1. Clinical Trials in Rare Diseases Brendan M. Buckley MD DPhil FRCPI College of Medicine and Health University College Cork Insights into Successful Research in Rare Disease: Dublin : 26 March 2012 b.buckley@ucc.ie

2. Disclaimer The views expressed are solely those of the author and do not necessarily reflect positions or policies of the organisations to which he is affiliated. No conflicts of interest potentially affect this presentation Insights into Successful Research in Rare Disease: Dublin : 26 March 2012

3. EU defines ‘Rare Disease’ based on prevalence of < 5 per 10,000 of the population Total EU population is about 500 x 10 6 Maximum number of people with any specific rare disease is about 250,000 However, the large number of diseases fitting the definition means that an estimated 29 Million EU citizens are potentially affected by a rare disease Source: Eurostat http://epp.eurostat.ec.europa.eu Rare Diseases in the EU

4. Rare Diseases in Ireland 29 Million EU citizens of whom 250,000 are Irish citizens are potentially affected by a rare disease

5. Annual Numbers of Orphan Designations and Marketing Authorizations in the EU Orphan Designations Marketing Authorizations Number of Products Year Source: EU Commission, Jan 2011 2010

6. Annual Numbers of EMA Marketing Authorizations Data: EU Register of designated orphan medicinal products (as of March 2012)

7. Orphan medicinal products on the market from: Dr Jordi Llinares, EMA, 2011

8. Orphan drugs licensed in EU Predictors of Success in Applications for Authorization PredictorValueOdds Ratio* (95% CI) Other orphan drug approved for Indication No1.0 Yes17.3 (5.6-53.1) Product typeBiotechnology1.0 New ‘small molecule’ 1.9 (0.5-7.7) Existing ‘small molecule’ 3.9 (0.9-16.6) Heemstra H, et al.. Eur J Clin Pharmcol 2008; 64: 545-552 *Multivariate analysis

9. Orphan medicinal products marketed 60 unique orphan designated products authorized to May 2011 51% of these for diseases affecting less than 1/10,000 patients Average time OD to MA is 3 years Authorizations 38% under exceptional circumstances 6% conditional approval from: Dr Jordi Llinares, EMA, 2011

10. Clinical Development of Orphan Medicines Patients with rare diseases need medicines that are as safe as effective of the same quality as any commonly used medicine Clinical trials

11. Avicenna Abū ‘Alī al- Ḥ usayn ibn ‘Abd Allāh ibn Sīnā' The effect of the drug must be seen to occur constantly or in many cases, for if this did not happen, it was an accidental effect." from: Kitāb al-Qānūn fī al- ṭ ibb The Canon of Medicine (1025) ‘Avicenna’

12. A Clinical Trial A Prospective study of an intervention Designed to measure the impact of a treatment Compared with a control treatment On a future possible outcome.

13. Steps before doing a Clinical Trial  Validate a good relevant non-human in vivo model  Obtain proof of principle  Work towards GMP production of the medicinal product  Apply for orphan status and avail of the incentives  Raise the money  Interest partners

14. Regulators work to protect the public health by assuring availability of medicines which are safe effective and of adequate quality. Don’t Fear the Regulators (IMB / EMA) !

15. Steps in doing a clinical trial - 1  Design a workable protocol  Focus on the hypothesis; avoid unnecessary, ‘interesting’, questions  Obtain protocol assistance and scientific advice from EMA  Obtain adequate funding  Recruit the right investigators  Obtain prompt regulatory and ethical approval to proceed  Recruit sufficient subjects  Recruit the right subjects

16. Steps in doing a clinical trial - 2  Conduct the study to highest standards of Good Clinical Practice  Monitor (quality assure) the study efficiently  Collect the data  Process the data  Report the data  Communicate the data  Use the data

17. Recruitment to Clinical Trials Everyone with the Disease Everyone with the Diagnosis Accessible patients Suitable patients Volunteers for Trial Recruited to Trial Registers

