Workshop on Extrapolation and Evidence Synthesis in the Development and Therapeutic Use of Medicines in Children Oscar Della Pasqua WP4

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1 Workshop on Extrapolation and Evidence Synthesis in the Development and Therapeutic Use of Medicines in Children Oscar Della Pasqua WP4 th June 203 Strathclyde University, Glasgow, UK

2 Outline - The problem with children - The problem with the scientific and clinical community - The problem with the EU legislation and governance bodies - regulatory expectations and ethical considerations: level of evidence - evidence generation - evidence synthesis - Operational challenges - alternative ti techniques and technologies - novel study designs - Clinical and conceptual challenges Clinical and conceptual challenges - dose rationale - differences between disease in adults and children - biomarkers

3 The problem with children 3 months 7 months year 2 years 3 years 4 years 5 years 3

5 Empirical treatment decisions

6 Clinical Pharmacology & Therapeutics, 200

7 The problem with the scientific and clinical community

8 Regulatory Implications Prescriber Information & Summary of Product Characteristics Indications and Usage 2 Dosage and Administration 3 Dosage Forms and Strengths 4 Contraindications 5 Warning and Precautions 6 Adverse Reactions 7 Drug Interactions 8 Use in Specific Populations 9 Drug Abuse and Dependence 0 Overdosage Description 2 Clinical Pharmacology 3 Nonclinical Toxicology 4 Clinical Studies 5 References 6 How Supplied/Storage and Handling 7 Patient Counseling Information We must ensure that children get access to treatment(s) that have been evaluated rigorously according to scientific, ethical and regulatory requirements. 8

9 Evidence generation vs. Evidence Synthesis

10 ICH E Evidence generation No No paediatric development Will the drug be used in children? No Yes Is the indication the same as for adults? No Clinical efficacy PK & safety data Yes Is the disease process similar to that seen in adults? Yes No Is the outcome of therapy likely to be similar in children and adults? No PD PK & safety data (Efficacy extrapolated ed from adult data) Yes Does efficacy correspond with blood levels in No adult? Yes Is the dose-conc. relationship likely to match that of adults? PK & safety data Yes (Efficacy extrapolated ed from adult data)

11 ICH E Evidence generation

12 ICH E Evidence generation Methods 95 EPARs for medicinal products used in paediatric indications and approved between 995 and 2007 were reviewed 00% 00% % 80% 80% 70% 60% 50% 40% 60% 40% p It was assessed whether symptoms and 69 4 signs of the disease, as well as its progression or natural history, PKPD relationships, and clinical endpoints could be assumed to be similar or different 30% 20% 20% 0% 0% Needed 2 required 2 2 Growth distur rbance Diab betes I RSV di sease Indinav Pompe d vir isease Acute lauk aemia Lennox-Gastaut syn ndrome Laron synd drome PPHN MPS I Nelfinav MPS vir III MPS VI Mesyla Wilson te Urea cycle dis orders Enfuvirtid Dia de betesii Tyrosi inemia NAGS defic ciency Amprenav Paediatri vir c CML Protein C defic ciency Juvenile chronic a rthritis Lopinav vir/ Nephrotic cyst tinosis ere myclonic Ritonav epilepsy in in nfancy ir PDA Adrenal carc inoma Anemia i n CRF Haemop philia A Abacav Iron ov vir verload Superficial skin infe ections Allergic asthma Haemop philia B Primariy Immun. Defi ciency Severe my ycosis Chronic he epatitis Nevirapin ne Pulmonary artery hyperte ension Allergic conjun ctivitis Allergic rhinitis Lamivudi ne HIV Partial onset seizures in ep pilepsy Atopic der rmatitis Occlusive crisis syckl e cells Immunosuppressive th herapy Glioblastoma mult iforme Infl luenza Thalassemia major Ga aucher 0% 0 0 Partially Non required Efaviren nz Emtricitabin ne Stavudin ne Ritonav vir between adults and children. Taking into account the decision tree outcome and the clinical studies Seve supporting the paediatric indication, a ranking was used in which the available clinical trials were classified as needed, partially required, and non required.

