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.