The Biologicals Regulatory Framework was implemented to fill a regulatory gap in the regulation of cellular and tissue-based therapies. However, whether a product falls within the Framework can be a complex question.

Introduction

On 31 May 2011, the TGA implemented the Biologicals Regulatory Framework to assess and regulate human cell and tissuebased products as a distinct category of therapeutic goods called “Biologicals”.

Before the introduction of the Biologicals Regulatory Framework, cell and tissue products were either:

  • not regulated
  • regulated as medicines or medical devices, or
  • exempt from application of specific parts of the Therapeutic Goods Act 1989 (TG Act) (example: banked tissue may be exempt from the requirements for entry in the Australian Register of Therapeutic Goods, but may still be subject to compliance with other parts of the TG Act, including compliance with manufacturing principles).

This trichotomy in the regulation of biological products has formed the basis of the current Biologicals Regulatory Framework. The new framework is intended to provide more clarity and more effective regulation by applying different levels of pre-market requirements for biologicals based on the risks associated with their use, much like the regulatory classification system now in force for medical devices. Whilst the Biologicals Regulatory Framework is still in its early days, teething problems are surfacing and there is no doubt that on-going review of the framework will improve its operation and its clarity.

Currently, whether a product indeed falls into the Biologicals Regulatory Framework is a complex question. In this article, we examine some of the issues that can potentially arise when considering whether a product is regulated as a biological.

What is a Biological?

The definition of a “biological” is found in section 32A of the TG Act to mean a “thing” that:

  • either:
    • comprises, contains or is derived from human cells or human tissues, or
    • is specified by the Secretary by legislative instrument, and
  • is represented in any way to be, or is, whether because of the way in which it is presented or for any other reason, likely to be taken to be:
    • for use in the treatment or prevention of a disease, ailment, defect or injury affecting persons
    • for use in making a medical diagnosis of the condition of a person
    • for use in influencing, inhibiting or modifying a physiological process in persons
    • for use in testing the susceptibility of persons to a disease or ailment, or
    • for use in the replacement or modification of parts of the anatomy in persons.

Under section 32A(3) of the TG Act, the Secretary may also determine, by legislative instrument, that a specified “thing” is not a “biological”.

Therefore, in summary, for a “thing” to be a biological, it must:

  • be a therapeutic good (as defined in the TG Act)
  • not be an ‘excluded good’
  • either meet the definition of a biological or be specified by legislative instrument to be a biological, and
  • not be specified as a “thing” that is not a biological’.

‘Excluded Goods’

The Secretary may, by legislative instrument, declare that products are not therapeutic goods even though they fall within the definition of a therapeutic good having regard to their use. These products are ‘Excluded Goods’ and are therefore not regulated by the TGA. Excluded Goods are specified in the Therapeutic Goods (Excluded Goods) Order No. 1 of 2011. It excludes, for example, human tissue and cells for autologous use and fresh viable human organs for direct donor-to-host transplantation from therapeutic goods regulation. It is possible, therefore, that a biological will be deemed to be an excluded good, and therefore not subject to regulation by the TGA, by virtue of its use.

Therapeutic Goods that are not Biologicals

The legislation also allows the Secretary to declare, again by legislative instrument, that specific therapeutic goods are not biologicals. Such products are specified in the Therapeutic Goods (Things that are not Biologicals) Determination No.1 of 2011. Therapeutic goods declared not to be a biological are regulated by the TGA as either a medicine or a medical device.

Interestingly, blood and blood components such as red cells, white cells, progenitor cells, platelets and plasma, have been declared to not be ‘biologicals’ but are regulated as medicines1 even though blood and blood products are not generally included in the Australian Register of Therapeutic Goods. Instead, blood and blood components are regulated through the audit and licensing of manufacturers to ensure compliance with product standards and Good Manufacturing Practice requirements.2

Therefore it is important to check the Determination and seek advice as to whether your product falls under the purview of the TGA and what requirements are applicable.

Problematic regulation

The Biologicals Regulatory Framework is complex. Understandably, in an industry of rapid and emerging technologies, it is difficult to implement a regulatory framework that is all-encompassing and yet flexible enough to accommodate the dynamic nature of the sector. Whilst this means it is difficult for the Regulator to develop and implement policies in a timely manner, it can also lead to confusion for Sponsors.

Having an overarching definition of “Biologicals” and including/excluding products by legislative instrument as they are developed can be quite problematic as the types of products included/excluded in the Biologicals Regulatory Framework may change over time.

From an historical legislative point of view, the trichotomoy is clear. However, in practice, there is a fine line between what constitutes a biological, what is an Excluded Good and what is a therapeutic good but not a biological.

The complexities of the Biologicals Regulatory Framework can be illustrated by the following case study on haematopoietic progenitor cells.

Haematopoietic Progenitor Cells - A case study

Human cellular therapy products such as stem cells and progenitor cells, other human cell-based products such as fibroblasts, epithelial cells, chondrocytes, immunotherapy products such as cellbased tumour vaccines and human cellular vaccines and genetically modified cells fall within the definition of a ‘biological’ because they “comprise, contain or are derived from human cells or tissues” and are put to therapeutic uses.

At first glance, haematopoietic progenitor cells, which are stem cells found in blood which are capable of forming various blood cells, should be regulated as biologicals.

However, regard must be had to the Therapeutic Goods (Excluded Goods) Order No. 1 of 2011 where clause 4(p) declares that “fresh viable human haematopoietic progenitor cells for direct donor-to-host transplantation for the purpose of haematopoietic reconstitution” are not therapeutic goods and are, therefore, not regulated by the TGA.

A further complicating factor is that clause 3(a) of the Therapeutic Goods (Things that are not Biologicals) Determination No.

1 of 2011 states that “haematopoietic progenitor cells used for haematopoietic reconstitution” are therapeutic goods that are not biologicals.

It is easy to see the confusion that sponsors can encounter when trying to determine the appropriate regulatory regime for their product. Without experience and understanding of the historical background to the Biologicals Regulatory Framework, such conundrums are hard to resolve.

The distinction between the haematopoietic progenitor cells that are biologicals, those that are Excluded Goods and those that are therapeutic goods but not biologicals is not immediately clear. The intended use of the haematopoietic progenitor cells plays a central role in its classification. Haematopoietic progenitor cells that are used for purposes other than for blood reconstitution could be regulated under the Biologicals Regulatory Framework. However, there is a finer distinction between haematopoietic progenitor cells that are excluded from the therapeutic goods regulatory regime and those that are not biologicals but are regulated as therapeutic goods.

What this clearly demonstrates is the importance of identifying the indication and the extent that the haematopoietic progenitor cells have been manipulated in order to properly determine the appropriate regulatory framework which applies. It illustrates the potential complexities involved in classifying products that could fall under the Biologicals Regulatory Framework.

Conclusion

The case study above illustrates the legal and technical minefield which exists in navigating through the Biologicals Regulatory Framework. Although the framework has been structured to ensure flexibility in the context of an ever-changing area of research and technology, such flexibility seems to have come at a cost of clarity for Sponsors.

Companies are encouraged to seek advice regarding the regulation of their products to avoid incurring unnecessary expense in satisfying the regulatory requirements for supply in Australia.