Labels A Century Ago 918 . Source: www.wellcomecollection.org

1. Ethical, Social, and Good Clinical Practice (GCP) Aspects Of Drug Development In Children And In PaediatricClinical TrialsKlaus Rose,klausrose Consulting Pediatric Drug Development & More klaus.rose@klausrose.net

2. Labels A Century Ago 918. Source: www.wellcomecollection.org

3. Modern Drugs: Therapeutic Potential & Dangers • 1937 a liquid anibiotic was introduced • Solvent: Ethylen Glycole; highly toxic; no toxicity testing. > 100 deaths, 1/3 children • Led to revision of FDA legislation • Next catastrophe: Thalidomide1962 • Ten cases in the USA by ‘clinical studies’ • Led to the Kefauver-Harris amendments • Was the birth of modern labels

4. US Legislation Triggered Modern Drug Labels klausrose Consulting Date back to US legislation 1962: enforced proof of efficacy. Use in children mostly off-label since then. Voluntary Pediatric Exclusivity (PE): BPCA* 2007 after first laws 1997 & 2002. Biologics excluded. Mandatory ped development: PREA*** 2003. All age groups. Biologics included. Applies to same indication as in adults only. Re-authorized 2012 as FDASIA*** BPCA &PREA resulted in multiple pediatric research on patented drugs. Both seen by FDA as major success *BPCA Best Pharmaceuticals for Children Act **PREA Pediatric Research Equity Act ***FDASIA FDA Safety & Innovation Act - 6 -

5. EU Pediatric Regulation klausrose Consulting In force since January 2007 Combines mandatory development with reward Pediatric Investigation Plan (PIP) mandatory end of human PK Without approved PIP Marketing Authorisation Application (MAA) is blocked PIP must cover all age groups Pediatric Committee (PDCO) assesses PIPs, waivers & deferrals Reward of six months SPC* prolongation *SPC Supplementary Protection Certificate - 7 -

6. EU Pediatric Regulation: Core Elements • FDA startedwithlookingfor ‘some‘ pediatricdata • EU wants, asfaraspossible, fullpediatricindication(s) • Want thenecessarydataassoonaspossibleformarketeddrugsandasearlyaspossiblefornewdrugs • Expecteachcompanytobeknowledgeable + uptodate • EMEA / PDCO style: hasevolvedsince 2007. Claim tobescience-driven, but havedeveloped a toughattitude • Somerequestscanbeperceivedasexaggerated. Dictateclinicaltrialsevenifthey do not make sense klausrose Consulting - 9 -

7. EU Pediatric Investigation Plan (PIP): mandatoryat end of human PK FDA: Early dialoguerecommended; Ped Plan mandatoryatsubmission Regulatory & Scientific Challenge: Earlier Inclusion of Children In Drug Developemnt Basic Research Entry into Man Proof of Concept (PoC) Phase II+III Registration 1st Country Patent-protected Market Patent Expiry  Generic Competition klausrose Consulting - 10 -

9. Pediatric Homework • Doesthe same indicationexist in children? • Diagnostics: whichotherdiseasesmightbediagnosed? • Drugs: whichotherpediatricdiseasesmightbequalifiedasbeingwithinthe ‘condition’ thedrugisdeveloped in? • PDCO view: potential futureuse in children. May be different fromfuture adult use. • Whichtherapeutic alternatives exist in children? • Risk/benefit assessment of ped development klausrose Consulting

10. PIP Structure b klausrose Consulting

11. PDCO Oral Explanation: Room & Sitting 15 m PDCO Chairman Applicant‘s Speaker PDCO Members EMA Representatives Applicant Representatives klaus.rose@klausrose.net

12. Case Study Coronary Artery Disease (CAD) • Nykomed requested a full waiver for a diagnostic agent for coronary artery disease (CAD), a disease listed on the class waiver list • EMA: condition is “Visualisation of myocardial perfusion for diagnostic purposes”. Myocardial perfusion deficits exists in children (congenital heart defects, coronary anomalies, cardiomyopathies) • Negative opinion 2008 • Applicant took EMA to EU Court of Justice; 1st instance backed EMA • US originator company negotiated a new PIP with EMA, agreed 2011 • Danish company continued law suit . EU General Court backed EMA 2011: otherwise it would be too easy for companies to circumvent pediatric development. klaus.rose@klausrose.net

