Updates from the Prescription Medicine Authorisation Branch Prescription medicine reforms Adrian Bootes, Kaylene Raynes, Mark McDonald, Prescription Medicines Authorisation Branch Health Products and Regulation Group, Department of Health ARCS Annual Conference 2018, Sydney, NSW 22 August 2018
Session overview Three parts: I. Options for new medicines: Priority, Provisional, Orphans and COR II. International work-sharing initiatives III. Scheduling Policy Framework and PI/CMI initiatives 1
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Prescription Medicines Authorisation Branch (PMAB) Structure • Branch is comprised of 6 Clinical Evaluation Units (CEU) and 4 business sections • ~85 staff across 4 cities (Canberra, Sydney, Melbourne, Brisbane) Branch Head Medical adviser (Assistant Secretary) Adrian Bootes John McEwen Clinical Evaluation Business Systems, Application Entry, Application and Transparency, Units Review and Support and Export Advisory Reforms and Reporting Management Evaluation Support (1–6) Nitin Bagul Kaylene Raynes Kaylene Raynes Melissa Quinn Mark McDonald Ting Lu Jason Ferla Michael Coory Monique Stone Neil Everest (a/g )
Prescription Medicines Registration Pharmacovigilance and Special Access Branch Medicines Regulation Medical Devices & Scientific Laboratories Division Product Quality Division Evaluation Branch Branch Prescription PM Medicines Manufacturing Registration Authorisation Quality Branch Processes Branch Scheduling & Product Billing Committee & Industry Support Assistance Section Section Regulatory Practice & Support Division Pharmaceutical Benefits Division
Submission Pathways – Overview TGA clock in working days Designation Registration for decision timing ('Milestone 7') non-generic and for the different pathways provisional generic priority COR-A COR-B TGA clock application submitted STARTS STOP-CLOCK, − 40 dossier s.31 questions submitted 0 120 150 155 175 220 255 0 20 to sponsor Round 1 Round 2 evaluation evaluation orphan, legislated MS1 MS2 MS3 MS4 MS5 MS6 priority, timeframe (optional) (except for COR) provisional ACM (if required) expert advice (optional) MS7 TGA clock STOPS • Multiple submission pathways ranging from 120-220 target days to grant market approvals 5
Options for new medicines International perspective NCEs* Australian perspective • Aim to increase options for Australian patients Country 2017 - New active • Limit regulatory burden on sponsors and the substances regulator EU 30 • Benefit for EOIs in addition to NCEs (reduces US 50 target timeframe from 220 to 150 work days) Canada 33 Japan 22 New actives substances approved by all 5 regulators* Switzerland 29 TGA 24 *CIRS R&D Briefing 67 Bujar M, McAuslane N, Liberti L. 2018. R&D Briefing 67: New drug approvals in six major authorities 2008 – 2017: Focus on the availability of medicines and company size. Centre for Innovation in Regulatory Science. London, UK
TGA: NCEs & NBEs (past 5 years) Biosimilars: expected ↑
TGA: EOIs (past 5 years) Considerations • Expecting increasing number of medicines with same resources • Necessity to work smarter & more flexibly while avoiding lack of clarity or transparency
Options for new medicines – expedited pathways Priority Review Provisional Approval • Implemented on 20 March 2018 • Implemented on 1 July 2017 • Determination eligibility criteria • Determination eligibility criteria • Dossier – preliminary clinical data • Dossier - substantial evidence • Expedited through accepting early data where • Expedited through flexible business process the benefit of availability outweighs the risk • Exit criteria to standard pathway • Target time frame – 220 working days • Target time frame – 150 working days • Time limited registration, full registration if • Full registration on ARTG approved after evaluation of confirmatory data • Satisfactory quality, safety & efficacy • Confirmatory safety and efficacy data required for the intended use Medicine and Medical Devices Review (MMDR) reforms
Determination/designation: Process • Only medicines likely to provide the most benefit are eligible • A designation/determination must be in force to access pathways and/or fee waiver • Designation/determination in force for 6 months • 6 months extension if registration application not submitted (1 month prior expiry not for priority) • Sponsor may re-apply for orphan designation once lapsed, but criteria must be met (e.g. show benefit against self) • Orphan designation applicable to all 5 pathways (standard, priority, provisional, COR A & B) • Consistent & transparent process 10
