Clinical trial options for rare diseases


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Presented to The Fourth Margaret River Region Forum
28 April – 1 May 2010

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Clinical trial options for rare diseases

  1. 1. Rare diseases – Small Populationsthe challenge of clinical trial design <br />Albert Farrugia<br />Plasma Protein Therapeutics Association <br />& <br />ALMAR Therapeutics Pty Ltd<br />The Fourth Margaret River Region Forum<br />28 April – 1 May 2010<br />
  2. 2. The drug development process<br />
  3. 3. Trials in Rare diseases: 2 settings<br />IF<br /><ul><li>Chronic progressive diseases with variable clinical course </li></ul>OR<br /><ul><li>Treatment aim is NOT cure (e.g. palliation)</li></ul>No individual outcome can be attributed to therapy<br /><ul><li>Eg – Multiple Sclerosis – IgG therapy
  4. 4. IF
  5. 5. Condition with a very homogeneous clinical course (rapidly progressive/stable disability)</li></ul>AND<br /><ul><li>Treatment aim is cure/dramatic improvement</li></ul>Any success (e.g. 1 case of cure) can be attributed to therapy<br /><ul><li>Eg – congenital coagulation defect – factor therapy</li></ul>P Bruzzi on<br />
  6. 6. Regulators are reasonableRare plasma protein deficiencies<br />FDA approval of Baxter Protein C – pivotal study n=18 patients with deficiency<br />FDA approval of CSL fibrinogen – pivotal study n=15 patients with afibrinogenemia<br />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.<br />
  7. 7. Conventional Statistical Reasoning<br />Starting hypothesis (Null hypothesis - H0): <br /><ul><li>new treatment = standard one </li></ul>To demonstrate: new treatment >> standard<br /><ul><li>reject null hypothesis (p<0.05)</li></ul>To reject null Hypothesis: <br /><ul><li>Large Sample Size</li></ul>Only information collected within the experiment can be used in interpretation of study results<br />P Bruzzi on<br />
  8. 8. The statistical burden<br /><ul><li>A study must have an adequate size
  9. 9. Required Size, based on:
  10. 10. Significance level (usually 5%)
  11. 11. Minimal clinically worthwhile difference
  12. 12. Power (usually 80-90%)
  13. 13. Results: Test of significance
  14. 14. P<0.05 = Positive Study
  15. 15. P>0.05 = Negative Study</li></li></ul><li>The statistical burden Effect of sample size on power<br />Disorder frequency<br />1 : 50 000<br /><ul><li>Demonstration of a</li></ul>50%reduction in the occurrence of an end-point with 95% confidence<br />No overlap in CI’s – endpoint attained<br />Overlap in CI’s – endpoint not attained<br />
  16. 16. The ideal<br />Randomization<br />Equipoise<br />Controls<br />Blinding<br />100<br />100<br />Clinical Trial<br />
  17. 17. The use of RCTs should be questioned when…<br />Results are readily observable or dramatic<br />High morbidity/mortality occurs even with best available therapy<br />Patients/physicians show reluctance to placement in non-treatment control arm<br />Crossing-over from positive observable results<br />‘Orphan-type’ unmet indication where RCT costs are prohibitive and may stifle innovation<br />Professor Archie Cochrane 1909 - 1988<br /> “The [randomised controlled trial] is a very beautiful technique, of wide applicability, but as with everything else there are snags.”<br />IN OTHER WORDS — MANY OF THE INDICATIONS FOR PLASMA THERAPIES<br />
  18. 18. Thinking outside the boxAlternative approaches<br />There must be some other way….<br />Interim analysis<br />N of 1 trials<br />Sequential designs <br />Bayesian analysis<br />RCT<br />There is !<br />
  19. 19. Bayesian methodology<br />Less direct evidence is required for decision when prior evidence is taken into account – SO<br />Uses Prior Evidence (a crucial component in the interpretation of any finding)<br />Bayesian statistics allows us to combine prior evidence with trial results <br />Prior information  probability distribution of the likely effect of the experimental treatment<br />Posterior Probability distribution of the likely effect of the experimental treatment <br />(range of plausible effects)<br />+<br />=<br />Trial results (if necessary and possible)<br />
