different phases of clinical trials, indications, sample size

1. Clinical Trials: Phases
Professor Tarek Tawfik Amin
Epidemiology and Public Health, Faculty of Medicine, Cairo University
Geneva Foundation for Medical Education and Training
Asian Pacific Organization for Cancer Prevention
International Osteoporosis Foundation
Wiley Innovative Panel
amin55@myway.com dramin55@gmail.com
September 2015, Faculty Of Medicine, Cairo University, Cairo, Egypt.

2. Clinical Trials
• A clinical trial : prospectively planned
experiment for the purpose of evaluating
potentially beneficial therapies or treatments
• In general, these studies are conducted under
many controlled conditions so that they
provide definitive answers to pre-determined,
well-defined questions.
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3. Why Clinical Trials?
1. Most definitive method to determine
whether a treatment is effective.
• Other designs have more potential biases
• In an uncontrolled setting whether an
intervention has made a difference in the
outcome?
• Correlation versus causation: The problem of false
positive in observational designs
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4. Examples of False Positives:
correlation vs. causation
1.High cholesterol diet and rectal cancer
2.Smoking and breast cancer
3.Vasectomy and prostate cancer
4.Red meat and colon cancer
5.Red meat and breast cancer
6.Drinking water frequently and bladder cancer
7.Not consuming olive oil and breast cancer
Replication of observational studies may not overcome confounding and bias
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5. 2. Help determine incidence of side
effects and complications.
Example: Coronary Drug Project - for patients with
documented MI, does taking lipid modifying drugs
reduce mortality?
A. Detection of side effect (other arrhythmias)
Clofibrate 33.3%
Niacin 32.7% P> 0.05
Placebo 28.2%
B. Natural occurring side effect (nausea)
Clofibrate 7.6%
Placebo 6.2% P > 0.05
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6. 3.Theory not always best path
• Intermittent positive pressure breathing
(IPPB)  reduced use, no benefit
• High [O2] in premature infants 
Retrolental Fibroplasia, Harmful
• Tonsillectomy  Reduced use
• Bypass Surgery  Restricted use
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7. Examples of clinical trials
• Physicians HealthStudy(PHS)
– risks and benefits of aspirin and beta carotene in the prevention
of cardiovascular disease and cancer
– started recruitment of US male physicians in 1982
– 2x2 factorial structure
– Primary endpoint: total mortality
– Secondary endpoint: myocardial infarction
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8. • Eastern Cooperative Oncology Group (ECOG)
–multicenter cancer clinical trial
–Elderly women with stage II breast cancer
–tamoxifen vs. placebo
–Double blind study
–primary: tumor recurrence/relapse, disease-free survival
–secondary: total mortality
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9. Placebo
Used as a control treatment
1. An inert substance made up to physically
resemble a treatment being investigated
[sometimes we use active placebo].
2. Best standard of care if “placebo” unethical
3. “Sham control” [performing fake procedures]
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10. Adverse event (AE)
An incident in which harm resulted to a
person receiving health care.
– Examples: Death, irreversible damage to liver,
nausea
• Not always easy to specify in advance
• May be known adverse effects from earlier trials
• Not necessarily linked to assigned treatment
• Rare AEs may be seen only with very large
numbers of exposed patients and/or long term
follow-up: COX II inhibitors (pain reduction vs.
cardiovascular AEs)
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11. Surrogate Endpoints
• Variables used to address research questions
often called endpoints
• Alternative to desired or ideal clinical outcomes
are Surrogates
• Examples
– Suppression of arrhythmia (Sudden death)
– T4 cell counts (AIDS or ARC)
– Cholesterol (Infarction)
• Used in therapeutic exploratory trials
• With caution in confirmatory trials
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Types of RCTS
Treatment trials.
Preventive trials (vaccine).
Diagnostic or screening tests.
Trials of health care delivery.
Trials of health care policy.

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Types of Treatment Trials
Pharmaceutical (treatment, prevention,
biological, synthetic).
Device (prosthesis, sensory aids).
Procedure (surgery, laser, radiological).
Behavior change (smoking cessation,
dietary modification, exercise).
Other (counseling, information provision).

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Clinical [pharmaceutical]
Trials Phases – Phase I
Purpose: Determine basic safety and pharmacological
information:
I. Route of administration.
II. Safe dosage range.
III. Toxicity.
IV. Pharmacokinetics
oTreat: small numbers of patients over short period of
time.
oUsually no control group.
oHealthy adult volunteers or patients who have exhausted
all other options (cancer patients) with normally
functioning organs.

