Preparing ourselves for the future regulatory world Industry Forum on GMP

Adjunct Prof John SkerrittDeputy Secretary for Health Products RegulationDepartment of Health21 November 2019

Government and community expectations of regulators

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On one hand – a continued emphasis onRegulatory burden reduction – and asking whether regulation is the best policy approachCongestion busting - regulator efficiency Regulator performance framework – KPIs for TGA’s interaction with the regulated industryPublic reporting of performance metrics

On the other hand – some recent serious findings of inadequate regulatory oversight, e.g.

Banking Royal CommissionAged Care Royal Commission

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Regulator performance frameworkThe six KPIs are:

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2.3.4.5.6.

Regulators do not unnecessarily impede the efficient operation of regulated entitiesCommunication with regulated entities is clear, targeted and effectiveActions undertaken are proportionate to the regulatory risk being managedCompliance and monitoring approaches are streamlined and co-ordinatedRegulators are open and transparent in their dealings with regulated entitiesRegulators 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.

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Lessons from the banking royal commission•

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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 •

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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

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How did the industry go in 2018-19?Inspection status (Australia) Number of inspections 195 Satisfactory compliance 152 (78%) Marginal compliance 29 (15%) Unacceptable 8 (4%) (Close-out in progress for 6 inspections)

Inspection status (overseas)Number of inspections 75 Satisfactory compliance 64 (85%) Marginal compliance 11 (15%) Unacceptable 0 (0%)

GMP clearance applications completed Approved 6252 (88%)

(up from 5041 in 2017/18)

Rejected 854 (12%)

Total completed 7106

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room for compliance improvements remains incomplete documentation is leading to many GMP clearance rejections

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Risk based approach to compliance and enforcementTGA compliance strategy

Help and support Inform and advice Correct behaviour Enforcement action

Make ongoing compliance easy Help to become and stay compliant

Deter by detection

Regulated entity – attitude to compliance

Voluntary compliance Accidental non-compliance Opportunistic non-compliance Intentional non-compliance

• Effective compliance systems

• Management is compliance oriented

• Ineffective and/ordeveloping compliance systems

• Management compliance oriented but lacks capability

• Resistance to compliance• Limited or poor compliance

systems• Management not

compliance oriented

• Deliberate non-compliance• No compliance systems • Criminal intent

Committed to doing the right thing

Trying to do the right thing but don’t always succeed

Don’t want to comply but will if made to

Decision to not comply

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Recent reforms built new regulatory frameworks (2017-19)•

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New facilitated premarket review pathways for medicines and devicesComparable Overseas Regulator reviewsPriority Review of prescription medicines and devicesProvisional Approval for new prescription medicinesAustralian 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 frameworkNew complementary medicines pathways and strengthened compliance

But the Review did NOT look at how new technologies should be regulated7

New therapeutics pose new manufacturing challenges

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Faecal Microbiota Transplantation (FMT) Medicinal CannabisChimeric Antigen Receptor (CAR-T) therapy -leukaemias and lymphomasCRISPR genome editing - inherited disorders e.g. beta thalassemia

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Curative medicines for major therapeutic challenges••••

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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 challengesDrift in structure of monoclonal antibodies with time and between manufacturing sitesIndividual patient manufacture part of delivery of some therapies e.g. CAR-T Developers often smaller companies and hospitals

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New device technologies create regulatory dilemmas

In 2019/20 regulatory frameworks being reviewed for :

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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

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3D printed devices – most regulatory changes impact manufacturing requirements

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New definitions for different types of 3D printed devices define levels of oversightSuppliers must to provide additional information to TGA and patients and allow TGA to inspect manufacturing sitesA “medical device production system” framework to allow healthcare providers to produce lower risk personalised devices without manufacturing certification3D-printed models of patient anatomy to be regulated as devices3D printed devices with a human cellular component to be regulated as devices not biologicalsModifiers of an already-supplied personalised medical device become the manufacturer

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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

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that learn and change over time

and are not “locked” by the manufacturer

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Targeting patients who will benefit from new medicines

Personalised medicine•••

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Diagnosing/preventing genetic disease Cancer diagnosis and treatment Determining patient suitability for particular medicinesChronic multi-genic conditions –diabetes, heart disease

