facilitate prioritisation: the accelerate-ema paediatric ... · ema • immune environment in...

Facilitate prioritisation: The ACCELERATE-EMA Paediatric

Strategy Forums

Andy Pearson and Nicole Scobie

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Organising Committee

ACCELERATE

Gilles Vassal, Andy Pearson

EMA

Franca Ligas, Giovanni Lesa and Koen Norga

Secretariat

ACCELERATE

Elena Botanina, Samira Essiaf

EMA

Isabel Perez

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The ACCELERATE-EMA Paediatric Strategy Forums

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Mechanism of action biology-driven early drug development

• Aggregated database of paediatric biological tumour drug targets

• Joint academic–pharmaceutical industry pre-clinical platform to analyse the activity of new drugs (ITCC-P4)

Paediatric Strategy Forums

• Molecular profiling of paediatric tumours at diagnosis and relapse

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“Novel drugs with a similar MoA can then be

‘compared’ in a non-competitive space, such that

precious resources are not wasted, and paediatric patients

are not enrolled on sub-optimal clinical studies

unlikely to benefit them. However, this process

involving multiple stakeholders will involve significant

challenges.”

Pearson AD, Herold R, Rousseau R, Copland C et al on behalf Members of Working Group 1 of the Paediatric Platform of ACCELERATE. Implementation of mechanism of action biology-driven early drug development for

children with cancer. Eur J Cancer. 2016; 62:124-31.

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To facilitate dialogue and provide an opportunity for constructive interactions between relevant stakeholders (clinicians,

academics, patient representatives, pharmaceutical companies and regulators) on topics requiring open discussion in the best

interests of children and adolescents with cancer

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Goals

• Share information, in a pre-competitive setting, to inform paediatric drug development strategies and subsequent decisions

• Facilitate development of innovative medicines for the treatment of children with cancer and ultimately introduce these medicines into the standard-of-care for children

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Content

• Biology of target

• Therapeutic needs including epidemiology, clinical features, standard therapy current needs and future therapeutic plans – Europe and North America

• Non-clinical and clinical data on compounds

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2017 ACELERATE Conference

Paediatric Strategy Forum for ALK Inhibition in Paediatric Malignancies Pilot Forum

30 & 31 January 2017

• Target focused Forum

• Comprehensive overview of the biology and therapeutic needs of patients and clinical and pharmacological information of currently available 6 compounds

• Greatly increased the knowledge of participants so that future decisions will be well informed

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• Disease centric Forum

• Current therapy for high-risk mature B cell malignancies - EFS~ 95%

• Acute toxicity – significant, but most survivors - no or mild long term toxicity

• Current unmet therapeutic needs are to:

i) develop innovative treatments for patients remaining incurable

ii) reduce high acute toxicity of current therapy; further reduction of intensive therapy leads to reduced cure and salvage regimens are not effective

Many medicines in development for B cell malignancies in adults; most malignancies in adults differ from those in children

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Paediatric Strategy Forum - Mature B cell malignancies in children

Challenges

• To identify which of the many potential new drugs has optimal probability of improving cure rates in paediatric patients with chemo-resistant disease

• To design and execute scientifically sound studies in very small populations with relapsed mature B cell malignancies

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• 73 Participants

• 20 Medicinal products discussed

• 15 Pharmaceutical companies

• European and North American experts in mature B cell malignancies in children and drug development

• Patient representatives from Unite2Cure (Europe) and Children’s Cause for Cancer Advocacy (US)

• Regulators from EU national competent authorities, EMA & US FDA

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Classes of medicinal products• Antibody drug conjugates

• CAR T Cells

• Monoclonal antibodies

• T-cell Engagers

• Checkpoint inhibitor

• Cell signalling inhibitors

• Immunomodulatory imide drugs (IMiDs) and CELMoD

• Cytotoxic

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Conclusions

• Combined adult and paediatric trials: Except for Primary Mediastinal B cell lymphoma specific paediatric studies are

needed primarily due to different biology

Inclusion of adolescents (aged 12 to 17 years) in adult trials is very strongly encouraged

• Joint leukaemia-lymphoma clinical trials are not feasible

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Conclusions

• Development of new front-line therapies

Current frontline therapy very successful de-escalation can only be undertaken with an effective salvage regimen

Priority should be directed at developing treatment for relapse

• Development of therapies for relapse

Very small numbers of patients - global strategy

Combination approach rather than monotherapy

• Trials for relapsed disease must integrate correlative biology studies

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Conclusions

• Consensus of clinicians

Antibody drug conjugates (excluding a vinca alkaloid drug)

CAR-T cells (as take 4 weeks for production - not products for initial use but only for consolidation)

T-cell Engagers

have the greatest probability of being beneficial in relapse

• In view of very small numbers of patients, new additional trials of cell signalling inhibitors should not commence until the results of the ongoing SPARKLE trial known

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Conclusions

• 14 related Paediatric Investigation Plans (PIPs) agreed / under assessment • Clinicians and pharmaceutical companies :-

Proposed that PIPs be adaptable in response to new data (‘PIP development Life-cycle’ approach)

Proposed that PIPs should not include obligation for front-line trials, until there are effective salvage regimens, except for PMBL

Expressed concerns about number of agreed PIPs, in view of the small number of eligible patients

• Benefits of conducting academic sponsored clinical trials with adaptive design of compounds from different pharmaceutical companies and differentmechanism of action - designed with “intent to file” with early input from regulators

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Output

• Summary for participants

• Short summary for EMA website

• Published manuscript

• International working group to develop a clinical trials strategy

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• An evolving concept• Increasing dialogue - Pharmaceutical companies, academia and

regulators• Increasing dialogue - EU and US• European, US and other international academic clinical cooperative

groups work closely together• Critical role of patient representatives• Third Forum - Checkpoint inhibitors used in combination - 5 & 6

September 2018 at the EMA • Fourth Forum - Potential topic - Acute Myeloid Leukaemia

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The patient representatives’ perspective

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• Why is our voiceimportant?

• How do we see the future of these forums?

Together, we can make a difference

Third Forum Checkpoint inhibitors used in combination

5 & 6 September 2018 EMA

• Immune environment in paediatric tumours• Early results of early phase trials of checkpoint inhibitors in children • Opportunities for paediatric studies of check-point inhibitors in

combination • Other possible approaches

Advert soon and Expressions of interest

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