2.7 Assessment of differences between the trial setting and the Australian setting after listing

Page last updated: September 2016

Subsection 2.7 explores possible differences between the observed comparative benefits and harms in the trial setting, and the benefits and harms that are likely to occur in the Australian setting after listing on the PBS.

2.7.1   Identification of important differences across settings

Use Table 2.7.1 to tabulate important differences between the trial setting and the Australian setting. Consider factors relating to differences in the populations, disease or condition, circumstances or treatments as conducted in the trial compared with what would be expected were the proposed medicine reimbursed according to the requested restriction (Subsections 1.1.2 and 1.4) and in accordance with the proposed clinical management algorithm (Subsection 1.2). Table A4.1 (Appendix 4) contains a list of example factors that, when different across settings, may result in a difference in treatment effect, adverse events or patient management across those settings.

Alongside the identified differences, select one of the following conclusions in Table 2.7.1 about the influence of the identified difference across the settings on estimates of effectiveness, safety or patient management:

• differences across the settings are unlikely to have an effect; or
• differences across the settings may have an effect or, where it is unclear whether the differences would have an effect, differences across the settings require further investigation.

For differences across the settings that may have an effect, or for which an effect is unclear, address these in Section 3A.3.2. Provide an explanation of why differences are unlikely to have an effect. Where the explanation requires an analysis of trial or other data, mark this as requiring further investigation and present the translation study in Section 3A.3.2.

Differences between the trial setting and the Australian setting that may affect the comparative effectiveness or safety may undermine the key assumptions required to pursue a cost-minimisation approach. Where the submission identifies such differences, present a supplementary analysis in an attachment of the impact of the differences, using the approach outlined in Subsections 3A.3.2 and 3A.3.3, to support the validity of the therapeutic claim in the context of a cost-minimisation approach.

2.7.2   Extended assessment of comparative harms

Clinical trials are often inadequate for providing data on comparative harms for two key reasons:

• Trials tend to enrol patients who are healthier, have fewer comorbidities or concomitant medications, and have more stringent monitoring than the target population.
• Trials are usually underpowered and of insufficient duration to detect important adverse events.

Trial applicability to the Australian setting

Discuss whether any differences between the settings (identified in Subsection 2.7.1) may affect the comparative safety of the proposed medicine if used in the Australian setting.

Factors that will influence the discussion include:

• the prevalence and severity of the adverse event, and whether it is likely to be related to the medicine
• any difference in the rate of the serious adverse events between the patients receiving the proposed medicine and the main comparator
• factors for which the trial setting differs from the Australian setting that may affect the expected rate of the serious adverse event.

Extended safety of the proposed medicine

Commonly, the main comparator has been available for longer than the proposed medicine, and its safety profile in terms of rare and serious adverse events may be better understood. To address this potential asymmetry, present additional safety data and an overall conclusion on the safety of the proposed medicine compared with the main comparator.

A broader assessment of harms is especially important for serious adverse reactions that might occur in the long term or rarely; when the proposed medicine has a new mechanism of action; or when the mechanism of action or evidence of early physiological or biochemical changes suggests an increased potential for subsequent harms.

Where the proposed medicine is registered with the TGA, present the list of important risks and missing information from the approved risk management plan. Discuss these factors in the context of the safety of the proposed medicine compared with the nominated comparator.

Where the proposed medicine is not yet TGA registered, present the following evidence for harms:

• any randomised trials against the nominated comparator that were excluded in Subsection 2.2
• any randomised trials against other comparators that were excluded in Subsection 2.2
• the most recent periodic safety update report for the proposed medicine
• the most recent development safety update report for the proposed medicine
• any pharmacovigilance studies (completed or ongoing postmarket surveillance studies)
• any studies identified in a separate search, including nonrandomised study designs (eg registry data, observational studies) and studies involving the proposed medicine in other indications (or justify why this may not be appropriate).

Describe the search strategy for identifying nonrandomised studies and studies involving the proposed medicine in other indications. Provide any identified publications, the periodic safety update report and the development safety update report in an attachment. Only present the most relevant studies, which will tend to be larger or longer than the studies included in Subsection 2.2. Do not report on case studies, small case series, studies of short duration or those that provide little additional value. Where the number of studies found is large and studies are excluded on the basis of study size, state the threshold for exclusion.

Present a summary of the findings from each source of evidence, and provide additional detail or tabulated data in an attachment, if relevant. State whether the source of evidence does not report safety, or the safety conclusions are no different from those in the included studies. Summarise all of the sources and propose an overall conclusion of comparative safety against the nominated comparator.

If superiority cannot be justified on the basis of trial data from Subsection 2.2, the extended assessment of comparative harms should not be used to form the basis of a claim of superiority for safety of the proposed medicine compared with the nominated comparator.