Drug Development in Paediatric Oncology

Transcription

1 Drug Development in Paediatric Oncology Koen Norga, MD, PhD Paediatric Oncology, UZA External clinical expert, FAMHP PDCO, vice-chair and member (BE), EMA CHMP, co-opted member (pharmacology), EMA

2 Drug development: the path to reimbursed access Preclinical studies: theoretical rationale to support administration to patients, toxicology is animals Pharmaceutical development: from molecule to medicinal product Clinical trials (commercial / academic): to establish safety / efficacy in a controlled setting Compassionate use / medical need programs Marketing authorisation: positive benefit/risk? Reimbursement: cost-effectiveness? Real-world data: pharmacovigilance

3 Clinical development in oncology Early exploratory studies (in the past: phase I/IIa) Small (10-50 pts?) Single arm, single agent Lots of biology, biomarker validation Basket/umbrella design Dose-finding For safety, but also for signs of activity (rarely efficacy) In advanced disease, last resort option No curative intent Late confirmatory studies (in the past: phase IIb/III) Post-authorisation studies (in the past: phase IV)

4 Clinical development in oncology (cont d) Late confirmatory studies Randomised controlled In combination More patients (100s to 1000s?) Frontline? Curative intent? Efficacy (and safety) compared to standard therapy Post-authorisation studies Registries Real-world data Investigator-initiated therapy optimisation studies Late effects (safety)

5 Drug development in paediatric oncology By academic consortia No support from industry Tremendously successful Using available products (post-authorisation studies) Curative intent (mostly) Complex combination multimodal therapy Therapy optimisation studies as standard-of-care -> How to use this paradigm for development of new, expensive, unknown targeted drugs?

6 Survival improved in consecutive studies Cytotoxic medicines Paediatric regulation 7 Paediatric oncology Rössig et al.: Effective childhood cancer treatment: The impact of large scale clinical trials in Germany and Austria. Pediatric Blood & Cancer 2013 doi: /pbc.24598

7 EU Paediatric Medicines Regulation More and better authorised medicines for children Stimulate high-quality research in children Increased information on use of medicines in children Obligation to develop new medicines also for children Paediatric Investigation Plan (PIP) Rewards and incentives for pharma Avoid unnecessary studies Develop age-appropriate formulations adult indication is starting point for identification of paediatric development obligation

8 Paediatric Oncology and commercial drug development Reimbursement and access

9 Paediatric and overall development 1 0 Paediatric oncology Vassal et al.: New drugs for children and adolescents with cancer: the need for novel development pathways. Lancet Onc 2013 doi: /s (13)

10 Centrally authorised anti-cancer medicines Paediatric regulation 1 1 Paediatric oncology Own analysis

11 Therapeutic areas of agreed PIPs (11/2016) 149 Pulmonology/allergology 121 Infectious diseases 100 Endocrinology/metabolism 93 Oncology (representing >50 mechanisms of action) 76 Immunology 58 Haematology-Haemostaseology 52 Cardiovascular 55 Neurology 44 Vaccines 1 2 Paediatric oncology progress indicators

12 Support for anti-cancer medicines for brain tumours Orphan designated: 42 medicines incentivised to be developed for HGG Scientific advice: >15 medicines supported for HGG Paediatric inv. plans: 7 agreed, 2/7 discontinued in adults, 2/7 completed Assessed: 4 medicines authorised, 4 other refused 1 3 Paediatric oncology

13 Stakeholders comment on PIPs and flag public health issues 1 4 Paediatric oncology

14 Challenges and opportunities Developments mostly driven by adult needs/market Biology of the target? Differences between adult vs paediatric tumor biology? Loop holes in the law: class waivers and deferrals Too many new products? First-in-class vs best-in-class Different treatment goals in children, compared to adults Integration with combination therapy schemes New types of paediatric safety issues (related to developmental effects of targeted agents) -> Where to position in children? (last resort front line?)

15 Feasible and timely high-quality studies in children Feasibility of studies Equipoise in paediatric RCT after adult PoC? Rare disease paradigm Research capacity Lack of commercial trial infrastructure in paediatric oncology centers (for exploratory studies) Lack of familiarity of industry with paediatric setting (for confirmatory studies) -> Extrapolation? -> Adaptive licensing / early access?

16 Research and development first trials 1 7 Paediatric oncology Source: EudraCT

17 Innovation in medicinal therapy for paediatric oncology Small molecule inhibitors of intracellular signal transduction Monoclonal antibodies Advanced therapy medicinal products (ATMP)

18 Small molecule inhibitors of intracellular signal transduction Need for adapted age-appropriate formulations Off-target effects? Proof-of-principle: imatinib, others??

19 Monoclonal antibodies Mechanisms of action now well understood: tumor cell death immune modulation of tumor environment Target = cell membrane receptor (anti-cdx?) Sophisticated constructs (bi-specific, engager, conjugate ) Proof-of-principle: rituximab (note: not authorised!)

20 Advanced therapy medicinal products (ATMP) CAR-T cells GVHD prophylaxis

21 Thank you! Questions? 03/