Presentation: NATA TGA IVD Information Session 2 Data requirements and assessment approach - including Companion Diagnostics

Andrew Griffin 

It’s just on 12.30, welcome everyone to the second session we’re hosting on behalf of TGA. Today we have Rebecca Coorey who is a senior evaluator at Device In Vitro Diagnostics Section at TGA, obviously a colleague of Shraddha and Euan’s going to speak on Tuesday next week. So again we have a fair size audience today so we’re not going to take questions live. If you could provide any questions you have to the email addresses shown on Tuesday, and I think, Rebecca you’ve got the email at the end of your presentation. But the preference email is NATATGAIVD@nata.com.au, so if you could send any questions you have to that email address, we will endeavour to answer the questions prior to the meeting on Tuesday. 

We’ve had a number of questions from Tuesday’s presentation which Shraddha, I think she’s answered most of them. There were a couple that need some, had quite complex answers so I think she’s working on getting those directly to the person who asked them.

We will actually provide a frequently asked questions of all of the 3 sessions and it be made available when we provide the 3 session recordings.

TGA will put those on their website, the recordings and I think we’ll do the same so you will have a good opportunity to see these recordings again should you wish.

Again house keeping, this is being recorded as I’ve just said so, just you’ve agreed to that by logging on today.

I think I will now hand over to Rebecca to start and I’ll just fade myself out. Thanks Rebecca. 

COOREY, Rebecca 
Thank you Andy. 
Hi everyone, my name is Rebecca Coorey. Firstly, I would like to acknowledge the traditional owners and custodians of the lands on which we meet today and pay my respects to Elders past and present.

I would like to extend that acknowledgment and respect to any Aboriginal and Torres Strait Islander peoples here today.

In this session, I will be speaking about companion diagnostics, what they are, how they are defined in our Regulations, the regulatory requirements for labs seeking to undertake companion diagnostic testing the assessment approach and data requirements, a case study on a fictional laboratory seeking to accredit a companion diagnostic test, and work we currently have underway for companion diagnostics and in-house IVDs.

So what is a companion diagnostic? An IVD companion diagnostic, or CDx, is an in vitro diagnostic medical device which provides information that is essential for the safe and effective use of a corresponding medicine or biological. 

I would like to draw particular emphasis on the word essential, that is, it must be used with a corresponding medicine or biological.

The term IVD companion diagnostic is defined as follows, it is an IVD medical device or an in-house IVD medical device; and it is intended by its manufacturer to be used for the examination of a specimen from the body of an individual: 

• to identify whether the individual would likely to benefit from the use of a particular medicine or biological; or 

• to identify whether an individual is likely to be at particular risk of a serious adverse reaction to the use of the particular medicine or biological; or 

• to monitor the individual’s response to a particular medicine or biological; and It is mentioned in the product information for the medicine or the instructions for use of a biological as being essential for the safe and effective use of the corresponding medicine or biological; and it is not intended by the manufacturer to be used for the examination of the specimen merely to determine whether the medicine or biological is compatible with the individual. And I will talk a little more around this word, compatible, and what it means in the next slide.

A copy of this presentation will be published after these sessions, and you can visit the TGA website and click on these links for more information.

What medicine or biological indications require companion diagnostic testing?

The Product Information for the medicine or biological must state that CDx testing is essential for the relevant use of the medicine or biological to be safe and effective, and

And the corresponding IVD claims that is intended for the relevant use of the medicine or biological.

This is to ensure that the person prescribing the medicine or the biological is aware that the patient needs companion testing and also for the testing laboratory to be aware of the intended purpose of the IVD.

The wording in the product information or instructions for use are reviewed and determined during the registration process for the medicine or biological.

Medicines and biologicals sponsors are encouraged to use the companion diagnostic testing identification guide to help identify whether a proposed medicine or biological indication requires CDx testing.

So on this slide, you can see a simplified version of this guide, Starting in the top left

Is the IVD essential for the safe and effective use of the medicine/biological? If the answer is no or the patient population may show some benefit, then no CDx testing is required. If the answer is yes, that is testing is essential, then we proceed to ask

Is the purpose of the testing solely to determine cell or tissue compatibility?

We’ve had frequent enquiries around this term of compatibility from IVD manufacturers, which we intend to further clarify in our next round of guidance updates to be published on our web site, but in short Compatibility here refers to tests to determine ABO compatibility for blood transfusions or HLA testing for organ transplantation.