  20. 20. IVIG vs Plasma Exchange for children with GBSBayesian approach<br />Initial 86% probability that IVIg was not inferior to PE (Prior).<br />Also include adult experience through previous trials<br />Trial population size then needed to show non-inferiority with power of 77% is 160 kids<br />With conventional design population needs to be 750 kids!<br />Using Bayes we show that IVIG can be used instead of PE in children, and spare 500 kids from having to be trialed!<br />Clinical Trials 2005; 2:305-310<br />
  21. 21. 6.8<br />0.98<br />0.99<br />0.94<br />0.999<br />0.999<br />0.73<br />Inhibitors in previously transfused hemophiliacs (PTPs)<br />Problem - Inhibitors in PTPs <br />Need – to identify risky products<br />FDA trial proposal (2003) – conventional method BUT most FVIII would be off the market<br /> Bayesian alternative (Lee & Roth 2005) - can identify risky products and keep the other products on the market<br />Upper threshold of the true population incidence of inhibitors (%)<br />Product<br />ITT Observedinhibitorincidence (%)<br />A<br />B<br />C<br />D<br />E<br />F<br />2.3<br />2.3<br />2.9<br />0.9<br />1.0<br />5.7<br />
  22. 22. The role of sequential analysis in RCTs<br />In sequential trials:<br />data are analysed after each participant’s results become available<br />the trial continues until a clear benefit is seen in one of the comparison groups, or it is unlikely that any difference will emerge<br />duration is shorter than fixed-length trials when there is a large difference in the effectiveness of the interventions being compared<br />Use of this methodology is restricted to conditions where the outcome of interest is known relatively quickly<br />
  23. 23. Sequential trial design Efficacy of Viagra in men with erectile dysfunction caused by spinal cord injury<br />Mar 1, 1996<br /><ul><li>Data studied in Jan, Feb and March
  24. 24. Using Z and V statistics
  25. 25. Boundaries specified through correction for discrete looks – crossing boundary completes trial
  26. 26. Reached in March
  27. 27. By using a series of interim looks –
  28. 28. A strong conclusion could be drawn from treating 26 subjects
  29. 29. A fixed sample size trial would have required 57 subjects</li></ul>Feb 1, 1996<br />Jan 1, 1996<br />NEUROLOGY 1998;51:1629-1633<br />
  30. 30. N of 1 trailsTrial of therapy<br />Randomized clinical trial used in just one patient <br />Patient undergoes pairs of treatment periods <br />one period is the experimental treatment <br />other period is the comparator (placebo or alternative treatment<br />Considered to provide the strongest level of evidence<br />Do not permit any generalization of the findings<br />BUT - may be combined<br />through meta‐analysis<br />through a Bayesian random effects model <br />Combination provides a population estimate for treatment effectiveness <br />Retains the capacity to provide a distinct effectiveness estimate for each individual patient<br />?New and emerging indications for IgG<br />
  31. 31. Some thoughts on…………<br />......Meta Analysis<br />
  32. 32. Problems with meta-analyses<br />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.)<br />Adjusting for random error through sequential analysis reveals false positive results in many meta-analyses ieprediction of an effect when none exists (International Journal of Epidemiology 2008;1–12)<br />
  33. 33. Use of Trial Sequential Analysis (TSA) to analyze Meta - Analyses Cochrane Neonatal Reviews<br />!!!!!!<br />!!!!!!<br />!!!!!!<br />International Journal of Epidemiology 2008;1–12<br />
  34. 34. Regulatory relief?<br /><ul><li>FDA approval of Baxter Protein C – pivotal study n=18 patients with deficiency
  35. 35. FDA approval of CSL fibrinogen – pivotal study n=15 patients with afibrinogenemia
  36. 36. 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.</li></li></ul><li>Here’s what’s important!<br />RCTs are difficult with rare disorders<br />Other ways exist<br />Effort and commitment are needed<br />By regulators<br />By industry<br />Like Cochrane – we must always question what we do, and try to improve<br />The aim should always be – <br />TO GET EFFECTIVE AND SAFE THERAPIES TO THOSE WHO NEED THEM<br />THERE IS ALWAYS A WAY !<br />Professor Archie Cochrane – 1909 - 1988<br />“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”<br />