Statistical and regulatory considerations on registrational trials in pediatric cancer

1. Statistical and regulatory considerations on registrational trials in pediatric cancer Jingjing Ye, PhD Lead Mathematical Statistician OB/OTS/CDER/FDA The 3rd Stat4Onc Symposium Apr. 27, 2019

2. Outline • Background and current landscape • Current guidance and working groups • Statistical and design considerations • Case study • Conclusions www.fda.gov Stat4Onc Symposium

3. Disclaimer This talk reflects the views of the author and should not be construed to represent FDA’s views or policies. www.fda.gov Stat4Onc Symposium

4. Cancer Drug Development for Children and Adolescents • Well recognized, long-standing challenges-biologic, societal, economic • Widely leverages adult drug discovery and development • Many targeted agents likely applicable to cancers in children Dr. Gregory Reaman, ODAC presentation, June 2018 https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM612244.pdf

5. U.S. Legislation and Pediatric Drug Development BPCA • Drugs and biologics • Voluntary studies with incentives • Studies relate to entire moiety and may expand indications • Studies may be requested for orphan indications • Pediatric studies must be labeled PREA • Drugs and biologics • Mandatory studies • Requires studies only on indication(s) under review • Orphan indications exempt from studies • Pediatric studies must be labeled Dr. Gregory Reaman, ODAC presentation, June 2018 PREA: Pediatric Research Equity Act; BPCA: Best Pharmaceuticals for Children Act

6. RACE for Children Act: • Incorporated as Title V of the FDA Reauthorization Act (FDARA), enacted Aug. 18, 2017 • Requires evaluation of new molecularly targeted drugs and biologics “intended for … adult cancers… at a molecular target substantially relevant to the growth or progression of a pediatric cancer” • Molecularly targeted pediatric cancer investigation: clinically meaningful study data • Elimination of orphan exemption for pediatric studies for cancer drugs directed at relevant molecular targets https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/OCE/ucm544641.htm Dr. Gregory Reaman, ODAC presentation, June 2018; RACE for Children Act: Research to Accelerate Cures and Equity Act; will come into force, 8/18/2020

7. Current Landscape in Pediatric Cancers • Pre-FDAMA (pre-1997): 15 labeling updates on pediatric cancers • Post-FDAMA (1997-present): 26 approvals and labeling updates (20 pediatric indications and 6 supportive care) FDAMA (Food and Drug Administration Modernization Act), reauthorized as the Best Pharmaceuticals Act for Children [BPCA], 2003

8. Pediatric Specific Indication (N=20) Supportive Care (N=6) • Gemtuzumab • Arsenic trioxide • Clofarabine • Nelarabine • Dasatinib • Imatinib • Nilotinib • Ipilimumab • Denosumab • Everolimus • Erwiniaasparaginase • 6-mercaptopurine oral solution • Pembrolizumab • Avelumab • Tisagenlecleucel • Teniposide • emapalumab • Pegfilgrastim • Rasburicase • Palifermin • Levoleucovorin • Tocilizumab • Voraxaze Labeling Updates Prior to FDAMA (N=15)

9. FDA Approvals for Pediatric Indications and Labeling Updates* New Molecular Entity Post-FDAMA Pre-FDAMA Methotrexate (ALL, meningeal leukemia, osteosarcoma, NHL) Nelarabine (T-cell ALL) pegfilgrastim (Decrease incidence of infection, increase survival in patients exposed to mylosuppressive doses of radiation) Everolimus (SEGA) Thioguanine (Acute non-lymphocytic leukemia) Lomustine (Brain tumors, HL) Palifermin (Decreased incidence and duration of severe oral mucositis) emapalumab (primary HLH, refractory or recurrent) Arsenic trioxide (APML) Levoleucovorin(Rescue after HD-MTX) Dactinomycin (Ewing Sarcoma, sarcoma botryoides) Procarbazine (HL) Mercaptopurine (ALL) L-Asparaginase (Leukemia) Denosumab(Giant cell tumor of the bone) Erwiniaasparaginase (ALL) Avelumab (metastatic merkel cell carcinoma) PEG-Asparaginase (ALL) 2007 1997 1995 2000 1979 1953 1959 1965 2010 1971 2013 2016 2018 6-mercaptopurine (ALL) Gemtuzumab (R/R CD33+ AML) Daunorubicin (ALL) Voraxaze (Treatment of toxic plasma methotrexate concentration) Tretinoin (APML) Cyclophosphamide (leukemia, lymphoma, NBL, retinoblastoma) nilotinib (Ph+ CML) Vinblastine (Histiocytosis, testicular germ cell carcinoma, HL) Tisagenlecleucel (R/R ALL) Doxorubicin (Wilms tumor, NBL, soft tissue sarcoma, HL, other lymphomas, ALL, AML) Clofarabine (Refractory ALL) Tocilizumab (CAR-T induced CSR) Dasatinib (Ph+CML) Teniposide (Refractory ALL) Vincristine (ALL, lymphomas, Wilms, rhabdomyosarcoma, NBL) pembrolizumab (Refractory classical cHL, MSI-H) Cytarabine (Acute non-lymphocytic leukemia) Rasburicase (Management of plasma uric acid levels at risk for TLS) Imatinib (Ph+ALL, Ph+CML) pembrolizumab (Refractory primary mediastinal large B-cell lymphoma, metastatic merkel cell carcinoma) Ipilimumab (Unresectable or metastatic melanoma) *Refer to US Prescribing Information for details.