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Clinical Trials Phases – Phase II
Purpose: Evaluate the study drug in patients who suffer
from the disease or condition that the drug is proposed
to treat:
Provide preliminary evaluation of efficacy.
Identify group of patients most likely to benefit.
Collect additional dosage and safety data.
Usually comparison group but not always
randomized.

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Clinical Trials Phases – Phase III
Purpose: further evaluate the efficacy and safety:
Randomized.
⌂ New agent compared to placebo or current
therapy.
⌂ Usually multi-center.
⌂ Serve as basis for NDA i.e. new drug
application for marketing approval.

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Outcomes of Trial Phases
Phase I : maximum tolerated dose.
Phase II : biological effect, adverse events.
Phase III : efficacy, adverse events.
Phase IV : long term effectiveness and safety.

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Summary of Phases I-III
# Subs. Length Purpose % Drugs
Successfully
Tested
Phase I 20 – 100 Several
months
Mainly Safety 70%
Phase II Up to
several
100s
Several
months- 2
yrs.
Short term safety;
mainly
effectiveness
33%
Phase III 100s –
several
1000
1-4 yrs. Safety, dosage &
effectiveness
25-30%

19. Characterization of Trials
Phase Single Center Multi Center
Randomized Non-Rand. Randomized Non-Rand.
I Never Yes Never Sometimes
II Rare Yes Yes Sometimes
III Yes Use of
Historical
Controls
Yes Use of
Historical
Controls
Carrying out a multi-center randomized clinical trial is the most difficult way to generate scientific information.
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20. • The foundation for the design of controlled experiments
established for agricultural experiments
• The need for control groups in clinical studies recognized,
but not widely accepted until 1950s
• No comparison groups needed when results dramatic:
– Penicillin for pneumococcal pneumonia
– Rabies vaccine
• Use of proper control group necessary due to:
– Natural history of most diseases
– Variability of a patient's response to intervention
Phase III Trial Designs
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21. Phase III Design
• Comparative Studies
• Experimental Group vs. Control Group
• Establishing a Control
1. Historical
2. Concurrent
3. Randomized
• Randomized Control Trial (RCT) is the gold
standard [Eliminates several sources of bias]
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22. Purpose of Control Group
• Allow discrimination of patient outcomes
caused by test treatment from those caused
by other factors.
– Natural progression of disease
– Observer/patient expectations
– Other treatment
• Fair comparisons: Necessary to be informative
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23. Goals of Phase III
Clinical Trial
• Superiority Trials
– A controlledtrial may demonstrateefficacyof the test treatment
by showing that it is superior to thecontrol
• No treatment
• Best standard of care
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24. • Non-Inferiority Trials
Controlled trial may demonstrate efficacy by showingthe test
treatment is similar in efficacy to a known effective treatment
• New treatment cannot be worse by a pre-specified
amount
• New treatment may not be better than the
standard but may have other advantages:Cost,
Toxicity and Invasiveness
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25. Name the design and phase of the trial
1- A phase (--) study with carfilzomib and vorinostat was conducted in 20
B-cell lymphoma patients. Vorinostat was given orally twice daily on
days 1, 2, 3, 8, 9, 10, 15, 16, and 17 followed by carfilzomib (given as a
30 min infusion) on days 1, 2, 8, 9, 15, and 16. A treatment cycle was 28
days. Dose escalation initially followed a standard 3+3 design, but
adapted a more conservative accrual rule following dose de-escalation.
The maximum tolerated dose was 20 mg/m2 carfilzomib and 100 mg
vorinostat (twice daily). The dose-limiting toxicities were grade 3
pneumonitis, hyponatremia, and febrile neutropenia. One patient had a
partial response and 2 patients had stable disease. Correlative studies
showed a decrease in NF-κB activation and an increase in Bim levels in
some patients, but these changes did not correlate with clinical
response.
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26. 2- We performed a phase (---) clinical trial to evaluate the efficacy and safety of ledipasvir and sofosbuvir, with or
