Updates from the Prescription Medicine Authorisation Branch - - PowerPoint PPT Presentation
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
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
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Branch Head
(Assistant Secretary)
Adrian Bootes
Transparency, Reforms and Evaluation Support
Mark McDonald
Business Systems, Review and Reporting
Kaylene Raynes
Application Entry, Support and Export
Melissa Quinn
Clinical Evaluation Units (1–6)
Nitin Bagul Ting Lu Jason Ferla Michael Coory Monique Stone Neil Everest (a/g)
Application and Advisory Management
Kaylene Raynes
Medical adviser
John McEwen
Medical Devices & Product Quality Division Medicines Regulation Division Pharmaceutical Benefits Division PM Registration Processes
Prescription Medicines Authorisation Branch Scientific Evaluation Branch Pharmacovigilance and Special Access Branch Laboratories Branch Manufacturing Quality Branch
Regulatory Practice & Support Division
Scheduling & Committee Support Section Product Billing & Industry Assistance Section
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Registration Designation
MS2 MS7 220 255 20
priority, provisional (if required)
−40
legislated timeframe (except for COR) application submitted
MS1
(optional) dossier submitted TGA clock in working days for decision timing ('Milestone 7') for the different pathways
120 150 175
STOP-CLOCK, s.31 questions to sponsor TGA clock STARTS
MS3 MS4
Round 1 evaluation
MS5
Round 2 evaluation ACM expert advice (optional) TGA clock STOPS
MS6 155 COR-A priority COR-B generic provisional non-generic and
Country 2017 - New active substances EU 30 US 50 Canada 33 Japan 22 Switzerland 29 TGA 24
regulator
target timeframe from 220 to 150 work days)
New actives substances approved by all 5 regulators* *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
medicines with same resources
flexibly while avoiding lack of clarity
for the intended use
the benefit of availability outweighs the risk
approved after evaluation of confirmatory data
Medicine and Medical Devices Review (MMDR) reforms
are eligible
access pathways and/or fee waiver
submitted (1 month prior expiry not for priority)
lapsed, but criteria must be met (e.g. show benefit against self)
(standard, priority, provisional, COR A & B)
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5 10 15 20 25 priority provisional
Number of Applications Number of determination and designation applications (1 July 2017 - 31 July 2018) withdrawn rejected approved Application type
* New orphan drug program (applications received from 1 July 2017)
Priority, 14/23 (61%) determined Provisional, 2/2 (100%) determined Orphan, 12/24 (50%) designated
determination : 19 working days
New program: 25 working days Previous program: 60 working days
8%
Approved orphan designations
Metabolic disorders Immunology Ophthalmology Oncology Haematology Respiratory diseases Neurological disorders Endocrinology 9% 9% 8% 8% 42% 8% 8%
n=12
64% 29% 7%
Approved priority determinations
Oncology Haematology Neurological disorders
n=14
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therapeutic goods
diagnosis, prevention or treatment
‒ compare against standard of care in the absence of a registered treatment ‒ line of therapy or disease stage are not a valid subgroup
Compare against standard of care if there is no registered treatment ? Improved safety or efficacy Medicine combinations Major therapeutic advance Provide comparison against all registered treatments /prophylaxis Separate applications for each active ingredient if not a fixed dose Provide justification of why the supporting evidence is substantial: e.g. progression free survival vs overall survival
use of biomarkers generally not
has been included.
force when the application and evaluation fees are payable (Regulation 45(12).
setting.
PPF batching process.
Guidance updates:
excludes provisional
Excerpt from CIRS R&D Briefing 67 Regulator 2017 median approval time (accelerated NAS) Calendar days Estimated Working days* EMA 235 168 FDA 240 171 PMDA 275 196 Health Canada 209 149 Swiss Medic 272 194
*overseas regulators: excludes weekends but includes public holidays, includes sponsor time; TGA: additionally excludes holidays and sponsor time
98 104 124 96 96 140 119 80 20 40 60 80 100 120 140 160 Alectinib Emicizumab Nivolumab Dabrafenib Trametinib Nivolumab Osimertinib Apalutamide
TGA Priority approval times 2017/18
Working Days
NCE/NBE EOI
Median approval time for NAS and EOIs 101 working days*
less new medicines (4/14)
group of patients & major therapeutic advance New medicine EOI TGA 4 /14 10 /14 & EMA accelerated 75% (3/4) 10% (1/10) & FDA priority 100% (4/4) 90% (9/10)
New medicine EOI TGA 9 /12 2 /12 also EMA orphan 89% (8/9) 50% (1/2) also FDA orphan 78% (7/9) 100% (2/2)
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a comparable overseas regulator following a de novo evaluation.
Unredacted COR evaluation reports must be provided by the applicant.
