Clinical%20Trials

1
Clinical Trials

• Penny Hogarth, MD
• OHSU Department of Neurology
• April 6th, 2007

2
What is a clinical trial?

• A clinical trial is a tool for testing a drug,
  device or technique

3
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

4
Guiding Principles

• Ethics
• Scientific validity integrity
• Medical relevance
• Regulatory medico-legal considerations
• Cost

5
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 studys objectives

6
Observational studies

• Case reports
• Case-control studies
• Cohort studies

7
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

8
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

9
Interventional studies

• Cross-over trials
• Subject acts as own control
• Decreases variability
• Parallel group trials

10
Study population
Random assignment
Active treatment
Control treatment
washout
Active treatment
Control treatment
11
Study population
Random assignment
Active treatment
Control treatment
Follow-up period
NO
YES
YES
NO
Outcome of interest
12
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

13
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

14
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

15
Phase IV studies

• Post-marketing studies
• Long-term risks, benefits, optimal use

16
Anatomy of a study protocol

• Introduction and study rationale
• Study objectives
• Overall study design / study flowsheet
• Eligibility criteria
• Specific study procedures
• Sample size calculations / data analysis plan
• Ethical considerations

17
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

18
(No Transcript)
19
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

20
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

21
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
22
Huntington Disease

• Progressive neurodegenerative disorder
• Movement disorder
• Cognitive decline
• Psychiatric, behavioral disturbances
• Average age of onset 38 yo
• lt 10 juvenile onset lt 20 yo
• Late onset cases probably under-recognized

23
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

24
Gene discovery Venezuela 1993
25
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

26
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

27
Animal models 1996

• Transgenic mice
• Drosophila
• C. elegans

28
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

29
Aggregate formation
gln-gln-gln
mutant huntingtin
mutant huntingtin

caspases
gln-gln-gln-gln

• Transcriptional dysregulation

• Mitochondrial dysfunction

• Proteasome dysfunction

30
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

31
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

32
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) 413739
33
HDAC Inhibitor SPB ameliorates R6/2 HD mouse
phenotype

• Extended survival in dose-dependent fashion
• Improved motor performance
• Delayed neuropath sequelae

Ferrante et al. J. Neuroscience 23(28)94
34
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

35
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

36
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 pre-symptomatic
  individuals?

37
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

38
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

39
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)

40
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

41
MRI Scans in HD
Normal Subject Age 38 HD
Subject Age 31
42
Caudate
43
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

44
Striatal volume decreases as onset approaches
45
(No Transcript)
46
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 lt 4.6 cc were
  symptomatic all with caudate volume gt 5.3cc were
  presymptomatic
• All subjects with putamen volume lt 3.3cc were
  symptomatic all with putamen gt 5.1cc were
  asymptomatic

47
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)

48
Striatal volumes as surrogate endpoint

• No existing good clinical measures for pre-sx
  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

49
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 lt12 years from the
  initiation of the trial
• Trial would be approximately 30 months duration
• Would need approximately 84 presymptomatic
  subjects per group

50

• 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

51
Acknowledgement

• Elizabeth Aylward, PhD
• University of Washington
• Seattle, WA