13 Evidence Synthesis

14 Evidence Synthesis

15 Evidence generation vs. Evidence Synthesis

16 Operational and Clinical Challenges in Paediatric Research

17 Operational Considerations Clinical endpoints validation of clinical scales calibration of biomarkers and PKPD relationship tailored equipment correlation between adults and children Sampling techniques sparse sampling sensitive bioanalyticalmethods collection techniques Experimental protocol & data analysis Informative designs Population methods, Bayesian statistics

18 Operational Considerations - Sampling

19 Blood spots Aliquot 5μL blood per spot 3 spots per sample plus spare Using a pipette or capillary Do NOT allow tip to touch card surface! Dry for approx 2 hours at room temperature Ship & store in sealable bags containing desiccant

20 Understanding differences in disease

21 Are diseases in children comparable to adults? Conclusions The most common clinical manifestations of LCH of the spine were neck or back pain, followed by restricted motion of spine, neurologic symptoms, and deformity. Neurologic deficits were more frequent in adult patients. Vertebral plana is the typical imaging feature in children and adolescent patients but seldom in adults. Computed tomography is best for characterizing anatomy of the involved vertebra, and MRI is best for delineating marrow and soft tissue. The oversleevelike sign on MRI may be a feature of spinal LCH as well as vertebra plana in children and adolescents. Needle biopsy under CT guidance should be performed before a treatment strategy is determined.

22 Are diseases in children comparable to adults? Conclusions Clinical features and comorbidities are very important for the allergic march, and in both adults and children there is some evidence of association between AR and asthma. ARIA classifications of both symptom duration (intermittent, persistent) and severity (mild, moderate, severe) have been validated in both adult and pediatric populations. Based on the duration and severity of patient s disease, an appropriate treatment strategy has been issued for both adults and children, which consists of patient s education, allergen avoidance, and pharmacological as well as allergen-specific immunotherapy treatment. The present review will attempt to compare the characteristics of AR between children and adults, either in the epidemiology, clinical features, impact on QOL, and management of the disease..

23 Are diseases in children comparable to adults? Conclusion Our findings suggest that changes in type I IFN gene and chemokine scores as well as in levels of IL-6, IL-8, and TNFα may serve as sensitive and responsive longitudinal biomarkers of change in disease activity in juvenile and adult DM, even in the presence of immunomodulating agents.

24 Objectives es The ultimate goal is of this workshop is not to provide participants with details of our technical expertise, but to show how the risks and benefits of an intervention ti can be assessed by inferential methods (incl. extrapolations) ti and thereby assist researchers, authorities and sponsors about the suitability of a medicinal product / dose for the paediatric population. It also our intention to discuss the expectations of regulators with regard to the level of evidence on efficacy and safety of a medicine that is required for regulatory approval and how evidence synthesis can satisfy or complement such requirements.

25 Questions to be addressed. What can we do to reach consensus about the level of evidence required for the approval of paediatric medicines? 2. What is needed to ensure that opportunities to improve evidence generation are considered (and endorsed) during the interaction with regulatory agencies? 3. What is needed d to ensure that t evidence synthesis is considered d before evidence generation is proposed as the basis for approval of paediatric medicines. 4. Are qualification procedures the best process to enable the systematic use extrapolation and inferential methods in regulatory trials? 5. Are patients and parents sufficiently aware of the availability of alternative methods to clinical trials and its implications for the approval of medicines?

Workshop on Extrapolation and Evidence Synthesis in the Development and Therapeutic Use of Medicines in Children

Workshop on Extrapolation and Evidence Synthesis in the Development and Therapeutic Use of Medicines in Children Dr Oscar Della Pasqua WP 4 11th June 2013 Strathclyde University, Glasgow, UK Project AIMS