COR-A – 120 working days COR-B – 175 working days *depending on extent of TGA evaluation required.
overseas MA < 1 year ago critical review of the COR assessment evaluation of label PI & RMP, no additional data evaluated
No limit to currency of overseas MA Critical review of COR assessment reports additional data analysis required (e.g. updated stability data, or pivotal study data)
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*32% of New Active Substance Applications (NAS) had post market safety events *Accelerated applications were associated with higher rates *Medicines approved through expedited pathways are associated with increased safety related label changes after approval particularly for the types of changes representing the highest risk warnings
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medicines to: – reduce the class of persons for whom the medicine is suitable – change the directions for use – add a warning or precaution – change the Product Information related to the medicine
pharmacovigilance inspections)
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*After 5 to 6 years, 20% of postapproval studies had not been started, 25% were delayed or ongoing, ~half completed. *15% of incomplete postapproval studies were ‘released ‘ *Crucial to ensure that open questions at registration are quickly resolved *Products marketed prior to completion of confirmatory trials accelerated approvals ↑ over time *Only a small portion of indications have failed to verify clinical benefit
Presentation title 23
OPINION: *’ confirmatory studies should include both overall survival and quality of life ’ *’randomized control design of post- market studies can be lost due to the crossover from the control to treatment group or vice versa, raising questions about the true treatment effect ‘ * most drugs retain FDA approval and remain on the market when post-market studies show no clinically meaningful benefit compared with placebo OPINION: *’ Conditional approvals share some parallels with the early termination of clinical trials, which are known to overestimate treatment benefits and underestimate harms’ *It is hard to believe that a few more trials—mostly phase II, open label,…..., possibly against inappropriate comparators—can fill the knowledge gap at the time of conditional approval.’
medicines where further confirmatory data can be collected
clinical setting (by agreement)
clinical data within 6 years required at the ‘early’ determination stage
clinical trial plan
Over the past 25 years more than one third of new oncology indications received accelerated approval Debate - appropriate endpoints for oncology:
disease can trigger changes in clinical management
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…that were the primary basis for approval for accelerated or traditional pathways
“Some prescription medicines can now be approved faster” “Not everything about a medicine is known when it is first approved” “We will watch medicines that have been approved for a short period of time more closely” “Report side effects to your health professional or call 1300 134 237” “ Some prescription medicines will be approved for a short period of time while more information about them is collected
Health Professionals & Patients
Videos
Facebook Webinars
Blogs Journal articles TGA website Twitter
against international regulators
from all stakeholders
guidelines and processes
learned
regulators and establish processes
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Health Portfolio Budget Statements Outcomes 1 & 5 Department of Health & TGA
1: Health system policy, design & Innovation 5: Regulation, Safety & Protection
Outcome 1.5 International Policy - Engaging
Outcome 5.1 Protect the Health and Safety of the Community through Regulation
Delivery
Dept engaged in several international fora (WHO, OECD etc) to integrate evidence-based international Stds Develop & forge new bilateral relationships with target countries Protection of Health & Safety of Australian community…...through regulation of therapeutic goods using International best practice Participate in International Engagement & Work- sharing activities with CORs 31
Regulatory Engagement Activities
Market Authorisation TGA HC HSA Swiss medic
regulators across multiple areas: Therapeutic Goods Administration (TGA) Health Canada (HC) Singapore Health Sciences Authority (HSA) Switzerland’s Therapeutic Products Agency (Swissmedic)
to market authorization
Market Authorisation
Quality Assessment Toxicology Evaluation Clinical Evaluation
TGA HC HC TGA
Separate Sovereign Decisions
Confidence Building – a prelude to formal WS
Understanding regulatory framework (process, stop clock, Qs, prescreen, timeframes) Sharing of evaluation reports across all areas Retrospective analysis of decisions to date ACSS NCE pilot – General NCE WS model
Market Authorisation
Quality Assessment Toxicology Evaluation Clinical Evaluation
TGA HC TGA
X TGA Retrospective analysis of previous PM decisions (HC:TGA)
dosages or registration conditions
Compound ‘X’ - becoming familiar
complete
evaluators had access to the EMA & FDA review.
effort (15 working days)
for systems to be built to support greater collaboration
included: a) Details reported for some evaluations of Phase 1 studies b) Level of importance placed on some studies over others – same data, interpreted differently c) Number of Q’s: HC = 39 & TGA = 22; with ~5 common Q’s
‒ an overall favorable R/B balance ‒ Approved identical indication & dosage
by Sponsor, aligning with FDA and EU post-marketing requirements.
