contained in Title 21 of the Code of
    Federal Regulations Parts
  • 50,56,312,314,812,820, etc.
  • Designed to
  • Protect the safety and rights of human research
  • Ensure the quality and integrity of data.
  • Protocol
  • Investigator selection
  • Monitoring (and training of)
  • Documentation
  • Reporting
  • Test article accountability
  • Computer system

The Basic Principles of Good Clinical Practices
Current Standard Operating Procedures Informed
Consent process Institutional Review Board
approval Compliance with study protocol and
related procedures Controls of investigational
supplies Sponsor/Monitor/Investigator
responsibilities Adequate safety
surveillance Quality Assurance
Where are the GCPs Anchored? Their Origin
  • Regulations
  • Food, Drug and Cosmetic Act
  • US Public Service Act
  • Ethical Codes and initiatives
  • Nuremberg Code
  • Declaration of Helsinki
  • National Research Act
  • National Bioethics Advisory Commission
  • Office for Human Research Protections

Ethical Principles on which the Practice of
Clinical Research is Based ie ., GCP
Nuremberg Code Declaration of
Helsinki Belmont Report
Nuremberg Code (What it really means)
1. Voluntary consent is essential… 2. Research
should yield fruitful results for the good of
society. 3. Research should be based on animal
experiments and a knowledge of pathophysiology of
the disease to justify the research… 4. Research
should be conducted to avoid all unnecessary
physical and mental suffering/injury… 5.
Research should not be conducted where there is
prior knowledge to that death or disability will
occur… 6. Research should be conducted only
where the benefit outweighs the risk….
Nuremberg Code (What it really means)
Continued 7. Research should be conducted in
adequate facilities to ensure against the
possibilities of injury, disability, or
death. 8. Research should be conducted only by
scientifically qualified individuals. 9.
Research should be constructed to permit the
human research subject to terminate
participation. 10. Research should be designed
to permit the qualified individual in charge to
terminate the trial at any stage if there is the
possibility of injury, disability, or death...
Where are the GCPs Anchored? The Core
Regulations for informed consent Regulations for
IRBs Regulations defining the responsibilities
of the sponsor and investigator Guidelines for
the monitoring of clinical investigations FDA
information sheets (www.fda.gov/oc/oha/irb/toc.htm
) ICH GCP consolidated guidelines
Good Clinical Practices and the Investigative
It is a standard for the... Design Conduct
Performance Monitoring Analysis
Good Clinical Practices and the Investigative Site
It provides assurance that the... Data and
reported results are credible. Rights,
integrity and confidentiality are
observed. Research subjects are adequately
protected. Integrity and Quality meet FDA
Characteristics of Good Clinical Practices
- Principles and Practices
  • Clinical research trials are designed to answer
  • Clinical research should be scientifically sound.
  • Foreseeable risks and inconveniences are to be
    considered against anticipated benefits.
  • Clinical research should be conducted in
    accordance with the ethical principles of the
    Nuremberg code and Declaration of Helsinki and
    consistent with applicable FDA requirements.
  • Available preclinical and clinical information of
    the investigational product should provide
    adequate knowledge to support the clinical
  • Rights, safety, and well-being of the research
    subject are of the utmost importance.
  • Medical care provided to a research subject
    should always be the responsibility of a
    qualified individual.
  • Clinical research should be conducted in
    compliance with a protocol that has received IRB

Principles of Clinical Research The Good
Clinical Practices (GCPs)
  • Continued
  • The qualified individual must always understand
    and be willing to carry out his/her
    responsibilities (FDA Form 1572).
  • Informed consent should be obtained from every
    research subject prior to clinical trial
  • All clinical trial information should be
    recorded, handled, and stored in a way that will
    afford and ensure accurate reporting, monitoring,
    interpretation and verification.
  • Insure confidentiality of records that could
    identify the research subject.
  • Investigational products should be handled and
    stored in accordance with GMPs.
  • Investigational products should be dispensed and
    administered in accordance with approved
  • All serious adverse experiences should be
    reported to the sponsor and IRB in accordance
    with and in a manner consistent with
    institutional policies, federal regulations and
    the sponsors SOPs.

