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TGA presentation given at the Sydney Children's Hospital Network Research Governance, 31 March 2015

22 May 2015


These presentation papers are provided on the TGA's website solely for the purpose of indicating or suggesting what TGA representatives spoke about to the various conferences and seminars to which it relates. The papers are not legislative in nature and should not be taken to be statements of any law or policy in any way.

The Australian Government Department of Health (of which the TGA is a part) advises that (a) the presentation papers should not be relied upon in any way as representing a comprehensive description of regulatory requirements, and (b) cannot guarantee, and assumes no legal liability or responsibility for, the accuracy, currency or completeness of the information contained in the presentation paper.


  • Presented by: Dr Tony Gill, Senior Medical Adviser, Market Authorisation Division
  • Presented at: Sydney Children's Hospital Network Research Governance, 31 March 2015
  • Presentation summary: This presentation provided an overview of the TGA's role in controlling access to unapproved therapeutic goods, including in clinical trials.


Clinical trials - TGA role

Dr Tony Gill
Senior Medical Adviser
Market Authorisation Division

Sydney Children's Hospital Network Research Governance

Slide 1 - Overview

  • TGA role
  • Unapproved therapeutic goods
  • Clinical trials

Slide 2 - Who is Australia's regulator?

  • The Therapeutic Goods Administration was established in 1990 to "safeguard and enhance the health of the Australian community through effective and timely regulation of therapeutic goods"
  • It provides a national system of controls relating to the quality, safety, efficacy and timely availability of therapeutic goods used in, or exported from, Australia

Slide 3 - TGA - how we operate

  • We are part of the Australian Government Department of Health
  • Every decision the TGA makes is based on the Therapeutic Goods Act 1989
  • Main offices in Canberra - satellite offices in Sydney, Melbourne, Adelaide and Brisbane
  • Operates on a 100% cost-recovery basis - industry pays fees for making applications and annual charges for products they are responsible for

Slide 4 - TGA role

  • The Therapeutic Goods Act, 1989 (the Act) and associated Regulations establishes a uniform, national system of regulatory controls to ensure the quality, safety, efficacy and timely availability of therapeutic goods for human use.
  • Responsibility for the regulatory controls lies with the Therapeutic Goods Administration (TGA) as the national regulatory authority for therapeutic goods.

Slide 5 - What is an unapproved therapeutic good?

  • Therapeutic goods must be entered in the Australian Register of Therapeutic Goods (ARTG) before they can be lawfully supplied in or exported from Australia unless exempt from being entered in the ARTG, or otherwise authorised by the TGA.
  • Generally, unapproved goods are goods which are not on the ARTG or ARTG goods which are being used outside of TGA approved indications.
  • Unapproved goods have not been evaluated by the TGA for quality, safety or efficacy and are therefore considered 'experimental' products

Slide 6 - Access to unapproved medicines

flow chart showing access to unapproved medicines

Slide 7 - Special Access Schemes

Category A

  • Defined in the Regulations and Medical Device Regulations as "persons who are seriously ill with a condition from which death is reasonably likely to occur within a matter of months, or from which premature death is reasonably likely to occur in the absence of early treatment"
  • Notification by doctor of use of unapproved therapeutic goods on an individual patient

Category B

  • Category B all other patients
  • Application for a nominated doctor to prescribe an unapproved therapeutic good to a nominated patient for a specific condition

Slide 8 - Authorised Prescriber Scheme

Application for a nominated doctor to prescribe an unapproved therapeutic good for a specific condition to any patients with that condition

  • Requires ethics approval
  • Requires a protocol
  • Requires informed consent

To be an Authorised Prescriber the medical practitioner must:

  • Have the training and expertise appropriate for the condition being treated and the proposed use of the product;
  • must be able to best determine the needs of the patient; and
  • to monitor the outcome of therapy.

An Authorised Prescriber is allowed to supply the product directly to specified patients under their immediate care and not to other practitioners who prescribe/administer the product. Use of the product under an authorisation must be at all times in line with the conditions specified in the authorisation.