Determinations/designations: applications Number of determination and designation • Approved applications (to 31 July 2018) applications (1 July 2017 - 31 July 2018) 25 Priority, 14/23 (61%) determined Provisional, 2/2 (100%) determined 20 Number of Applications Orphan, 12/24 (50%) designated 15 • Average time to priority and provisional withdrawn determination : rejected 10 approved 19 working days • Average time to orphan designation : 5 New program: 25 working days 0 Previous program: 60 working days priority provisional orphan Application type * New orphan drug program (applications received from 1 July 2017)
Designations/determinations: therapeutic area Approved orphan designations Approved priority determinations 8% 9% Metabolic disorders 7% 8% 9% Immunology Ophthalmology Oncology 8% 8% 29% Oncology Haematology Haematology 8% 64% Respiratory diseases Neurological disorders Neurological disorders 42% Endocrinology n=12 n=14 12
Designation/determination: Tips for success Compare against Main rejection reasons: standard of care if there Provide comparison • Comparison against registered is no registered against all registered treatment therapeutic goods treatments /prophylaxis Improved • Major therapeutic advance safety or efficacy Provide justification of why the supporting Separate applications Orphan drug considerations: evidence is substantial: for each active e.g. progression free ingredient if not a • Prevalence: calculated differently for survival vs overall survival fixed dose diagnosis, prevention or treatment ? • Subgrouping: ‒ compare against standard of care in the absence of a registered treatment Major Medicine ‒ line of therapy or disease stage are not a therapeutic combinations valid subgroup advance
Updates to guidance documents Provisional Approval Orphan Drug Program • Confirmatory trial data may be in a clinical setting. • Subsetting of conditions with the • Provisional applications will be included in the use of biomarkers generally not PPF batching process. acceptable. Additional clarification Guidance updates: has been included. - comparison • The designation must been in excludes provisional force when the application and - clarification evaluation fees are payable Priority Review - rewording (Regulation 45(12). - restructure • Designation replaced by determination.
Priority review registrations Median approval time for NAS and EOIs 101 working days * Excerpt from CIRS R&D Briefing 67 NCE/NBE TGA Priority approval times 2017/18 EOI Regulator 2017 median approval Apalutamide 80 time (accelerated NAS) Osimertinib 119 Calendar Estimated days Working days* Nivolumab 140 EMA 235 168 Trametinib 96 FDA 240 171 Dabrafenib 96 PMDA 275 196 Nivolumab 124 Health Canada 209 149 Emicizumab 104 Swiss Medic 272 194 Alectinib 98 * overseas regulators : excludes weekends but includes 0 20 40 60 80 100 120 140 160 public holidays, includes sponsor time; TGA: additionally Working Days excludes holidays and sponsor time
Priority /Orphan: considerations Priority Review Orphan drug • No applications for new dosage form medicines • No applications for the COR A/B • None on the basis of lack of financial viability • Most applications were for EOIs, in comparison • No applications that used the COR A/B pathway less new medicines (4/14) • Applications on the basis of benefit in a sub- • Most applications for NCEs/NBEs (9/12) group of patients & major therapeutic advance • Applications on the basis of rare diseases New EOI New EOI medicine medicine TGA 9 /12 2 /12 TGA 4 /14 10 /14 also EMA orphan 89% (8/9) 50% (1/2) & EMA accelerated 75% (3/4) 10% (1/10) also FDA orphan 78% (7/9) 100% (2/2) & FDA priority 100% (4/4) 90% (9/10) 16
Options for new medicines - COR A and B • For medicines with full marketing approval from Experience (from 2 January) a comparable overseas regulator following a de • Only few applications received to date novo evaluation. • COR A- identical medicine and manufacturing • Six overseas regulators identified as CORs. overseas MA < 1 year ago Unredacted COR evaluation reports must be critical review of the COR assessment provided by the applicant. evaluation of label PI & RMP, no additional • data evaluated Two approaches*: • COR B COR-A – 120 working days No limit to currency of overseas MA COR-B – 175 working days Critical review of COR assessment reports additional data analysis required (e.g. *depending on extent of TGA evaluation required. updated stability data, or pivotal study data) 17
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