Research Methodology for Rare Diseases
Rare Disease Group14:00 3rd October 2012
Richard Lilford
• Basic mechanisms of disease
• Incidence and prevalence over time and place
• Prognosis
• Diagnosis
Research Methodology
XX
XX
Treatment
What Do We Want When We Evaluate?Effects of Treatment
Precision Accuracy+
What Does Precision Depend On?(In Frequentist Paradigm)
Risk of false positive / negative trial results(α + β)
Absolute difference (Δ) in event rates(binary outcome)
Sample Size Calculation – Examples
Delta based on 25% improvement;alpha = 0.05; beta = 0.1
Control Event Rate (%)
Sample Size (total – nearest 100)
40 1,00020 2,50010 5,5005 11,000
Implications for Sample Size for Evaluations of Treatments for
Rare Diseases
(‘Optimistic’ 25% reduction in an event with 40% probability in the control group (α = 0.05, β = 0.1)
Prevalence(per 1,000)
Example(approximate)
Total Population Needed
@ 50% ‘recruitment’
10 Rheumatoid arthritis / schizophrenia
100,000 200,000
1 Multiple Sclerosis 1,000,000 2,000,000
0.5 Cystic Fibrosis (Europeans) 2,000,000 4,000,000
0.1 Huntington’s Disease 10,000,000 20,000,000
0.05 Wilson’s Disease 50,000,000 100,000,000
Rare Diseases: You Are Not Alone!
• Diagnostic tests
• Sub-groups (personalised medicine)
• Rare variants of common diseases
Diagnostic / Screening Tests
Population Prevalence:Test Positive +
Disease Positive Treatment effect
Prior Probability Posterior Probability Contingent Probability
Initial Sample Test Positive
Test Positive + Disease
Treatment Effect
Risk AttributableRisk
Example: Diagnostic Test
Suppose a disease has a prevalence of 10%, We want to detect an improvement in sensitivity of 10%.Death rate 50% if detected late, and 25% if detected early.
Disease Present (%)
DetectedEarly
Detected Late
Deaths Difference
New Test
Old Test
10
10
9
8
1
2
2.75
3.0
0.25
Rare Diseases: You Are Not Alone!
• Diagnostic tests
• Sub-groups (personalised medicine)
• Rare variants of common diseases
Genetic analysis can identify those patients who will benefit from a given drug
Giaccone G, et al. J Clin Oncol. 2004;22:777-84.Mok T, et al. N Engl J Med 2009;361:947-57.
Gefitinib no more effective than placebo in non-stratified population
Gefitinib more effective than standard treatment if EGFR+
Gefitinib less effective than standard treatment if EGFR-
Rare Diseases: You Are Not Alone!
• Diagnostic tests
• Sub-groups (personalised medicine)
• Rare variants of common diseases
Panoramic Meta-Analysis
Hemming et al. Stat Med. 2012; 31(3): 201-16.Bowater et al. Ann Surg. 2009; 249: 551-6.
Adjuvant Chemotherapy
Bowater et al. Ann Surg Oncol. 2012;
19(11): 3343-50.
What to do in Cases of Rare Diseases?
• Non-terminal events:1. Cross over studies2. n = 1 trials
• Terminal events:1. Adaptive designs
(Chow & Chang. Orphanet J Rare Dis 2008; 3: 11)
2. α = β > 0.05(Lilford & Johnson. NEJM 1990; 322: 780-1)
3. Bayesian methods
Factors Influencing Belief
1. THE DATA– Size of effect observed• Precision• Accuracy
2. ‘PRIOR’ BELIEF
Posterior odds (of disease)
=priorodds X L R
Posterior odds (of null hypothesis)
= priorodds
X L R
Prob test +ve given disease
Prob test +ve given no disease
Prob data given alternativehypothesis
Prob data given null
Clinical trials and rare diseases: a way out of a conundrum.Lilford RJ, Thornton JG, Braunholtz D. BMJ 1995; 311:1621-5.
Rare diseases and the assessment of intervention: What sorts of clinical trials can we use?
Wilcken B. J Inherit Metab Dis 2001; 24(2): 291-8.
Strategy for randomised clinical trials in rare cancers.Tan S-B, et al. BMJ 2003; 327:47.
Evidence-based medicine for rare diseases: Implications for data interpretation and clinical trial design.
Behera M, et al. Cancer Control 2007; 14(2): 160-6.
Clinical research for rare disease: Opportunities, challenges, and solutions.Griggs RC, et al. Mol Genet Metab 2009; 96(1): 20-6.
A framework for applying unfamiliar trial designs in studies of rare diseases.
Gupta S, et al. J Clin Epidemiol 2011; 64(10): 1085-94.
Trials in rare diseases: The need to think differently.Billingham L, et al. Trials 2011; 12(s1): a107.
Current Conception of Clinical Trials
Clinical trials and rare diseases: a way out of a conundrum.Lilford RJ, Thornton JG, Braunholtz D. BMJ 1995; 311:1621-5.
Clinical trials and rare diseases: a way out of a conundrum.Lilford RJ, Thornton JG, Braunholtz D. BMJ 1995; 311:1621-5.
Interaction Between Prior Beliefs, Surrogate Outcomes, and Mortality Data from a Bayesian Viewpoint.
Are Underpowered Trials Unethical?
Edwards et al. Lancet. 1997; 350: 804-7.
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