Good Clinical Practices
Guidelines for Clinical Trials (IND)
  • FDA Guideline for Monitoring of Clinical
    Investigations (1988).
  • FDA Information Sheets for Investigators/IRBs.
  • FDA Compliance Program Guidance Manuals
  • IRB
  • Investigators
  • Sponsor/Monitors
  • FDA Clinical Guidelines, Points to Consider, and
    Related Guidelines.
  • FDA Draft Consolidated Guidelines, ICH… GCP, May
  • FDA IND Process and Review Procedures (MaPP

Good Clinical Practices
  • Regulations for Clinical Trials
  • (IND)
  • Protection of Human Subjects
  • 21 CFR part 50
  • Institutional Review Board
  • 21 CFR part 56
  • Investigational New Drug Application
  • 21 CFR part 312 (Subpart D- Responsibilities of
    Sponsors and Investigators)

Good Clinical Practices
Regulations for Clinical Trials
  • Elements-
  • Investigational plans and strategies
  • 21 CFR 312.23 (a) (3)
  • Protocols - development and review 21 CFR 312.23
    (a) (6)
  • Monitors - selection and training
  • 21 CFR 312.53 (d)
  • Investigators Sites - selection
  • 21 CFR 312.53 (a)

Good Clinical Practices
Regulations for Clinical Trials
  • Continued
  • Information to investigators - provisions
  • 21 CFR 312.55
  • Investigational drug - control
  • 21 CFR 312.59 312.61
  • Monitoring - clinical trials
  • 21 CFR 312.56
  • Safety information - receipt and transfer
  • 21 CFR 312.32 312.33 312.58 312.64

Commitments of the Clinical Investigator Responsi
bility and Accountability
What is the FDA Form 1572? 21 CFR 312.53(c)
  • State meet of Investigator.
  • Contract between investigator and FDA (TAKE IT
  • Federal document required by FDA prior to
    conducting a clinical trial on a drug under an
  • Provides detailed information about the
    investigator, protocol (beyond the title and
    number, it is provided as an attachment), phase
    of the study, location of the study site, IRB,
    sub-investigators/support staff assisting, and
    the location of the clinical laboratory and/or
    where specimens will be analyzed.
  • Specifically lists the obligations of the
    investigator(s) Section 9.
  • Study drug can only be shipped to address listed
    on 1572.

What are the Investigators Commitments?
  • Conduct the study according to the protocol.
  • Personally conduct or supervise all research.
  • Fully inform participating patients and obtain
    IRB approval for the protocol and informed
  • Report all adverse experiences.
  • Acknowledge that he/she has read the
    investigators drug brochure, including sections
    on risks and side effects to patients.
  • Ensure that the study staff assisting in the
    study are informed of its obligation.
  • Keep adequate records and have them available for
  • Utilize an IRB that complies with FDA
  • Compliance with all other federal requirements.

Your Responsibilities - FDA Form 1572 You Signed
it -Youre Accountable!
  • Who is responsible and why?
  • To whom can you delegate authority?
  • How do you document delegation of authority?
  • What are the responsibilities of the Principal
  • FDA Form 1572, Section 9 - Commitments

Commitments of the Sponsor Responsibility, Authori
ty and Ultimate Accountability
Good Clinical Practices
Sponsor Responsibilities
Protocol development Investigator
selection Product information Supplying and
handling of investigational drug Monitoring of
clinical trials Safety monitoring Developing
SOPs Data management and reporting Quality
What are the Responsibilities of the
Sponsor/CRO? It pays to understand the
  • Develop and maintain SOPs
  • Select investigators
  • Conduct pre-study site visit
  • Develop, maintain and distribute the
    Investigators Drug Brochure
  • Conduct study initiation
  • Develop objectives for the monitoring visit
  • Follow progress of study

What are the Responsibilities of the
Sponsor/CRO? It pays to understand the
  • Continued
  • Confirm investigator compliance to the protocol
  • Ensure research subject protection
  • Verify the completeness and accuracy of data
  • Act as a logical resource
  • Objectives of the monitoring visit report
  • Disposition of research subjects
  • Disposition of investigational drug
  • Identifying, recording and reporting of adverse
    experiences and follow up
  • Clarification of illegible entries on CRFs
  • Verification of concomitant medications and
    concurrent illnesses

What are the Responsibilities of the
Sponsor/CRO? It pays to understand the
  • Continued
  • Documentation and adherence of
    Inclusion/Exclusion criteria
  • IRB communication and reporting
  • Objectives of the close-out
  • Investigator should be available to answer any
    questions arising from the sponsors review of
    study data.
  • Investigator must ensure that all CRFs,
    regulatory documents and study related files
    should be safely stored and available for FDA
  • Investigator must notify the IRB that the study
    is closed and documentation is provided that all
    SAEs are summarized and reported.