A companion diagnostic is essential To identify patients who have a biomarker and thus will respond …..……. but to not inflict the wrong treatment on unresponsive patients

What we are doing in 2019/20Priority reviews for targeted medicines

but this puts pressure on GMP inspection timeframes

New orphan drug framework to cancer and rare disease drugs

increasingly being produced by small-medium sized companies less familiar with GMP requirements

Developing a regulatory scheme for companion diagnostics for targeted medicines

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Self tests in Australia

Most self tests are currently not permitted, when the test results are returned directly to the consumer.•

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These include testsfor 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

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Move to a more a global regulatory system

What we are doing in 2019/20: •

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Worksharing with Canada/ Singapore/Switzerland on New Chemical Entities and generic drugs

US FDA “Project Orbis” on new oncology drugsComparable Overseas Regulator pathways for medicines and devices

Medical Devices Single Audit ProgramWorking with WHO and DFAT on regulatory strengthening and medicines quality in SE Asia and Pacific TGA has led international reliance through GMP clearance pathways

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Generic medicine quality and supply shortages

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Drug and US FDA approval date2 - atorvastatin (1996)1 - rosuvastatin (2003)3 - esomeprazole (2001)4 - pantoprazole (2000)5 - perindopril (2009)6 - cephalexin (1971)7 - amoxicillin (1972)8 - metformin (1972 Canada)9 - amoxicillin and clavulanic acid (1984)10 - escitalopram (2002)

Old, generic drugs still account for most prescriptions

Average approval date is 1990-91

Holden Commodore was Australia’s best

selling car

The 10 most PBS prescribed drugs

in Australia

(by number of prescriptions in

2017-18)

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Medicines shortages - often these are old generic drugsWhat we are doing in 2019/20:•

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Improved reporting and management of medicine shortages Mandatory reporting and publication from 1 Jan 2019High numbers of critical shortages – about half due to manufacturing problemsIdentifying/ arranging alternative products – but sometimes only 1-2 sources of API globally Convening clinician meetings to identify alternatives if the same product is unavailableDilemma is that responding to GMP inspection findings can lead to medicine shortages

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Quality problems – often old generic drugs too•

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Worrying numbers of quality defects and recalls globally

Often of older products, low profit margin generics where there has been little investment in innovation

Short-term focus on inspections of affected facilities, but longer term culture changes and process changes needed

International cooperation under leadership of agency heads on quality risk management – exchange on best practices PIC/S guidance on an effective quality system and risk based change management systems ICH looking at revision of ICH Q9 guideline on quality risk management

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Nitrosamine crisis – what went wrong with manufacturing ?All N-nitroso-substances are considered as highly mutagenic carcinogens (ICH M7)•

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2018 - notifications of presence of N-Nitrosamine impurities in APIs for certain sartan anti-hypertensives (valsartan, losartan, irbesartan)2019 – found in many ranitidine products, and possibly other APIs (pioglitazone, etc.)

Regulatory actions implemented to protect public health testing and recalls, suspension of product authorisationadditional inspections, certificates under reviewinformation to media, healthcare professionals and patients

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Root causes of N-nitrosamine contamination unclear•••••

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Sodium nitrite impurities reacting with the API?API amine degradant or impurity from API synthesis?Contaminated recovered and recycled solvents and reagents? Contamination from shared equipment and containers used in API manufacture?Heating of the finished product during blister foil packaging?

Recent GMP inspections by EU country inspectors have revealedInsufficient understanding of Quality Risk Management Principles or of process development Inadequate Out-of-Specification managementRoot cause investigations too superficial - focusing only on main API synthesis route Ineffective change management systemCompanies did not provide all or complete requested documentation

How do we equip ourselves for the future ?•

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Manufacturing quality is central to the regulatory system

Impacts on GMP processes and demand must be considered when implementing reforms to medicines regulationFurther business improvements underway

International alignment and work-sharing

Regulations and skills need to adapt to manage emerging technologies

Medicines shortages and quality problems may seem “old hat” but they have major patient impact

But we need to be realistic about our small size

TGA 700 staff and contractors

USFDA 17,000 staff

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