13. EMA Decisions Perflubutane • EMA decision of 28 November 2008 on the application for product specific waiver for perflubutane EMEA-000194-PIP01-08 in accordance with Regulation (EC) No 1901/2006 of the European Parliament and of the Council as amended. http://www.ema.europa.eu/docs/en_GB/document_library/PIP_decision/WC500005753.pdf • EMA decision of 18 May 2011 on the agreement of a paediatric investigation plan and on the granting of a deferral and on the granting of a waiver for perflubutane (EMEA-000194-PIP03-10) http://www.ema.europa.eu/docs/en_GB/document_library/PIP_decision/WC500107411.pdf

14. EU Court of Justice Decisions • Order of the President of the Court of First Instance of 24 April 2009 – Nycomed Danmark v EMEA (Case T-52/09 R). http://curia.europa.eu/juris/document/document.jsf?text=&docid=73453&pageIndex=0&doclang=EN&mode=lst&dir=&occ=first&part=1&cid=327397 • Judgment Of The General Court (Third Chamber) 14 December 2011. http://curia.europa.eu/juris/document/document.jsf?text=&docid=116583&pageIndex=0&doclang=EN&mode=doc&dir=&occ=first&part=1&cid=234507 klaus.rose@klausrose.net

15. PIP Decisions • So far > 1000 PIPs have been submitted • The key elements are published, but not the details • Details are always confidential • Nevertheless, we can see trends in specific areas • Melanoma • Joint injuries • Vaccines • Drugs for preterm newborns • Drugs developed only for children • Rare diseases

16. Melanoma • Class waiver for melanoma was revoked • Justification: 1.7/ 100’000 15-19ys olds in US statistics Surveillance, Epidemiology & End Results (SEER), www.seer.cancer.gov • 6 PIPs if you search with ‘melanoma’: Ipilimumab (2); MAGE-A3 recombinant protein; GSK1120212; GSK2118436; RO5185426 • Ipilimumab [BMS] conditions: melanoma (PIP 1) and solid malignant tumours excluding melanoma (PIP 2) • Mage-A3 recombinant protein: Condition: melanoma • GSK1120212: Condition: Melanoma & malignant solid tumours (excluding melanoma) • GSK2118436: Condition: Melanoma & malignant solid tumours (excluding melanoma) • RO5185426: Condition: Melanoma

17. Ipilimumab (Yervoy) • Condition: melanoma and non-melanoma solid tumors (2 PIPs) • Studies for melanoma: • i.v. study of pre- and postnatal development in cynomolgus monkeys with a 6-month postnatal evaluation. • OL, dose escalation clinical trial of intravenously administered ipilimumab in children from 2 to less than 18 years (and in young adults to 21 years) with untreatable, refractory or relapsed solid malignant tumours. • OL multi-centre, single-arm i.v. ipilimumab in 12 to <18 y with untreated/ previously treated advanced/metastatic melanoma. • OL randomized active-controlled study: adjuvant ipilimumab anti-CTLA4 therapy vs. high-dose interferon α-2b in kids 12 - < 18 y (and adults) with resected high-risk melanoma.

18. Does This Make Sense? klausrose Consulting Obviously, PDCO wants to do “something” for children with melanoma. No doubt about their good intentions. It would be unethical to disallow adolescents or children with melanoma participation in adults trials. Once an adult melanoma drug is registered in adults, of course clinicians will use it in children as well. Too few patients for statistically significant results As companies have to commit to studies to be finished in a defined time horizon, the pediatric patients with melanoma are now blocked for PDCO-triggered clinical trials. Has started to affect e.g. US children with cancer, although the clinical community sees other priorities In consequence, danger of blocking promising treatments

