Updates from the Therapeutic Goods Administration For medicine sponsors Adrian Bootes First Assistant Secretary A/g, Medicines Regulation Division Therapeutic Goods Administration 8 th Annual EyeforPharma Conference
TGA: Major applications 2013-2018 Updates from the Therapeutic Goods Administration 1
TGA: options for new medicines Approval on basis Orphan Drug Program of substantial • Standard approval pathway Incentive for rare disease evidence Approval on basis • Priority review pathway of substantial • Comparable Overseas Regulator (COR) evidence process • Work-sharing (pilot ) (with faster review) Approval on basis • 100% fee waiver for registration of earlier data • Provisional approval pathway (available years earlier) Updates from the Therapeutic Goods Administration 2
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 application TGA clock submitted STARTS − 40 dossier STOP-CLOCK, submitted 0 120 150 155 175 220 255 0 20 s.31 questions to sponsor Round 1 Round 2 evaluation evaluation orphan, MS1 MS2 MS3 MS4 MS5 MS6 legislated priority, timeframe (optional) provisional ACM (except for COR) expert advice (if required) MS7 (optional) TGA clock STOPS • Multiple submission pathways ranging from 120-220 target days to grant market approvals • Evaluation questions to sponsors occur at different time points depending on the pathway • Orphan designation applicable to all 5 pathways (standard, priority, provisional, COR A & B) • International collaboration applicable to most pathways (excepting provisional approval) Updates from the Therapeutic Goods Administration 3
Priority review: Implemented 1 July 2017 Approved priority determinations by therapeutic area: Priority determination applications by status: 1 July 2017- 30 September 2018 1 July 2017-30 September 2018 Number (%) 6% 6% Oncology Applications lodged 28 Haematology 23% Approved 17 (60.7%) Endocrine/Metabolic disorder 65% Opthamology Rejected 9 (32.1%) Updates from the Therapeutic Goods Administration 4
Priority medicines approved: as at 30 September 2018 New chemical entity Extension of Indication • 9 priority medicines approved TGA priority review approval times 3 new chemical entities, 6 extension of indication Apalutamide 80 7/9 indications in Oncology Osimertinib 119 Nivolumab (renal cell carcinoma) 140 Nivolumab (melanoma) 124 • We are faster than our target Trametinib 96 timeframes Dabrafenib 96 Cerliponase alfa 129 Emicizumab 104 • Apalutamide also a work-sharing pilot Alectinib 98 with Health Canada 0 50 100 150 Working Days Updates from the Therapeutic Goods Administration 5
Priority review pathway: key issues Priority review eligibility criteria • Justification for the ‘major’ in major therapeutic advance New prescription or new indications medicine Provide justification of why the supporting Seriously debilitating or life-threatening condition evidence is substantial: e.g. progression free Comparison against registered therapeutic goods survival vs overall survival ( excludes provisional registration and off-label use, • Comparison considers alternate treatment and clinical significance) ‒ Compare against all relevant registered goods ‒ Compare against standard care if there is no registered treatment Major therapeutic advance ( the magnitude of the effect is, or is expected to be well beyond minimum • Separate determination applications for each requirement for clinical significance, major impact on active ingredient if not a fixed dose patient outcomes… ) Updates from the Therapeutic Goods Administration 6
Provisional approval: Implemented March 2018 • Expedited through accepting early data where the Provisional approval eligibility criteria benefit of availability outweighs the risk New prescription or new indications medicine • Confirmatory safety and efficacy data required • Up to 6 years to apply for transition to full registration Seriously debilitating or life-threatening condition • Like other regulators the pathway provides Comparison against registered therapeutic goods “Early access to certain prescription medicines” ( excludes provisional registration and off-label use, considers alternate treatment and clinical significance) Major therapeutic advance ( the magnitude of the effect FDA is, or is expected to be well beyond minimum requirement for clinical significance, major impact on patient outcomes… ) Clinical study plan (evidence to submit comprehensive data before the end of 6 years) Updates from the Therapeutic Goods Administration 7
