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Australian clinical trial handbook

Guidance on conducting clinical trials in Australia using ‘unapproved’ therapeutic goods

12 October 2018

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Manufacturing

Trial sponsors undertake the ultimate responsibility for all aspects of the clinical trial including the quality of investigational products.

Different parts of the Therapeutic Goods Act 1989 apply to the manufacture of medicines, biologicals and other therapeutic goods (Part 3-3 of Chapter 3) and to the manufacture of medical devices (Part 4-3 of Chapter 4). In addition, manufacturers must comply with any relevant state and territory legislation.

Manufacturing medicines and biologicals for use in a clinical trial

Manufacture in Australia

Australian facilities participating in the manufacture of a medicine or biological for use in a clinical trial must hold a manufacturing licence issued by us. However, certain persons or goods are exempt from this requirement.

Even if a pilot facility is dedicated for the development of dosage forms and new products, and is not used for the manufacture of saleable product, it is still subject to inspection and licencing by us unless an exemption applies.

Manufacturers need to comply with:

Further information regarding obtaining a manufacturing licence can be found at Australian manufacturing licences and overseas GMP certification.

Manufacturing principles

Good manufacturing practice (GMP) is applied to the manufacture of investigational medicinal products or investigational biologicals to ensure those products are fit for their intended use and do not place participants at risk due to inadequate quality, safety or efficacy.

Section 5.13.1 of the Guideline for Good Clinical Practice states that the trial sponsor must ensure that investigational products, including active comparators and placebo, are manufactured in accordance with any 'applicable GMP'. The applicable GMP in Australia is specified in the current Therapeutic Goods (Manufacturing Principles) Determinations. These principles require manufacturers to demonstrate that manufacturing practices comply with a relevant code of GMP. There are different codes of GMP depending on the type of therapeutic good:

  • Medicines; and biologicals that comprise or contain live animal cells, tissues or organs (PIC/S Guide to Good Manufacturing Practice for Medicinal Products)
    • Part I of the PIC/S Guide to Good Manufacturing Practice for Medicinal Products applies to the manufacture of finished investigational medicinal products (including placebos):
      • In particular, Annex 13 of the PIC/S Guide to Good Manufacturing Practice for Medicinal Products specifically applies to the manufacture of investigational medicinal products that are required to comply with the manufacturing principles. Note: refer to Annex 13 for information regarding when reconstitution is not subject to manufacturing authorisation.
    • Part II of the PIC/S Guide to Good Manufacturing Practice for Medicinal Products applies to the manufacture of active pharmaceutical ingredients:
      • Section 19 outlines the GMP requirements that apply to the manufacture of active pharmaceutical ingredients for use in clinical trials.
    • The Annexes of the PIC/S Guide to Good Manufacturing Practice for Medicinal Products may also apply where relevant to the specific manufacturing operations. For example, Annex 1 applies to the manufacture of sterile products and active pharmaceutical ingredients.
  • Human blood, blood components, haematopoietic progenitor cells (HPCs) and biologicals that comprise, contain or are derived from human cells and tissues (The Australian Code of Good Manufacturing Practice for Blood and Blood Components, Human Tissues and Human Cellular Therapy Products)

PIC/S has also published an Aide-Memoire on GMP particularities for clinical trial products (PI 021-2) in 2007, which acknowledges that investigational medicinal products should be produced in accordance with the principles and guidelines of GMP for medicinal products. This also notes that there may be added risks to participants compared to patients treated with 'marketed' products.

Departure from Annex 13

In exceptional circumstances it may not be possible to meet the requirements of Annex 13 of the PIC/S Guide to Good Manufacturing Practice for Medicinal Products for labelling investigational products. In this case, the trial sponsor must contact us if they wish to request a departure from the requirements of Annex 13. Subclause 3 of the Therapeutic Goods (Manufacturing Principles) Determination 2018 provides the criteria that we must be satisfied with if an alternative procedure to the procedure or requirement set out in the PIC/S Guide to Good Manufacturing Practice for Medicinal Products is adopted.