Once a medical practitioner becomes an 'Authorised Prescriber' they do not need to notify the TGA when they are prescribing the unapproved product, however they must report to the TGA the number of patients treated on a six monthly basis.

Slide 9 - Clinical Trials

Slide 10 - New trial notifications that include a medicine or biological (single & multi-site trials)

2012 2013 2014
Jan-Jun Jul-Dec Jan-Jun Jul-Dec Jan-Jun Jul-Dec
Total 343 416 326 355 449 518

Total new trial notifications that include a medicine or biological for singe and multi-site trials for Jan-Jun (343) and Jul-Dec 2012 (416), Jan-Jun (326) and Jul-Dec 2013 (355) and Jan-Jun (499) and Jul-Dec 2014 (518)

Slide 11 - Clinical trial statistics 1 July 2013 - 31 December 2013

Total Notifications - 1,648

Total New Trials - 355

Total notifications by state: Vic 507, NSW 492, QLD 268, SA 193, WA 123, ACT 33, TAS 31 and NT 1

Total new trials by state: NSW 164, Vic 106, SA 41, QLD 33, WA 10 and TAS 1

Slide 12 - New trial notifications that include a medicine or biological received by phase (single & multi-site trials)

2012 2013 2014
Jul-Dec Jan-Jun Jul-Dec Jan-Jun Jul-Dec
Phase 1 143 115 123 94 131
Phase 2 465 355 374 421 436
Phase 3 842 890 1020 978 1088
Phase 4 120 96 95 210 116
Bioavailability/equivalence 5 4 5 5 4
None specified 9 17 31 154 125
Total 1584 1477 1648 1862* 1900*

Slide 13 - Clinical trial regulation in Australia

  • Access to unapproved therapeutic goods in Australia is regulated under:
    • Therapeutic Goods Act 1989
    • Therapeutic Goods Regulations 1990
    • Therapeutic Goods (Medical Devices) Regulations 2002
  • 2 Schemes:
    • Clinical Trial Notification (CTN) Scheme - trial sponsor notifies the TGA of their intention to conduct a clinical trial using an unapproved therapeutic good.
    • Clinical Trial Exemption (CTX) Scheme - TGA reviews information about the product and decides whether or not to approve the proposed Usage Guidelines of the product.

Slide 14 - TGA's role in clinical trials differs from some regulators

  • Our main focus is on access to (as yet) unapproved medicines and devices for trials rather than end-to-end regulation of trials e.g. FDA
  • CTX/CTN schemes for any product not entered on the ARTG or use of a product in a clinical trial beyond the conditions of its marketing approval
  • TGA is a "user" of clinical trial information in the market authorisation processes for devices and medicines and biologicals
  • Key references on TGA website:
    • Access to unapproved therapeutic goods: clinical trials in Australia, Oct 2004
    • Note for guidance on Good Clinical Practice, July 2000 (adaptation of ICH guideline)

Slide 15 - Clinical Trial Regulation in Australia

Notification under CTN Scheme or application under CTX Scheme required where investigational use of a product involves:

  • Any product not entered on the ARTG, including:
    • any new formulation of an existing product
    • any new route of administration,
    • in the case of an existing medical device, new technology, new material or a new treatment modality
  • Use of a product beyond the conditions of its marketing approval, including:
    • new indications extending the use of a medicine to a new population group
    • extension of doses or duration of treatments outside the approved range.

Slide 16 - Separate and distinct good

A separate and distinct good is defined in Section 16 of the Therapeutic Goods Act 1989 and includes the following particulars:

  1. formulation, composition or design specification; or
  2. strength or size (disregarding pack size); or
  3. dosage form or model; or
  4. name; or
  5. indications; or
  6. directions for use; or
  7. type of container (disregarding container size).