Good Clinical Practices
Monitor Responsibilities
Monitoring procedures (SOPs). Pre-study
visits. Periodic visits. Review subject
records/source documents. Study close-out
visit. Documentation of monitoring
visits. Effectively manage site.
Clinical Research-perception vs reality and is
there really adequate protection of human
research subjects?
  • The effective clinical research process depends
    on the publics perception and understanding of
    what we do.
  • The effective clinical research process as part
    of the research and discovery of new
    pharmaceuticals depends on successful patient
    recruitment and their retention in clinical
  • In clinical research, industry must never
  • allow the patient to be exposed to unnecessary
    risks or give the patient the perception of being
    treated like a guinea pig,
  • cut corners to seek FDA approval at the expense
    of the healthcare receipt,
  • forget our responsibility to oversee/monitor the
    physician conducting the clinical trial,
  • forget to remember than our image is easily

In Summary….
GCPs are designed to accomplish two primary
goals To protect the rights and welfare of
human research subjects participating in clinical
research. To ensure the quality and integrity of
the data obtained from clinical research.
GCPs- The Practical Side of Patient Care
In clinical research we only see what we expect
and recognize what we know.
Additional Information The Pharmaceutical
Industry- A state of excitement and transition
The Role of the Pharmaceutical Company in Todays
Health Care Marketplace
  • Discover and develop new and innovative drugs
    using the latest technologies.
  • Rapidly and safely develop these drugs into
    useful therapeutic tools.
  • Manufacture and distribute these drugs according
    to current Federal regulations.
  • Invest the profits to develop new therapies in a
    timely and cost efficient manner.

Facts about the U.S. Pharmaceutical Industry
  • In 1998, 30 unique and innovative drugs were
    approved for alzheimer's, epilepsy,
    schizophrenia, depression, etc.
  • Many of these new drugs were approved by FDA in
    record time - 3 to 9 months, average time 11.7
  • In 1999, research-based pharmaceutical companies
    will invest 24 billion in RD, 14 increase over
  • Of the 24 billion, 16 billion will be spent on
    clinical development 5 billion ---gt CROs
  • The pharmaceutical industry is now facing
    significant challenges
  • increasing RD expenses
  • new regulations
  • major patent expiration
  • major competition to be first
  • consolidations

If a new drug does reach the market in a timely
manner, another problem faces the pharmaceutical
industry… Under managed care, FDA approval of a
new drug does not guarantee complete and
unrestricted access to the physician/patient… FDA
approval only permits the manufacturer to
petition for formulary committee approval before
the drug can be prescribed to the patient of the
health care plan… The physician is no longer the
deciding factor in selecting the treatment
available to the patient… The industry must
struggle to penetrate the therapeutic
marketplace…its slower and more controlled.
A very important reality… Clinical trials are
becoming increasingly complex
  • Greater number of subjects per trial
  • Broader range of subjects characteristics -
    disease complexity
  • More documentation and case report forms per
  • Increased number of procedures per subject in all
  • Longer subject participation time in a trial to
    ensure S/E
  • Increasing focus on chronic rather than acute
  • Increasing number of study sites per trial-
    including wider geographical distribution
  • Pediatric, gender and radial balance
  • Increasing reliance on CROs
  • Implementation on GCPs, ICH-GCPs, and new
    European Directives
  • Differences in medical practice across
    participating countries
  • Regulatory audits and QA inspections - sponsor
    and FDA

The New Realities of Drug Development
  • Combinatorial chemistry- create new drugs at
    10,000 times the recent rate of discovery at 1/10
    of the cost.
  • High throughput screening- automation, robotics,
    and miniaturization - increase screening of new
    drugs by 100.
  • Genomics- will enable the development of 3,000 to
    10,000 gene-targeted by 2010.
  • Industry has to catch up!

Prolific discovery and pharmacogenomics present
tremendous RD opportunities and marketing
challenges for industry in its existing form
The New Realities of Drug Development
  • Regulations are stringent and review approval
    process is lengthy.
  • FDA Modernization Act - 1997 Highlights
  • Pediatric Studies
  • Streamlining clinical research on drugs
  • Study and approval of fast track drugs
  • Number of clinical trials
  • Data requirements for drugs and devices
  • Reports of post-marketing trials
  • Special review for certain trials
  • Gender and racial balanced clinical trials
  • Expanding humanitarian use of devices

Approval Times for New Drugs (MEAN) and Total
Number of New Drugs Approved Each Year
Time Drugs Approved 1998___11.7
………………………………………………….30 1997____16.2………………………………………
…………39 1996_____17.8………………………………………………..53 1995___
___19.2………………………………………………28 1994_______19.7…………………
…………………………..22 1993__________26.5…………………………………………2
5 1992___________29.9……………………………………….26 1991______
______30.3……………………………………...30 1990___________27.7…
……………………………………..23 1989_________________32.5………………
……………….23 1988_____________________31……………………………20
1987___________________________32.4…………………21 FDA
The Benefits of New Drug Development
Disease App. of pts App. Annual of New
Drugs cost (billions)
RD Alzheimers 4,000,000 100
17 Arthritis 40,000,000 55 28 Asthma
14,000,000 6 17 Cancer
8,000,000 107 316 CHF 14,000,000 20
17 CHD 13,900,000 96 38 Depression
17,600,000 53 13 Diabetes
15,700,000 98 21 Hypertension
50,000,000 32 10 Osteoporosis
10,000,000 14 27 Schizophrenia
1,500,000 43 12 Stroke 4,000,000 43
Includes medical expenditures and lost
productivity (Pharma 1999)
Annual Cost to Treat Disease
Schizophrenia (43 drugs in RD) 1.5 million
patients 10 billion in direct direct/indirect
costs 13 billion in lost productivity Cancer
107 billion (940 drugs in RD) 37 billion in
direct indirect costs 59 billion in mortality
costs 11 billion in lost productivity Cardiovas
cular Disease (360 drug in RD) 59 million
people suffer from some form of cardiovascular
disease. 960,000 die from CVD each year. 274
billion in direct/indirect costs
The RD Commitment to Research of New
Pharmaceuticals (dollar figures in billions)
  • 1999 RD investment - 24 billion
  • CNS 5.6
  • Metabolic Cancer 4.8
  • Biologicals 2.0
  • Digestive Genito/Urinary 0.8
  • Respiratory 1.3
  • Infectious Disease 3.4
  • Cardiovascular 3.5

