Preparing ourselves for the future regulatory world Industry Forum on GMP Adjunct Prof John Skerritt Deputy Secretary for Health Products Regulation Department of Health 21 November 2019
Government and community expectations of regulators On one hand – a continued emphasis on • Regulatory burden reduction – and asking whether regulation is the best policy approach • Congestion busting - regulator efficiency • Regulator performance framework – KPIs for TGA’s interaction with the regulated industry • Public reporting of performance metrics On the other hand – some recent serious findings of inadequate regulatory oversight, e.g. • Banking Royal Commission • Aged Care Royal Commission 1
Regulator performance framework The six KPIs are: 1. Regulators do not unnecessarily impede the efficient operation of regulated entities 2. Communication with regulated entities is clear, targeted and effective 3. Actions undertaken are proportionate to the regulatory risk being managed 4. Compliance and monitoring approaches are streamlined and co-ordinated 5. Regulators are open and transparent in their dealings with regulated entities 6. Regulators actively contribute to continuous improvement of regulatory frameworks Reported after review of proposed ratings by the TGA Industry Consultative Committee. Complemented by six monthly TGA performance statistics reports. 2
Lessons from the banking royal commission • The law was often not enforced at all or not enforced effectively • Policies about enforcement did not preclude regulators from taking stronger steps - the problem is one of culture at the regulators • Regulated entities should not be viewed as ‘clients’ – a regulator does not perform its functions as a service • Some entities struggled to understand their fundamental obligations • Regulators must consider what regulatory response will be appropriate • An unconditional preference for negotiated compliance renders an agency susceptible to capture • Protracted negotiations indicate an unwillingness to remediate wrongdoing • Review implementation to identify where policies were not effective 3
Compliance requirements – the standard of quality • For GMP, it is through the PIC/S Guide to Good Manufacturing Practice for Medicinal Products • Simply testing product after manufacture is not sufficient to ensure quality • Quality must be built into each batch of a product during all stages of the manufacturing process 4
How did the industry go in 2018-19? Inspection status (Australia) GMP clearance applications completed Number of inspections 195 Approved 6252 (88%) Satisfactory compliance 152 (78%) (up from 5041 in 2017/18) 29 (15% ) Marginal compliance Rejected 854 (12%) Unacceptable 8 (4%) Total completed 7106 (Close-out in progress for 6 inspections) Inspection status (overseas) So: Number of inspections 75 • room for compliance improvements remains Satisfactory compliance 64 (85%) • incomplete documentation is leading to many Marginal compliance 11 (15%) GMP clearance rejections Unacceptable 0 (0%) 5
Risk based approach to compliance and enforcement TGA compliance strategy Help and support Inform and advice Correct behaviour Enforcement action Make ongoing compliance easy Help to become and stay Deter by detection compliant Regulated entity – attitude to compliance Voluntary compliance Accidental non-compliance Opportunistic non-compliance Intentional non-compliance • Effective compliance • Ineffective and/or • Resistance to compliance • Deliberate non-compliance systems developing compliance • Limited or poor compliance • No compliance systems • Management is compliance systems systems • Criminal intent oriented Management compliance Management not • • oriented but lacks capability compliance oriented Committed to doing the right Trying to do the right thing but Don’t want to comply but will if Decision to not comply thing don’t always succeed made to 6
Recent reforms built new regulatory frameworks (2017-19) • New facilitated premarket review pathways for medicines and devices – Comparable Overseas Regulator reviews – Priority Review of prescription medicines and devices – Provisional Approval for new prescription medicines – Australian notified bodies for devices • Enhanced post-market safety systems for medicines and devices • New Special Access Scheme systems • Stronger compliance and enforcement powers • New advertising regulatory framework • New complementary medicines pathways and strengthened compliance But the Review did NOT look at how new technologies should be regulated 7
New therapeutics pose new manufacturing challenges • Faecal Microbiota Transplantation (FMT) • Medicinal Cannabis • Chimeric Antigen Receptor (CAR-T) therapy - leukaemias and lymphomas • CRISPR genome editing - inherited disorders e.g. beta thalassemia 8
Curative medicines for major therapeutic challenges • Medicines to cure diseases rather than treat symptoms • Promise of “ one shot” rather than lifelong treatments • Move from tissue-specific to biomarker based disease targets e.g. for cancers • Addressing still-difficult to treat diseases and disorders Which can pose new manufacturing quality challenges • Drift in structure of monoclonal antibodies with time and between manufacturing sites • Individual patient manufacture part of delivery of some therapies e.g. CAR-T • Developers often smaller companies and hospitals 9
New device technologies create regulatory dilemmas In 2019/20 regulatory frameworks being reviewed for : • 3D printed devices • Software as a medical device/ apps • Artificial intelligence/ machine learning • Self-test IVDs for disease testing and genetic screening Manufacturing aspects are critical in all cases SMEs and IT developers often develop these devices rather than traditional device industry sponsors 10
3D printed devices – most regulatory changes impact manufacturing requirements 1. New definitions for different types of 3D printed devices define levels of oversight 2. Suppliers must to provide additional information to TGA and patients and allow TGA to inspect manufacturing sites 3. A “medical device production system” framework to allow healthcare providers to produce lower risk personalised devices without manufacturing certification 4. 3D-printed models of patient anatomy to be regulated as devices 5. 3D printed devices with a human cellular component to be regulated as devices not biologicals 6. Modifiers of an already-supplied personalised medical device become the manufacturer 11
Machine learning / artificial intelligence - how do we regulate manufacturing of diagnostic apps? Regulators and industry need to develop Quality Management Systems for medical devices products with “adaptive” algorithms • that learn and change over time • and are not “locked” by the manufacturer 12
Targeting patients who will benefit from new medicines What we are doing in 2019/20 Personalised medicine • Priority reviews for targeted medicines • Diagnosing/preventing genetic disease – but this puts pressure on GMP • Cancer diagnosis and treatment inspection timeframes • Determining patient suitability for particular medicines • New orphan drug framework to cancer • Chronic multi-genic conditions – and rare disease drugs diabetes, heart disease – increasingly being produced by small- medium sized companies less familiar A companion diagnostic is essential with GMP requirements • To identify patients who have a biomarker and thus will respond ….. • Developing a regulatory scheme for ……. but to not inflict the wrong companion diagnostics for targeted treatment on unresponsive patients medicines 13
Self tests in Australia Most self tests are currently not permitted , when the test results are returned directly to the consumer. • These include tests – for pathogenic organisms or transmissible agents (other than HIV) – to diagnose serious diseases or conditions or their precursors – and genetic tests for susceptibility to multigenic diseases or determination of carrier status e.g. prenatal testing • Public consultation until 22 Nov 2019 to seek views on whether or how Government should change the regulations • Manufacturing quality issues are important for self-test kits as they are used by lay people and often not stored optimally 14
Move to a more a global regulatory system What we are doing in 2019/20: • Worksharing with Canada/ Singapore/Switzerland on New Chemical Entities and generic drugs • US FDA “Project Orbis” on new oncology drugs • Comparable Overseas Regulator pathways for medicines and devices • Medical Devices Single Audit Program • Working with WHO and DFAT on regulatory strengthening and medicines quality in SE Asia and Pacific • TGA has led international reliance through GMP clearance pathways 15
Generic medicine quality and supply shortages 16
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