Following lengthy consultations with industry, Australia’s Therapeutic Goods Administration (TGA) has released its new regulatory framework for in vitro companion diagnostics (IVD CDx) that becomes effective in February.

Until now, Australia did not have a framework for CDx. Rather, the TGA assessed the associated therapy and CDx separately – a situation that did not always permit a comprehensive evaluation of the benefits and risks of using the therapy and device together, the TGA said.

Identified as a priority area given the increase of targeted therapies, the framework is in line with government recommendations to align regulations more closely with the EU, as well as using international regulators’ assessments.

Due to a lack of a clear definition in Australia, the premarket assessment of IVD CDx devices has not been consistent. That inconsistency has resulted in challenges identifying those devices in an application when coordinating assessments, as well as difficulty identifying those devices once they're included on the Australian Register of Therapeutic Goods (ARTG).

The TGA is catching up with the U.S. FDA in the regulation of CDx, and it sought to introduce a legal definition and ensure the appropriate level of premarket scrutiny, said John Skerritt, TGA Health Products Regulation Group deputy secretary.

“The goal was to coordinate the review with the corresponding treatment where possible and to align with other regulators,” Skerritt said.

To that end, the TGA has borrowed definitions from both the FDA and EU to define a CDx as an IVD medical device or an in-house IVD medical device that is intended to be used for examining a specimen to identify whether a person likely would benefit from a particular drug or biologic. A CDx also is defined as a test used to identify whether the person is likely to be at particular risk of a serious adverse reaction to the use of a drug, or to monitor the individual's response to the use of a drug.

As part of the definition, the IVD CDx should be mentioned in the product information for the corresponding drug or biologic as being essential for the safe and effective use of the drug.

In reaction to industry comments, the agency provided additional information to be included in the instructions for use (IFU) of a test to stipulate how the IVD is intended to be used with the corresponding drug. The IFU also should reference the international non-proprietary name (INN) of the corresponding drug, and the TGA provides examples of some approved IFUs to illustrate these requirements.

The framework clarifies that a manufacturer can’t make claims that the IVD is intended for use as a CDx unless the corresponding drug or biologic has been approved in Australia, or there are concurrent applications pending approval for both the CDx and the drug.

The agency said this approach “would allow for collaborative evaluation of clinical evidence by relevant sections of the TGA prior to inclusion of the IVD companion diagnostic on the ARTG, but it does not require concurrent approval dates for the companion diagnostic and the related medicine.”

Once the regulations are implemented fully, references to a “validated test” may no longer be acceptable, the agency said, noting that the product information should point to the “TGA-approved IVD companion diagnostic.”

Classification and transitional arrangements

All IVD CDx will be classified as class III IVDs, including laboratory-developed, or in-house, IVDs. Applications submitted after Jan. 31, 2020, must comply with the new regulations; however, CDx that are included in the ARTG before the commencement date are subject to transitional arrangements, giving sponsors until June 30, 2022, to submit a new application for inclusion in the ARTG.

Transitional arrangements also will apply to IVD CDx that are not included in the ARTG on the Jan. 31, 2020, deadline, but are covered by a current conformity assessment certificate issued by the TGA. Transitional arrangements also will apply to in-house IVDs that are class I, II or III, and will be class III under the new regulations.

Beginning Feb. 1, 2020, new ARTG applications for IVD CDx must feature a separate application for a unique product identifier (UPI) to be included in the ARTG. In this application, sponsors will need to provide a functional description for the device. IVDs also will undergo a mandatory application audit.

Clinical evidence guidelines for IVDs are being drafted, the TGA said, and are expected to be released in early 2020. Since August 2018, the TGA has accepted certification from comparable overseas regulators and assessment bodies as evidence of compliance with conformity assessment procedures.

Since the TGA is aligning its regulatory requirements with the EU and FDA, sponsors may request reductions in audit assessment fees when using evidence from these overseas regulators in their applications. Applications must include the technical assessment report to EU or FDA requirements for these tests.

Certain changes are subject to mandatory audits as well, including a change in the name of the CDx. A change to the intended purpose to detect different biomarkers or additional biomarkers also will trigger a mandatory audit, as will a change to the intended purpose to add a new therapy, specimen or target patient population. The agency said that ideally, an IVD CDx and its corresponding drug should be developed contemporaneously, with the clinical performance of the IVD CDx and suitability of the biomarker established using data from the drug clinical trial. Although not mandated, concurrent submission and assessment of applications for an IVD CDx and the corresponding drug is highly recommended.

Still, the TGA acknowledges that there will be circumstances in which this may not happen, such as when an application is submitted for a new CDx for a drug that has been approved.

Assessment of both the safety and performance of the device and suitability of the biomarker will be carried out collaboratively between the relevant TGA sections. Moreover, the agency stressed that the validity of the clinical claims being made for an IVD CDx cannot be assessed without considering the evaluation of the corresponding drug that will determine whether the use of the IVD is essential for the safe and effective use of the drug. The TGA will publish a list of IVD CDx that have been approved for supply in Australia. The list will include laboratory-developed, or in-house, IVD CDx as well.

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