Section 1 – Context

Page last updated: September 2016

The following information requests are relevant to Part A, Section 1, of a submission to the PBAC.

Details about the biomarker, the test and the medicine

1 (O) Current reimbursement arrangements

Include in Subsection 1.4

Indicate whether the proposed biomarker(s) has been previously accepted as valid by MSAC and the PBAC for the proposed clinical indication (eg validated using another test). Describe current reimbursement arrangements for the test and the medicine.

The response to this item defines whether the submission is integrated or streamlined (see Subsection P4.1).

2 (T) Test sponsor

Include in Subsection 1.1.1 or 1.1.3

Identify the source(s) of the test options (eg commercial sponsor, research laboratory, National Association of Testing Authorities [NATA]-accredited pathology provider, pathology practice). This includes clinical sponsors of tests, given that tests guide both the initiation and cessation of therapy. If a specific test (eg the evidentiary standard; see Item 5) is not specified, this item is not needed.

3 (M) Medicine sponsor

Include in Subsection 1.1.1 or 1.1.3

Identify the sponsor of the medicine. This enables a different sponsor to be identified, if necessary, for each component of the codependent technology.

4 (O) Biomarker

Include in Subsection 1.1.2

Describe the biomarker in a way that is consistent with the proposed MBS item descriptor and to enable differentiation from other possible biomarkers. Additional detail can be provided at Item 8.

The most common type of integrated codependent submission has involved pharmacogenetic technologies assessing genetic DNA biomarkers whereby one genetic locus at a time is evaluated. However, codependent technologies that include genetic panel testing or genomic testing (ie assessment across the genome, testing hundreds or thousands of loci simultaneously) can also be submitted.

5 (T) Proposed test(s)

Include in Subsections 1.1 and 1.4

First describe the evidentiary standard test method (ie the test used in the key evidence supporting the requested listing). Include sufficient detail for a laboratory technician to be able to perform it. If more than one test is proposed or available, then specify the range of techniques used to measure the biomarker (eg polymerase chain reaction, high-resolution melting), and indicate which method, if any, is regarded as the reference or ‘gold standard’ test.

List the other available test options that fall within the scope of the proposed MBS item descriptor. If other test options are available in Australia, or the evidentiary standard test is not available in Australia, then provide a comparison of all available tests for the biomarker that fall within the scope of the requested MBS item descriptor.

Include the proposed MBS item descriptor by modifying Subsection 1.4 to ‘Proposed MBS and PBS listing’.

6 (O) Medical condition or problem being managed

Include in Subsection 1.1.2

Describe the population proposed for testing for the biomarker in terms of what previous tests have been undertaken or what clinical signs are present. Describe whether the proposed population has been enriched in terms of biomarker prevalence.

Issues to consider when judging the value of adopting any enrichment or triaging strategy include:

• the quantified effect on the Australian prevalence of being test positive (and hence on the number of patients who would need to be tested to target treatment)
• the confidence in the clinical diagnosis being able to identify likely patients with the biomarker and to minimise erroneous inclusions and exclusions from the patient pool selected as eligible for the test
• the consequences of misallocation of treatment due to false positive or false negative test results brought about by these erroneous inclusions and exclusions, which can vary across clinical settings – for example, between first-line therapy (where there are effective alternative treatments) and last-line therapy (where there are not)
• the amount of tissue needed to make multiple types of diagnosis when tumour tissue is limited (eg via fine needle aspirate biopsy) and so the need for larger tumour samples or re-sampling has implications for harm to patients and costs to the health care system
• whether the clinical diagnosis itself might also modify the treatment effect, independent of the testing strategy (eg the effect of the proposed medicine might vary according to histology type, in addition to biomarker status).

If different test result thresholds are likely to determine eligibility for the medicine, or if eligibility for the medicine is determined subjectively, consider providing alternative requested PBS listings in Subsection 1.4.

7 (O) Clinical management pathways

Include in Subsection 1.2

Describe and compare the proposed clinical management of a typical patient up to the point of being offered the proposed test and subsequent therapy with the proposed medicine, as compared with the currently existing clinical pathway(s) where the proposed test and/or medicine is not available.

Ensure that the clinical management pathways outline all alternative tests/test strategies (whether the tests occur in series or concurrently) and all alternative treatments (including nonmedicine treatments) for the target clinical indication, both with and without knowledge of the patient’s biomarker status.

Identify tests and treatments that are commonly used and likely to be supplemented or replaced by the codependent technologies (see Item 14).

If it is important for patients with a rapidly progressive disease or condition to ensure that a timely test result is available to determine eligibility for the medicine, indicate whether the test is likely to be performed earlier in disease or condition progression than currently (also see Item 12).

