3B.2 Estimation of equi-effective doses

Page last updated: September 2016

3B.2.1 Equi-effective doses

Identify whether the medicines are intended to be used over a fixed course of treatment or used indefinitely as an ongoing medicine (while indicated).

For medicines set by fixed protocols, compare the total doses required over the entire duration of therapy.

For medicines that are ongoing, the ‘steady state’ dose comparison is generally most relevant. Calculate equi-effective doses at steady state (ie the average dose after dose titrations are complete and after excluding participants who discontinue the medicine). Assess the impact of extrapolating dose titration if there is evidence that the trial was of inadequate duration for the doses to have reached steady state.

If there is more than one trial or study, calculate the weighted average dose using the number of participants still on the medicine at steady state as the weighting factor. Generally, it is not justifiable to weight the doses between studies by both the duration of therapy in the study and by the number of participants. Justify the exclusion of any studies not incorporated into the equi-effective dosing calculations.

Where a sponsor does not have access to a study’s primary data, present the calculations the way the doses are in the published report. For example, the average doses might have to be weighted by the number of participants enrolled rather than the number of participants at steady state.

Use one of the following formats as a guide to report the conclusion on the equi-effective dose calculations:

• for doses set by fixed protocols – ‘proposed medicine A mg for B frequency of dosing over C duration of therapy, and main comparator D mg for E frequency of dosing over F duration of therapy are equi-effective’
• for doses established at steady state after full titration – ‘proposed medicine X mg and main comparator Y mg are equi-effective’.

Preferred sources of evidence

When estimating equi-effective doses, use the following sources of evidence (presented in order of preference):

• direct randomised trials where doses of both medicines are titrated against a response, or where doses of both medicines are fixed if the medicines are given in regular clinical practice according to a fixed protocol used in the trials
• direct randomised trials where doses of one or both medicines are arbitrarily fixed in a way that does not reflect regular clinical practice. Medicines might not have reached the same point on their respective dose-response curves if the doses are fixed. Therefore, present dose-response data for the two medicines to indicate whether the fixed doses are derived from a similar point on the respective dose-response curves, and to confirm that the selected doses do not represent suboptimal doses or doses on the plateau of the dose-response curve. Fixing the dose of just one medicine introduces an unbalanced approach. Note also that calculating the average dose from a trial in which subjects are randomised to different doses of the same medicine does not form an acceptable basis for directly determining equi-effective doses. However, a randomised trial designed to compare many fixed doses of the proposed medicine and its main comparator, each in separate arms, might usefully demonstrate the existence and extent of dose-response effects, and thus directly generate comparative dose-response curves as an alternative basis for inferring equi-effective doses
• indirect comparisons of two or more sets of randomised trials involving one or more common references
• nonrandomised studies where both dose and effect are measured
• nonrandomised studies (including market research data) where dose, but not effect, is measured. This source of evidence is the least preferred. It may be preferable to calculate doses from prescribing or dispensing data, such as the PBS prescription dataset, rather than using market research data.

Indicate whether these data are consistent with those recommended in each medicine’s TGA-approved product information about:

• the doses (and fixed-dose regimens, where relevant) used

the methods of titration (eg frequency of titration steps, any thresholds of outcomes used to guide a change in dose, extent of dose variation, duration of titration period).