Slide 17 - Clinical trial regulation in Australia standards

  • Therapeutic Goods Regulations 1990 - Regulation12AD
  • Therapeutic Goods (Medical Devices) Regulations 2002 - Regulation 7
  • Medical Device Standards Order (Standard for Clinical Evidence) 2008

Requires that use of unapproved therapeutic goods for experimental purposes in human be in accordance with:

  • National Statement on Ethical Conduct in Human Research, NHMRC, 2007
  • The Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95)
  • AS ISO 14155 - 2004 Clinical Investigation of Medical Devices for Human Subjects

Slide 18 - Clinical trials exemption (CTX) and notification (CTN)

CTX Scheme is an approval process

  • Sponsor submits an application to TGA for evaluation of the usage guidelines of the investigational product
  • HRECs can require an application to go through the CTX route

CTN Scheme is a notification scheme

  • HREC responsible for assessing the validity of the trial design, the safety and efficacy of the product and the ethical acceptability of the trial and for approval of the protocol
  • TGA Clinicians informally review protocols, particularly for first in human studies

Slide 19 - CTN vs CTX schemes - Overview


  • Notification process
  • One step process to notify
  • Can be used for medicines, devices or biologicals
  • No TGA review of data prior to trial
  • Trial cannot commence without valid notification and fee paid
  • Assurances pertaining to the trial conduct and protocol are provided by the sponsor, HREC, PI and AA
  • Each additional trial site must be notified before commencing trial at that site


  • Approval process
  • Two step process - Part 1 (approval) Part 2 (notification)
  • Can be used for medicines, devices or biologicalss but REQUIRED for class 4 biologicals
  • TGA must evaluate and approve
  • Trial cannot commence without Part 1 being approved
  • Assurances pertaining to the trial conduct and protocol are provided by the sponsor, HREC, PI and AA
  • May conduct any number of clinical trials under the CTX application without further assessment by the TGA, provided use of the product in the trials falls within the original approved Usage Guidelines.
  • Each trial conducted must be notified to the TGA

Slide 20 - GCP and GMP requirements for Clinical Trials Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95)

GCP compliance provides:

  • "public assurance that the rights, safety and well being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical data are credible."

Requirement for GMP under GCP notes:

  • "2.12 Investigational products should be manufactured, handled and stored in accordance with applicable good manufacturing practice (GMP)."

Slide 21 - PIC/S Guide to Good Manufacturing Practice for Medicinal Products, PE 009-8 Annex 13 Manufacture of Investigational Medicinal Products

"The application of GMP to the manufacture of investigational medicinal products is intended to ensure that trial subjects are not placed at risk, and that the results of clinical trials are unaffected by inadequate safety, quality or efficacy arising from unsatisfactory manufacture. Equally, it is intended to ensure that there is consistency between batches of the same investigational medicinal product used in the same or different clinical trials, and that changes during the development of an investigational medicinal product are adequately documented and justified."

Slide 22 - GMP issues

Requirement for GMP under GCP:

  • Schedule 7 Therapeutic goods exempt from the operation of Part 3-3 of the Act unless supplied as pharmaceutical benefits
    • Item 1 - goods prepared for the initial experimental studies in human volunteers
  • Generally refers to Phase 1 studies which betters suits medicines than biologicals
  • In the end sponsor requirement to be assured that they have appropriate GMP for investigational product

Slide 23 - Legal responsibilities

  • All trials under TGA regulation must have an Australian sponsor - initiates, organises and supports a clinical study and carries the medico-legal responsibility
  • If there is a major protocol change to the protocol such that the ethics committees require a change to the conditions of their approval a new notification to the TGA may be required
  • TGA has the authority to audit clinical trials on safety grounds and investigate non-compliance with either Good Clinical Practice guidelines or legislative requirements
  • Sponsor responsible for reporting serious and unexpected adverse events during trials directly to TGA
    • Clinical Investigators to report adverse events to both HREC and Sponsor

Slide 24 - Adverse Event Reporting

Reporter Reports what? To whom? In what timeframe?
Sponsor of trial Serious and unexpected adverse drug reactions TGA

For fatal or life-threatening ADRs, send initial report within 7 calendar days of first knowledge. Follow up with complete report within 8 additional calendar days.

