P1.1  Listing fixed-dose combination products

Page last updated: September 2016

Additional Information Requests

  • Comply with all information requests in Part A of these guidelines, where applicable
  • Provide additional information for Section 1:
    • the main comparator products (Subsection 1.1)
    • the TGA status of the combination product and its components (Subsection 1.3)
    • that listing the combination product would not result in inappropriate dosing or unnecessary proliferation of products or dosage forms (Subsection 1.4)
  • Show additive beneficial effectiveness of the components (Section 2)
  • Substantiate other claims, such as:
    • improved patient convenience or compliance in terms of their impact on improving health outcomes (in Sections 2 or 3)
    • reduced provision of other health care resources (in Sections 2 or 3)
    • reduced expenditure in the Australian Government health budget (in Section 4)
  • Show that inappropriate usage (misuse or increased usage) would not occur (Section 4)

Requests for information in this subsection are in addition to the requests in the main body of the submission, which should be completed for the combination product.

P1.1.1 Additional information for Section 1

Main comparators (Subsection 1.1)

In the context of the guidance provided in Subsection 1.1, nominate the following main comparators identified in the following comparisons:

  • The combination product versus its component products given concomitantly, as the basis for a cost-minimisation approach (this need not apply where the combination product consists of the individual dosage forms in composite packaging).
  • The combination product (or its components given concomitantly) versus each of the component products given alone, as the basis for establishing at least an additive beneficial effectiveness.
  • The combination product versus the therapy that prescribers would most replace in practice, if expected to vary from the current concomitant use of the individual components.

TGA status (Subsection 1.3)

Confirm that all components in the combination product are approved by the TGA. Confirm that any requested indication is consistent with, or within the approved indication, for each component of the combination product.

Listing status (Subsection 1.4)

For each component of the combination product:

  • provide information on reimbursement through the PBS or the NIP
  • confirm that any restriction for each component is consistent with any proposed restriction for the combination product
  • present the doses available for each component and compare them with the doses available for the combination product
  • confirm that current dosing with individual components would remain unchanged upon patients transitioning to the combination product, or describe the expected change
  • confirm that the combination product does not risk unnecessary proliferation of products or dose forms.

P1.1.2 Additive effectiveness (Section 2)

Demonstrate an additive effect of the combination product using any of the following methods:

  • The outcome(s) upon which the components were listed.
  • If it is not feasible to measure this outcome, a validated surrogate outcome (eg blood pressure, forced expiratory volume).
  • In the case of fixed combination vaccine products, no loss of beneficial effectiveness of the components across different diseases or strains of pathogens (see Product type 3).
  • Where the proposed fixed-dose combination product contains medicines for different indications, present evidence for relevant outcomes related to all indications.

P1.1.3 Substantiate other claims (Sections 2 and 3)

To inform a cost-minimisation approach, demonstrate equivalence (or noninferiority) of the combination product to its component medicines. If using a cost-minimisation approach, the pricing of a combination product would normally be no greater than the sum of its individual components (at the current price to pharmacy level for PBS products or at the price to the Australian Government for NIP products), usually calculated on a per-milligram basis.

Where the combination product(s) is expected to substitute for two or more strengths of the component products, ensure that the price to pharmacy reflects the sum of the individual components as a function of the expected proportions of substitution.

The submission may claim a price advantage where evidence of acceptable cost-effectiveness through improved health outcomes or acceptable cost offsets is demonstrated. Where all the components of the combination medicine are currently available on the PBS or routinely used in clinical practice, evidence of improved health outcomes may be difficult to establish compared with the individual components.

The submission may claim improved compliance, improved health outcomes or a reduction in toxicity. Subsection 101(4AC) of the National Health Act 1953 requires the PBAC to advise the Minister for Health when the committee is satisfied that therapy involving a combination item, compared with alternative therapies, provides one of the following for some patients:

  • a significant improvement in patient compliance with the therapy
  • a significant improvement in efficacy or reduction in toxicity.

Any advice provided by the PBAC under subsection 101(4AC) will be relevant to both existing combination items and new combination items when they are recommended for listing.

Justify these claims in the submission. Unsupported or inadequately substantiated claims of improved compliance, improved health outcomes or reduced toxicity will render these claims uncertain.

Supporting a claim of improved compliance (Section 2)

The PBS subsidises medicines that improve health outcomes and provide value for money. Compliance with medication regimens is one factor that can influence the achievement of health outcomes and affect the cost-effectiveness of a medicine. Therefore, the PBAC evaluates the evidence on the extent of compliance with medicines and the effect on health outcomes when considering therapies to be recommended for subsidy.

This section provides guidance on the approach required for supporting a claim of a significant improvement in compliance for a combination product compared with its comparator. To support this claim, provide evidence:

  1. of improved compliance
  2. to support why this improvement is significant, most often by establishing that the improvement in compliance would result in a meaningful change to patient health.

