Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of...
Transcript of Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of...
![Page 1: Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of metabolism (?) ... • Mechanism-based modeling to enhance understanding of exposure-effect](https://reader034.fdocuments.net/reader034/viewer/2022050506/5f976c85fa71fa35a72cbb6d/html5/thumbnails/1.jpg)
Modeling & Simulation for Pediatric Investigation Plans (PIPs):
challenges and opportunities for drug development
Steven Kern, Ph.D. University of Utah
Salt Lake City, Utah USA
Sabbatical ProfessorNovartis Pharma AG
Basel Switzerland
![Page 2: Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of metabolism (?) ... • Mechanism-based modeling to enhance understanding of exposure-effect](https://reader034.fdocuments.net/reader034/viewer/2022050506/5f976c85fa71fa35a72cbb6d/html5/thumbnails/2.jpg)
Conflicts & Disclaimers
• On sabbatical from U of Utah at Novartis– Funding from Utah and Novartis – Funding from other pharma companies in the
past
• Opinions expressed are mine– Utah as member of NIH Pediatric
Pharmacology Research Units– Novartis experience reviewing PIPs and
responses from EMEA & PDCO
![Page 3: Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of metabolism (?) ... • Mechanism-based modeling to enhance understanding of exposure-effect](https://reader034.fdocuments.net/reader034/viewer/2022050506/5f976c85fa71fa35a72cbb6d/html5/thumbnails/3.jpg)
Non-clin Phase 1 Phase 2 Phase 3 Post approval
Paed. Investig. PlanCompliance check:- Paediatric data
- OR deferral
- OR waiver
MA
Amendments
Paediatric Committee(PDCO)
Scientific advice (by SAWP)EC
NCA
EMEA PIP Time line
Adapted from: www.emea.europa.eu
![Page 4: Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of metabolism (?) ... • Mechanism-based modeling to enhance understanding of exposure-effect](https://reader034.fdocuments.net/reader034/viewer/2022050506/5f976c85fa71fa35a72cbb6d/html5/thumbnails/4.jpg)
1
10
100
1000
0 20 40 60 80 100 120 140 160 18
Time (minutes)
Dru
g C
once
ntra
tion
( ng/
mL)
Typical Phase I PK Experiment in Adults
![Page 5: Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of metabolism (?) ... • Mechanism-based modeling to enhance understanding of exposure-effect](https://reader034.fdocuments.net/reader034/viewer/2022050506/5f976c85fa71fa35a72cbb6d/html5/thumbnails/5.jpg)
What is known at EOP1(maybe)…
• Preclinical pharmacology
• Dose-exposure in healthy adults
• Impact on a biomarker of interest (?)
• Some idea of drug effect (?)
• Perhaps some indication of metabolism (?)
![Page 6: Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of metabolism (?) ... • Mechanism-based modeling to enhance understanding of exposure-effect](https://reader034.fdocuments.net/reader034/viewer/2022050506/5f976c85fa71fa35a72cbb6d/html5/thumbnails/6.jpg)
What needs to be known…
• Dose-exposure in adult patients• Dose-exposure-response similarity (or not)
between adult and pediatric populations• Differences in exposure across pediatric age
groups• Scalability of biomarker of interest or
concentration – effect relationship
![Page 7: Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of metabolism (?) ... • Mechanism-based modeling to enhance understanding of exposure-effect](https://reader034.fdocuments.net/reader034/viewer/2022050506/5f976c85fa71fa35a72cbb6d/html5/thumbnails/7.jpg)
What needs to be known…
Non-clin Phase 1 Phase 2 Phase 3 Post approvalMA
Amendments
• Dose-exposure in adult patients• Dose-exposure-response similarity (or not)
between adult and pediatric populations• Differences in exposure across pediatric age
groups• Scalability of biomarker of interest or
concentration – effect relationship
![Page 8: Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of metabolism (?) ... • Mechanism-based modeling to enhance understanding of exposure-effect](https://reader034.fdocuments.net/reader034/viewer/2022050506/5f976c85fa71fa35a72cbb6d/html5/thumbnails/8.jpg)
“Established” M & S for PIPs
• Allometric scaling from Adult PK when rational– Many examples presented
• Incorporation of known/expected maturation affects on disposition– Example of Famvir
• Bridging between known and unknown data– Example with Trileptal
• Impact of limited resolution– PK Assay LLOQ– Dose selection and discretization
![Page 9: Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of metabolism (?) ... • Mechanism-based modeling to enhance understanding of exposure-effect](https://reader034.fdocuments.net/reader034/viewer/2022050506/5f976c85fa71fa35a72cbb6d/html5/thumbnails/9.jpg)
“Emerging” M & S for PIPs
• PBPK as means to bridge preclinical and early dosing information
• Mechanism-based modeling to enhance understanding of exposure-effect relationship
• In silico approaches to anticipate differences in pediatric patients
• Novel statistical methods for maximizing information from limited populations
![Page 10: Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of metabolism (?) ... • Mechanism-based modeling to enhance understanding of exposure-effect](https://reader034.fdocuments.net/reader034/viewer/2022050506/5f976c85fa71fa35a72cbb6d/html5/thumbnails/10.jpg)
PIP Amendments are a dialogue
• Dialogues can be difficult
• PIP adaptation may be needed as more knowledge is gained in adult trials
• Sponsors must provide support and rationale to help HAs understand adaptations based on pharmacometrics
• HAs need to integrate this understanding into decision making and action
![Page 11: Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of metabolism (?) ... • Mechanism-based modeling to enhance understanding of exposure-effect](https://reader034.fdocuments.net/reader034/viewer/2022050506/5f976c85fa71fa35a72cbb6d/html5/thumbnails/11.jpg)
Are HA’s ready for the dialogue?
