Albert FarrugiaPlasma Protein Therapeutics Association

& ALMAR Therapeutics Pty Ltd

The Fourth Margaret River Region Forum28 April – 1 May 2010

Rare diseases – Small Populationsthe challenge of clinical trial design

The drug development process

Trials in Rare diseases: 2 settings

IF• Condition with a very

homogeneous clinical course (rapidly progressive/stable disability)

AND• Treatment aim is cure/dramatic

improvementAny success (e.g. 1 case of cure) can be

attributed to therapy Eg – congenital coagulation defect –

factor therapy

IF• Chronic progressive diseases

with variable clinical course OR

• Treatment aim is NOT cure (e.g. palliation)

No individual outcome can be attributed to therapy

Eg – Multiple Sclerosis – IgG therapy

P Bruzzi on www.icord.se/documents/icord_2009/presentations/Bruzzi.ppt

Regulators are reasonableRare plasma protein deficiencies

• FDA approval of Baxter Protein C – pivotal study n=18 patients

with deficiency

• FDA approval of CSL fibrinogen – pivotal study n=15 patients

with afibrinogenemia

• EMEA approval for Novoseven in FVII deficiency - data on 32

patients with FVII deficiency treated in 28 different sites in 6

countries between 1988 and 1999.

Conventional Statistical Reasoning

1. Starting hypothesis (Null hypothesis - H0):

new treatment = standard one

2. To demonstrate: new treatment >> standard

reject null hypothesis (p<0.05)

3. To reject null Hypothesis:

Large Sample Size

4. Only information collected within the experiment can be used in

interpretation of study results

P Bruzzi on www.icord.se/documents/icord_2009/presentations/Bruzzi.ppt

The statistical burden• A study must have an adequate

size• Required Size, based on:

– Significance level (usually 5%)– Minimal clinically worthwhile

difference– Power (usually 80-90%)

• Results: Test of significance – P<0.05 = Positive Study – P>0.05 = Negative Study

Relative reduction in event rate %

Needed number of events

50 71

40 125

30 252

20 635

10 2830

Α = 0.05 power = 80%

The statistical burden Effect of sample size on power

Disorder frequency1 : 50 000Demonstration of a50%reduction in the occurrence of an end-point with 95% confidence

No overlap in CI’s – endpoint attained

Overlap in CI’s – endpoint not attained

The ideal

Clinical Trial

Controls

100

Blinding

Random

ization

Equipoise

100

The use of RCTs should be questioned when…

• Results are readily observable or dramatic

• High morbidity/mortality occurs even with best available therapy

• Patients/physicians show reluctance to placement in non-treatment control arm

• Crossing-over from positive observable results

• ‘Orphan-type’ unmet indication where RCT costs are prohibitive and may stifle innovation

IN OTHER WORDS — MANY OF THE INDICATIONS FOR PLASMA THERAPIES

“The [randomised controlled trial] is a very

beautiful technique, of wide applicability,

but as with everything else there are

snags.”

Professor Archie Cochrane 1909 - 1988

Thinking outside the boxAlternative approaches

RCT

Bayesian analysis

Sequential designs

Interim analysis

N of 1

trials

There must be some other way….

There is !

Bayesian methodology• Less direct evidence is required for decision when prior

evidence is taken into account – SO

• Uses Prior Evidence (a crucial component in the interpretation of any finding)

• Bayesian statistics allows us to combine prior evidence with trial results

Prior information probability distribution of the likely effect of the experimental treatment

Trial results (if necessary and possible)

Posterior Probability distribution of the likely effect of the experimental treatment (range of plausible effects)

+

=

IVIG vs Plasma Exchange for children with GBSBayesian approach

• Initial 86% probability that IVIg was

not inferior to PE (Prior).

• Also include adult experience through

previous trials

• Trial population size then needed to

show non-inferiority with power of

77% is 160 kids

• With conventional design population

needs to be 750 kids!

Clinical Trials 2005; 2:305-310

Using Bayes we show that IVIG can be used instead of PE in children, and spare 500 kids from having to be trialed!

Inhibitors in previously transfused hemophiliacs (PTPs)

• Problem - Inhibitors in PTPs • Need – to identify risky

products• FDA trial proposal (2003) –

conventional method BUT most FVIII would be off the market

• Bayesian alternative (Lee & Roth 2005) - can identify risky products and keep the other products on the market

ABCDEF

Product

2.32.32.90.91.05.7

ITT Observedinhibitor

incidence (%)

0.980.990.94

0.9990.9990.73

6.8

Upper threshold of the true population

incidence of inhibitors (%)

The role of sequential analysis in RCTs

• In sequential trials:– data are analysed after each participant’s results

become available

– the trial continues until a clear benefit is seen in one of the comparison groups, or it is unlikely that any difference will emerge

– duration is shorter than fixed-length trials when there is a large difference in the effectiveness of the interventions being compared

• Use of this methodology is restricted to conditions where the outcome of interest is known relatively quickly

Sequential trial design Efficacy of Viagra in men with erectile dysfunction

caused by spinal cord injury

Jan 1, 1996

Feb 1, 1996

Mar 1, 1996

NEUROLOGY 1998;51:1629-1633

• Data studied in Jan, Feb and March• Using Z and V statistics• Boundaries specified through

correction for discrete looks – crossing boundary completes trial

• Reached in March• By using a series of interim looks –

– A strong conclusion could be drawn from treating 26 subjects

– A fixed sample size trial would have required 57 subjects

N of 1 trailsTrial of therapy

• Randomized clinical trial used in just one patient • Patient undergoes pairs of treatment periods

– one period is the experimental treatment – other period is the comparator (placebo or alternative treatment

• Considered to provide the strongest level of evidence• Do not permit any generalization of the findings• BUT - may be combined

– through meta analysis‐– through a Bayesian random effects model

• Combination provides a population estimate for treatment effectiveness • Retains the capacity to provide a distinct effectiveness estimate for each individual

patient

?New and emerging indications for IgG

......Meta Analysis

Some thoughts on…………

Problems with meta-analyses

• The outcomes of 12 large randomized, controlled trials were

not predicted accurately 35 percent of the time by the meta-

analyses published previously on the same topics. (N Engl J

Med 1997;337:536-42.)

• Adjusting for random error through sequential analysis reveals

false positive results in many meta-analyses ie prediction of

an effect when none exists (International Journal of

Epidemiology 2008;1–12)

Use of Trial Sequential Analysis (TSA) to analyze Meta - Analyses

Cochrane Neonatal Reviews

International Journal of Epidemiology 2008;1–12

!!!!!!

!!!!!!

!!!!!!

Regulatory relief?• FDA approval of Baxter Protein C – pivotal

study n=18 patients with deficiency

• FDA approval of CSL fibrinogen – pivotal

study n=15 patients with afibrinogenemia

• EMEA approval for Novoseven in FVII

deficiency - 32 patients with FVII

deficiency who were treated in 28 different

sites in 6 countries between 1988 and

1999.

Here’s what’s important!

• RCTs are difficult with rare disorders• Other ways exist• Effort and commitment are needed

– By regulators– By industry

• Like Cochrane – we must always question what we do, and try to improve

• The aim should always be – TO GET EFFECTIVE AND SAFE THERAPIES

TO THOSE WHO NEED THEMTHERE IS ALWAYS A WAY !

“He was a man with severe porphyra who smoked too much and was without the consolation of a wife, a religious belief or a merit award – but he didn’t so badly”

Professor Archie Cochrane – 1909 - 1988