Overweight, Obesity, and Weight Loss : Frequently Asked questions #2

Saturday, November 7, 2009

Q: How can physical activity help?
A: The new 2008 Physical Activity Guidelines for Americans state that an active lifestyle can lower your risk of early death from a variety of causes. There is strong evidence that regular physical activity can also lower your risk of:

• Heart disease
• Stroke
• High blood pressure
• Unhealthy cholesterol levels
• Type 2 diabetes
• Metabolic syndrome
• Colon cancer
• Breast cancer
• Falls
• Depression

Regular activity can help prevent unhealthy weight gain and also help with weight loss, when combined with lower calorie intake. If you are overweight or obese, losing weight can lower your risk for many diseases. Being overweight or obese increases your risk of heart disease, high blood pressure, stroke, type 2 diabetes, breathing problems, osteoarthritis, gallbladder disease, sleep apnea (breathing problems while sleeping), and some cancers.

Regular physical activity can also improve your cardiorespiratory (heart, lungs, and blood vessels) and muscular fitness. For older adults, activity can improve mental function.

Physical activity may also help:

• Improve functional health for older adults
• Reduce waistline size
• Lower risk of hip fracture
• Lower risk of lung cancer
• Lower risk of endometrial cancer
• Maintain weight after weight loss
• Increase bone density
• Improve sleep quality

Health benefits are gained by doing the following each week:

• 2 hours and 30 minutes of moderate-intensity aerobic physical activity
or
• 1 hour and 15 minutes of vigorous-intensity aerobic physical activity
or
• A combination of moderate and vigorous-intensity aerobic physical activity
and
• Muscle-strengthening activities on 2 or more days

This physical activity should be in addi-tion to your routine activities of daily living, such as cleaning or spending a few minutes walking from the parking lot to your office.

If you want to lose a substantial (more than 5 percent of body weight) amount of weight, you need a high amount of physical activity unless you also lower calorie intake. This is also the case if you are trying to keep the weight off. Many people need to do more than 300 minutes of moderate-intensity activity a week to meet weight-control goals.

Moderate Activity
During moderate-intensity activities you should notice an increase in your heart rate, but you should still be able to talk comfortably. An example of a moderate-intensity activity is walk-ing on a level surface at a brisk pace (about 3 to 4 miles per hour). Other examples include ballroom dancing, lei-surely bicycling, moderate housework, and waiting tables.

Vigorous Activity
If your heart rate increases a lot and you are breathing so hard that it is dif-ficult to carry on a conversation, you are probably doing vigorous-intensity activity. Examples of vigorous-intensity activities include jogging, bicycling fast or uphill, singles tennis, and pushing a hand mower.

Q: What drugs are approved for long-term treatment of obesity?
A: The Food and Drug Administration has approved two medicines for long-term treatment of obesity:

• Sibutramine (si-BYOO-tra-meen) suppresses your appetite.

• Orlistat (OR-li-stat) keeps your body from absorbing fat from the food you eat. These medicines are for people who:

• Have a BMI of 30 or higher

• Have a BMI of 27 or higher and weight-related health problems or health risks If you take these medicines, you will need to follow a healthy eating and physical activity plan at the same time. Before taking these medicines, talk with your doctor about the benefits and the side effects.
  

• Sibutramine can raise your blood pressure and heart rate. You should not take this medicine if you have a history of high blood pressure, heart problems, or strokes. Other side effects include dry mouth, headache, constipation, anxiety, and trouble sleeping.

• Orlistat may cause diarrhea, cramping, gas, and leakage of oily stool. Eating a low-fat diet can help prevent these side effects.

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Overweight, Obesity, and Weight Loss : Frequently Asked questions

Thursday, November 5, 2009

Q: How many women in the United States are overweight or obese?
A: Over 60 percent of U.S. adult women are overweight, according to 2007 estimates from the National Center for Health Statistics of the Center for Disease Control and Prevention. Just over one-third of overweight adult women are obese.

Q: How do I know if I’m overweight walking or obese?
A: Find out your body mass index (BMI). BMI is a measure of body fat based on height and weight. People with a BMI of 25 to 29.9 are considered over- weight. People with a BMI of 30 or more are considered obese.

Q: What causes someone to become overweight or obese?
A: You can become overweight or obese when you eat more calories (KAL-oh- rees) than you use. A calorie is a unit of energy in the food you eat. Your body needs this energy to function and to be active. But if you take in more energy than your body uses, you will gain
weight.

