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Assessed listed medicines evidence guidelines
Version 1.1, August 2018
6. Alignment of indications and evidence
Regardless of how scientifically sound a study is, its suitability as evidence in support of an application for an assessed listed medicine will depend on how closely the proposed indications for the product match the results and conclusions of the study.
The indications used on a product and the supporting evidence must:
- refer to the same medicine or active ingredient(s);
- have the same meaning and intent; and
- refer to the same therapeutic action and the same context (e.g. the same target population).
Indications must also remain valid for the entire life cycle of the medicine.
6.1 Formulation and use
Applicants must ensure that there is a high level of concordance between the study parameters and the product formulation, dosage, and intended target population. The product used in the evidence provided and the product intended for listing should have the same:
- dosage form
- route of administration
- frequency and duration of use
If there are differences noted, further evidence and justifications are required to address the data gaps identified (refer to Biopharmaceutic studies).
Differences in excipients and formulation may be extremely significant. For example, modified release dosage forms of a medicine designed for slow or delayed release of an active ingredient may not be relevant to support indications that imply health outcomes that are achieved rapidly (e.g. 'for the rapid relief of pain').
For traditional use formulations, modifications of the traditional medicine should ensure that the principles of the tradition relating to preparation, constituents and use are followed. If significant modifications are made, these may need to be accounted for through a comprehensive justification.
When evidence relates to a biological substance (herb, herbal extract, probiotic, animal-derived product), the species, sub-species, strain, parts, quantity of active component, and preparation should be identical to that described in the clinical trial. Given that the chemical profile of any complex substance can vary even if standardised to specific markers, it is unlikely that deviations from the formulation described in a clinical trial will be accepted in these cases.
6.2 Duration of studies
Studies must be of an appropriate duration for the indication or claim. The required duration will depend on the nature of the health benefit, but must be sufficient for that benefit to be clearly demonstrated. For example, products that claim a long-term health benefit must be supported by studies of sufficient duration for a sustained response to be apparent. This is particularly critical for indications relating to risk reduction and modulation of biomarkers, as homeostatic mechanisms may reverse changes in the longer term.
Applicants should determine and justify the study duration used to support an indication. Studies of insufficient duration will not be accepted as primary evidence.
Indications should reflect the primary outcome of a study with an adequate sample size. Indications based on secondary outcomes may be acceptable in some cases where these outcomes are statistically and clinically meaningful.
Regardless of the level of the evidence, the indications must not:
- exaggerate the extent, nature, or prominence of the effects achieved in a study; or
- suggest greater scientific certainty than the study is capable of providing; or
- imply efficacy in all instances.
Evidence describing the biological effect, rather than the clinical effect, is not generally a suitable basis for an indication - although it may contribute to establishing the biological plausibility of a proposed primary benefit. This is particularly pertinent in the case of indications that refer to the favourable modulation of biomarkers (e.g. blood glucose levels, cholesterol levels etc.). A small change in a given biological surrogate may be associated with negligible clinical outcomes or increases in risk.
Efficacy studies are usually conducted under tightly controlled conditions in order to control for confounding variables. Studies conducted in this way are ideal for estimating potential efficacy but may not reflect effectiveness within its target population e.g. due to different population groups, diets, etc.
Applicants should therefore carefully assess the aspects of the study that were controlled and establish whether the absence of these controls in 'real use' are likely to impact on the benefits experienced by consumers. For example, a study showing a weight loss benefit of a substance may control all participants' caloric intake. Consequently, it is unlikely that the same benefits would be experienced in situations where caloric intake was not controlled.
In such cases, contextual qualifiers should be included in an indication so that it accurately reflects the evidence base. For example:
'May assist with weight loss when used with calorie controlled diet and exercise'.
'May assist with weight management when used with calorie controlled diet and exercise'.
In situations where real-life effectiveness is likely to be significantly less than that observed in trials, the expected result in the general population should still be clinically meaningful.
6.5 Target population and generalisation/extrapolation
For the results of a study to be generalisable to the Australian context, the study used to support the indications for an assessed listed medicine should be conducted using a sample population that:
- consists of both female and male participants
- consists of individuals aged 18-65 years
- consists of healthy, or only mildly unwell, individuals
- is demographically similar to the Australian population
If the indication on the product relates to a specific population, then the study should be carried out in that specific population.
Additionally, indications should not extrapolate or generalise the outcomes of a study to populations that differ significantly from that used in the study. Specifically:
- It is not appropriate to use studies carried out on populations with significant health concerns to support an indication for assessed listed medicines; unless the indication relates directly to a population with a serious condition (i.e. a restricted representation). If the indication relates to the general healthy Australian population, the extrapolation of study findings from a diseased study population to the healthy Australian population can be misleading. For example, data generated from studies on subjects with biomarker levels outside of normal limits may not be relevant to maintenance of normal biomarker levels in healthy people.
- It is not appropriate to generalise from studies using defined sub-groups to the general population (e.g. it is not appropriate to use a study on 60-65 year old adults to support a claim of efficacy in the general population).
- Similarly, if the study was carried out on a mixed sample population, it is not appropriate to claim efficacy in a select sub-group, unless the study specifically addresses efficacy in that sub-group (e.g. if the study was conducted on a mixed sample of adult women and men, it is not appropriate for the indication to relate to pregnant women).
- The results of a study conducted on a homogenous ethnic population group may not be applicable to the general Australian public, given that the Australian population is culturally and ethnically diverse.
If the target population and the study sample population or sub-group are significantly different, applicants must submit a robust scientific justification accounting for the suitability of the extrapolation (refer to Justifications).
This justification should consider biological factors as well as environmental and behavioural factors, including the influence of health practitioner intervention which may differ between populations. The mechanism of action of the medicine and whether it is applicable to the population/sub-group should be addressed, given that the same results may not be achievable in other populations or sub-groups due to physiological differences. Further, as any favourable effect is likely to be dose-dependent, consideration should be given to whether the dose requires modification. The justification may use studies on different population groups, non-clinical studies, and in vitro studies to support the pivotal study.
6.6 Balance of evidence
Indications must not indirectly, or by implication, lead consumers to believe that the medicine will assist in a health benefit that is not explicitly supported by the balance of evidence - i.e. the weight of good quality evidence should be in agreement with the proposed indication. The indication cannot be based on a study that is not consistent with the surrounding body of knowledge (refer to Balance of evidence and conflicting results).
An indication that is consistent with the broader knowledge base and is supported by the balance of evidence is more likely to remain valid for the life of the medicine as new research becomes available.