Biologicals regulation in AustraliaEvolving perspectives

Albert Farrugia

Senior Principal Research Scientist

Therapeutic Goods AdministrationPresented to the Second Asian Bio Manufacturing Conference, Kuala Lumpur, Malaysia, November

2007

Current position

• TGA Act recognises medicines and medical devices as regulated therapeutic goods (no definition of biologicals)

• Products such as blood products, biotechnology medicines, vaccines etc are regulated as prescription medicines

• Products of tissue engineering eg autologous chondrocytes regulated as devices

• Some products eg fresh blood, banked tissues not subject to pre-market review and ARTG so – only regulated outcome is GMP license

Current responsibilitiesBiologicals

• DSEB – all registrable biologicals which are medicines eg

• Biotechnology medicines – monoclonal a/bs, recombinant products etc• Vaccines (including cell based vaccines)• Plasma derivatives

• ODBT – Devices section – all registrable biologicals which are devices

–Recalls section – advice re blood, blood product and tissue recalls

• MAB – manufacturing license for products subject to the requirement

Role of the Blood and Tissues Unit

• Situated within the ODBT – historical reasons – link to GMP

• Reviews pre-market data for biotech drugs – plasma products, recombinants etc

• Reviews technical files for fresh blood components, cord blood

• Develops policy for blood, tissues and biologicals• Provides advice on pathogen safety – viruses, prions• Interfaces with government(s) on blood and tissue

policy issues

International relationshipsBTU

• WHO Expert Committee on Biological Standardisation

• Council of Europe Committee of Experts on Blood transfusion

• Council of Europe Committee on cells, tissues and organs

• European Pharmacopeia Group pf Experts 6B – Blood Products

• WHO Global Collaboration for Blood Safety

• [World Federation of Hemophilia Medical Advisory Panel]

Current structureBlood and Tissues Unit

• Unit head (SPRS)– Cells and tissues EL2

• Evaluators EL1 (x 3)

– Blood and Plasma products EL2• Evaluators EL1 (x4), APS6

– Pathogen safety, PMFs EL2• Evaluators EL1 (x1), APS6 (x2)

– Operations Manager EL2• EA, APS5

Medical Advisor ODBT

Drivers for changeBiologicals regulation in Australia

• Internationally accepted principle

• Difficulties in using traditional paradigms eg medicinal

GMPs for biologicals

• High public and political interest

• Publicly funded activities

Regulation of biologicalsProposed approach

Scope• Blood, blood components and blood products• Biotechnology equivalents of blood, blood components and blood

products– Recombinant clotting factors– Haemoglobin solutions– Etc

• Cell and tissue therapies– Banked “non-viable” tissue– Cellular therapies– (under government policy review) solid organs, reproductive

tissue

Regulation of biologicalsProposed approach

Principles

• All products to be subject to requirements of

registration ie pre-market review for safety,

quality and efficacy before market entry

• Level of review linked to classification system

• Office of Biologicals established as the

Regulator within the agency

Regulation of biologicalsProposed approach

Class 1, 2 & 3 - Basis for classification

• Risk-benefit ratio

• Governance arrangements

• Level of manipulation

• Intended use

Regulation of biologicalsProposed approach

• Class 1 – goods which are– Governed through medical practice – specific donor-patient r’ship– Of low risk compared to benefit for individual patient– Processed with minimal technology – will be defined

– Eg solid organs, autologous/directed HPCs in clinical units,

autologous/directed blood, hospital based blood manufacture• Class 1 will be regulated through Standards established by professional

bodies• Class 1 standards will be overseen and attested by the regulated entity

– declaration of conformance or by facility accreditation (NATA)

The requirements are not “lower” than other Classes – different governance

Regulation of biologicalsProposed approach

• Class 2 – goods which are– Governed through manufacturing practice – long term banking– Of moderate risk compared to benefit – established medical indications,

safety profile – for population– Processed with moderate technology – will be defined – including banking– Have a homologus function ie same function in recipient as in donor– Eg banked tissue, banked HPCs detached from medical environment, non-

autologous/directed, mainstream blood components

• Class 2 will be regulated through standards for safety and quality in product and manufacture which will be overseen by the agency

• Class 2 efficacy requirements will be minimal and based on established knowledge eg literature, no clinical trials will be solicited

Regulation of biologicalsProposed approach

• Class 3 – goods which are– Governed through manufacturing practice– Of potentially high risk compared to benefit, for population and indvidual– Processed with industrial technology – will be defined – Eg plasma derivatives, biotechnology medicines, cellular therapies

• Class 3 cell and tissue products will be further subdivided into 2 types – Depending on whether function is homologous or not– Different requirements for clinical trials/efficacy assessment

• Class 3 will be regulated through standards for safety, quality and efficacy in product and manufacture which will be overseen by the agency

• Class 3 efficacy requirements will be based on clinical trials which will be staged on risk based principles

Regulatory model for biologicals

• Class 1 (many still under policy review) – Haematopoietic progenitor cells – Autologous blood transfusions– Solid organs

• Class 2– Mainstream blood components– Banked cord blood – haematopoietic reconstitution– Banked tissues

• Class 3– Plasma products– Biotech equivalents of blood products eg rVIII etc– Cell based vaccines

Class 1

Unbanked/unprocessed

Medical practice governance

Class 2

Banked/unprocessed

Manufacturing practice governance

Homologous function

Class 3

Banked/processed

Manufacturing practice governance

Organs

Blood Progenitor (stem) cells

Hospital based manufacture

Banked blood components

Banked tissues

Processed cells and tissues

Manufactured blood products

“Class III” – homologous function

“Class IV” – non-homologous function

Plasma products

Recombinant plasma products

Processed blood components eg virally inactivated platelets

Currently exempt

Currently regulated through GMP – no ARTG

Currently regulated as medicines or therapeutic devices

“listable” Biologicals – no efficacy requirements

“registrable” Biologicals –efficacy requirements

Proposed regulatory model for Biologicals

Clinical trial frameworkProposed approach

• Two levels

– CTX – detailed safety data reviewed by regulator

– CTN – less detailed data requirements

• Role of HRECs

• For biologicals –

– Class 3 Cell therapies are CTX

– Gene therapy when vehicled through cell therapies is CTX

– Xenotransplantation is CTX

– New substances may be CTN if overseen by HREC – NHMRC new system

- National minimum dataset of reportable adverse events- Agreed definitions of these events, with standards for their investigation- Collection within institution or blood establishment-- Notification to the competent authority (TGA) of any serious adverse events -and serious adverse reactions

Rapid Report generated by hospital

Adverse event in public or private hospital and/or pathology service

Health Department

RegulatorTGA

Supplier

Rapid validation process

Haemovigilance