Many factors can play a role in becoming overweight or obese. These factors include:

• Behaviors, such as eating too many calories or not getting enough physical activity

• Environment and culture

• Genes

Overweight and obesity problems keep estimates from the National Center getting worse in the United States. for Health Statistics of the Center for Some cultural reasons for this include:

• Bigger portion sizes

• Little time to exercise or cook women are obese. healthy meals
  

• Using cars to get places instead of walking

Q: What are the health effects of being overweight or obese?
A: Being overweight or obese can increase your risk of:

• Heart disease

• Stroke

• Type 2 diabetes

• High blood pressure

• Breathing problems

• Arthritis

• Gallbladder disease

• Some kinds of cancer

• Problems getting pregnant But excess body weight isn’t the only health risk. The places where you store your body fat also affect your health.

Q: What is the best way for me to lose weight?
A: The best way to lose weight is to use more calories than you take in. You can do this by following a healthy eating plan and being more active. Before you start a weight-loss program, talk to your doctor.

Safe weight-loss programs that work well:

• Set a goal of slow and steady weight loss — 1 to 2 pounds per week
• Offer low-calorie eating plans with a wide range of healthy foods
• Encourage you to be more physically active
• Teach you about healthy eating and physical activity
• Adapt to your likes and dislikes and cultural background
  
• Help you keep weight off after you lose it

Q: How can I make healthier food choices?
A: The U.S. Department of Health and Human Services (HHS) and Department of Agriculture (USDA) offer tips for healthy eating in Dietary Guidelines for All Americans.

• Focus on fruits. Eat a variety of fruits — fresh, frozen, canned, or dried — rather than fruit juice for most of your fruit choices. For a 2,000-calorie diet, you will need 2 cups of fruit each day. An example of 2 cups is 1 small banana, 1 large orange, and 1/4 cup of dried apricots or peaches.

• Vary your veggies. Eat more:

• Dark green veggies, such as broccoli, kale, and other dark leafy greens

• Orange veggies, such as carrots, sweet potatoes, pumpkin, and winter squash

• Beans and peas, such as pinto beans, kidney beans, black beans, garbanzo beans, split peas, and lentils

• Get your calcium-rich foods. Each day, drink 3 cups of low-fat or fat-free milk. Or, you can get an equivalent amount of low-fat yogurt and/or low-fat cheese each day. 1.5 ounces of cheese equals 1 cup of milk. If you don’t or can’t consume milk, choose lactose-free milk products and/or calcium-fortified foods and drinks.

• Make half your grains whole. Eat at least 3 ounces of whole-grain cereals, breads, crackers, rice, or pasta each day. One ounce is about 1 slice of bread, 1 cup of breakfast cereal, or 1/2 cup of cooked rice or pasta. Look to see that grains such as wheat, rice, oats, or corn are referred to as “whole” in the list of ingredients.

• Go lean with protein. Choose lean meats and poultry. Bake it, broil it, or grill it. Vary your protein choices with more fish, beans, peas, nuts, and seeds.

• Limit saturated fats. Get less than 10 percent of your calories from saturated fatty acids. Most fats should come from sources of polyunsaturated and monounsaturated fatty acids, such as fish, nuts, and vegetable oils. When choosing and preparing meat, poultry, dry beans, and milk or milk products, make choices that are lean, low-fat, or fat-free.

• Limit salt. Get less than 2,300 mg of sodium (about 1 teaspoon of salt) each day.

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GUIDELINE ON CLINICAL EVALUATION OF MEDICINAL PRODUCTS USED IN WEIGHT CONTROL (CPMP/EWP/281/95 Rev. 1) ADDENDUM ON WEIGHT CONTROL IN CHILDREN #3

Wednesday, November 4, 2009

4. ASSESSMENT OF EFFICACY OF NEW MEDICINAL PRODUCTS FOR THE
TREATMENT OF OBESITY IN CHILDREN

It is recommended that the primary endpoint is a change in BMI Standard Deviation Score; however, change in adiposity should also be measured in BMI (%) units4. In adults a 10% weight reduction is accepted as a clinically meaningful effect. However, in the paediatric population the degree of change should be justified by the applicant.

While it is important to obtain statistically significant results, it is also important to consider clinical relevance defined via the responders’ rate. Research in this area is encouraged. In the meantime, justification should be provided for all design approaches to show clinically relevant effects.

Parameters relating to co-morbidities are secondary endpoints and can include improved glucose control, improved lipid profile, enhanced exercise tolerance, better mental health and/or quality of life, reduced use of adjunct medications etc. Choice of endpoints should be justified.

Behavioural changes are considered as secondary endpoints. Validated psychological tools must be used and justification for their use should be provided.


