Pediatric Cancer Drug Development: Impact of US Regulations

Transcription

1 Pediatric Cancer Drug Development: Impact of US Regulations Martha Donoghue, M.D. Acting Associate Director, Division of Oncology Products 2 Office of Hematology and Oncology Products Center for Drug Evaluation and Research US FDA

2 Financial Disclosure I have no financial relationships to disclose. 2

3 Outline Overview of US pediatric regulations Impact of US regulations on pediatric oncology drug development Current and future FDA approaches to expedite pediatric oncology drug development 3

4 Pediatric Research Equity Act (PREA) Authorizes FDA to require pediatric assessments Triggered by NDA/BLA submission or a supplement with a new indication, active ingredient, dosage form, dose regimen or route of administration Applies only to indication(s) included in the submission Drugs with Orphan Designation are exempt from PREA FDA can grant full or partial waiver or deferral for pediatric studies if specific criteria are met Almost no relevance to pediatric cancer drug development dances/ucm pdf 4

5 Best Pharmaceuticals for Children Act (BPCA) Provides a financial incentive to voluntarily conduct pediatric studies under a Pediatric Written Request (WR) A sponsor may request the FDA to issue a WR by submission of a Proposed Pediatric Study Request (PPSR) or FDA may issue WR without PPSR PPSR should contain rationale for studies, detailed study designs and plans for formulation development 5

6 Pediatric Exclusivity Applicants who fulfill the terms of a WR are eligible to receive pediatric exclusivity Additional 6 months of exclusivity Exclusivity attaches to all existing marketing exclusivities and patents for the drug moiety Pediatric exclusivity does not require positive pediatric studies or granting new indication 6

7 PREA and BPCA Programs PREA Drugs and biologics Mandatory studies Requires studies only on indication(s) under review Orphan indications exempt from studies Pediatric studies must be labeled BPCA Drugs and biologics Voluntary studies Studies relate to entire moiety and may expand indications Studies may be requested for orphan indications Pediatric studies must be labeled 7

8 Factors for Selection of Candidate Therapies for WRs Mechanism of action suggests potential for activity Scientific rationale exists for the drug to be evaluated in pediatric cancers Activity in preclinical models of pediatric cancers Efficacy has been shown in a related adult cancer Has potential to improve a clinical outcome for pediatric patients, with evidence that it may have: increased efficacy or similar efficacy and reduced toxicity compared to existing therapy Sufficient information to choose an appropriate starting dose and provide a reasonable expectation of safety 8

9 PPSR Review Considerations What is the public health benefit? Are the study designs feasible? Are the studies capable of providing sufficient data to support dosing, safety, and efficacy? Are there other approved products for the indications to be studied? Are all the pediatric populations and potential indications addressed? 9

10 Impact of Pediatric Regulations in Oncology Over 55 Written Requests issued by OHOP 20 oncology drugs granted exclusivity New labeling information added for 15 oncology drugs Approx. 25 drugs are being investigated under the WR/BPCA program Since 2002, 9 of 10 New Drug Applications for pediatric cancer indications have received FDA approval 4 oncology drugs studied under a Written Request received FDA approval for pediatric use 10

11 Everolimus Example Everolimus (Afinitor, Zortress) Multiple indications in cancer and transplant WR issued 4/1/2010 Single arm trial in patients with SEGA in the setting of TS Randomized, double blind, placebo-controlled trial Granted exclusivity in 2012 The recommended starting dose and subsequent requirement for therapeutic drug monitoring to achieve and maintain trough concentrations of 5 to 15 ng/ml are the same for adult and pediatric patients with SEGA 11

12 Written Requests Issued Crizotinib Cabazitaxel Peginesatide Ipilimumab Carfilzomib Eribulin Trabectidin Sonidegib Nivolumab Bosutinib Trametinib Denosumab Lenalidomide Pomalidomide Dabrafenib Nab-paclitaxel Ruxolitinib Atezolizumab Blinatumomab Defasirox Copanlisib EPZ-6438 ABT-414 FDA is issuing Written Requests more frequently 12

13 Improving the Positive Impact of Regulations Early and frequent engagement among Investigators/Industry/FDA/Advocates/Others crucial to prioritize agent investigation/development assess research strategy harmonize goals and increase efficiency Under BPCA, OHOP holds quarterly meetings with representatives of academic community to discuss promising new agents OHOP encourages stakeholder participation in Pediatric Subcommittee of Oncologic Drugs Advisory Committee Meetings Aid in selection of candidates for WR Optimize design of studies requested in WR 13

14 Pediatric Subcommittee of the Oncologic Drugs Advisory Committee (ODAC) Forum where industry sponsors can obtain input from key academic and community opinion leaders regarding an ongoing or potential pediatric development program gauge investigator interest in exploring pediatric development programs for products in various stages of adult development select possible drug candidates for a Written Request provide feedback to industry on trial design, pediatric regulations Interactive discussion of a key topic in designing trials for pediatric patients with cancer Ideal to come early in drug development timeline (prior to original NDA submission) Sponsors are encouraged to seek an invitation if there are questions regarding or interest in a pediatric development program 14

15 Addressing the Challenge of New Drug Development When No Adult Indication Exists Not adequately addressed by current legislation Rare Pediatric Disease Priority Review Vouchers (RPDPRV) Reauthorized as part of 21 st Century Cures in December 2016 United Therapeutics received RPDPRV in 2015 with dinutuximab approval Effectiveness uncertain at this point Potential for dilution of benefit over time Public/Private Partnerships essential FDA outreach increasing to promote communication, consensus-building Global collaboration needed Optimize use of Orphan Drug Act 15

16 Orphan Drug Act 1983 Promotes development of products for rare diseases (<200,000 persons in US) Designation: prevalence/promising clinical efficacy Financial incentives PDUFA exemption ( $2.4 M FY 16) 50% tax credit for clinical study costs Orphan grant program eligibility $14M/yr 7 years marketing exclusivity 1/3 of all NMEs and 2/3 of all BLAs have designation 37% of oncology products Same approval standards for safety and effectiveness, but regulatory flexibility and scientific judgment Substantial clinical trial design diversity 16

17 Future Directions Fully leverage existing Regulatory Authority Optimize use of Orphan Drug Product Act in pediatrics Timely issuance of WRs Develop rational, science-based strategy for prioritizing which new products to study in what diseases, determine timing of evaluation Expand opportunities for evaluating Precision Medicine approaches Paradigm shifts in study design and conduct Identify promising treatments earlier & fail faster Promote data sharing, use of big data and computer algorithmic analyses Increase integration of pediatric development plans into adult development FDA commitment to more patient-centered drug development, provision of timely multidisciplinary advice to sponsors, and judicious use of regulatory flexibility when needed Increase collaboration Patients/families- Investigators Industry Regulatory Agencies 17

18 Summary BPCA is the primary regulatory mechanism for promoting pediatric oncology drug development in the US WRs have resulted in approvals and informative labeling for pediatric patients with cancer Barriers to pediatric oncology drug development include exemptions from mandatory evaluation, waivers for orphan drugs New approaches and increased collaboration needed to accelerate development of safe and effective new pediatric cancer drugs 18

19 Acknowledgements Many thanks to Dr. Gregory Reaman Dr. Amy Barone Dr. Denise Casey Dr. Leigh Marcus 19