10. Current Guidance and Working Groups

11. Guidance • General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products – Guidance for Industry • Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials Guidance for Industry • Cancer Clinical Trial Eligibility Criteria: Minimum Age for Pediatric Patients: Guidance for Industry

12. General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products – Guidance for Industry https://www.fda.gov/downloads/drugs/guidances/ucm425885.pdf

13. Other Helpful Guidance • Enrichment Strategies for Clinical Trials to Support Determination of Effectiveness of Human Drugs and Biological Products Guidance for Industry • Adaptive Designs for Clinical Trials of Drugs and Biologics Guidance for Industry

14. ITCC-SIOPE Multistakeholder Paediatric Platform https://www.accelerate-platform.eu/

15. Statistics Working Group • ASA Biopharmaceutical Pediatric Scientific Working Group • Proposed by OB/CDER/FDA • Collaboration with industry, academia, EMA (European Medicines Agency), PMDA (Pharmaceuticals and Medical Devices Agency) and Health Canada • Umbrella working group including DIA Bayesian scientific working group (BSWG)

16. Statistical and Design Considerations • Pediatric specific indication • Partial extrapolation

17. Pediatric specific indication • Rare cancers mainly in pediatrics, e.g. Wilms tumor, neuroblastoma • Cancers high prevalence in pediatrics, e.g. Acute Lymphoblastic Leukemia (ALL)

18. Design Considerations Partial Extrapolation • Uniform internationalmaster protocol for biomarker-directed studies • Platform trial • Common control Pediatric Specific Indication • Uniform internationalmaster protocol for biomarker-directed studies • Platform trial • Common control • External control

19. Innovative Analysis- Bayesian • Account uncertainty in prior knowledge • Decision making and interpretation with probability thinking • Use relevant prior information • If not sure of relevance, incorporate P(relevance) • If very sure of relevance, be skeptical about potential efficacy unless you trust ‘experts’ Adapted from slides by Prof. Frank Harrell, FDA presentation (2017)

20. Bayesian on Pediatric Cancers Partial Extrapolation • Bayesian analysis • Adult • Older age group Pediatric Specific Indication • Bayesian analysis • Older age group • Control • Discount priors • Sensitivity on the priors • Interpretation on efficacy in posterior probability

21. Discounting Methods for Priors • Mixture prior • Power prior • Commensurate prior • Hierarchical shrinkage model • Adaptive down-weighting

22. Pediatric Cancer Case Study • Bayesian analysis • Bayesian sequential monitoring

23. NDA22068 Nilotinib Philadelphia chromosome positive chronic myeloid leukemia (Ph+CML) MMR: major molecular response (MMR; BCRABL/ABL ≤0.1% IS); * Results are for MMR, for other information refer to USPI https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022068s027lbl.pdf

24. Prior Distributions • Probability of applicability: • Prior=(1-a)*f(D) + a*g(D) • f(D): skeptical prior, g(D): adult study posterior • a=P(applicability of adult results)

25. Posterior Distribution

26. Posterior Probability of Efficacy • Even given skeptical prior, the posterior probability is 99%+

27. Bayesian Sequential Monitoring

28. Sequential Monitoring • First evaluation when N=5 patients results available • Evaluate as data accumulate

29. Sequential Monitoring • Posterior prob > 97.5% when 5 responders observed out of 12 enrolled

30. Bayesian Characteristics • Skeptical prior: centered at no clinically-meaningful response and low probability of observing higher response • Adult/Enthusiastic prior: centered at adult efficacy and low probability of observing low response

31. Sequential Design Property • Accrual up to 50 patients • Stop for efficacy if Posterior Pr(R>0.2|Data, Skeptical) >= 0.975 • Stop for futility if Posterior Pr(R<0.3|Data, Enthusiastic)>=0.85

32. Approaches on Addressing Challenges • International collaboration in pediatric cancer trials when possible, avoid duplication and competition • Bayesian designs and analysis • formally incorporate prior knowledge into the trials • quantify uncertainty • intuitive interpretation based on probability thinking

33. Addressing Challenges (Cont’d) • Bayesian sequential monitoring offers flexible monitoring of pediatric trial results as data accumulates • Combined with Skeptical and enthusiastic priors, the plan offers good trial design properties, including frequentist-equivalent controlled false-positive rate and sufficient power • Offers options to stop for trial early for both efficacy and futility, advantage of requiring fewer patients

34. Acknowledgements • Frank Harrell • Mark Rothmann • James Travis • Rebecca Rothwell • Gregory Reaman • R. Angelo De Claro • Rajeshwari Sridhara • Thomas Gwise • Weishi (Vivian) Yuan

35. References • https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/OCE/ucm544641.htm • https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/ucm612242.htm • https://www.fda.gov/downloads/drugs/guidances/ucm425885.pdf • https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM609513.pdf • https://www.fdanews.com/ext/resources/files/2019/03-14-19-Trials.pdf?1552594371 • https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM633138.pdf

36. References • https://www.fda.gov/downloads/drugs/guidances/ucm201790.pdf • Woodcock, J., LaVange, L.M., 2017, Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both., NEJM, 2017; 377:62-70https://www.ncbi.nlm.nih.gov/pubmed/28679092 • Harrell, F., 2017, Why is Bayes relevant to CDER? FDA seminar • Fayers at al. Tutorial in Biostatistics: Bayesian Data Monitoring in Clinical Trials, Stat in Medicine, 1997 • Psioda, 2018, An Introduction to Bayesian Sequential Monitoring of Clinical Trials, FDA Seminar

37. Back-up

38. Regulatory Waiver Considerations • Serious developmental toxicity-consideration for full or age dependent partial waiver • Second or third “in class” product without compelling evidence of substantial differences in efficacy, safety, PK profiles or formulation to warrant additional pediatric studies • Feasibility and practicability due to small study population potentially addressed by limited study requirements and innovation in study design and conduct Dr. Gregory Reaman, ODAC presentation, June 2018