If the test’s sole purpose is to determine cell or tissue compatibility, then no CDx testing is required, but if it is not the sole purpose, then we ask Was the testing that was used to generate the pivotal clinical data consistent with mainstream pathology testing in Australia?

The intention here is to rule out mainstream pathology tests that are core laboratory assays, that are well established tests with widespread and extensive usage experience across Australia, such that inter testing variability is unlikely to be clinically meaningful, and to rule out tests which, for which standardised reference material is readily available to ensure consistent performance, such that the results of testing are generally interchangeable. 

Examples of such testing that are not considered CDx include serum gentamicin level, full blood count, liver function tests or INR for patients undergoing warfarin therapy.

If the medicine does not use mainstream tests, then CDx testing is required. If it is a mainstream test, we ask

Is there confidence that use of standard-of-care local Australian testing in conjunction with the medicine or biological would result in comparable clinical outcome to those seen in the clinical trial?

If the answer is yes, no CDx testing is required. If the testing has a high level of variability or utilise biomarkers with heterogeneity or is a mainstream test used in a novel way, then the reduction in confidence means that CDx testing will be required.

What are the regulatory requirements for CDx?

All companion diagnostics are Class 3 IVDs or class 3 in-house IVDs. Prior to the introduction of the new CDx regulations, commercial CDx IVDs could be included in the Australian Register of Therapeutic Goods under the same ARTG number as Class 3 IVDs in this concept we have known as devices of a kind. The ARTG would not include the name of the CDx device which meant we could not retrieve this information quickly or easily.

What the new CDx regulations require is a separate ARTG inclusion for each CDx IVD, with a Unique Product Identifier, and a functional description of the device that is displayed on the ARTG certificate and public summary.

Any new CDx applications submitted after 1st of February 2020 must have complied with these Regulations, Existing companion diagnostic IVDs supplied as devices of kind can still continue to be supplied and have until 26^th May 2026 to transition into the new Regulations.

For commercial CDx IVDs, our preference is to receive concurrent applications for the medicine or biological and the CDx IVD, however, this is not always possible so we have allowed medicines and biologicals to be registered first provided there is a plan in place to allow access to testing.

Class 1 to 3 in house IVDs do not require inclusion in the ARTG, however, they still need to meet the requirements for exemption which were covered in Session 1 of this series, including accreditation by a national accreditation body such as NATA and to meet the NPAAC standard for in-house IVDs.

Laboratories need to identify their in-house CDx IVDs in the test list they provide to TGA as part of the notification process, and this will be detailed in next Tuesday’s presentation, Session 3.

Another requirement which was mentioned in session 1 was compliance with the Essential Principles.

The Essential Principles are safety and performance requirements for medical devices, including in vitro diagnostic devices.

Laboratories must at all times have information available to demonstrate compliance with the Essential Principles and as part of the in-house notification form that labs submit to the TGA, it requires the laboratory to certify that IVDs complies with the EPs.

Practically though, NATA does not audit for compliance with the EPs during accreditation process, rather compliance with the NPAAC standard for in-house IVDs will be taken as compliance with the relevant essential principles for the safety and performance of an in-house IVD medical device, and this is because they do align to a certain extent.

This is a quick overview of the Essential Principles. The detail required for compliance with each EP can be found in this handy checklist for medical devices available on the TGA website.

While not every EP is applicable to IVDs, there are six general Essential Principles that apply to all devices relating to health and safety, including long-term safety, and benefits outweighing the risks. A further nine Essential Principles about design and construction that apply to devices on a case-by-case basis. And for those of you who have quickly browsed to the end of this list will have noticed that EP 15 is only applicable to IVDs.

The assessment approach taken for Class 1 to 3 in-house IVDs involves audits by NATA, with TGA assistance as required. NATA will assess the laboratory’s QMS against ISO 15189 or 17025. Technical documentation will be reviewed by NATA inspectors as part of laboratory accreditation, but the Medical Devices Regulations also allow the TGA to request this documentation at any time.

The level of rigour for the review of selected Class 1-3 in-house IVDs will be commensurate with their risk class, that is, the higher risk Class 3 in-house IVDs will be subject to greater scrutiny than lower class, lower risk Class 1 in-house IVDs.

The memorandum of understanding which you heard about in the first session, allows information sharing and allows NATA to request assessors from the TGA to assist with audits, and this is typically in the form of desktop reviews of the information provided by the laboratory. And of course, subject to agreement from the lab.

In terms of in-house companion diagnostics tests, the approach is similar to any Class 3 in house tests but with a few caveats. The most important thing to keep in mind is that the medicine or biological determines the requirement for companion testing.