![Page 12: Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of metabolism (?) ... • Mechanism-based modeling to enhance understanding of exposure-effect](https://reader034.fdocuments.net/reader034/viewer/2022050506/5f976c85fa71fa35a72cbb6d/html5/thumbnails/12.jpg)
Is Industry ready for the dialogue?
![Page 13: Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of metabolism (?) ... • Mechanism-based modeling to enhance understanding of exposure-effect](https://reader034.fdocuments.net/reader034/viewer/2022050506/5f976c85fa71fa35a72cbb6d/html5/thumbnails/13.jpg)
The Novartis Long Te rm Vis ion ofMode l Bas e d Drug Deve lopment
Full Release
Monitored Release
Full Approval
Confirm the model
ProvisionalApproval
Build themodel
l------------Continuous sharing of data with He alth Authority--------l
Biomarke rs
Mode ling & Simulation
Novartis Model-based Drug Development
![Page 14: Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of metabolism (?) ... • Mechanism-based modeling to enhance understanding of exposure-effect](https://reader034.fdocuments.net/reader034/viewer/2022050506/5f976c85fa71fa35a72cbb6d/html5/thumbnails/14.jpg)
Third Rails
www.wikipedia.org
![Page 15: Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of metabolism (?) ... • Mechanism-based modeling to enhance understanding of exposure-effect](https://reader034.fdocuments.net/reader034/viewer/2022050506/5f976c85fa71fa35a72cbb6d/html5/thumbnails/15.jpg)
Third rail for the future - power or shock?
• Use modeling & simulation to bridge between what we know and what we don’t
• Establish “best practices” in approaches• Develop studies that require the fewest possible
numbers of subjects– “Waste not a drop…”– Tradeoff of utility vs. futility
• Maximize our use of quantitative knowledge
![Page 16: Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of metabolism (?) ... • Mechanism-based modeling to enhance understanding of exposure-effect](https://reader034.fdocuments.net/reader034/viewer/2022050506/5f976c85fa71fa35a72cbb6d/html5/thumbnails/16.jpg)
Waste not a drop…
Benjamin et al. Hypertension 2008; 51:834-840
![Page 17: Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of metabolism (?) ... • Mechanism-based modeling to enhance understanding of exposure-effect](https://reader034.fdocuments.net/reader034/viewer/2022050506/5f976c85fa71fa35a72cbb6d/html5/thumbnails/17.jpg)
Back to the future
![Page 18: Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of metabolism (?) ... • Mechanism-based modeling to enhance understanding of exposure-effect](https://reader034.fdocuments.net/reader034/viewer/2022050506/5f976c85fa71fa35a72cbb6d/html5/thumbnails/18.jpg)
The Pediatric Challenge
• Factors in pediatric drug development challenge “traditional” methods of drug evaluation trials– “Volunteer” studies are with patients– Limited sampling volumes– Challenges in consent– Challenges to placebo trials
• Doing more with less• Risks of futility
![Page 19: Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of metabolism (?) ... • Mechanism-based modeling to enhance understanding of exposure-effect](https://reader034.fdocuments.net/reader034/viewer/2022050506/5f976c85fa71fa35a72cbb6d/html5/thumbnails/19.jpg)
The Pediatric Opportunity
• Greater acceptance by Health Authorities of pharmacometric methods for pediatric drug development
• Better methods of drug development for all populations
• Greater acceptance by Health Authorities of pharmacometric methods for ALL drug development
![Page 20: Modeling & Simulation for Pediatric Investigation Plans (PIPs) · • Perhaps some indication of metabolism (?) ... • Mechanism-based modeling to enhance understanding of exposure-effect](https://reader034.fdocuments.net/reader034/viewer/2022050506/5f976c85fa71fa35a72cbb6d/html5/thumbnails/20.jpg)
Conclusion
• Use of M & S in pediatrics is increasing
• Role in design & analysis of drug studies in pediatrics
• Methodologies to be continually evaluated, refined, tailored
• Joint responsibility and effort of industry, health authorities, and academia