Clinical Trials and Good Clinical Practice

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Clinical Trials and Good Clinical Practice

• M Suzanne Stratton, PhD
• Research Assistant Professor of Medicine
• Director, Prostate Cancer Prevention Program
• Co-Chair, Institutional Review Board

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Lecture objectives

• Become familiar with clinical trial types/phases
• Gain familiarity with government oversight of
  clinical trial practices
• Learn about what it takes to bring a drug from
  bench to bedside
• Learn about Good Clinical Practice using the
  example of an ongoing Phase III trial testing
  selenium as a chemopreventive agent

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What is a clinical trial?

• A clinical trial (also clinical research) is a
  research study in human volunteers 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.
• Interventional trials determine whether
  experimental treatments or new ways of using
  known therapies are safe and effective under
  controlled environments.
• Observational trials address health issues in
  large groups of people or populations in natural
  settings.
• What are the steps to drug approval or (in the
  clinic)?

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Types of clinical trials

• Treatment trials test experimental treatments,
  new combinations of drugs, or new approaches to
  surgery or radiation therapy.
• Prevention trials look for better ways to prevent
  disease in people who have never had the disease
  or to prevent a disease from returning. These
  approaches may include medicines, vitamins,
  vaccines, minerals, or lifestyle changes.
• Diagnostic trials are conducted to find better
  tests or procedures for diagnosing a particular
  disease or condition.
• Screening trials test the best way to detect
  certain diseases or health conditions.
• Quality of Life trials (or Supportive Care
  trials) explore ways to improve comfort and the
  quality of life for individuals with a chronic
  illness.

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Interventional clinical trial phases

• Clinical trials are conducted in phases. The
  trials at each phase have a different purpose and
  help scientists answer different questions
• In Phase I trials, researchers test a
  experimental drug or treatment in a small group
  of people (20-80) for the first time to evaluate
  its safety, determine a safe dosage range, and
  identify side effects.
• In Phase II trials, the experimental study drug
  or treatment is given to a larger group of people
  (100-300) to see if it is effective and to
  further evaluate its safety.
• In Phase III trials, the experimental study drug
  or treatment is given to large groups of people
  (1,000-3,000) to confirm its effectiveness,
  monitor side effects, compare it to commonly used
  treatments, and collect information that will
  allow the experimental drug or treatment to be
  used safely.
• In Phase IV trials, post marketing studies
  delineate additional information including the
  drug's risks, benefits, and optimal use.

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Phase I Trials

• First time in humans
• May not be required if drug is well-known dietary
  supplement, e.g. Vitamin E or selenium for
  chemoprevention
• Primary objective is safety
• Pharmacokinetic data is often obtained
• Small numbers of subjects
• Usually healthy subjects (not in cancer)
• Identifies likely dose range
• Dose tolerance/escalation performed especially if
  dose is to be based on toxicity (cancer
  therapeutic drugs)

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Phase I Trials (Continued)

• Length several days to several weeks
• Closely monitored
• Special indications (Cancer, HIV)
• Performed in subjects with condition for whom
  conventional therapies have failed or are not an
  option

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Phase II Trials

• Safety efficacy in select population
• Larger than Phase I (50-200 subjects)
• Usually no comparator arm
• Chemoprevention Phase IIa
• Dose-finding based on efficacy in small of
  patients
• Chemoprevention Phase IIb
• Efficacy study of one dose, often compared to
  placebo in larger of patients
• Seeking maximum benefit with minimal side effects
  

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Phase III Trials

• Definitive studies, Multicenter,
• Confirm safety efficacy in large population
  (100 2500 subjects/study)
• Randomized comparison is drug vs. placebo (or
  current standard of care)
• 2 pivotal studies generally required
• Demonstrates reproducibility of results
• NDA approval will be based on data from these
  studies

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Phase III Trials (Continued)

• Provides adequate basis for labeling
• Therapeutic market advantages
• Broad demographics required for generalization
• Ethnic geographic representation required

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Phase IV

• Studies often compare a drug with other drugs
  already in the market
• Studies are often designed to monitor a drug's
  long-term effectiveness and impact on a patient's
  quality of life
• Many studies are designed to determine the
  cost-effectiveness of a drug therapy relative to
  other traditional and new therapies.