The IVD or the test is often developed by a different organisation to those involved in the development of the medicine or biological.

When we received an application for a commercial CDx IVD, the first check point is to ensure there is a concurrent submission for the relevant indication of the medicine or biological. And this is the same for in-house CDx IVDs that apply for accreditation with NATA.

If there is no concurrent application and the medicine or biological has already been included in the ARTG, it would have been included with an appropriate companion testing plan that provides the details of the laboratory who will conduct the testing using their in-house CDx.

A companion testing plan is information provided by the sponsor of the medicine or biological and details how Australian patients are supposed to access the companion test once the medicine or biological is approved.

It can be details of the application they’ve submitted for ARTG inclusion of a commercial test, it can be the name of the laboratory that’s about to be accredited to perform the test, or it can be details of an overseas’ test that is an interim solution while they explore their options to bring the test onshore.

The purpose of the companion testing plan is to provide reassurance that there is access to at least one adequate IVD for companion testing and to ensure the Australian patients can be treated for that indication safely and effectively.

The intended purpose for the in-house CDx must align with the approved indication for the medicine or biological.

The Product Information for a medicine will include a CDx flag statement in line with the following for all new indications that require CDx testing and it will look something like For safe and effective use of pembro to treat non small cell lung carcinoma, testing of formalin fixed paraffin embedded samples to detect the expression of PD-L1 is essential. Testing used in clinical practice should be adequately comparable to the testing used in the pivotal studies.

For the corresponding in-house CDx test, the intended use statement must include:

selection of patients for treatment with a particular medicine or biological; or monitoring of patients who are being treated with a particular medicine or biological; or both depending on the intended use of the assay.

For example, The PD-L1 assay intended to be used as a companion diagnostic to be ordered by Australian medical oncologists to identify non small cell carcinoma patients with PD-L1 expression, who may benefit from treatment with pembro in combination with standard therapy.

We verify that the intended use statement aligns with the indication of the medicine and does not extend beyond the indication approved for use in Australia.

The data requirements that a lab must provide for accreditation of CDx test are listed in the NPAAC standard for in house IVDs which include the particular requirements that are listed here. I’ve placed in brackets some of the equivalent EPs that are applicable in the commercial IVD space.

The next few slides will focus on the clinical and analytical performance requirements for companion diagnostics.

There are several scenarios when it comes to the accreditation or registration of a CDx. One, the Proposed CDx is the original CDx that is the same as the clinical trial assay. Two, The Proposed CDx is the transfer of the clinical trial assay to an Australian laboratory Or three, the laboratory seeks to develop their own in-house IVD for use as a proposed CDx.

We have used the term subsequent CDx to describe any CDx that is not the original test used in the clinical trial assay. In other regulatory jurisdictions, some of these are referred to as “follow-on” CDx but follow-on CDx has a very specific definition in the US and we decided not to adopt this term as it caused confusion among the commercial CDx manufacturers.

In these scenarios, we expect that the clinical studies are well-designed. Aspects such as the prevalence of the target analytes, the statistical confidence and the adequate characterisation of all samples included in the study must have been considered.

For subsequent CDx IVDs, testing laboratory needs to demonstrate substantial equivalence of the subsequent IVD with the original CDx used in the clinical trial assay.

And what does this substantial equivalence entail? So it would require a bridging study or studies to show a high level of agreement in the clinical performance of the clinical trial assay and new CDx. Specimens used in the bridging studies should be representative of those tested in the original pivotal clinical trials.

Ideally, re-testing of the original clinical trial specimens with the new CDx to demonstrate a high agreement in the results, although we acknowledge that this is not always possible.

And it must include analytical, clinical sensitivity and specificity as well as positive and negative predictive values must be available for the relevant condition, as per the NPAAC particular requirements.

Some additional considerations, all the specimen types claimed to be used with the device must be included in the clinical study. It is not acceptable to use specimen equivalence to leverage specimen type claims especially if the samples are contrived.

For example, a test that makes claims for use with plasma and capillary blood cannot only have plasma samples as a specimen type in the clinical study.

As technology advances, NGS tests and panels are going to become more commonplace, a few considerations for clinical validation of NGS tests include clear documentation of the end to end workflow, use of automated extraction methods,

details of the instruments, platforms and any associated software, details of the bioinformatic workflow or interpretative software used, details of the comparator method, acceptance criteria for sequencing quality metrics whether it’s at the sample, variant or flow cell level. And any prescribe, prespecified clinical cut off used to enrol the patients into the clinical study.