For all other serious and unexpected ADRs, full report no later than 15 calendar days of first knowledge by the sponsor.

Other reactions and adverse events TGA On request by TGA.
Clinical investigator(s) Adverse reactions/events HREC As required by HREC
Sponsor of trial As per study protocol

Slide 25 - Guidelines for clinical trials

  • Before commencement of a clinical trial, all regulatory stakeholders must be satisfied that the conduct of the proposed trial is in accordance with:
    • the NHMRC National Statement on Ethical Conduct in Research Involving Humans (2007);
    • the current World Medical Association Declaration of Helsinki;
    • the CPMP/ICH Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) or the ISO 14155 Clinical Investigation of Medical Devices, whichever is applicable;
    • the requirements of the Therapeutic Goods Administration as outlined earlier and
    • any requirements of relevant Commonwealth and/or State/Territory laws.
  • In addition, generally, a facility manufacturing therapeutic goods, including Investigational Medicinal Products (IMP) and placebo, for supply in Australia must comply with appropriate GMP standards and must be licensed accordingly. The TGA has adopted the PIC/S Guide for Good Manufacturing Practice for Medicinal Products 2009, with Annex 13 of this guide referring to the manufacture of IMP.

Slide 26 - Roles of the stakeholders in CTN/CTX

TGA role

  • Process CTN Submission and provide acknowledgement as submitted by Sponsor (or review/approve CTX)
  • Request IB &am; P documents for review
  • Audit and Investigate non-compliance with GCP
  • Stop clinical trials
  • Collate ADR submissions

Approving authority role

  • The institution or organisation at which the trial will be conducted
  • Gives the final approval for the conduct of the trial at the site, having due regard to advice from the HREC.

HREC role

  • Review all material relating to the proposed trial as supplied by trial sponsor
  • Assess the scientific validity of the trial design, the safety and efficacy of the medicine or device, the ethical acceptability of the trial process
  • Approve the trial protocol (CTN)

Principal investigator role

  • Personally supervises the trial at that site
  • Only makes change to protocol with approval by sponsor/HREC
  • Must monitor safety
  • Must comply with record management and reporting requirements for adverse events

Slide 27 - Roles of the Stakeholders

Sponsor role

  • Must be an Australian entity
  • Take overall responsibility for conduct of trial
  • Meets or agrees to meet HREC conditions
  • Ensures persons conducting trial have appropriate training and experience
  • Ensures adequate resources for proper conduct
  • Agrees to report all serious and unexpected adverse reactions to the TGA
  • Generally submits the CTN or CTX to the TGA and provides payment ('client')

Consumer/Participant role

  • Have an in-depth, informed discussion with their primary health care provider and the researchers regarding the risk/benefit of participation
  • Provide informed consent
  • Payment may be required
  • Ask questions and be informed!

Slide 28 - Common issues re developmental drugs/devices

  • Lack of understanding on regulatory issues/requirements
  • Collecting right data for TGA approval
  • Running clinical trials
  • Manufacturing licence
  • Conformity Assessments for medical devices

Slide 29 - TGA does not develop its own clinical guidelines on trial requirements for medicines

  • US FDA and European Medicines Agency develop various guidelines on good clinical practice
  • To assist sponsors and clinical researchers, TGA does endorse a number of the European guidelines for clinical development of different groups of medicines (although references to EU legislation in those guidelines do not apply)
  • TGA is planning to develop clinical guidelines for different types of devices but these will reference international approaches where possible and will not be prescriptive
  • Conduct of clinical trials to International standards of Good Clinical Practice is able to be monitored by TGA - see

Slide 30 - Collecting data

  • Ensuring right information is collected that will allow submission to TGA/FDA/EMA
  • Requires consideration when designing trial
  • Different data to PBAC/MSAC requirements but pre-requisite

Slide 31 - Online submission of CTN / CTX

  • Currently paper driven
  • Re-entered into a database
  • Online process through TGA E-Business portal
  • Will be trialled soon

Slide 32 - Questions?

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