The PIC/S Guide to Good Manufacturing Practice for medicinal products recognises that there are acceptable methods, other than those described in the guides that are capable of achieving the principles of GMP established in the guides. The trial sponsor may choose to use an alternate method if a risk assessment demonstrates that the alternative approach provides the same or greater quality and safety. However, a formal risk management plan must be documented and included with the trial documentation if the requirements are not met. Annex 20 of the PIC/S Guide to Good Manufacturing Practice for Medicinal Products outlines approaches to be used and tools which a trial sponsor may choose to use when applying a formal quality risk management approach.

Manufacture overseas

We are unable to enforce GMP standards applicable in Australia to the manufacture of investigational products in another country. Therefore, we recommend that the trial sponsor ensures that they have a thorough understanding of the principles of GMP and ensure that the manufacture of medicines and biologicals for use in clinical trials is in accordance with the principles of GMP. We recommend that the trial sponsor ensures that the GMP licensing for other countries adheres to the principles of GMP as set out in the PIC/S Guide for Good Manufacturing Practice for Medicinal Products or the Australian code of Good Manufacturing Practice for blood and blood components, human tissues and human cellular therapy products in order to assess the quality of the product.

Labelling medicines

The labelling therapeutic goods orders TGO 69, TGO 91 and TGO 92 do not apply to investigational medicinal products. Instead, labelling requirements are specified in Annex 13 of the PIC/S Guide to Good Manufacturing Practice for Medicinal Products. This document outlines the information to be included on labels, unless its absence can be justified, for example, use of a centralised electronic randomisation system.

Complete details on primary and secondary packaging and labelling requirements can be found in Annex 13 of the PIC/S Guide to Good Manufacturing Practice for Medicinal Products. However, some items have been discussed further below.

Notes on clauses in Annex 13
Clause Notes
26(a) The main contact details for information on the product, clinical trial and emergency unblinding must be an Australian contact.
26(b) For closed blinded trials, the labelling should include a statement indicating “placebo or [name/identifier] + [strength/potency]”.
26(d) The trial reference code used should identify the particular trial site, unless provided elsewhere or its absence can be justified. This is the case even for trials involving multiple sites.
26(d) The trial reference code used should identify the Australian trial sponsor, unless provided as the main contact (clause 26(a)) or its absence can be justified. It is not sufficient to identify only an overseas trial sponsor in the case of a multinational trial.
26(f) The name of the principal investigator should appear on the label unless already included in a trial reference code or unless its absence can be justified.
27 Allows for a participant to be provided a leaflet or card that contains the address and telephone number of the main contact for information on the product, clinical trial and for emergency unblinding. The participant must be instructed to keep this in their possession at all times.
32 'Certain characteristics' refers to non-commercial clinical trials performed by researchers without the participation of the pharmaceutical industry. These trials are often performed with registered (or listed) products that are obtained from the market for use in a clinical trial. The requirements in this clause relate to the way these products are to be labelled.
33 We do not allow labels to omit an expiry, use-by or re-test date. Trial sponsors must comply with the requirements of this clause.

Labelling is a manufacturing step under the Therapeutic Goods Act 1989. However, an exemption from the requirement to hold a manufacturing licence may apply to certain persons identified within Schedule 8 of the Therapeutic Goods Regulations 1990, to allow relabelling of the investigational medicinal product with name and address of the new sponsor. See Manufacturing exemptions.

If there is a change of Australian trial sponsor, the clinical trial medication should be re-labelled appropriately with the details of the new trial sponsor at the time of transfer.

Labelling and centralised electronic randomisation systems

The labelling requirements of Annex 13 of the PIC/S Guide to Good Manufacturing Practice for Medicinal Products must generally be met, however, certain information may be omitted from the label where centralised electronic randomisation systems (CERS) are used.

When CERS are used, and investigational medicinal products are:

  • distributed to participants to administer at home, the label should contain:
    • sufficient information so that any person can readily identify the product if required (such as in an emergency), and
    • the main contact for product information, clinical trial and emergency unblinding, and
    • directions for use, and
    • storage conditions and expiry, use-by or re-test date
  • administered by dedicated trial staff and no additional investigational medicinal product is retained by participants, it may be possible to:
    • omit information (except the expiry date) from the labels in a readable format, provided that alternative means of accessing, verifying and retaining relevant information is provided by the CERS.