19. Societal Impact of EU & US Pediatric Legislation Increases cost of drug development For large companies costs are still marginal. Can be different for an individual small / medium company SME office @ EMA offers help, but PDCO treat all applicants equally Higher costs for pediatric medicines have not yet reached calculations of insurers / reimbursement institutions Takes decision power away from originating companies Does not contribute to pharmaceutical innovation in Europe Has increased the weight of academic pediatrics Many clinicians still have a generally positive view Assessment of relation of resources assigned to resulting clinical benefit for children almost impossible due to confidentiality klausrose Consulting

20. Light at The End of The Tunnel? • EMA report to EU Commission emphasizes need for penalties • EMA 5 years report July 2012 to EU Commission & EU Parliament: “Work is well advanced to promote less detailed PIP proposals, including the key elements in PIP opinions. The simplification of applications and subsequently of PDCO opinions should benefit early PIP applications …” • First changes were presented by EMA at the EFGCP/DIA/EMA pediatric conference September 2012 in London, UK • General revocation of class waivers in pediatric oncology was announced a few days ago • Revision of pediatric regulation in 2018: reasonable modification of the regulation to be expected? klaus.rose@klausrose.net

21. Conclusions • Drug development no longer possible without considering children • Increases cost & complexity of drug development • Mosaicofgoodwill, scientificinput, bureaucracywithoutchecks & balances, disproportionateuseofresources, limited clinicalbenefit • PIP skills needed: intimate knowledge of PDCO, EMA & procedures • Potential for saving resources is highest during early PIP preparation • Aim for individual company: negotiate PIP that will serve child health in the far future and lets company survive • Revision 2018: divergent proposals will be made • EU Council’s Lisbon strategy 2000: EU by 2010 “to become the most competitive and dynamic knowledge-based economy in the world” • EU pediatric legislation should be seen in this framework. Is one of many EU challenges. Good intentions are not enough • Legislation will stay no alternative thantocontinuethedialogue klaus.rose@klausrose.net

22. ThankYouForYour Attention! klausrose Consulting

23. klausrose Consulting Back-Ups

24. Better Medicines for Children or Better Use of Adult Medicines in Children? • EU & US pediatricpharmaceuticallegislationtriestoclose a gap - in theuseofexistingadultdrugs in children • So far, thereisnoindustrythatdevelopsdrugsforchildren • Such an industrycouldexistiftherewouldbe a market • Thereareenough rare diseasestokeepthousandsofresearchersbusy – but somebodyhastopay • Today, not even a strawfacilitatingintakeofantibioticsisreimursed in Germany – formulation was abandoned • We talk abouttwoissues: (1) Handling additional pediatricrequests in adult development, and (2) nicewording: ‘bettermedicinesforchildren’ klaus.rose@klausrose.net

25. Age Groups (ICH E 11) Preterm newborn infants(0 - 27 days) *ICH E 11 Term newborn infants(0 - 27 days) Infants and toddlers(28 days to 23 months) Children (2 - 11 years) Adolescents (12 to 16-18 years): US 16 y / EU 18 y klausrose Consulting

26. klausrose Consulting

27. Will bereleased May 2010 klausrose Consulting

28. PDCO Summary Report Template D.1.b: ” The Regulation considers the need for data in the paediatric use. This can be based on the potential for off-label use in children. The Regulation does not require that the PIP is limited to the proposed wording of the adult indication, but it is assumed that there should be some relationship” klausrose Consulting

29. EMA/ PDCO Feedbacks & Reports klausrose Consulting Requests for modification for validation Day 30 report: no action required from applicant Day 60 report: lists requested modifications: must be answered Day 90 report: lists requested last modifications Day 120: Showdown AND only chance for F2F Oral Explanation (OE)

30. Waivers klausrose Consulting Waiversaregivenfor all childrenorspecificagegroups Age classifcationbased on ICH E 11 Waiversonlyfor 3 conditions: • Drug probablyineffectiveorunsafe • Diseasedoesn‘texist in children • Nosignificanttherapeuticbenefit

31. Deferrals klausrose Consulting Allowscompanytoperformpediatricmeasures (studies, technicaldevelopment etc.) at a laterdefined time point Onlyconcretemeasurescanbedeferred Basic frameworkoutlined in ICH E 11: • Will formostnewdrugsbegrantedaslongasthereare not sufficientsafety & efficacydata in adults • Will formarketeddrugswith off-labelpediatricusebeverydifficulttoobtain