Compliance is a broad term that encompasses consumers’ acceptance of, adherence to and persistence with a prescribed medicine. These terms are defined below:

  • Acceptance – the consumer’s informed decision to undertake behaviours that are expected to lead to improved health outcome (eg taking a medicine that has been prescribed).52
  • Adherence – the extent to which the consumer conforms to the agreed behaviours, with respect to timing, dosage and frequency of medication taking.53
  • Persistence – the duration of time from initiation to discontinuation of therapy.53
Approach to support a claim of improved compliance

Address the following to support a claim of improved compliance for the combination product compared with the main comparator:

  • Provide information for the combination product and for its alternative therapies. In general, the alternative therapy of interest is the use of the individual components of the combination product.
  • Where some of the individual components are already available as a fixed-dose combination product, the comparison would be against the product used in combination with additional components.
  • Where the main comparator is not the components of the combination product, clearly establish this in Subsection 1.1.
Current level of compliance

Describe the current level of compliance for the components of the combination product and for the combination product. Provide detail on the acceptance, adherence and persistence of each medicine. Relevant sources of information may include:

  • a structured literature review or systematic review
  • current persistence in PBS administrative data and prescription claims data
  • other studies of compliance, including validated self-report, direct observation, pill counts, prescription refills and electronic medicine monitoring.

Estimate the compliance and state the source of information used. State any assumptions used to generate estimates of compliance and provide evidence to support the assumptions. Where possible, present evidence from multiple sources and discuss differences between the sources. Estimate the uncertainty for the data provided.

Discuss where there is evidence of poor compliance, and reasons commonly given by consumers for poor compliance. State whether there are subgroups of the population with different levels of compliance and present reasons why.

State whether the estimates of compliance are relevant to the target Australian population and setting.

Factors likely to affect compliance

Describe the factors that affect compliance for these medicines – for example:

  • patient or caregiver characteristics or behaviours
  • disease or condition characteristics
  • prescriber or practitioner characteristics
  • health system or setting factors
  • characteristics of the medicine such as cost, adverse effects, formulation and regimen.

Where a factor that may influence compliance is identified, discuss whether this is relevant to the Australian setting. State whether the factor predicting compliance is not relevant to the proposed population, proposed use of the medicine or the Australian health care system.

Although factors that affect compliance should be relevant to the use of the proposed medicine, provide some supporting evidence that the factors identified are relevant across other medicines or settings. Explain any difficulties in establishing the effect of certain factors on compliance, where there is not a consistent relationship across alternative scenarios. Relevant sources of information for addressing this include:

  • qualitative and quantitative studies of factors affecting compliance
  • cross-sectional surveys of reasons for noncompliance
  • self-report surveys in randomised trials that include reasons for noncompliance.
Effect of the combination product on factors affecting compliance

Describe how using the combination product, compared with its alternative(s), affects the factors contributing to noncompliance in the population of interest. Include a plausible explanation of the link between the use of the combination product and the factors affecting compliance. Support the explanation with published studies, prescriber surveys and/or consumer surveys.

Evidence of improvements in compliance

Provide evidence of a measurable difference in compliance associated with use of the combination product compared with its alternative therapies. Estimate the extent of the difference in compliance and the uncertainty in this estimate.

Source evidence of improved compliance from comparative studies of compliance (observational or pragmatic trials) for the combination item compared with alternative therapies. Ensure that study patients who are taking the combination product and their settings are similar, in terms of factors that may predict compliance, to those taking the alternative therapy. Compare the patients, in terms of the factors identified above, who are receiving the two therapies in the study purporting to show differences in compliance. Comment on the similarity of the overall study population and setting to the Australian population and setting.

Evidence of compliance affecting health outcomes

Discuss how important compliance is to achieving the desired health outcomes for the medicine.

Present evidence that the extent of improvement in compliance (previously described) would have an effect on health outcomes. State whether the difference in health outcomes that is likely to occur is clinically significant.

Possible sources of evidence to establish a link between compliance and health outcomes include:

  • studies of the effect of compliance on health outcomes (preferably from studies designed to measure compliance that also include measures of health outcomes)
  • pharmacokinetic studies
  • dose-response studies, including data on duration of medicine usage
  • outcomes data from randomised trials.
Financial implications

PBS expenditure for combination products changes when there is an accepted claim of improved compliance. Generally, a combination product will have the same cost as its components and, when one component undergoes a statutory price reduction, this will affect the price of the combination product. Therefore, for combination products claiming improved compliance, present the estimate on PBS expenditure at the currently listed price and present the estimate of PBS expenditure following price reductions applied from component medicines.

Supporting a claim of improved efficacy or reduced toxicity (Section 2)

To enable PBAC consideration of whether the relevant combination item provides, for some patients, a significant improvement in efficacy or a significant reduction in toxicity compared with alternative therapies, supply information about the impact of the efficacy improvement or toxicity reduction on clinical importance and patient relevance. Such improvements in health outcomes for patients need not necessarily arise from significant improvements in compliance.

P1.1.4 Inappropriate usage (Section 4)

Ensure that any growth in the market that may occur in response to listing the fixed-dose combination product is captured in Section 4. Discuss whether the predicted growth in the market represents an inappropriate increase in overall use of its individual components, or an inappropriate use of one or more of the components in specific patient groups.

P1.1.5 Quality use of medicines (Section 4)

Fixed-dose combination products may have unique QUM issues, such as starting patients on combination drugs without trialling a single agent in the first-line setting (where this is required by the listing), inadvertent duplication of fixed-dose combination product and single agent prescriptions, and patient confusion. Discuss these and other potential QUM issues associated with the proposed listing of the fixed-dose combination product according to the guidance provided in Subsection 4.7.