Tuesday, November 3, 2009
3. TRIAL POPULATIONS
Studies in children, whose age is determined by the proposed indication, are required.
In general the results of studies in adults cannot be extrapolated to adolescents or from adolescents to younger children. Study results from weight loss trials outside Europe could, however, be extrapolated to the European population when it is established that the response to the therapy is not dependent on any ethnic background. Justification should be provided for using extrapolation data. Lifestyle factors may, however, have an important effect on efficacy in that a drug may be more effective in some populations with, for example, a low degree of physical activity and this should be considered in performing trials. The population studied should largely reflect the population intended for treatment in real life.
3.1 Non-pharmacological measures
Design of clinical trials on obesity in children should include, and precisely define, all types of
intervention (lifestyle changes, diet, physical activity, parental involvement). As discussed below, trials should consist of three phases: a run-in phase; an active treatment phase; and a follow-up phase. The run-in period (without any medication) should last 3 to 6 months. All non-pharmacological interventions should begin in the run-in phase and continue during the blind treatment phase and during the follow-up phase. Relevant details about the medical history of the patient and the family should be collected and all co-morbidities well documented before enrolling the child into the trial. Any approach to specific interventions should be justified and the interventions proposed should be relevant and appropriate for the target population and not only for the trial purposes. As described above, two populations of children should be differentiated: pre- and post-pubertal. It is recognised that some pre-pubertal children may enter puberty during the clinical trial.
3.2 Surgical interventions in obesity in children
Surgical intervention is normally restricted to adults. It is considered to be a last resort therapy. While it is acknowledged that comparison studies between surgical intervention and medical intervention might be useful, at present too little data are available to recommend such a design.
3.3 Goals of pharmacotherapy in obesity in children
Pharmacotherapy is only one aspect of a weight loss regimen. Pharmacological treatment of childhood and adolescent obesity and whether treatment translates into less obesity and/or less morbidity in later life is poorly understood. Treatment goals are composite and need to encompass age, stage of growth and development, degree of overweight and the presence of associated co-morbidities. Halting abnormal/excess weight gain or decreasing the rate of weight gain are important goals in paediatrics and could be primary endpoints. For those subjects with obesity related complications weight loss is a primary endpoint.
3.4 Design of clinical studies in the development of medicinal products for the treatment of
obesity in children
Pivotal trials should preferably be conducted by physicians experienced in the management of childhood obesity. They should be performed in centres with access to the relevant multidisciplinary teams that can provide expertise in drug monitoring, diet, psychological support, behavioural interventions and physical activity.
Inclusion criteria: It is recommended that separate trials for pre-pubertal (6 years to puberty) versus post-pubertal children (post-puberty to 18 years) are performed. This is because of the considerable physiological changes in body composition, metabolic responses and behaviour occurring during puberty. Patients should be obese and have a documented history of failing to lose weight by means of lifestyle modification, before enrolment into the pharmacological phase of a study. After the run-in 5/7 phase, study participants who do not have associated co-morbidities should not enter the active phase of the study if the results of the non-medicinal interventions suggest adequate weight loss i.e. if they no longer fulfil the definition of obesity. Conversely, those participants free of any co-morbidity should be enrolled if the run-in phase did not result in significant weight reduction. Children or
adolescents with severe obesity should enter the active phase of the trial irrespective of the weight changes obtained during the run-in phase when at least one of the co-morbidities exists. Children of all ages should be represented in sufficient large proportions in the study.
Overweight patients with obesity-related co-morbidities could be included in the study.
Exclusion criteria: patients with secondary causes of childhood obesity such as mental retardation, chromosomal problems or syndromic obesity (e.g. Prader-Willi syndrome) should be excluded from the pivotal trials. Separate trials are needed for children with secondary causes of obesity. It is recommended that subjects suffering from severe co-morbidities be excluded from pivotal trials. This is because these severely obese children may require more intense medical management than is available in clinical trial conditions. Patients who have undergone any surgical intervention for the management of obesity e.g. bariatric surgery should also be excluded from a trial because this intervention may affect outcome. Conversely, post-pubertal children who have responded well in the suggested minimal 3 to 6 months run-in period should not be excluded unless they are no longer
obese. Patients with confirmed bulimia nervosa disorder should be excluded from trials.
3.5 Trial methodology
Trials should be randomised, double-blind, placebo-controlled trials. There should be a run-in phase, followed after randomisation by a blinded treatment phase and follow-up. Non-pharmacological interventions (lifestyle changes, dietary manipulation, physical activity etc.) should be standardised and remain unchanged during all three phases of the study. The use of food questionnaires could be considered in special cases although it is considered that the standardisation of food intake per se is not feasible and the reproducibility of such studies is relatively low.
The treatment phase should last for at least 1 year, as stabilisation of the effect is needed. As with adults, the problem of drop outs is recognised in both the placebo and active treatment groups. Historically there have been high rates of premature subject withdrawal in trials of medicinal products used in the management of overweight and obesity. Every effort should be made to follow-up these patients fully and include them in the intention to treat analysis. Patients should be seen on a regular basis and their weight monitored from baseline to final analysis. If possible, patients who drop out from a 1 year study should have a body weight measurement at the time he or she would have completed the study after 1 year of taking part.
After discontinuation from the study the patients must be followed to assess maintenance of effect and any evidence for relapse and/or rebound. It is recommended that the observation phase after stopping drug therapy should last 6 months at least.
The applicant should indicate how he proposes to ensure the long-term follow-up of possible adverse reactions to the use of the medicinal product and efficacy in the paediatric population as outlined in Paediatric Regulations.
The possibility of an excessive pharmacodynamic effect, e.g. excessive weight loss, is unlikely and would relate to dose problems rather than to the duration of the study. In the case where investigators would like to conduct studies of shortened duration scientific advice should be sought.
Body composition analysis using a validated methodology is necessary in a representative sample of trial patients to ensure that any weight reduction is caused primarily by a reduction in fat content and not lean-body mass.
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