We are well aware that software is another hot topic that we unfortunately haven’t covered in this series but the TGA is exploring the possibility of bringing you another information session in collaboration with NATA on software regulation and software IVDs.

In terms of analytical performance requirements for CDx, the TGA requires studies to demonstrate claims for Specimen stability, especially for those that require cold storage and transport. Specimen equivalence, not to be confused with specimen equivalence in the clinical study which is a separate requirement, a single specimen type can be accepted in analytical studies provided specimen equivalence is demonstrated. Sensitivity including limit of detection, limit of blank, limit of quantitation as appropriate. Assay cut off values or decision points for an assay, which is particularly important to those drug monitoring companion diagnostic tests.

Specificity including interference, cross-reactivity, inclusivity, any Hook Effect or prozoning, linearity or measuring range, precision, and accuracy.

Quality control material including reference materials or internal standards utilised. And If it is a semi- quantitative or quantitative assay, calibration material must be available and expressed in acceptable or transferable units of measurement.

In the next couple of slides I will run through a fictional scenario of a laboratory seeking accreditation for an in-house CDx.

So Aussie Lab decides to adapt a Research Use Only (RUO) product to develop a subsequent CDx IVD intended to be used as an aid in selecting patients whose melanoma tumours carry BRAF V600 mutations, for treatment with medicinemab.

Aussie Lab has entered into an agreement with the sponsor of medicinemab to provide CDx testing for Australian patients. The medicine’s sponsor has already included the medicine in the ARTG with a companion testing plan that uses the clinical trial assay to test Australian patients in an overseas laboratory as an interim solution. Now they want to bring testing onshore.

Aussie Lab proposes to take an RUO product, a nucleic acid amplification test that can detect BRAF mutations and validate the test for use as a subsequent CDx in-house IVD. Aussie Lab must conduct the appropriate clinical and analytical validation studies to demonstrate that the subsequent CDx is substantially equivalent to the clinical trial assay, while complying with NPAAC standards and the EPs.

In conducting the clinical studies, the medicine’s sponsor provides access to some of the specimens used in the clinical trial assay. However, the samples numbers are not statistically significant. Aussie Lab must conduct an additional bridging study using specimens representative of those tested in the clinical trial assay from Australian patients, that is patients with melanoma carrying BRAF V600 mutations, and confirm agreement by testing these additional samples using the original CDx.

Aussie Lab also conducts all the necessary analytical validation, including specimen stability for the intended tissue type of formalin fixed paraffin embedded tissues, limit of detection for the assay expressed as copies/ml, assay cut off expressed as Ct values, inclusivity analysis of the primer and probe sequences for BRAF, repeatability and reproducibility, accuracy, and validation of the control materials included as part of the RUO kit.

The results of the clinical and analytical validation demonstrate that the subsequent CDx is substantially equivalent to the clinical trial assay, and so Aussie Lab applies to have the test NATA accredited under the category of Molecular genetics - Companion diagnostic genetic testing.

Aussie Labs are audited by NATA with the assistance of TGA’s NATA assessors and receive accreditation to performance companion diagnostic testing for medicinemab. They must also meet their regulatory obligations by notifying the TGA by the 1 July of that year of their new CDx test and to maintain documentation related to post-approval activities and report any adverse events.

TGA has work underway to publish a list of all companion diagnostic tests approved under the new Regulations. Initially the list will include only commercial CDx IVDs with the intention of adding in-house CDx IVDs in the near future.

We have also updated the guidance for companion diagnostics which has undergone internal and target external stakeholder consultation and is about to be released for public consultation soon. We strongly encourage labs to review these updates and provide feedback into this public consultation.

There will be updates to the guidance for Regulatory requirements for in-house IVDs as well, which ties in with next Tuesday’s session on the Introduction of new the In-house IVD notification form. We hope that you will join us for this session.

Please submit questions you have about any of the sessions so far to either the NATA TGA IVD email or the IVDs inbox. I hope you have found this session informative, thank you for joining us today.

Andrew Griffin   29:40
Thank you, Rebecca. That was great. Lots of information there so I’m sure you’ll get a lot of questions. Really interesting thank you and we’re close to 150 people so that’s a really good turn out again.

So again, thank you to you Rebecca, thank you to everyone for joining us today, and please send your questions to those email addresses and we’ll try and answer them as soon as we can. And I’ll see you all hopefully on Tuesday at the same time. Thank you and we’ll close the session now.