london limitation of clinical trials
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Limitations of Clinical Trials in Sickle CellDisease: A case study of the Multi-centerStudy of Hydroxyurea Trial (MSH) and the
Stroke Prevention Trial (STOP)
Michael R. DeBaun, MD, MPH
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Objectives
Strength of randomized clinical trials
Limitations of clinical trials
Multi-Center Study of Hydroxyurea in Sickle Cell
Anemia (MSH) STOP Trial
Secondary Analysis MSH
Clinical Drift MSH
Summary and Recommendations
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Strengths of Clinical Trials
Sackett, DL. BMJ. 1996 Jan 13;312(7023):71-2
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Limitations of Clinical Trials
Narrow inclusions criteria Over interpretation of secondary analyses
Expensive Cost of MSH ~ $10 million Cost STOP I ~ $12.1 million; STOP II ~ $11 million Silent Infarct Transfsuion Trial~ $18.5 million
Time consuming Length from conception to completion of the trial
Silent Infarction Trial ~15 years
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Multi-Center Study of Hydroxyurea (MSH)(N Engl J Med 1995;332:1317-22.)
HypothesisHypothesis Hydroxyurea willsubstantially reduce the frequency of
painful episodes in adults with Hgb SS
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Multi-Center Study of Hydroxyurea
Inclusion CriteriaInclusion Criteria
minimum of 18 years of age
Only accepted those with Hgb SS
At least 3 painful episodes in the last year No documentation was required
No previous use hydroxyurea
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Methods of the MSH Trial
Randomized trial
299 participants spanning 21 clinics in the U.S. and Canada
Patients were given pre-prepared doses ofhydroxyurea or placebo on a regular basis
Primary endpoint
Pain
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Results of the MSH Study
Pain episode rate (p < 0.001) The hydroxyurea group - 2.5 per year
The placebo group - 4.5 crises per year
When considering severe pain requiringhospitalization the median annual rate (p < 0.001) hydroxyurea group -1.0 hospitalization per year
placebo group -2.4 hospitalization per year
Acute chest syndrome rate (p < 0.001) hydroxyurea group-16%
placebo group-35%
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Conclusion of the MSH Study
Hydroxyurea therapy can ameliorate theclinical course of sickle cell anemia insome adults with three or more painful
crises per year
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Stroke Prevention Trial (STOP)(N Engl J Med 1998;339:5-11)
HypothesisHypothesis - Prophylactic blood transfusiontherapy in patients with elevated cerebral bloodflow as measured by transcranial doppler will
lower the risk of stroke by 70 percent ascompared with the risk associated with standardcare
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Design of the STOP Study
Randomized trial
Patients with an average mean velocity > 200cm/sec received one of two options:
Standard supportive care Blood transfusion therapy designed to keep the Hb S
concentration below 30%
Primary endpoint Stroke rates in the treated and control groups
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Methods of STOP Trial
Inclusion criteria Hemoglobin SS or S beta thalassemia zero
Ages 2-16 years of age
All enrolled patients had a mean cerebral blood flowof > 200 cm/sec
Stroke was defined as: focal neurological deficitand MRI findings
130 patients were enrolled
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Adams, R. J. Arch Neurol 2007;64:1567-1574.
Kaplan-Meier estimates of the probability of remainingstroke free in children randomized to receive
either regular blood transfusions or standard care
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Conclusions of the STOP Study
Children with hemoglobin SS or SBthalassemia zero between 2 and 16 yearsof age should be screened with TCD
measurement
If the patient meets the high-risk TCDcriterion
regular blood transfusions are recommendedfor an indefinite period of time
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Secondary Analyses
Define Assessment of non-primary outcome measures that
were collected in the course of the trial
MSH- Primary Outcome Measure = Painful episodes STOP- Primary Outcome Measure= Strokes
Difference between primary and secondaryoutcome measures
Sample size is based on primary outcome Less rigorous adjudication process
Intention to treat analysis is often not applied
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Secondary Analyses(continued)
MSH: Secondary outcome measures-listed in theprimary manuscript
Incidence of ACS
blood transfusions therapy hepatic sequestration
death
STOP
None listed in primary manuscript
Level of significance for secondary analyses MSH- 0.01
STOP- none listed
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Secondary Analysis of MSH Trial(Effect of Hydroxyurea on Mortality and Morbidity inAdult Sickle Cell Anemia-JAMA. 2003;289:1645-1651 )
Objective
To determine whether hydroxyurea attenuates mortality inpatients with SCA
Design Nine year observational follow-up study of mortality in
patients MSH follow-up
Results
Taking hydroxyurea was associated with a 40% reductionin mortality (P= .04)
Conclusions
Adult patients taking hydroxyurea have reduced mortality
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Bias in Observational Studies Volunteer bias
Individuals who volunteer for studies are healthier thanpeople who do not Healthy user bias
Individuals who engage in activities that are good forthem are fundamentally different from those who dont
Adherence bias Individuals that adhere to a therapy are quite different
than those that do not Wealthy bias
Individuals who are wealthy, and able to participate inclinical trials are different than those who are not
Hematologist bias Hematologist may be more likely to encourage and
continue hydroxyurea among individuals with lower co-
morbidities i.e. no renal disease
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Secondary Analysis of MSH Trial(Effect of Hydroxyurea on Mortality and Morbidity inAdult Sickle Cell Anemia-JAMA. 2003;289:1645-1651 )
The MSH was not designed to detect specifieddifferences in mortality
The strength of statistical evidence forsecondary analysis was pre-determined at amore stringent level than the primary end pointtrial design of alpha = .05
The nominal Pvalues should be regarded asindicators of association, not tests ofa priorihypotheses, and should be interpretedcautiously
METHODS Section (taken from manuscript)
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Secondary Analysis of MSH Trial(Effect of Hydroxyurea on Mortality and Morbidity inAdult Sickle Cell Anemia-JAMA. 2003;289:1645-1651 )
Implications
Many Sickle Cell Disease programs have
elected to use hydroxyurea among adults withsickle cell disease based on these data
Opportunity for a formal trial testing thebenefit of hydroxyurea on survival is less likely
to occur lack of equipoise among hematologists
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0.01Fetal hemoglobin insickle cell anemia:
determinants of
response to hydroxyurea
Steinberg, et al.(1997)
0.05Cost-effectiveness of
hydroxyurea in sickle cellanemia
Moore, et al.