18. Incidence -v- Prevalence High Incidence with Short Survival Low Incidence with Long Survival Low Incidence with Short Survival Easy to recruit Short time to outcomes Difficult to recruit Long time to outcomes V. Difficult to recruit Short time to outcomes Common diseases may be rare ! e.g. primary adenocarcinoma of pancreas

19. ‘Rare diseases’ that are quite common ! primary adenocarcinoma of pancreas renal cell carcinoma Barrett’s oesophagus high-grade dysplasia malignant glioma multiple myeloma hepatocellular carcinoma Incidence -v- Prevalence

20. Great majority of diseases listed have a prevalence < 1x 10 -6

21. November 2009. Orphanet Report Series. Prevalence of Rare Diseases, Bibliographic data. http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_decreasing_prevale nce_or_cases.pdf 25,000 cases each in EU

22. A Pivotal Trial using just One Patient Before insulinAfter insulin

23. Small numbers may adequate if treatment effect is large

24. Orphan drugs can’t always get big trials Some rare diseases affect fewer than 100 accessible patients in the EU. Hyperammonaemia associated with N-acetylglutamate synthase (NAGS) deficiency was identified over 20 years from 1980 to 2001 Orphan medicine, ‘Carbaglu’, was licensed on the basis of a trial on 12 patients with retrospective data collected on 20 patients in only 42 patients from 28 families, of whom 34 were definitely diagnosed as NAGS deficient, 8 siblings having died without precise diagnosis.

25. Orphan drugs don’t always get big trials Eaton-Lambert Myasthenic Syndrome Prevalence in EU: 0.1 per 10 000 (45,000 individuals in EU) Zenas ® (amifampridine) blocks voltage-dependent K + channels to prolong pre- synaptic membrane depolarization. Authorization based on a mixed application, and pivotal efficacy data were based on published studies. Four randomized placebo-controlled studies & one active controlled study published and Cochrane reviewed. Two studies were considered as pivotal. Total number of participants in both: 38. Other controlled trials published in abstract form or as a short book article considered as supportive. Also, some reports of uncontrolled investigations and case reports which provided supportive information on efficacy. EU M.A. 23/12/2009

26. Orphan drugs don’t always get big trials Eaton-Lambert Myasthenic Syndrome Prevalence in EU: 0.1 per 10 000 (45,000 individuals in EU) Zenas ® (3,4-diaminopyridine phosphate: amifampridine) “ The CHMP recommended granting marketing authorization for Zenas under exceptional circumstances, because the indication for which this product is intended is encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence. Therefore the applicant has agreed to provide further evidence as specific obligations relating in particular to the safety and efficacy of Zenas including a risk management plan.... including a registry to be established to monitor patients undergoing treatment “ Doc. Ref.: EMEA/793638/2009 ASSESSMENT REPORT FOR Zenas International Nonproprietary Name: amifampridine Procedure No.: EMEA/H/C/001032

27. Ofatumumab (Arzerra ® ) EMA Marketing Authorisation 2010: Procedure No. EMEA/H/C/001131 Indication: Chronic Lymphocytic Leukaemia (CLL) in patients refractory to fludarabine and alemtuzumab : Prevalence: CLL is 3.5 per 10,000 EU population. Primary Evidence of Efficacy: results of interim analysis of ongoing pivotal study Hx-CD20-406 (Phase II, open- label, single arm, ongoing: N =154. supported by efficacy results from one completed supportive study, Hx-CD20-402 open-label. dose-escalation, completed. N=33 Arzerra Public Assessment Report, European Medicines Agency, London, 20 January 2010 Doc.Ref.: EMA/CHMP/195135/2010

