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The Obesity Society provided comments on
the FDA Draft Guidance for Industry on Developing Products for Weight
Management. To read the entire comment, please refer to the position
statement on The Obesity Society Website.
The Draft Guidance addresses (a) weight
management (b) medical weight loss and (c) obesity.
Obesity Society Comment:
"Weight management" is a broad category including prevention of
weight gain in both overweight and obese patients and in the
non-overweight category as well as weight gain in populations
experiencing involuntary weight loss, such as patients with HIV/AIDs,
some cancers and other diseases. Therefore, it is too broad for the
content of the Guidance. "Medical Weight Loss" is also a broad
category encompassing both obesity and non-obesity conditions and may
encompass different interventions than drugs. Since this document
addresses obesity (as defined by Body Mass Index cut points) we suggest
that the document be re-named, "Draft Guidance for Industry on
Developing Products for the Treatment of Obesity."
The Guidance states that weight loss and
weight management be demonstrated over the course of at least one year
before a product can be considered effective for weight management. Thus,
the weight management indication incorporates and signifies weight loss
and weight maintenance.
Comment: One product may
produce significant weight loss continually with no maintenance. Another
product might successfully maintain present body weight but not produce
significant weight loss. It appears to be asking a great deal of one
product to effect both meaningful weight loss and long term weight
maintenance. We recommend that these be made separate indications.
The Guidance stipulates that the use of
a weight- management product should be contemplated only after a
sufficient trial of lifestyle modification has failed and the risks of
excess adiposity and the anticipated benefits of weight loss are expected
to outweigh the known and unknown risks of treatment with a particular
weight-management product.
Comments: While agreeing that lifestyle modification is
important in obesity management, we do not agree that the patient must
have failed on a "sufficient trial" of lifestyle modification.
We note that public opinion polling has consistently observed that large
numbers of American adults are trying to lose weight at any one time. We
observe that other, similar conditions like high blood pressure and high
cholesterol, which may also be positively affected by lifestyle
modifications, do not have similar restrictive language from the Food and
Drug Administration. In practice, for these conditions lifestyle changes
and drug treatments are often instituted simultaneously not sequentially.
The Guidance states that individuals
with BMIs greater than or equal to 30 kg/m2 or greater than or equal to
27 kg/m2 if accompanied by weight-related comorbidities represent patient
groups with sufficient baseline risk to justify inclusion in studies of
investigational weight-management products.
Comment: Latitude should be
given to investigators looking for safety and efficacy in such important
subgroups at lower BMI levels.
The use of weight-management products in
pediatric patients, as in adults, should be contemplated only after a
sufficient trial of lifestyle modification has failed and the risks of
excess adiposity and the expected benefits of weight loss are believed to
outweigh the known and unknown risks of treatment with a particular
weight-management product.
Comment: we are not aware of
any evidence that outcomes are better in adolescents who engage in
lifestyle modification before starting a drug regimen compared to those
initiating both lifestyle modification and drug intervention at the same
time.
The Guidance states that the efficacy of
a weight management product should be assessed by analyses of both mean
and categorical changes in body weight >Mean: The difference in mean
percent of loss of baseline body weight in the active-product versus
placebo-treated group. > Categorical: The proportion of subjects who
lose at least 5 percent of baseline body weight in the active-product
versus placebo-treated group.
Comment:DEXA, plethysmography and bioelectrical impedance
are better measures of excess adiposity than body weight. While not all
subjects need to be measured by these techniques, a subgroup should be so
measured to correlate loss of body weight with loss of adipose tissue.
The Guideance recommends that the
efficacy and safety of fixed-dose combinations be compared with the
individual product components of the combination and placebo in phase 2
trials of sufficient duration to capture the maximal or near-maximal
weight- management effects of the products. However, a fixed- dose
combination that is associated with at least twice the weight loss
observed with each of the individual components will be viewed more
favorably than combinations that do not achieve this degree of relative
weight loss.
Comment: A doubling of the weight loss effect in combination
therapy is too high a threshold for combination therapies. Some additive
value should be demonstrated or a reduction in adverse events.
The Guidance states that patients
eligible for participation in trials examining the efficacy and safety of
products for the treatment of medication-induced weight gain should have
a documented increase in body weight of at least 5% within 6 months of
starting a drug known to cause weight gain.
Comment:We recommend that trials of weight management
medications for patients with medication-induced weight gain or
obesity-associated comorbidities be conducted with patients from the time
they are placed on such medications and further recommend that the primary
outcome measures be differences between experimental and control groups
in weight gain and development of comorbidities risk factors.
The Guidance states that for a
weight-management product to obtain a stand-alone indication for the
prevention or treatment of type 2 diabetes, dyslipidemia, hypertension,
or any other weight-related comorbidity, it should be shown that the
product effectively prevents or treats the comorbidity through a
mechanism that is independent of weight loss.
Comment: "Independent" effect should be
eliminated. It is inexplicable that obesity products would have to
demonstrate improvement in blood pressure, lipid levels, glucose and
insulin metabolism for approval but could not receive an indication for
these conditions for lack of an "independent" mechanism. Such a
requirement only serves to keep patients and their doctors unaware of the
powerful effects of weight loss on improving these coronary heart disease
risk factors.
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