(2000)
0.05Effect of hydroxyurea onmortality and morbidity inadult sickle cell anemia:risks and benefits up to 9
years of treatment
Steinberg, et al(2003)
0.01Hydroxyurea and sicklecell anemia: effect on
quality of life
Ballas, et al.(2006)
Level ofsignificance
Title
MSH
Secondary analysis
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Implications of the MSH trialfor Pediatrics
Blood. 1999 Sep 1;94(5):1550-4
One short term single arm safety trial wascompleted among children Age 5 to 15 years with hemoglobin SS
no child with a diagnosis of hemoglobin SC
Follow up 68 children reached maximum tolerated dose (MTD)
52 were treated at MTD for 1 year
No significant toxicity
Efficacy was not assessed
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Drift in Clinical Practice afterCompletion of Landmark Trials
Defined Physician practice that is based on the results
from a landmark clinical trials to in groups ofpatients that were not included in the trial
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Drift in clinical practice based onresults of MSH Trial
Physicians have elected to treat children withhydroxyurea after multiple episodes of ACS
Two major assumptions ACS is similar in adults and children
Risk and Benefit ratio for adults is the sameas for children
A h i A i d i h ACS i
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0
20
40
60
80
100
0-2 2-4 4-6 6-8 8-10 10-12 12-20
Age (yrs)
ACS
rate(/1
00p
t-yrs)
AsthmaticNot Asthmatic
Blood 2006;108(9):2923-7
Asthma is Associated with ACS in
Children with Sickle Cell Anemia
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Increased Presenting Temperature (> 390C) in ACS by Age
0
10
20
3040
50
60
70
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Presenting Symptoms of Patients with ACS by Age
0
10
20
3040
50
60
70
8090
100
Fever Cough Chest Pain Shortness of
Breath
Severe Chest
Pain
Symptom
PercentPresenting
Ages 2-4
Above Age 20
Blood. 1997 Mar 1;89(5):1787-92.
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ACS In ChildrenDifferent than Adults
Asthma is a risk factor for ACS amongchildren
ACS occurs more often in children thanadults
ACS presents differently in children thanadults
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Not statedCan peak systolic velocities be used for prediction of stroke in sicklecell anemia?
Jones, et al.(2004)
Not statedStroke and conversion to high risk in children screened withtranscranial doppler ultrasound during the STOP study
Adams, et al.(2004)
0.05Magnetic resonance angiography in children with sickle cell diseaseand abnormal transcranial doppler ultrasonography findings
enrolled in the STOP study
Abboud, et al.(2004)
0.05Effect of long-term transfusion on growth in children with sickle cellanemia: results of the STOP trial
Wang, et al.(2005)
0.05Regular transfusion lowers plasma free hemoglobin in children withsickle cell disease at risk for stroke
Lezcano, et al.(2006)
Not statedSTOP: extended follow-up and final resultsLee, et al.(2006)
0.05Elevated blood flow velocity in the anterior cerebral artery andstroke risk in sickle cell disease: extended analysis from the STOPtrial
Kwiatkowski, et al.(2006)
Level of significanceTitle
Secondary analyses from the STOP Trial
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Risk-Benefit ratio for HU in children
may not be the same as adults
The majority of pediatric drug use is offlabel because most therapeutic agentshave not been labeled by the FDA for use
in children In 1997 Congress approved the Food and
Drug Administration Modernization Act
An attribute of this act is the authorization of6-month marketing protection extensionincentive for the pharmaceutical company
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Peer-Reviewed Publication of Clinical
Trials Completed for Pediatric ExclusivityJAMA. 2006;296:1266-1273
Systematic evaluation of 253 pediatric trials 30% had negative results
changes included no meaningful clinical activity
black box warning increased mortality reported in the product compared to
placebo
In the case of hydroxyurea limited incentive for pharmaceutical companies to
support a trial for pediatric exclusivity Pediatric Academic Community must become
advocates for such trials NIH, ASH, ASPHO
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Implications of the MSH trialfor Pediatrics
One short term single arm safety trial wascompleted among children
Age 5 to 15 years with hemoglobin SS no child with a diagnosis of hemoglobin SC
Follow up 84 children followed 6 months
34 children followed 4 months
Hydroxyurea Usage
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Hydroxyurea Usageamong 24 Pediatric Clinical sites
0-5%
5-10%
>10%, < 20%
> 20%
Highest use-30%Lowest use-3%
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A Simple Approach
Quarterly survey of patients with 3 or moreadmissions for pain (ICD 9 code for pain)
Evaluation for asthma If no asthma begin discussion of HU
If asthma, maximize treatment before use of HU
Re-evaluate understanding of pain action plan
Medical Social Worker assessment
Full disclosure and Parent Handbook- returnback to clinic to start HU
Persistence of missed appointment-removedfrom taking the HU
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Thank You!