Nicola Ruperto, MD, MPH PRINTO Senior Scientist EULAR Centre of Excellence in Rheumatology IRCCS Istituto G. Gaslini, Genoa, Italy

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1 Prioritising drug development for children with rhumatologic diseases The Paediatric Rheumatology InterNational Trials Organization (PRINTO) perspective Nicola Ruperto, MD, MPH PRINTO Senior Scientist EULAR Centre of Excellence in Rheumatology IRCCS Istituto G. Gaslini, Genoa, Italy

2 Outline PRINTO outline Opportunities/weakness of the pediatric legislation

3 Paediatric Rheumatic Diseases (PRD) PRD are rare diseases and the most common chronic illnessess in childhood PRD are highly debilitating and potentially affecting the entire life The most common diseases are - Juvenile Idiopathic Arthitis (JIA) - Juvenile Systemic Lupus Erythematosus (JSLE) - Juvenile Dermatomyositis (JDM) and others

4 (> 60 countries)...to foster, facilitate, and conduct high quality research in the field of paediatric rheumatology... PRINTO bylaws 1996 >11,000 people/day

5 PRINTO Organisation Chart ADVISORY COUNCIL Chairman 4 Counsellors Senior Scientist INTERNATIONAL CO- ORDINATING CENTRE International Trials Coordinator NATIONAL CO- ORDINATING CENTRE Director NATIONAL CO- ORDINATING CENTRE Director INDIVIDUAL CENTRE Director INDIVIDUAL CENTRE Director INDIVIDUAL CENTRE Director INDIVIDUAL CENTRE Director

6 PRINTO bottom up approach Standardized criteria to evaluate response to therapy in JIA, JSLE and JDM - ACR pediatric criteria in JIA (FDA, EMA Standardised web information to families Non for profit clinical trials (JIA, JDM, JSLE) Training to young researchers Liaisons with pharmaceutical industries Main source of funding European Union, AIFA, pharmaceutical companies

7 PRINTO not-for-profit studies (>35,000 pts) West Europe East Europa Latin America North America Others Totals MTX HRQOL 3,988 1, JSLE JDM Cyclosporine MTX Vasculitis JDM Eurofever EPOCA MAS Pharmachild

8 PRINTO publications 122 peer-reviewed manuscripts 547 authors (38%) multiple publications

9 Open questions Is there a role for academia for drug approval? Which are the problems encountered by academia? - The case of the MTX paradox for JIA and Regulation (EC) no 1901/2006 (pediatric legislation) - The case of the PRINTO JDM standard of care trial and the Clinical Trial Directive 2001/20/EC - The case of the ethical provision of drugs to chronically ill children especially from developing countries - The issue of funding for independent research

10 The paradox of Methotrexate Mainstream for treatment, proven efficacy and safety - NEJM 1992, Arthritis Rheum 2005, PRINTO Arthritis Rheum 2005-JAMA 2010 Used in combination in several biologic agents trials (infliximab, adalimumab, abatacept, etc) No interest from companies (off patent, low cost) Not approved for use in JIA in many countries JIA pts treated with biologics required to fail MTX! Now MTX finally approved by mutual recognition in many EU countries

11 Open questions Is there a role for academia for drug approval? Where are the paediatric centres?

12 new version > people/day from over 130 countries Ruperto Annals Rheum Dis. 2005

13 > people/day from over 130 countries

14 > people/day from over 130 countries

15 Open questions Is there a role for academia for drug approval? Where are the paediatric centres? Do we need standardised clinical trial training?

16 PRINTO research training Fellowships (1-12 months) - > 120 physicians from 24 countries - Funding: EU, EULAR, Government, self-financing - International PhD on-going PRINTO joint assessor certificate (required by FDA for clinical trials)

17 Open questions Is there a role for academia for drug approval? Where are the paediatric centres? Do we need standardised clinical trial training? Can we simplify ethics committee rules (at least for academic paediatric studies)?

18 The standard of care PRINTO JDM trial 160 EC Approvals Patient Enrolled Patient Not Enrolled months Ruperto et al for PRINTO. Lancet 2015

19 Ethics Committeee submission Country Austria National approval Local approval X CA approval Insurance GCP monitoring Drug supply/no authorizati on off-label Belgium X X X X Bulgaria X X X X EudraC T Financial Agreeme nt Croatia X X X X Czech Republic X Denmark X X X Finland X X X France X X X X X Germany X X X Greece X Hungary X X X Italy X X X X EC payment Ruperto Archives Dis Child 2011

20 Ethics committee hurdles 103 approvals from 30 different countries for JDM trial (essentially no comments) in two years - 3 refused approval because drugs were not approved for use in children! - Some request insurance for a standard of care study (20,000 or 8% of the budget from AIFA) Move from directive to regulation for - Insurance not required for standard of care studies - logistic management of ethics approval: eg one per the entire EU or one per country (new rules ongoing)

21 Ethics evaluation or ethics bureaucracy? In the new rules no specific provision for pediatric studies especially if run by academia

22 2000: a radical change 1999 FDA pediatric rule 2007 EMA and EU parliament: pediatric legislation - Mandatory to companies Pediatric Investigation Plan (PIP) Pediatric networks - PRCSG: USA - PRINTO: Europe and ROW (>60 countries) PRINTO/PRCSG response to therapy standardisation Introduction of biologic agents

23 Open questions Is there a role for academia for drug approval? Where are the paediatric centres? Do we need standardised clinical trial training? Can we simplify ethics committee rule (at least for academic paediatric studies)? Is there a role for an academic CRO? Opportunities/weakness of the pediatric legislation