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Apalutamide (ERLYAND/ERLEADA) Approved in 80 WD Market Authorisation Quality Assessment Toxicology Evaluation (+impurities) Clinical Evaluation (-BE, PopPK) Clinical Evaluation (+BE, PopPK)
TGA HC TGA HC
Separate Sovereign Decisions
TGA ERLYAND ERLEADA HC
Swissmedic were observers
in February 2018
/Canadian) – rolling Q’s
studies & popPK) and Full toxicology assessment + impurities
issues, rolling Q’s & the subsequent responses to Q’s shared (clarifaxes/TGA’s rolling Q’s)
Janssen-cilag feedback:
“…….congratulate the TGA and Department of Health for their commitment to ongoing reforms to policy and process in ensuring better health outcomes for Australians. The collaboration between the Australian and Canadian health authorities in achieving such an expedited approval of this important medicine for men with prostate cancer is indicative of the Government’s genuine commitment to …. approval of new, innovative therapies,” - Mr Bruce Goodwin, Managing Director Janssen Australia and New Zealand.”
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submission
Evaluation
Sovereign decisions
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Yes and on a similar date, and preferably with the same dossier (or minor local specific modifications)
Priority review - Q’s raised during the evaluation will be sent to the respective local affiliate for a response, then shared with partnering regulators (& affiliate to support complete eCTD) Standard review - consolidated Q’s will be sent to both local affiliates simultaneously based upon the review milestones established jointly by partnering regulators.
laws and frameworks exist between the countries that will affect decisions on the final text and product labelling.
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to enable additional controls for newly down- scheduled (prescription to OTC) substances
the scheduling consideration and market authorisation process for substances moving from prescription to OTC.
for interim decision consultation.
presentations to the scheduling committees
using risk-benefit analysis
PF and Scheduling Handbook were published
2 meetings were held with stakeholders to discuss further evolution of scheduling reforms
Governance Decision Making Tools Process Improvements
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(Schedule 3) substances direct to consumers (DTC) should be permitted unless actually deemed unsuitable by the Scheduling Delegate
substance is not suitable for advertising:
1. The potential impact on public health a) Is there potential for inappropriate use, abuse, diversion that may be exacerbated by advertising? b) Are there potential interactions with the substances (drug- drug, drug-food) that require increased patient education to ensure safe use? c) Are there additional risks associated with the dosage form that may impact on safe use? d) Any other information that may be relevant, for example the substance has sedating properties, or there are safer alternatives available
Mandatory Requirements
the Therapeutic Goods Advertising Code (the Code)
for Schedule 3 substances: “Ask your pharmacist – they must decide if this product is right for you”
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substances should be added to Appendix H was closed on 9 July.
into two lists: those that can be advertised (added to Appendix H), those that are not suitable for advertising.
together with feedback from stakeholder meetings, the Delegate will do one or more of the following for each substance: 1. Make a decision to add a substance to Appendix H 2. Decide not to add a substance to Appendix H 3. Reconsider the initial proposal and seek further comment on an alternative proposal 4. Refer the substance to the ACMS for further advice.
from stakeholders.
added to Appendix H in the consultation paper will be added to Appendix H.
for further advice.
end of 2018.
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Outcomes of this review have been published on the website
– Regulation of vitamins and minerals – Sunscreens regulation.
good for the purposed of the Act, and over which we have no regulatory control) – Antiperspirants – Ear candles
regulatory requirements – Tampons and menstrual cups – Nappy rash creams – Some hard surface disinfectants
– A clean up of class I medical devices that should not be included on the ARTG – Further reform and streamlining of the regulatory framework for hard surface disinfectants – Further improvements to the way sunscreens are regulated
reform consideration are now being considered as part of a broader project addressing the food-medicine interface.
approach for aromatherapy and homeopathy products.
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10 20 30 40 50 60 70 80 90 100 2009 2010 2011 2012 2013 2014 2015 2016 2017 Number
TGA: Number of published Australian Public Assessment Reports (AusPAR) for Prescription Medicines :2009-2017
Calendar Year
(AusPAR) for prescription medicine published in 2009
publication)
referred to an advisory committee (ACV/ACM)
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entities
Outline of current AusPAR document
Also includes two attachments 1. The approved Product Information as at the time the AusPAR was prepared and first published 2. Extract from the clinical evaluation report containing more details of the clinical findings
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Priority areas of work Status Requires external consultation? 1.Boxed warning guidance
changes for significant safety issues 3.xml searchability for PI and CMI Consultation phase Planning phase Planning phase Yes Yes Yes
Boxed Warning
Teratogenic effects: Thalidomide has caused severe birth defects when taken during pregnancy. Thalidomide should never be used by women who are pregnant or who could become pregnant whilst taking the medicine or could become pregnant within 4 weeks after stopping the medicine. Even a single dose can cause birth defects
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warning statements in the Product Information to the prescriber.
potential for major impact on public health.
Australia and are also used in other jurisdictions.
to standardise the approach.
31 August 2018
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Boxed Warning in the PI
Format Content Applies prospectively, unless new information becomes available Required evidence base When a boxed warning is proposed
CMI and Promotional material
Stakeholder feedback Process
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