Transcript Document

Clinical Trials
Penny Hogarth, MD
OHSU Department of Neurology
April 6th, 2007
What is a clinical trial?
• A clinical trial is a tool for testing a drug,
device or technique
Why do a clinical trial?
• To answer a clinical problem
• To gain new knowledge about a new or
established treatment
• To support an application for government
regulatory approval
• To support the marketing of a drug, device,
or technique
Guiding Principles
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Ethics
Scientific validity & integrity
Medical relevance
Regulatory & medico-legal considerations
Cost
Guiding Principles
• Start with a hypothesis
– Put in the form of a statement
• Turn it into a question
– The question must be “answerable”
– This forms the basis of the study’s “objectives”
Observational studies
• Case reports
• Case-control studies
• Cohort studies
Case-control studies
• Retrospective
• Subjects classified on basis of outcome,
with prior exposure status determined after
outcome
• Case = those with outcome of interest
• Control = those without outcome of interest
Cohort studies
• Prospective / longitudinal / concurrent
• Subjects classified on basis of exposure to
some risk factor of interest and followed to
determine outcome
• Most rigorous of observational studies
Interventional studies
• Cross-over trials
– Subject acts as own control
– Decreases variability
• Parallel group trials
Study population
Random assignment
Active
treatment
Control
treatment
washout
Control
treatment
Active
treatment
Study population
Random assignment
Active
treatment
Control
treatment
Follow-up period
YES
NO
Outcome
of interest
YES
NO
Phase I studies
• Early human use of drug
• Often in normal subjects, rather than those
with disease of interest
• Mainly aimed at establishing tolerated dose
range, PK / PD, acute toxicity of compound
• Usually open-label, no control groups
• Small number of subjects: usually 10-100
• Days to weeks long
Phase II studies
• In human subjects with disease of interest
• Establishing safety, tolerability of
compound
• Preliminary measures of efficacy
• Usually controlled, randomized, blinded
• Larger numbers of subjects: ~100-300
• Weeks to months long
Phase III studies
• In subjects with disease of interest
• Establishing efficacy, long-term safety and
tolerability
• Raandomized, controlled, blinded
• Comparator may be placebo, or standard
treatment
• Large numbers of subjects: 100s - 1000s
• Months to years long
Phase IV studies
• “Post-marketing” studies
• Long-term risks, benefits, optimal use
Anatomy of a study protocol
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Introduction and study rationale
Study objectives
Overall study design / study flowsheet
Eligibility criteria
Specific study procedures
Sample size calculations / data analysis plan
Ethical considerations
Common errors in trial design
• Question to be answered unclear
• Population too broadly or narrowly defined
• Outcome measures not quantifiable, or not
relevant
• Controls inadequate
• Measures to protect against bias inadequate
• Study inadequately powered
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QuickTime™ and a
TIFF (Uncompressed) decompressor
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QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
From genetics to treatments
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Recognize and describe the phenotype
Identify the gene
Make an animal model
Use the model to understand the pathophysiology
of the disease
• Develop rational therapeutics based on the
pathophysiology
• Test in animal models
• Test in humans
From genetics to treatments
• Recognize and describe the phenotype
• Identify the gene
• Make an animal model
• Use the model to understand the pathophysiology
of the disease
• Develop rational therapeutics based on the
pathophysiology
• Test in animal models
• Test in humans
“There are three marked
peculiarities of this disease: its
hereditary nature, a tendency to
insanity and suicide, and its
manifesting itself as a grave
disease only in adult life…..”
George Huntington, 1872
Huntington Disease
• Progressive neurodegenerative disorder
– Movement disorder
– Cognitive decline
– Psychiatric, behavioral disturbances
• Average age of onset ~ 38 yo
• < 10% juvenile onset < 20 yo
• Late onset cases probably under-recognized
From genetics to treatments
• Recognize and describe the phenotype
• Identify the gene
• Make an animal model
• Use the model to understand the pathophysiology
of the disease
• Develop rational therapeutics based on the
pathophysiology
• Test in animal models
• Test in humans
Gene discovery: Venezuela 1993
Genetics of HD
• Autosomal dominant inheritance
• Expanded and unstable trinucleotide repeat
(CAG) on short arm of chromosome 4 
expanded polyglutamine tract in mutant
protein
• Age dependent penetrance
From genetics to treatments
• Recognize and describe the phenotype
• Identify the gene
• Make an animal model
• Use the model to understand the pathophysiology
of the disease
• Develop rational therapeutics based on the
pathophysiology
• Test in animal models
• Test in humans
Animal models: 1996
• Transgenic mice
• Drosophila
• C. elegans
From genetics to treatments
• Recognize and describe the phenotype
• Identify the gene
• Make an animal model
• Use the model to understand the pathophysiology
of the disease
• Develop rational therapeutics based on the
pathophysiology
• Test in animal models
• Test in humans
Aggregate formation
gln-gln-gln
caspases
gln-gln-gln-gln
• Transcriptional dysregulation
• Mitochondrial dysfunction
• Proteasome dysfunction
From genetics to treatments
•
•
•
•
Recognize and describe the phenotype
Identify the gene
Make an animal model
Use the model to understand the pathophysiology
of the disease
• Develop rational therapeutics based on the
pathophysiology
• Test in animal models
• Test in humans
From genetics to treatments
•
•
•
•
Recognize and describe the phenotype
Identify the gene
Make an animal model
Use the model to understand the pathophysiology
of the disease
• Develop rational therapeutics based on the
pathophysiology
• Test in animal models
• Test in humans
HDAC inhibitors in Drosophila
HD
Normal
Tx HD
Drosophila HD model treated with HDAC
inhibitors SAHA and butyrate show rescue of
neurodegenerative process
Steffan et al., Nature (2001) 413:739
HDAC Inhibitor SPB ameliorates
R6/2 HD mouse phenotype
• Extended survival in
dose-dependent fashion
• Improved motor
performance
• Delayed neuropath
sequelae
Percent Surviving
100
80
60
40
20
0
PBS
PBt 125mg/Kg
PBt 250mg/Kg
60 70 80 90 100 110 120 130 140
Age (days)
Ferrante et al. J. Neuroscience 23(28):94
From genetics to treatments
•
•
•
•
Recognize and describe the phenotype
Identify the gene
Make an animal model
Use the model to understand the pathophysiology
of the disease
• Develop rational therapeutics based on the
pathophysiology
• Test in animal models
• Test in humans
SPB in HD
• Dose-finding study of SPB completed here
at OHSU
• Pilot study of promising gene expression
biomarker
• Multi-center phase II study just comleted
Clinical trial design in HD
• Individuals carrying HD gene spend ~2/3
life pre-symptomatic, ~1/3 symptomatic
• If neuroprotective treatment identified,
when should it be started?