28. Orphan drugs licensed in EU Numbers of participants in clinical trials 201-500 101-200 <100 0 >500

29. Orphan drugs licensed in EU Mainly based on bibliographic / historic information DrugIndicationDate Marketing Authorization (EU) Evidence base Carglumic acid Hyperammonaemia due to N-acetyl glutamate synthase deficiency Jan /2003Pharmacokinetic (12), retrospective patient data (20) MitotaneAdvanced adrenal cell carcinomaApr /2004Bibliographic data only. No trials AnagrelideEssential thrombocythaemiaNov /2004Uncontrolled and compassionate use (1446 patients evaluable for efficacy) NitisinoneHereditary tyrosinaemia type 1Feb /2005Compassionate use (212) BetaineHomocystinuriaFeb /2007Spontaneous literature reports (202) HydroxycarbamideSickle cell diseaseJun /2007Bibliographic and registries Caffeine citratePrimary apnea of prematurityJul /2009Bibliographic data only. No trials Thiotepa Conditioning before haematopoietic stem cell transplantation Mar/2010Bibliographic data only. No trials

30. Helping to buck the numbers for orphan trials Pick a treatment with a big effect on outcome ! Optimize design, availing of Regulator’s scientific advice process Maximize recruitment: patient organizations can really help Keep long trials simple, so that participants don’t drop out

31. Helping to buck the numbers for orphan trials Formally identify components of variance and minimize them - diagnostic criteria, control matching - outcome measures Train investigators to competently and rigorously apply the protocol Quality assure the trial in real time and take firm corrective action

32. Investigator incompetence kills medicines ! Through: Poor detailed understanding of protocol (and GCP) Compassionate pressures to stretch inclusion / exclusion criteria Misunderstandings on adverse effects and efficacy measures Failure to react to changes in critical observations on participants Slow entry of data to study database

33. How different groups interpret trial data: Ofatumumab in chronic lymphocytic leukemia An expert panel of IRC members applied the protocol specified method of response determination to assure an independent, consistent and medically appropriate application of this composite measure of response in CLL. Differences in the response rate assessment according to the three measures largely reflected differences in clinical assessment of transient changes that an expert would not interpret as evidence of disease progression. The algorithmic approach by the sponsor did not account for this, and so represented the most stringent test of the response rate. CHMP ASSESSMENT REPORT for Arzerra (ofatumumab) Procedure No. EMEA/H/C/001131 London: EMA 2010

34. Barriers to Developing Orphan Medicines in Ireland Lack of expertise in translation from bench to patient Academic promotional systems Access to funding of required scale Access to potential trial participants

35. Opening the Bottlenecks Roles for Patient Organisations  Encourage the development of Pan-European Centers of Excellence  Lobby for easier trans-national patient access to them  Support patients who travel from abroad to them

36. Opening the Bottlenecks Roles for Patient Organisations Act as True Stakeholders in the Clinical Trial Process:  Help formulate the questions to be answered by trials  Give ethical guidance to Ethics Committees  Promote recruitment to good trials  Discourage recruitment to poor trials  Ensure publication of trial results

37. Patient Organisations can help Maximise effectiveness of rare disease trials  Effective multinational recruitment  Efficient use of scarce patient resources  Coordination of multiple study designs to facilitate meta-analyses  Long term open-label extension studies and structured post- marketing surveillance  Coordinated biobank use. Opening the Bottlenecks

38. Successful patient organisations Have a few clear research goals  Based on excellent scientific / medical advice  Verified by committed expert members Pursue their research agenda carefully  Fund research to fulfill that agenda  Manage the different agendas of researchers  Require practical results from researchers whom they fund  Are not easily deflected by ‘novelty’ into new projects

39. Successful patient organisations Commission research  rather than invite research proposals Have a clear roadmap for the clinical development of any promising treatment  Non-clinical studies in animal models  First-in man clinical studies  Further human studies Have a clear view of funding needs for clinical development  A business plan to achieve necessary funding.  Ownership of intellectual property.

40. Ireland and Orphan Drugs Research Success depends on virtuous integration between: Higher Education Patient Organisations Government - state funding agencies - EI and IDA EU agencies Capital

41. Thank You ! Brendan M. Buckley MD DPhil FRCPI College of Medicine and Health University College Cork Insights into Successful Research in Rare Disease: Dublin : 26 March 2012 b.buckley@ucc.ie