without ribavirin, in patients infected with HCV genotype 3 or 6.
METHODS:We performed an open-label study of 126 patients with HCV genotype 3 or 6 infections at 2 centers in New
Zealand, from April 2013 through October 2014. Subjects were assigned 1 of 4 groups that received 12 weeks of
treatment. Previously untreated patients with HCV genotype 3 were randomly assigned to groups given fixed-dose
combination tablet of ledipasvir-sofosbuvir (n=25), or ledipasvir-sofosbuvir along with ribavirin (n=26). Treatment-
experienced patients with HCV genotype 3 (n=50) received ledipasvir-sofosbuvir and ribavirin. Treatment-naïve or
-experienced patients with HCV genotype 6 (n=25) received ledipasvir-sofosbuvir. The primary endpoint was the
percentage of patients with HCV RNA <15 IU/mL 12 weeks after stopping therapy (SVR12).
RESULTS: Among treatment-naïve genotype 3 patients, 16/25 (64%) receiving ledipasvir-sofosbuvir alone achieved an
SVR12, compared with all 26 patients (100%) receiving ledipasvir-sofosbuvir and ribavirin. Among treatment-
experienced patients with HCV genotype 3, 41/50 achieved an SVR12 (82%). Among patients with HCV genotype
6, the rate of SVR12 was 96% (24/25 patients). The most common adverse events were headache, upper
respiratory infection, and fatigue. One patient with HCV genotype 3 discontinued ledipasvir-sofosbuvir because of
an adverse event (diverticular perforation), which was not considered treatment related.
CONCLUSIONS:In an uncontrolled, open-label trial, high rates of SVR12 were achieved by patients with HCV genotype 3
infection who received 12 weeks of ledipasvir-sofosbuvir plus ribavirin, and by patients with HCV genotype 6
infection who received 12 weeks of sofosbuvir-ledipasvir without ribavirin. Current guidelines do not recommend
the use of ledipasvir-sofosbuvir, with or without ribavirin, in patients with HCV genotype 3 infection.
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27. 3-Bcl-2/IgH-rearrangements can be quantified in follicular lymphoma (FL) from
peripheral blood (PB) by PCR. The prognostic value of Bcl-2/IgH levels in FL
remains controversial. We therefore prospectively studied PB Bcl-2/IgH levels from
173 first-line FL patients who were consecutively enrolled, randomized and treated
within the multicenter phase (---) clinical trial NHL1-2003 comparing
bendamustine-rituximab (B-R) with CHOP-rituximab (R-CHOP). From April 2005 to
August 2008 783 pre- and post- treatment PB samples were quantified by qPCR. At
inclusion 114 patients (66%) tested positive and 59 (34%) were negative for Bcl-
2/IgH. High pre-treatment Bcl-2/IgH levels had an adverse effect on PFS compared
to intermediate or low levels (high vs. intermediate: HR 4.28, 95% CI 1.70 - 10.77;
p=0.002; high vs. low: HR 3.02, 95% CI 1.55 - 5.86; p=0.001). No PFS difference
between treatment arms was observed in Bcl-2/IgH-positive patients. A positive
post-treatment Bcl-2/IgH status was associated with shorter PFS (8.7 months vs.
not reached; HR 3.15, 95% CI 1.51-6.58; p=0.002). By multivariate analysis, the
pre-treatment Bcl-2/IgH level was the strongest predictor for PFS. Our data suggest
that pre- and post- treatment Bcl-2/IgH levels from PB have significant prognostic
value for PFS in FL receiving first-line immuno-chemotherapy.
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28. 4- The authors describe the first mother-infant pair to complete an on-going,
prospective, open-label, Phase (---) trial (ALIU) UU3, NCT00418821) determining
the safety of laronidase enzyme replacement therapy (ERT) in pregnant women
with mucopolysaccharidosis type I (MPS I) and their breastfed infants. The mother,
a 32-year-old with attenuated MPS I (Scheie syndrome), received laronidase for
three years and continued treatment throughout her second pregnancy and while
lactating. A healthy 2.5 kg male was delivered by elective cesarean section at 37
weeks. He was breastfed for three months. No laronidase was detected in breast
milk. The infant never developed anti-laronidase IgM antibodies, never had
inhibitory antibody activity in a cellular uptake assay, and always had normal
urinary glycosaminoglycan (GAG) levels. No drug-related adverse events were
reported. At 2.5 years of age, the boy is healthy with normal growth and
development. In this first prospectively monitored mother-infant pair, laronidase
during pregnancy and breastfeeding was uneventful.
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29. Thank you
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