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Clinical trial oversight

• FOOD AND DRUG ADMINISTRATION (FDA) The U.S.
  Department of Health and Human Services agency
  responsible for ensuring the safety and
  effectiveness of all drugs, biologics, vaccines,
  and medical devices
• http//www.fda.gov/oc/gcp/default.htm
• Center for Drug Evaluation and Research (CDER)
• Assures safe drugs in the US

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CDER History

• 1902 - Harvey Wiley, the Chief Chemist of the
  Bureau of Chemistry, announced the formation of a
  Drug Laboratory within his organization.
• 1906 Pure Food and Drugs Act (one-man operation)
  FDA
• 1910 First challenge to enforce regulation when
  a bogus cancer drug was sold with false
  advertising
• 1926 First standardized manufacturing testing
  in response to several deaths from impurities in
  anesthetics
• 1937 FDA requirement of NDA
• 1940s FDA assumed oversight for testing of
  penicillin, insulin and use labeling
• 1966 Reformed organization
• Office of New Drugs
• Office of Drug Surveillance
• Office of Medical Review
• Bureau of Veterinary Medicine

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CDER History

• 1962 - Kefauver-Harris Amendments in response to
  the narrowly missed disaster of thalidomide
• To comply with the new amendment, previously
  approved drugs were tested for efficacy
• Of 3,443 products, 2,225 were found to be
  effective, 1,051 were found not effective (1984)
• 1972 the results of the ongoing review were
  published in a monograph entitled the Code of
  Federal Regulations (CFR)
• specifying the active ingredients, restrictions
  on formulations, and labeling by therapeutic
  category
• 1980 Center for Drugs and Biologics was formed
• 1987 Broken into two Centers
• Center for Biologics Evaluation and Research
  (CBER)
• Center for Drugs Evaluation and Research (CDER)
• 1995 CDER broken into divisions by indication
  type

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Mike Leavitt
Last revised January 11, 2006
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Bench to Bedside
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IND Application

• There can be exemptions
• Provides a means of advancing from pre-clinical
  to clinical testing
• Required for unmarketed/unapproved products
• May be required for already marketed products
• Formal application to study an intervention in
  patients
• Commercial - sponsor usually a pharmaceutical
  company
• Non-commercial
• investigator IND
• treatment IND

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IND contents

• Should include the following data
• Chemistry, manufacturing, and control information
  
• animal pharmacology / toxicology
• prior human use if applicable
• clinical protocol(s) and investigator information
• Other required documents
• Cover Sheet (Form 1571 or 2)
• Table of Contents
• Introductory Statement and General
  Investigational Plan
• Investigational Brochure
• Informed Consent Form

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IND review

• 30-day review clock
• Clinical hold
• Safety concerns (e.g., known risk, inadequate
  information, Investigators Brochure (IB)
  misleading, Principal Investigator (PI) not
  qualified)
• Design will not allow protocol objectives to be
  met
• Teleconference with sponsor and division director
  about what is required to lift the hold

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Bench to Bedside
Institutional Review Board (IRB) Human Subject
Protection Committee (HPSC)
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Good Clinical Practice

• Relationship between Sponsor and Investigators
• Focuses on the investigator commitments signed
  for on the FDA Form 1572
• Inspection and audits usually announced in
  advance
• Inspections are either routine or directed
• Compliance classifications
• NAI No Action Indicated. In compliance
• VAI Voluntary Action Indicated.
• OAI Official Action Indicated. Serious
  non-compliance Warning Letter, study rejection,
  investigator disqualification

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Sponsor investigator responsibilities

• Selecting qualified investigators
• Providing the investigators with the information
  they need to conduct an investigation properly
• Ensuring proper monitoring of the investigation
• Ensuring that the investigation is conducted in
  accordance with the general investigational plan
  and protocols
• Ensuring that the FDA, IRB, and other
  investigators are promptly informed of
  significant new adverse events or risks with
  respect to the drug
• Documentation
• Updated versions of Investigators Brochure
• Updated versions of the protocol
• Keep investigators aware of any safety issues

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Study conduct

• Make sure that the study is conducted as outlined
  in protocol
• Provide protocol amendments to IRB, FDA, and site
  investigators
• Report adverse events to IRB, FDA and site
  investigators
• Provide updated IB to IRB, FDA and site
  investigators
• Monitor site investigators compliance with
  protocol
• Remove non-compliant investigators
• Maintain records
• Permit FDA inspection
• Dispose of unused drug
• Provide reports to the FDA annual reports,
  safety reports, final study report, financial
  disclosure

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Required safety reporting

• Any AE associated with a drug that is both
  serious and unexpected
• Any findings from tests in laboratory animals
  that suggests a significant risk for human use
  (e.g., positive mutagenicity, carcinogenicity, or
  tetratogenicity) within 15 days of initial
  notification
• Any unexpected fatal or life-threatening AE that
  is associated with use of the drug within 7 days
  

