Preparing ourselves for the future regulatory world Industry Forum - - PowerPoint PPT Presentation

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

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Regulator performance framework

The six KPIs are:

1. 2. 3. 4. 5. 6. Regulators do not unnecessarily impede the efficient operation of regulated entities Communication with regulated entities is clear, targeted and effective Actions undertaken are proportionate to the regulatory risk being managed Compliance and monitoring approaches are streamlined and co-ordinated Regulators are open and transparent in their dealings with regulated entities 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.

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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

• ne 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

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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

So:

• room for compliance improvements remains

incomplete documentation is leading to many GMP clearance rejections

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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 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
• riented
• Ineffective and/or

developing compliance systems

• Management compliance
• riented 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)

• –

– – –

• 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

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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

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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

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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

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3D printed devices – most regulatory changes impact manufacturing requirements

1. 2. 3. 4. 5. 6. New definitions for different types of 3D printed devices define levels of oversight Suppliers must to provide additional information to TGA and patients and allow TGA to inspect manufacturing sites A “medical device production system” framework to allow healthcare providers to produce lower risk personalised devices without manufacturing certification 3D-printed models of patient anatomy to be regulated as devices 3D printed devices with a human cellular component to be regulated as devices not biologicals Modifiers 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

• 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

• –
• –
• Diagnosing/preventing genetic disease

Cancer diagnosis and treatment Determining patient suitability for particular medicines Chronic 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 2019/20

Priority 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.

• –

– –

• 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

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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

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Generic medicine quality and supply shortages

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Drug and US FDA approval date

2 - 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 drugs

What we are doing in 2019/20:

• –

– – – – Improved reporting and management of medicine shortages Mandatory reporting and publication from 1 Jan 2019 High numbers of critical shortages – about half due to manufacturing problems Identifying/ arranging alternative products – but sometimes

• nly 1-2 sources of API globally

Convening clinician meetings to identify alternatives if the same product is unavailable Dilemma is that responding to GMP inspection findings can lead to medicine shortages

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Quality problems – often old generic drugs too

• –

– – 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)

• 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 authorisation additional inspections, certificates under review information to media, healthcare professionals and patients

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Root causes of N-nitrosamine contamination unclear

• 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 revealed

Insufficient understanding of Quality Risk Management Principles or of process development Inadequate Out-of-Specification management Root cause investigations too superficial - focusing only on main API synthesis route Ineffective change management system Companies did not provide all or complete requested documentation

How do we equip ourselves for the future ?

• –

–

• Manufacturing quality is central to the regulatory

system Impacts on GMP processes and demand must be considered when implementing reforms to medicines regulation Further 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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