The decision to omit certain information should be made according to risk management principles and information should be checked immediately before administering the investigational medicinal product.

Labelling biologicals

Investigational biologicals must comply with the labelling requirements set out in the Australian Code of Good Manufacturing Practice for Blood and Blood Components, Human Tissues and Human Cellular Therapy Products. The exception is biologicals that comprise or contain live animal cells, tissues or organs, which must comply with Annex 13 of the PIC/S Guide to Good Manufacturing Practice for Medicinal Products.

Manufacturing medical devices for use in a clinical trial

There are no specific requirements prescribed in the Therapeutic Goods (Medical Devices) Regulations 2002 for the manufacture of investigational medical devices for use in clinical investigations, other than those that are incidental to the demonstration of compliance with the Essential Principles in relation to the construction of the device.

For medical devices, the mechanism for a manufacturer to apply a conformity assessment procedure has been defined for an investigational device under Regulation 3.10 of the Therapeutic Goods (Medical Devices) Regulations 2002. However, there is currently no requirement in the special conformity assessment procedures (Part 7 of Schedule 3 to the Therapeutic Goods (Medical Devices) Regulations 2002) for the manufacturer of such a device to apply a quality management system.

In practice, the regulation of the manufacture of medical devices is implemented by:

  1. the application of ISO 13485 – Medical Devices, Quality Management Systems Requirements for Regulatory Purposes, and
  2. certification by an independent third party

Manufacturing records and evidence of compliance

We acknowledge that a start-up medical device company may not yet have received third party certification for their quality management system at the time they are ready to start early pilot studies of their product.

However, it is expected that design, development, control of raw materials, environmental controls, quality controls and record keeping in the manufacture of medical devices for investigational purposes is conducted in accordance with the requirements of this standard; and that the manufacturer is actively preparing for certification.

An established medical device company that is manufacturing investigational medical devices should already have the appropriate conformity assessment certification, which includes the requirements of ISO 13485. We recommend that the manufacture of invasive investigational medical devices is undertaken by a certified manufacturer.

Sponsors of 'unapproved' medical devices that are intended for use in a clinical trial should ensure that the manufacturer of the medical device has evidence to substantiate compliance with the Essential Principles, that are relevant to their medical device, and may be found in Schedule 1 to the Therapeutic Goods (Medical Devices) Regulations 2002 (apart from those aspects of the Essential Principles that require the generation of clinical evidence). Evidence of compliance should be documented and available for review by those that have a role in the approval of the clinical trial (for example, the HREC).

Although a quality management system is not strictly required for the manufacture of an investigational medical device, some aspects related to the manufacturing (construction) of medical devices are specified in the Essential Principles. Evidence supporting compliance must be available prior to use in a clinical trial.

Technical documentation

In addition to the manufacturing records for the investigational medical device, a technical file, or design dossier, should be established for this purpose. As a general guide, the technical documentation that is held in this file by the manufacturer should include:

  • a general description of the medical device
  • the intended purpose of the medical device
  • drawings of the design of the medical device, including components, subassemblies or circuits
  • descriptions or explanations that are necessary to understand the drawings of the medical device and its intended purpose
  • a statement indicating whether or not the medical device incorporates, or is intended to incorporate, as an integral part, a substance that may be considered to be a medicine
  • a statement indicating whether or not the medical device, other than an IVD medical device, contains tissues, cells or substances of animal origin that have been rendered non-viable, or tissues, cells or substances of microbial or recombinant origin
  • for an IVD medical device - a statement indicating whether or not the device contains viable tissues, cells, or substances of human or animal origin
  • a description of any sterilisation processes used in the manufacture of the medical device
  • details of any standards used in relation to the manufacture of the medical device
  • design calculations, risk analyses and technical tests or any other investigations carried out on the medical device to establish compliance with the relevant Essential Principles
  • where the medical device is to be used in conjunction with (for example, connected to) other medical devices, results of tests demonstrating the safety and performance of each medical device is acceptable
  • a copy of the information to be provided with the medical device

The Essential Principles checklist is a useful tool when preparing a cross-reference or index to the evidence of compliance. There are many international standards relevant to the design, testing and manufacture of medical devices that are commonly applied to demonstrate compliance with the Essential Principles. Due to the alignment of Australian medical device requirements with those of Europe, the European harmonised standards for medical devices may be used as a reference.