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New Drug Application (NDA)

• Formal application to market a new product (drug)
• Requirement since 1938 (FD C Act)
• safety information
• Kefauver-Harris Amendments 1962
• evidence of efficacy and risk/benefit assessment
• NDA classification
• New Molecular Entity
• New Indication for Already Marketed Drug
• New Formulation
• New Combination of Two or More Drugs
• Others

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Basis for NDA approval

• Demonstration of efficacy with acceptable safety
  in adequate and well-controlled studies
• Ability to generate product labeling that
• Defines an appropriate patient population for
  treatment with the drug
• Provides adequate information to enable safe and
  effective use of the drug
• Accelerated approval
• Commonly used endpoints for approval
• Survival (the gold standard)
• Prolongation in time to recurrence or
  disease-free survival (commonly used in adjuvant
  studies)
• Prolongation in time to progression
• Palliation (objective response with reduction in
  tumor-related symptoms)
• Prevention of disease or surrogate endpoint

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Why NDAs fail

• Poor Drug Development
• Inadequate early development
• Study Design
• Populations, endpoint definitions, analysis plan
• Study Execution
• Failure to maintain adequate records (dose, drug
  disposition, adverse events)
• Failure to adhere to regulations

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IND Safety Reporting Shared Responsibility

• Sponsor
• Collect submit all safety data in a timely
  manner
• Must update IB
• Must notify PIs and IRB
• Initiate, audit, terminate clinical site
• FDA
• Review, analyze reports
• Require changes to protocol or consent as needed
  to protect patient safety

• PI
• Evaluate and report toxicities
• IRB
• Independently review toxicities and recommend
  changes
• Patient
• Education, adequate informed consent
• Repeat consent if necessary

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Phase III Study Testing Selenium as a
Chemopreventive Agent for Prostate Cancer in
High-Risk Men
How did we get up and running?How do we
run?What are some of the regulatory issues?How
will it end?
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Why selenium?

• Some cancer prevention studies work backwards
• Preclinical studies were not done before study
  initiation
• Mechanistic studies are now ongoing
• In vitro
• In vivo
• This is now rare and preclinical studies are
  required for natural products (vitamins and
  supplements)

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Selenium background

• Discovered in 1817 by Jons Jakob
• Named after Selene, the Greek Moon Goddess
• Initial interest due to toxicity
• Alkali disease, staggers, hoof deformaties
• Prevented liver necrosis in rats
• Livestock white muscle disease
• Low intake associated with Kashin-Beck and
  Keshans disease
• Deficiencies reported in New Zealand

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Selenium and overall cancer risk
Epidemiological
Results
Se Measure
Population
Study
Shamberger and Frost, 1969
Inverse
Grain/forage Blood
USA/Canada
Schrauzer, 1976
Inverse
Diet
27 countries
Clark, 1985
Inverse
Forage crop
USA
Yu, 1985
Inverse
Forage crop
China
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Epidemiological studies and prostate cancer
Results
Se Measure
n
Population
Study
0.30 (p trend 0.18)
Plasma
13
USA
Coates et al., 1988
1.15 (p trend 0.71)
Serum
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Finland
Knekt et al., 1990
Inv (p trend 0.44)
Plasma
60
USA
Criqui et al., 1991
0.69 (0.03-2.5)
Se in water
27
Italy
Vinceti et al., 1995
0.37 (0.18-0.71)
Se suppl.
USA
Clark et al., 1996
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1.27 (0.70-2.20) 0.84 (0.43-1.67)
Diet Self suppl.
317
Finland
Hartman et al., 1998
Relative Risk in highest versus lowest quartile.
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Epidemiological studies and prostate cancer
Results
Se Measure
n
Population
Study
0.35 (0.16-0.78)
Toenail
181
USA
Yoshizawa et al., 1998
0.50 (p trend 0.02)
Serum
249
Japan-Am
Nomura et al., 2000
1.14 (0.46-2.83)
Toenail
83
Canada
Ghadirian et al., 2000
Relative Risk in highest versus lowest
quantile. Source Vinceti, M. et al., The
Epidemiology of Selenium and Human Cancer.
Tumori, 86 105-118, 2000.
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Clinical studies with selenium
Results
Treatment
n
Population
Study
Chinese
0.87 (0.75-1.00)
81
50 mg
Blot et al., 1985
0.63 (0.47-0.85)
200 mg
USA
Clark et al., 1986
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Relative Risk in selenium exposed versus
selenium unexposed.
IND submitted and approved
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NPC Study Design

• Double-blind
• Randomized
• Placebo-controlled
• 1312 participants with a history of nonmelanoma
  skin cancer
• Randomized to receive 200mg selenized yeast daily
  or placebo
• Clinics in the Eastern U.S.

