DIA: Guidelines in Review
| Birka Lehmann of BfArM chaired a session on guidelines in review. She opened the session with discussion of the Paediatrics regulation. The paediatric committee (PDCO) has set up 7 subcommittees to produce consider guidelines for specific disease areas. They have already decided not to produce entirely new guidelines where they already exist in adults, but will adapt these guidelines where possible, looking for situations where findings from adult research can be used to inform paediatric research. This is particularly concerned with the selection of an appropriate endpoint. She then introduced Dr Kevin Blake of the Irish Medicines Board and a member of the CHMP-Efficacy Working Party, to give an update on the guideline on obesity and weight control. These guidelines were adopted late in 2007 and will come into effect in May 2008. He looked at some of the contentious issues during their development, and gave some suggestions on how they should be interpreted. The CHMP-EWP advises the CHMP under EMEA/P/24143/2004 and produces guidelines which, although not binding, are highly recommended. The new obesity guideline is CPMP/EWP/281/96 revision 1. He talked us through the timeline of its development, from April 2006 through to its adoption in November 2007. The group defined obesity in adults as a chronic clinical condition that needs long-term therapy, based on the WHO definitions. Dr Blake mentioned that comments were made on racial differences in definition of obesity, which were indeed included. The guideline acknowledged non-pharmacological options under certain conditions, but primarily discussed the pharmacological options, to be used alongside a calorie-controlled diet. Comments related to pulmonary artery hypertension risk with centrally acting anorectic agents. As weight loss can be controlled by behaviour modification alone, the dropout rate in pharmacological studies is high. As a result, they recommend a placebo group to be compared on dropout rate as well as efficacy. However, he suggested that dropouts should be followed up, to base the analysis on the full ITT population, asking participants to at least notify triallists of their weight after 1 year. Participants who withdraw their consent can make this difficult, so great care must be taken when obtaining initial consent. In terms of primary endpoint, they defined it as at least 10% of baseline weight from the start of the run-in period, and at least 5% greater than associated with placebo (with appropriate loss of body fat demonstrated). Comments to this questioned whether 5% weight loss might be appropriate in specific conditions (eg, comorbid diabetes); this was accepted, provided this subgroup of patients is pre-identified. Another query asked whether a change in concomitant medication might be acceptable as a secondary endpoint, but this was rejected. Moving to patient selection, the guidelines require a BMI >30 in otherwise healthy adults. Kevin had already mentioned a degree of controversy over run-in periods. Comments had questioned whether this was necessary, but he stated that it was crucial to establish a behavioural pattern and confirm motivation. This alone would skew the baseline, but this is overcome by taking the baseline from the start of the period. In the development of the addendum under development on paediatric obesity. This does not use the adult definition, nor the classical US definition, which are based on arbitrary cut-offs. Instead, it uses a statistical model based on pooled international data to link accepted adult cut-offs back to younger ages. Treatment goals are composite, encompassing age, stage of growth degree of overweight and presence of associated comorbidities. Halting or decreasing the rate of weight gain could be primary endpoints, while weight loss could be a primary endpoint for subjected with related complications. On selecting a trial population, children over 6 should be selected (split into pre- and post-puberty), with a run-in period of 3-6 months and only children not achieving adequate weight loss in this period being entered into the active study. |