The nomination of when to test compared with when to treat can be influenced by many factors, including:

• the urgency of knowing the test result to inform the start of medicine therapy
• the costs of block retrieval and costs (and patient harms) of obtaining new samples
• the confidence that the sample or previously obtained test result represents the status of the patient at the time of deciding which treatment to start (eg the stability of a mutation over time or in response to previous treatment, or between the primary tumour and metastatic disease)
• the clinical and cost-effectiveness consequences of misallocation of treatment due to false positive or false negative conclusions based on changes in mutation status.

A ‘no testing’ pathway and dealing with data scarcity

To demonstrate the test’s impact on patient health outcomes, indicate a pathway where testing for the biomarker is not undertaken. Then estimate the effectiveness (and cost-effectiveness) of the medicine using the economic model both with and without use of the test (see Item 37). This approach is requested because it may be more cost-effective to provide the medicine without the test if the test has poor accuracy and/or the medical condition is prevalent.

Because data are often scarce, the aim of codependent technology evaluation is to maximise the use of the available evidence on the two technologies. If the effect of the medicine in the total population is being estimated and data are not available on the biomarker negative population, it may be sufficient to use data/transition probabilities associated with the total population (ie biomarker positive and negative) if the prevalence of the biomarker is low in the total population and if sensitivity analyses are conducted to vary the estimates/inputs within a plausible range.

If the prevalence of the biomarker is high in the total population, it will be important to test whether it would be more cost-effective to deliver the medicine without use of the test. If the ‘biomarker negative’ arm is receiving usual care, then an effect that was consistent with treatment effects before the introduction of the new medicine would be expected. When the new medicine is replacing usual care and there are no data on the biomarker negative population, or in the event that there is a fairly even distribution of the biomarker negative and positive in the total population, then collect and extract data on false positive patients (ie true negatives with incorrect test result) to determine response to therapy in the alternative condition (biomarker negative group).

Rationale for the codependency

8 (O) Definition of the biomarker(s)

Include in Subsections 1.1.2 or 1.1.3, and 5.3

Describe the nature of the biomarker (eg single nucleotide polymorphisms, mutation, copy number variation).

Where relevant, include the following elements describing the context for the biomarker:

• the disease or condition
• the specific function of the biomarker
• the critical parameters which define when and how the biomarker should be identified.

If the biomarker is a specific genetic mutation, describe exactly what the test is identifying (eg an expression microarray of tumour tissue that identifies a cancer that can be inhibited by activating a particular pathway). Categorise any mutation biomarker as germline or somatic, or both. If a mutation biomarker is classified as germline, then consider issues related to heritability in Subsection 5.2 (eg testing of relatives and genetic counselling, ethical and medico‐legal implications of testing).

Issues to be considered when judging the optimal definition of the biomarker include the following:

• the patient and cost consequences of different sampling needs to support different test options when it is difficult to obtain sufficient material to test for the biomarker (eg tumour samples)
• the prevalence of the different types of mutations in the disease or condition identified, noting that the evidence is likely to be greater for common mutations compared with rare mutations
• the frequency and predictive consequences of multiple mutations in a single sample (eg tumour heterogeneity and mosaicism), or indeed the impact of mutations in genes other than those nominated that may influence the effectiveness of the proposed medicine
• the evidence of impact on health outcomes for each type of mutation, either directly (eg if it is included in the evidentiary standard definition and ideally shows treatment effect modification), or from in vitro studies, or by inference (eg if there is a biologically plausible basis to differentiate among different types of mutations, such as activating or inactivating mutations, or mutations that predict resistance, sensitivity or neutrality to the medicine effect)
• the clinical and cost-effectiveness consequences of misallocation of treatment because of false positive or false negative results based on these conclusions.

9 (O) Biological rationale for targeting that biomarker(s)

Include in Subsection 1.1

Present the initial evidence that was used to select the biomarker for targeting with the proposed medicine. Describe and explain the overall approach to the selection of the biomarker, including methods and relevant aspects of study design and statistical analysis. Describe the rationale for selection of the population sample studied in the biomarker qualification.

Where the biomarker is genetic, present the criteria used for selecting candidate genes (eg candidate by position or by function, based on expression profiling data). Justify, using molecular biological or pharmacological principles, the plausibility of treatment effect modification (ie interaction) between the biomarker itself and the medicine, or, alternatively, between the medicine and another factor for which the biomarker is a proxy. Advise whether this biological rationale preceded the data collection underpinning the key evidence.

10 (O) Other biomarker(s) that modify the comparative treatment effect of the medicine

Include in Subsections 1.1 and 5.3

If testing for any other biomarkers is already reimbursed for targeted treatment with the medicine for the same condition, consider these codependent technologies in the choice of comparator.

