Australian public assessment for Ibuprofen - Therapeutic Goods ...

AusPAR Caldolor Ibuprofen Phebra Pty Ltd PM-2010-02393-3-1
Final 2 January 2013
Therapeutic Goods Administration
administration of the first dose of study medication, compared to the corresponding
percentage in the placebo group.
There are no regulatory guidelines relating to efficacy outcomes in studies of antipyretic
medications. Published clinical studies have investigated a range of outcomes such as:
• the percentage of patients whose temperature decreased below a set threshold over a
predefined time period;
• the percentage of patients whose temperature decreased by a set amount over a
predefined time period;
• the mean, maximum or minimum temperature over a predefined time period;
• the rate of temperature change during a predefined time period;
• cumulative measures of effect on body temperature such as the area under the
temperature or change-in-temperature versus time curve over a predefined time
period or the weighted sum of temperature measurements at different time points.
Indirect efficacy measures such as the time to first use of rescue treatment have also been
studied. Depending on the focus of the trial, the time period over which efficacy is assessed
may be a single dose interval or may span several doses. For example, the PI for IV
paracetamol (Perfalgan) states that in the pivotal antipyretic study supporting the
registration of that product, the primary efficacy outcome was the mean change in body
temperature at several time points from 0.5 to 6 h after a single dose, compared to
placebo. However, that study also had a range of secondary efficacy outcomes
encompassing most of the types described above.
The thresholds for declaring a patient to be febrile and for subsequently declaring fever to
have responded to treatment have also varied across studies. The temperature for
declaring a therapeutic response is often lower than the temperature required for the
initial diagnosis of fever but it is not uncommon for the values to be the same in any one
trial, as was the case in CPI-CL-004. Harrison’s Principles of Internal Medicine defines a
fever as an oral temperature >37.2°C (>98.9°F) in the morning or >37.7°C (>99.9°F) in the
afternoon, these being the upper 99th percentiles for normal body temperature at the
respective times of day 11. The same text notes that rectal temperature (core temperature)
is generally about 0.4°C higher than oral temperature, and that for most fevers, body
temperature increases by 1°-2°C. Given these factors, the core temperature of 101°F
(about 38.3°C) that was used for diagnosing fever in CPI-CL-004 was not particularly
stringent. For comparison, the PI for Perfalgan states that in the pivotal antipyretic study,
which was conducted in children, the minimum temperature for diagnosing fever was
38.5°C.
Similarly, the use of the same temperature for diagnosing a fever and declaring a
treatment response meant that a response would have been relatively easy to obtain,
particularly when one realises that patients were also receiving treatment (such as
antibiotics, antimalarials) for the underlying cause of the fever. This was reflected in a
substantial placebo response, particularly over the full 24 h treatment period. For
comparison, in the pivotal study for Perfalgan the minimum temperature for diagnosing
fever was 38.5°C but the temperature for declaring a treatment response (one of the
secondary endpoints) was 38.0°C. This shortcoming of CPI-CL-004 was to some extent
addressed in the additional analyses requested by the FDA, which examined the time to
reach a temperature