5. ASSESSMENT OF SAFETY OF NEW MEDICINAL PRODUCTS FOR THE
TREATMENT OF OBESITY IN CHILDREN

Safety aspects are dependent on the mechanism of action of the investigational medicinal product. Appropriate safety data should be collected during the entire drug treatment period, which will usually be at least one year, and for the duration of the follow-up period. This data should notably encompass the adverse events related to lipid profile, liver function, cardiovascular system function and rebound phenomenon. For centrally-acting anorectic agents, in particular, it is recommended that special attention and monitoring is afforded to neuropsychiatric events such as depression, sleep pattern and nightmares, assessment of self-esteem, aggression or suicidality. Self-esteem could fall under both the efficacy and safety category.

In growing children height velocity should also be monitored in addition to standard safety evaluations and pubertal development should be assessed by determining Tanner stage at baseline and endpoint. For centrally-acting anorectic agents the abuse potential should be considered and factored into trial design in an appropriate manner. This is especially important in the adolescent age group.

GUIDELINE ON CLINICAL EVALUATION OF MEDICINAL PRODUCTS USED IN WEIGHT CONTROL (CPMP/EWP/281/95 Rev. 1) ADDENDUM ON WEIGHT CONTROL IN CHILDREN #2

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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GUIDELINE ON CLINICAL EVALUATION OF MEDICINAL PRODUCTS USED IN WEIGHT CONTROL (CPMP/EWP/281/95 Rev. 1) ADDENDUM ON WEIGHT CONTROL IN CHILDREN

Monday, November 2, 2009

INTRODUCTION
This Article is an addendum to the Guideline on Clinical Investigation of Medicinal Products used in Weight Control for Adults. It provides guidance on the clinical investigation of medicinal products used in weight control in the paediatric population and should be read in conjunction with the Annex I to Directive 2001/83/EC, as amended, and with relevant European or ICH guidelines for conducting clinical trials, as outlined in the adult guideline.

The prevalence of child obesity is increasing rapidly on a global scale. It is a serious issue with many health and social consequences that often continue into adulthood. Obesity occurs when an individual takes in more energy than they expend although some people may be genetically more susceptible than others. The rise in obesity has been too rapid to be solely attributable to genetic factors and thus must reflect changes in eating patterns and levels of physical activity. It is especially prevalent in industrialised countries where sedentary lifestyles are commonly coupled with high consumption of convenience foods.

Obesity is associated with a range of co-morbidities including type 2 diabetes or hyperinsulinaemia, hypertension, dyslipidaemia and social and psychological problems including stigmatisation, discrimination and prejudice. Coronary heart disease, cancers and joint and bone pain are comorbidities that are well documented in adult obesity, with coronary heart disease being the most common cause of premature death among obese people. Less clear are the links between cancer and obesity. The evidence is strongest for colon cancer where the risk is nearly three times higher in obese men and women.

As childhood obesity frequently continues into adulthood as described above, obesity in childhood is a risk factor for all of the above disease states in later life.

1. DEFINITION OF OBESITY IN CHILDREN
A wide variety of definitions for childhood obesity are in use, but a universally employed definition does not, however, exist. The body mass index (BMI = bodyweight (kilograms)/ (height [metres²]) is widely used in adult populations and a 30 kg/m² cut-off point is recognised internationally as a definition of adult obesity.

However, in children the situation is more complex as the BMI changes substantially with age. BMI cut-offs based on pooled international data that link the accepted adult cut-off points (a BMI of 25 Kg/m2 for overweight and 30 Kg/m2 for obesity) to cut-off points related to age and sex for children should be used to define overweight and obesity in the paediatric population Primary obesity is obesity due to primary causes including lifestyle and dietary habits coupled with lack of adequate physical activity. Secondary obesity refers to obesity where there may be an underlying medical condition such as genetic disorders, endocrine disorders or metabolic disorders.

2. AGE CLASSIFICATION
The ICH guidance Article on clinical investigation of medicinal products in the paediatric
population uses the following categorisation for age classification of paediatric patients:

Ages are defined in completed days, months, or years:

• preterm newborn infants;

• term newborn infants (0 to 27 days);

• infants and toddlers (28 days to 23 months)
  
  
• children (2 to 11 years);
  

• adolescents (12 to 16-18 years (dependent on region)).

It is recognised that there is considerable overlap in developmental (e.g., physical, cognitive, and psychosocial) issues across the age categories. In this guideline, however, the following two categories are used to define subgroups of the paediatric population: 1.Pre-pubertal and 2. Post-pubertal, categorised as follows:

1. Pre-pubertal: age 6 years old to onset of puberty as defined by a Tanner score of 2.
2. Post-pubertal: post-puberty to age 18 years.

For children aged 2 years to 6 years it is recommended that weight loss be attained through lifestyle modification only.

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