If another biomarker is a genetic mutation, then:

• provide details on the specific mutation and the nature of the mutation
• explain whether the treatment effect in patients with this other mutation is consistent with the effect under consideration.

Note: This item may be relevant even if these other biomarker(s) are claimed but a test for the biomarker is not yet reimbursed.

11 (O) Prevalence of the condition being targeted in the population that is likely to receive the test

Include in Subsections 1.1 and 3A.4

Estimate the prevalence of the condition being targeted as measured by the true positive biomarker; this is relevant to calculate the performance of a test in terms of its negative and positive predictive value.

Indicate in Subsection 1.1 whether there is a ‘gold standard’ or reference standard test to determine whether a patient is true positive for the biomarker. Provide evidence to estimate the prevalence of the biomarker in an Australian population.

In the absence of an accepted reference standard test to correctly identify biomarker status, use an alternative appropriate methodology to estimate the prevalence (eg adjudication by a third test or sensitivity analyses of the prevalence of the biomarker given different assumptions).

The denominator for the prevalence calculation (the source population) is the number of patients considered eligible for the test according to the proposed MBS item descriptor. The source population consists of patients in the clinical pathway up to the point of being offered the test or the medicine in the absence of the test.

Proposed impact of codependent technologies on current clinical practice

12 (T) Consistency of the test results over time

Include in Subsections 1.1 and 1.2

Where test results for a patient may change over time (eg between a primary tumour and subsequent metastases in cancer), provide sufficient detail to clarify the relationship and timeframes between test results and the appropriateness of treatment.

For example, rat sarcoma viral oncogene homolog testing of the primary colorectal cancer tumour is usually representative of the findings in metastases, regardless of therapy. In another example, epidermal growth factor receptor results change with, for example, exposure to radiotherapy, so the results of testing the primary tumour may not be representative of what is happening in non–small cell lung cancer metastases.

13 (T) Use of the proposed test with other treatments and/or for other purposes

Discuss in Subsections 1.2 and 4.2

If other treatments or purposes are relevant, consider whether their use is currently reimbursed or whether there is the possibility of leakage. Refer to the clinical management pathways provided in response to Item 7.

14 (T) Use of the test in the clinical management pathway

Include in Subsections 1.2, 3A.6, 4.2 and 4.5

Refer to the clinical management pathways provided in response to Item 7. The test is most likely to be an additional test, although occasionally, if the biomarker is a strong predictor, it could replace another test in the pathway.

15 (T) Provision of the test in Australia

Include in Subsections 1.2 and 1.3

Indicate whether the test is likely to be widely accessible or available in a few selected laboratories across the country. Explain how the test would be undertaken in practice, and what impact it would have on the patient and health professionals (Subsection 1.2).

Specify the TGA status of the proposed test options (if relevant). Assess access and quality assurance issues. Identify how many laboratories offering the test have NATA accreditation for that test (Subsection 1.3).

16 (T) Specimen or sample collection

Include in Subsection 1.1 (plus Subsections 2.5, 2.6, 2.7, 3A.6, 4.2 and 5.1 if a new specimen needs to be collected)

Identify the biospecimen or sample needed for the test – for example, blood, tumour material (formalin‐fixed paraffin embedded [FFPE] or fresh), bone marrow, cytology specimen or mouth swab.

Identify whether this specimen needs to be collected specifically for the test or has already been collected for another purpose. For example, tumour already removed can be tested if archival FFPE is available and the test can identify the biomarker from this tissue.

If a new specimen needs to be collected, specify the costs (Subsections 3A.6 and 4.2), risks (Subsections 2.5–2.7) and feasibility of collecting the sample (Subsection 5.1). In some instances, such as a blood sample, the costs and risks would be trivial. In other instances, such as when a new biopsy is required, there may be significant costs as well as safety risks for the patient.

17 (T) Use of the test for monitoring purposes (if relevant)

Include in Sections 1.1–1.4, 3A.4 and 4.2

If relevant, describe the need for subsequent testing to monitor the development of new somatic mutations and/or to guide dosage or cessation of therapy with the codependent medicine.

This will impact on the clinical need for the proposed test (discuss in Subsections 1.1–1.4), as well as associated transition probabilities (Subsection 3A.4) and costs (Subsections 3A.6 and 4.2). If a new biopsy is required, cross-reference to Item 16.

18 (O) Availability of other tests for the biomarker

Include in Subsection 1.1 (if other tests are publicly funded) or Subsection 5.1 (if other tests are not publicly funded)

Indicate whether the proposed medicine can be used with other specific tests for that biomarker, other than the test proposed. Describe the available methods for testing for the biomarker.

If other tests are publicly funded to identify the biomarker, amalgamate this item with Item 10. If other tests are available or are emerging but are not yet publicly funded, address this item in Subsection 5.1.