The RD Process Lengthens… Average Number of
Clinical Trials Per NDA
Phase III additional testing
FDLI Journal, vol 52, 1997
The RD Process Lengthens… NDAs Require More
Research Subjects
More first in class drugs
FDLI Journal, vol 52, 1997
Percentage of Sales Allocated to RD
Research-based Pharm. Co Office equipment
services Electrical and Electronics Telecommunicat
ions Automotive Aerospace and Defense Metals and
Mining Paper and Forest Products All industries,
excluding pharmaceuticals Pharma and Standard
and Poors Compustat, 1999
The New Realities of Drug Development
Potentially negative publicity regarding
fraudulent clinical research and inadequate
protection of human research subjects.
  • Important issues
  • Criticism of drug trials on the rise
  • Clinical research - perception vs reality
  • Is there really adequate protection of human
    research subjects?
  • There is an issue of trust-
  • in the process,
  • in the physician - investigator,
  • in the IRB, and
  • in the pharmaceutical industry.

Negative Publicity
  • Important Issues
  • Critisim of drug trials on the rise
  • Clinical Research - Perception vs Reality
  • Is there really adequate protection of human
    research subjects?
  • As an issue of trust-
  • in the process?
  • In the physician-investigator?
  • In the pharmaceutical industry?

Criticism of Drug Trials on the Rise
  • controversies involving clinical trials
  • Year Newspaper articles
  • 1995 19
  • 1996 30
  • 1997 50
  • Source CenterWatch review of 248 articles in
    105 newspapers form 1995-June 1997

What is Clinical Research?
  • Broadly divided
  • Therapeutic and Nontherapeutic
  • Sponsored/Funded and Regulatory
  • Specifically, regulatory research is for the
    purpose of the commercialization of a new drug
  • Systematic investigation of a new drug.
  • Discover or verify the effects or identify
    adverse events of a new drug.
  • Investigate the pharmacokinetics and
    pharmacodynamics of a new drug to determine its
    safety and efficacy.
  • Primary intention is to advance the knowledge of
    a new drug so that patients in general will not
    be harmed and may benefit

Clinical Research Considerations...
Clinical investigation follows two broad
pathways… Clinical Trials are well-defined
studies in human subjects involving a therapeutic
or diagnostic intervention with a drug, device or
other health care product to answer a specific
question as opposed to offering immediate
therapeutic benefit. Clinical trials involving
new drugs are developed with the risk to benefit
relationship in mind. Research enhances
generalizable knowledge as opposed to clinical
care which enhances the well-being of an
What is a Clinical Trial?
A clinical trial is a scientifically and
ethically designed experiment for the purpose of
answering some precisely framed question that
will yield generalizable information.
What is the Purpose of the Clinical Research
Trial in the Development of a New Pharmaceutical?
Clinical research should Define therapeutic
benefit Prove safety and demonstrate
efficacy. Show improved risk to benefit
relationship compared to existing
therapies. Define how to use the new
drug Indication Dosing Formulation Individualized
use Drug variability Tolerance Resistance Determi
ne the economics of using the new drug
What is the purpose of Clinical Research?
Primary objectives 1. Establish a therapeutic
benefit Demonstrate safety, tolerability, and
dose ranging… Demonstrate efficacy… Demonstrate
greater benefit to risk relationship… Determine
an improved quality of life and greater cost
What is the purpose of Clinical Research?
Primary objectives 2. Define how to use the
drug Indications- what is the population(s) most
likely to benefit from the new drug? Dosing- what
is the optimal drug exposure for maximal efficacy
with minimal adverse events? Formulation- what is
a practical formulation and drug delivery
method? Individualized use- how to characterize
the effects of individual patient physiology on
the drugs disposition and actions? Drug
variability- what are the effects of food,
concomitant medications, medical conditions, and
patient compliance? Tolerance- what is the
possibility that patients may be less responsive
to the new drug with prolonged exposure?
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