Provisional approval pathway All positive determinations and designations are published on the TGA website Updates from the Therapeutic Goods Administration 8
Provisional approval pathway: some issues How to judge when early data seems promising Use of Real- World data to supplement clinical trials Updates from the Therapeutic Goods Administration 9
Emerging trends: expedited approval • More products internationalised within the same time frame. Number Australian perspective of new active substances approved increased from 12 to 51 across 6 major regulators. Bujar M et al. 2018. R&D Briefing 67: New drug approvals in six major • Facilitate early access to medicines that authorities 2008-2017: Focus on the availability of medicines and company size. CIRS address unmet needs • Increase options for Australian patients – Benefit for extension of indication in addition to new chemical entities “ Though some drugs associated with an expedited program • Maintain standards for safety, efficacy may indeed provide noticeable clinical advances, this trend is and quality. being driven by drugs that are not first in class and thus potentially less innovative”. • Minimise regulatory burden on A S Kesselheim et al. Trends in utilization of FDA expedited drug development and approval programs, 1987-2014: cohort study. BMJ 2015;351:h4633 sponsors and the regulator Updates from the Therapeutic Goods Administration 10
New Orphan Drug program: Implemented 1 July 2017 • To provide an incentive to sponsors to bring Approved orphan designations by therapeutic area: medicines for a small population to market and 1 July 2017 – 30 September 2018 make medicines available that might otherwise not be registered 7% 14% Oncology 7% • New eligibility criteria Haematology • End of transition from the previous program - Endocrine/Metabolic disorder 30 June 2018 Opthamology 36% 36% • To be eligible for a fee waiver a related orphan Immunology designation must be in force when the relevant N=14 fee is payable Updates from the Therapeutic Goods Administration 11
“Will you receive the approval you hoped for?” Where the nuance of wording helps define usage of a new medicine! 12
Includes Case Study: Blincyto (blinatumomab) paediatrics • Type C application: • Sponsor’s proposed new indication – To extend the approved indications to include – Blincyto is indicated for the treatment of Philadelphia treatment of paediatric patients with Philadelphia chromosome-negative relapsed or refractory B-precursor chromosome-negative relapsed or refractory B- acute lymphoblastic leukaemia (ALL) cell precursor acute lymphoblastic leukamia (ALL) • Approved indication – post Advisory Committee on • Approved indication at the time: Medicines (ACM) – For the treatment of adults with Philadelphia – Blincyto is indicated for the treatment of Philadelphia chromosome-negative relapsed or refractory B- chromosome-negative relapsed or refractory B-cell cell precursor acute lymphoblastic leukaemia precursor acute lymphoblastic leukaemia (ALL). (ALL) Note to Indication: this indication is approved based on Phase II, non-randomised evidence. An improvement in clinical outcomes by direct prospective comparison in a randomised setting relative to other standard-of-care salvage therapies has not been established • Australian Public Assessment Reports (AuSPARs) published • Indication amended to reflect the level of evidence that the – Search http://www.tga.gov.au/ws-auspar-index submission relied on 13 Updates from the Therapeutic Goods Administration
Case Study: Opdivo(nivolumab)-priority review • Type C application to extend indications in the • TGA reasons for change setting of melanoma – reference to specific American Joint Committee on Cancer (AJCC) stages of disease, prefer to define • Indication proposed by sponsor in Type C the population without relying on third party staging application definitions (AJCC in this case) – Opdivo as monotherapy is indicated for the – Third party staging subject to change and the adjuvant treatment of patients with completely indication would therefore change with third party resected Stage III or Stage IV melanoma changes to definitions. • Type C approved indication – – Opdivo as monotherapy is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection. Updates from the Therapeutic Goods Administration 14
Other updates • Excluded goods • Permitted indications for listed medicines • Black Triangle Scheme • SME Assist • TGA Facebook and Twitter 15
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