32. Melanoma PIP Considerations • Classification as adolescent disease refers to US data 15-19ys olds. Ovarial carcinoma, 1.4/100’000 in 15-19y: class waiver stays. • Deducing 2/5 from 1.7 (18/ 19 y old are adults) & 2/5 of 1.4  lower limit 1.02 - 0.84/ 100’000 as limit for ultra rare disease? Not official • Melanom ist rare < 18; most are detected without metastases. With these case numbers no statistically significant results possible • Separate clin studies in adolescent melanoma ethically questionable • Adolescents should have the right to participate at adult studies, but • No PIPs for more frequent pediatric cancer types – because they don’t exist in adults & hence no business case for drug development • Starts to negatively impact pediatric cancer research worldwide as PDCO decisions block pediatric patients

33. Cartilage Disorders • ACT (autologouschondrocytetransplantation) routine in treatingcartilageinjuries. Belatedregistrationrequiredby German law PIP. • Twopublishedchondrocyte PIPs: • Autologouscartilagederivedculturedchondrocytes (Genzyme) • Culture expandedautologouschondrocytes (Fidia, Italy) • Genzyme: Retrospective investigation of S and prospective investigation of S&E data in ped patients treated for cartilage defects with autologous cartilage derived cultured chondrocytes. Pediatric population from closure of femoral epiphyseal growth plate to <18 y. • Fidia: Randomized MC S&E study of Hyalograft autologous chondrocyte implantationcomparedtomicrofracture in 16-17y olds • An adolescent‘skneeisbiologicallythe same as a youngadult‘sone • PDCO useslegalagetoordermedically & ethicallyquestionabletrials

34. More Examples • Vaccines: were developed for decades without PDCO • Drugs for preterm newborns: development team’s competence is sufficient to develop drug from research to registration – for which CHMP is responsible. Addition ‘input’ from PDCO not helpful. • Drugs developed only for children: there are a few companies who dare. Addition ‘input’ from PDCO not helpful. • Rare diseases starting in childhood. Drug development requires very special knowledge. MAA is discussed with CHMP. Mandatory additional PDCO discussion perceived as waist of time & resources by industry

35. Dosing In Adolescents • In an FDA hearing 2012 12 of 13 clinicians voted for the routine acceptance of adult doses in adolescents • Was based on an FDA report on adolescent PK Studies • Discussion is ongoing in the pediatric scientific press • FDA publications and massive advances in pediatric dosing in pharmaceutical companies

36. EU Ombudsman • Twocompaniescomplainedagainst EMA/PDCO @ EU ombudsman • The EU ombudsmanconcluded that in contrast to EMA’s position the complaint fell within the scope of ‘maladministration’ and hence, under his mandate. • The enquiry resulted in recommending, inter alia,EMA guidelines to assist PDCO to follow a coherent structure of analysis in future cases. • We will later today hear more directly from a representative of the EU ombudsman’s office! • alia, EMA guidelines to assist PDCO to follow a coherent structure of analysis in future cases

37. Resources klausrose Consulting Big companies: PIP is one of many many challenges SMEs: limited resources. Additional PIP challenge is usually much more time consuming than originally thought Estimated consulting dimensions: • Regulatory PIP consulting: 200-300 hours • Clinical input should come from the sponsoring company • Deep clinical consulting can increase the effort by factor 3 to 5 • This does not include additional internal costs by the sponsor and not the costs of PIP execution Even best external consulting will not allow the sponsoring company to just forget pediatrics

38. PIP Execution klausrose Consulting Ca. 20 – 30‘000 € / costs per patient  Study 100 adults ~ 2-3 Mio € Multiply with factor P for pediatric studies More patients  higher costs Additional costs: juvenile animal studies, pediatric formulation, establish a registry, etc. BD&L rough estimate if you buy a product where pediatric homework has not been done: ~ 20 Mio € (including study execution, provided your MAA is not blocked A part of this money must be invested before MAA, a part thereafter