• How can we measure efficacy of putative
neuroprotective treatment in presymptomatic individuals?
Clinical trial design in HD
• HD gene is perfect “trait” marker
• Current clinical measures are imperfect “state”
markers
• “Delay of symptom onset” as trial outcome
measure inaccurate and expensive
• Search for biomarkers, surrogate markers a
high priority
What is a clinical endpoint?
• A measure that reflects how a subject feels,
functions or survives
• Distinct measures used in a clinical trial that
reflect the effect of a therapeutic
intervention
– death, BP reduction, self-report of pain
– In pre-sx HD, onset of signs / sx
What is a biomarker?
“A characteristic that is objectively measured and evaluated
as an indicator of normal biologic processes, pathogenic
processes, or pharmacologic responses to a therapeutic
intervention.” (Downing, 2000)
“Marker of disease severity that reflects underlying
pathogenesis and predicts clinical events in the absence of
treatment, thus establishing the biological plausibility of
the marker.” (Mildvan, 2000)
What is a surrogate endpoint?
Characterization of a biomarker as a surrogate
endpoint requires it to be “reasonably likely, based
on epidemiologic therapeutic, pathophysiologic, or
other evidence to predict clinical benefit.” (FDA,
1997)
Examples: ↑ CD4 Cell Count in HIV
MRI Scans in HD
Normal Subject: Age 38
HD Subject: Age 31
Caudate
Putamen
Globus
Pallidus
Can we use striatal volume as biomarker
/ surrogate endpoint in HD?
Can be objectively measured
– High inter- intra-rater reliability
• Reflects pathogenic process
– Striatal volume decreased in pre-sx subjects
– Striatal volume decreases as approach onset sx
– Longitudinal change can be detected over relatively
short time
• Predicts clinical events
– Rate of change significant 10-12 years prior to sx onset
– Striatal volume can predict incident cases
Striatal volume decreases as onset approaches
12
Putamen Volume (cc)
+1 s.d. for
19 controls
Mean Volume
for 19 controls
9
-1 s.d. for
19controls
6
3
YTO > 8
YTO < 8
0
25
15
Estimated Years to Onset
5
-5
Mean caudate
volume for
controls
Caudate volume
Mean putamen
volume for
controls
Putamen volume
< 10
10-15
15-20
20-25
>25
(N = 67) (N = 67) (N = 42) (N = 22) (N = 16)
Years to Onset (current estimate)
Striatal volume predicts clinical
events
• Putamen and caudate volumes are about ½ of
normal volume at the time of diagnosis
• Functioning can remain normal even as basal
ganglia volumes are declining
• All subjects with caudate volume < 4.6 cc were
symptomatic; all with caudate volume > 5.3cc
were presymptomatic
• All subjects with putamen volume < 3.3cc were
symptomatic; all with putamen > 5.1cc were
asymptomatic
Application of striatal volume as
biomarker
“may be applied as a stratification variable in controlled
trials, distinguishing populations with varying degrees of risk
of disease.”
(Mildvan, 2000)
Biomarkers have several valuable applications, including:
 use as a diagnostic tool
 use as a tool for staging disease
 use as an indicator of disease
 use to predict and monitor clinical response to in
intervention (Downing, 2000)
Striatal volumes as surrogate
endpoint
• No existing good clinical measures for presx subjects
• Can be used in far-from-onset subjects, for
whom onset is not feasible measure
• Can use data from all subjects, not just
incident cases
• No practice effects, no placebo effects
• Relatively small study sample sizes needed
Striatal volumes as surrogate
endpoint
• Assume for sample size calculation:
– Treatment effective in reducing atrophy by one-half
– Trial included only those subjects whose estimated
onset was <12 years from the initiation of the trial
– Trial would be approximately 30 months duration
• Would need approximately 84
presymptomatic subjects per group
– MRI striatal volumes can be considered a
biomarker
– MRI striatal volumes can be used
• to select cases for future clinical trial
• to determine when the first neurobiological changes of
HD begin
– More evidence needed to consider MRI striatal
volume as a surrogate endpoint???
– Need to be ready with a cost-effective method
that is reliable and valid for future clinical trials
– Would likely be used in combination with other
proposed biomarkers / surrogate markers
Acknowledgement
Elizabeth Aylward, PhD
University of Washington
Seattle, WA