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NPC Study Design
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Summary of primary analyses
JAMA. 1996 Dec 25276(24)1957-63.
Smoking status
No apparent difference
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Site specific cancer incidence
JAMA. 1996 Dec 25276(24)1957-63.
Adjusted
Unadjusted
Case No.
Site
p
(95 CI)
HR
p
(95 CI)
RR
Plac
Se
Prostate
0.005
0.28-0.80
0.48
0.009
0.29-0.88
0.51
42
22
0.26
0.44-1.24
0.74
0.18
0.40-1.21
0.70
35
25
Lung
0.057
0.21-1.02
0.46
0.055
0.19-1.08
0.46
19
9
Colorectal
Other car.
0.44
0.24-1.88
0.67
0.44
0.19-2.07
0.66
9
6
62 decrease in incidence in prostate cancer
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Cumulative hazard ratio by treatment group
JAMA. 1996 Dec 25276(24)1957-63.
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Prostate Cancer Incidence by Tertile of Baseline
Plasma Selenium
BJU Int. 2003 May91(7)608-12
Adjusted
Unadjusted
No. Cases
Baseline
p
p
(95 CI)
HR
(95 CI)
RR
Plac
Se
Se ng/ml
0.009
0.03-0.61
0.14
0.002
0.02-0.59
0.14
15
2
106.4
0.02
0.13-0.82
0.33
0.03
0.14-0.99
0.39
16
7
106.8-123.2
0.75
0.51-2.59
1.14
0.66
0.50-2.97
1.20
11
13
gt 123.2
RR indicates relative risk CI indicates
confidence interval. P values derived from log
rank tests. HR indicates hazard ratio. P values
from the Cox proportional hazard model adjusted
for gender, age (continuous) and smoking
(never, former, current) at randomization.
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Prostate Cancer Incidence by Baseline PSA
BJU Int. 2003 May91(7)608-12
Adjusted
Unadjusted
No. Cases
Baseline
p
(95 CI)
HR
p
(95 CI)
RR
Plac
Se
PSA ng/ml
0.01
0.33
0.01
0.13-0.87
0.35
20
7
4.0
0.09
0.95
0.86
0.36-2.13
0.88
13
11
gt 4.0
RR indicates relative risk CI indicates
confidence interval. P values derived from log
rank tests. HR indicates hazard ratio. P
values from the Cox proportional hazard model
adjusted for gender, age (continuous) and
smoking (never, former, current) at randomization.
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Summary of Prostate Data

• Lower biopsy rate in the treatment group
• Lower incidence in two lower tertiles of baseline
  selenium
• Lower incidence with baseline PSA 4
• Smoking status and age No effect

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The Negative Biopsy Study (NBT)
Anticancer Drugs. 2003 Sep14(8)589-94
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Final analyses of primary endpoint (SCC
recurrence)
JNCI 95(19). Oct 1, 2003.
p
Adjusted (95)
RR
Baseline Se (ng/mL)
0.42
0.62-1.22
0.87
105.2
105.3-122.0
1.49
1.05-2.12
0.03
gt 122.0
1.59
1.11-2.30
0.01
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How did this affect trial conduct?

• Before data were published
• Contact the external Data Safety Monitoring Board
  (DSMB for recommendations )
• Contact IRB
• Contact NCI
• DSMB dictated to add information into the
  Informed Consent Form (ICF)
• Rreconsent patients
• FDA report

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Great Expectations
Drug Discovery 1-5 years 1 Million
Preclinical Dev 1-4 years 250k-850k
10,000 Compounds
250 Compounds
Phase I Clinical 1 year 100k 1 Million
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IND Application
Phase II Clinical 1-2 years 10-100 Million
5 Compounds
Phase III 2-8 years 10-500 Million
Reality
New Drug Application (NDA)
1 New Drug
80
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Topics for discussion

• What are examples of patient compliance issues
  and how are they handled?
• What are the differences between treatment and a
  clinical trial?
• What are ways to change trial conduct to reduce
  risk if a new toxicity is discovered?
• Why are studies blinded?
• What are the disadvantages of cancer prevention
  trials with regard to trial conduct?
• How can some of the disadvantages be circumvented?

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