Labelling medical devices

The requirements for medical device labelling are specified in clause 13.3 of Schedule 1 to the Therapeutic Goods (Medical Devices) Regulations 2002 (Essential Principles information to be provided with a medical device). This includes investigational devices.

The ISO 14155 states that the investigational device, the instructions for use or the packaging should indicate that the investigational device is exclusively for use in a clinical investigation.

Some of the principles outlined in Annex 13 of the PIC/S Guide for Good Manufacturing Practice for Medicinal Products, may also have relevance to investigational medical device labelling.

Manufacturing exemptions

Manufacturing exemptions for medicines and biologicals

Certain exemptions from Part 3 of Chapter 3 of the Therapeutic Goods Act 1989 are outlined below.

Therapeutic goods that are not medical devices and are manufactured in Australia may only be manufactured by persons who are licensed to manufacture (or to carry out a step in the manufacture of such goods at licensed premises) unless either the goods or the person responsible for the manufacture are identified in the legislation to be exempt.

The Guideline for Good Clinical Practice states that the trial sponsor should ensure that investigational products are manufactured in accordance with any 'applicable GMP' (see Manufacturing principles above). Therefore, we still recommend compliance with the principles of the PIC/S Guide to Good Manufacturing Practice for Medicinal Products (in particular Annex 13) and the Australian Code of Good Manufacturing Practice for Blood and Blood Components, Human Tissues and Human Cellular Therapy Products where an exemption applies.

Trial sponsors should ensure that they have thorough understanding of the principles of GMP in order to assess the quality of the therapeutic goods used in the trial. GMP compliance of the manufacturer is recommended to support the acceptance of clinical trial data overseas. We recommend the trial sponsor seeks independent legal advice to ensure compliance with the legislation. This may include the applicable legislation of the jurisdictions in which the trial material is used.

Therapeutic goods exempt from the operation of Part 3-3 of the Therapeutic Goods Act 1989 include:

  • goods prepared for the initial experimental studies in human volunteers as specified in item 1, Schedule 7 to the Therapeutic Goods Regulations 1990

Refer to Schedule 7 of the Therapeutic Goods Regulations 1990 for the full list of exemptions.

In practice, initial experimental studies in human volunteers means first-in-human trials. This will generally, but not always, be phase 0 and I trials (human pharmacology trials).

No such exemption exists for therapeutic goods used in other phase studies. Therefore, the manufacture of all other investigational medicinal products and biologicals in Australia is subject to inspection and licensing by us (unless a separate exemption applies).

Manufacturers of investigational products that are not initial experimental studies in human volunteers must hold a valid TGA licence that specifically authorises that site for the manufacture of clinical trial products in Australia (unless a separate exemption applies).

Persons exempt from the operation of Part 3-3 of the Therapeutic Goods Act 1989 include:

  • pharmacists who manufacture therapeutic goods in a pharmacy where the pharmacist practices and the pharmacy is open to the public and the goods are supplied from those premises and meet the requirements of item 2, Schedule 8 to the Therapeutic Goods Regulations 1990
  • pharmacists employed by a public hospital or public institution who manufacture therapeutic goods for supply in hospitals and public institutions in the same state or territory and meet the requirements of item 3, Schedule 8 to the Therapeutic Goods Regulations 1990
  • a person who applies supplementary labelling to a manufactured product, where the supplementary label contains only a name and address, the registration or listing number of goods, or the biological number of a biological as specified in item 5, Schedule 8 to the Therapeutic Goods Regulations 1990

Refer to Schedule 8 of the Therapeutic Goods Regulations 1990 for the full list of exemptions.

Manufacturing exemptions for medical devices

Full exemption from the penalties for non-compliance with the Essential Principles, is not normally available for any medical device, unless the medical device is for emergency use and has been granted an exemption under section 41GS of the Therapeutic Goods Act 1989.

However it is recognised that compliance with the Essential Principles that require clinical evidence, cannot be demonstrated until the clinical trial has been completed.

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