24 Drug development Protocol defined «offered» to academia Phase I Phase II Phase III Phase IV and post-marketing PIP Submission No specific pediatric requests by the legislation

25 Liaisons with pharma companies Scientific collaboration: - PIP/Protocol/CRF drafting, feasibility for site selection, training, PRINTO/PRCSG primary outcome evaluation, monitoring, analysis, reporting Clinical trials: - NSAIDs: meloxicam, rofecoxib - Biologic agents: Approved: etanercept, adalimumab, abatacept, tocilizumab, canakinumab On-going: certolizumab, belimumab, JAK3. Not approved: infliximab, golimuma (??) Starting point: FDA, EU pediatric legislation

26 Drug development/pip/printo PRINTO collaboration with pharmaceutical companies PRINTO academic pharmacovigilance pharmachild Phase I Phase II Phase III Phase IV and post-marketing PIP Submission No specific pediatric requests by the legislation

27 PRINTO-PRCSG Enrollment (N~3000) West East Latin North Others Totals Europe Europa America America Etanercept Etanercept Infliximab Adalimumab Too many trials Abatacept iv Abatacept sc Tocilizumab syst too few JIA Tocilizumab poly patients/families willing Canakinumab PII Canakinumab P III to be enrolled! Golimumab Meloxicam Adalimumab regi Tofacitinib Rilonacept

28 PRINTO perspective Early and repeated intervention by academia - Pre-PIP (attention to pk-dose finding) - Pre-protocol finalisation - Prioritization (eg anti IL6-IL1 first in children) - Feasibility for centre identification - Assistance during the conduct of the trial E.g. PRINTO/PRCSG as primary outcome independent certified assessors (NEJM, Lancet editors added in the methodds section) (??) revision of definitive protocol by PDCO

29 An appraisal of the legislation

30 The issue of the «me-too drugs» (e.g. anti-tnf) West Europe East Europe Latin America North America Total Etanercept Infliximab Adalimumab Abatacept Tocilizumab Tocilizumab Canakinumab Canakinumab Golimumab Certolizumab pegol PRINTO/PRCSG proposal to perform «just» pkdose finding/safety open label trials On going

31 The issue of the biosimilars (e.g. anti-tnf) West East Latin North Total Europe Europe America America Etanercept PRINTO/PRCSG Infliximab Adalimumab 57 proposal 26 to Abatacept Tocilizumab 1 perform 59 7 «at least» Tocilizumab Canakinumab 1 26 pk-dose 23 Canakinumab Golimumab finding/safety open Certolizumab pegol On going label trials Biosimilar anti-tnf1 Biosimilar anti-tnf2 Biosimilar anti-tnf3 NO PROVISION FOR PAEDIATRICS even for pk-dose finding studies

32 Are all studies needed or scientifically sounded? Study 1: strategies to limit/prevent safety events Study 2: graduated syringes to eliminate/reduce dosing error in children - All good questions but.agreed sample size 20 patients! Study 3: a proper formulation for little children - US: fixed dose regiment (half of the adult dose) - EU: initial marketing just for children > 12 years Study 4: adult dose to treat children - Study negative drug not registered for use in children but legislation requirements fullfilled

33 Pharmacovigilance in juvenile idiopathic arthritis patients (Pharmachild) treated with biologic agents and/or methotrexate. Study 5: pharmacovigilance study A Pediatric Rheumatology INternational Trials Organisation (PRINTO)/Pediatric Rheumatology European Society (PRES) mandatory registry. request to for funded by EU. No use (yet) by pharmaceutical company. No pediatric safetystudies PI Nico Wullfraat Co-Pi Nicola Ruperto 7,494 patients enrolled in the retrospective part 418 patients enrolled in the prospective part

34 Other open questions Do we need all these «unsufficient and unsounded studies»? Do we have «just» to replicate in children what is useful in adults Could/should academia intervene on the choice of the PDCO approved list of studies for pharmaceutical companies?

35 Open questions Is there a role for academia for drug approval? Where are the paediatric centres? Do we need standardised clinical trial training? Can we simplify ethics committee rule (at least for academic paediatric studies)? Is there a role for an academic CRO? Opportunities/weakness of the pediatric legislation Ethics and other provisions?

36 The ethical case The case: 35/190 children enrolled in a EMA/FDA approved clinical trial with biologic in JIA in Latin American countries. Drug provision stopped once drug approved for JIA. Most of the patients could not afford the drug and the disease relapsed PRINTO/PRCSG ethical mandatory request: - Provision of drug to patients until beneficial to child - Family reimbursement for travel related expenses

37 Other provisions Feasibilities for centre identifications through recognised networks: - European Network of Paediatric Research at the EMA (ENPr-EMA) Ruperto et al. Arch Dis Child 2012 Central network contract negotiation (e.g. minimum per patient fee for all participating countries) Authorship for collaborative publication (122 papers with ~550 co-authors)

38 The issue of public funding 3 millions in public grants from PRINTO as support for academic research with reinvestement of funding coming from pharmaceutical industries CARRA (North American network) 33 millioni $ in 2 years!

39 Open questions Is there a role for academia for drug approval? Where are the paediatric centres? Do we need standardised clinical trial training? Can we simplify ethics committee rule (at least for academic paediatric studies)? Is there a role for an academic CRO? Opportunities/weakness of the pediatric legislation Ethics and other provisions?

40 Possible proposals for directive s/regulations revision Strengthen the role of academia and independent research through regulation Simplify the logistics related to ethics approval in paediatrics in conjunction with the clinical trial regulation Demand the provision of drugs to patients (especially children) until beneficial Self-maintaining mechanism for academic independent research

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