Considerações sobre efeitos das drogas para tratar obesidade na revista "Diabetes, Obesity and Metabolism

1. review article
Diabetes, Obesity and Metabolism 13: 490–497, 2011.
© 2011 Blackwell Publishing Ltd
article
review
Pharmaceutical interventions for obesity: a public health
perspective
E. Caveney1 , B. J. Caveney2 , R. Somaratne1 , J. R. Turner1 & L. Gourgiotis1
1 Quintiles, Morrisville, NC, USA
2 Department of Occupational Medicine, Duke University Medical Center, Durham, NC, USA
The prevalence of obesity, a major risk factor for many chronic diseases, has risen in most developed countries over the past several decades.
The economic burden for both public and private health care systems is substantial. Although certain non-pharmaceutical interventions have
been proven efficacious in specific populations, the lack of scalability has caused many of these programmes to fail in sustainably decreasing
the percent of patients who are overweight or obese. The benefits of other interventions, such as pharmaceutical agents, medical devices and
surgery, should therefore be carefully considered: this article focuses on the first of these strategies. Various pharmaceutical products have
been plagued with safety concerns or patient non-adherence because of unpleasant side effects. Therefore, the need for additional antiobesity
drugs that are both safe and effective is considerable. This article discusses the regulatory landscape for the development of new antiobesity
compounds in the United States and Europe and considers the ramifications of greater or lesser regulatory burdens.
Keywords: antiobesity drug, behavioural factors, clinical trial, cost-effectiveness, medicines management, obesity, obesity therapy,
pathophysiological sequelae of obesity, pharmaceutical interventions, public health, regulatory guidance
Date submitted 5 August 2010; date of first decision 23 September 2010; date of final acceptance 2 December 2010
Introduction obese and projected that figure to increase to over 700 million
people by 2015 [3]. Currently, about 33.8% of adults ≥20 years
Obesity, defined by the World Health Organization (WHO) as
old in the United States and about 20% of European adults, in
excessive fat accumulation that presents a risk to health [1], is an
aggregate, are obese [4,5].
international public health concern of staggering proportions.
Because excess weight contributes to the development and
A common method of quantifying excess weight in adults
aggravation of a large number of chronic diseases, including
uses the body mass index (BMI), a simple relationship of
diabetes, hypertension, dyslipidaemia, cardiovascular disease
weight in kilograms to the square of height in metres (kg/m2 ).
and cancer of the colon, oesophagus, pancreas, gallbladder,
Originally, overweight adults were defined by a BMI between
kidney, breast and ovaries [6], the economic burden from
25 and 29.9 kg/m2 , whereas obese individuals were classified by
the increasing prevalence of obesity is enormous. Both direct
a BMI ≥ 30 kg/m2 . Obesity was further subclassified as obesity
medical expenses (preventive, diagnostic and treatment-related
class I (BMI 30–34.9 kg/m2 ), class II (BMI 35–39.9 kg/m2 )
medical system costs of patients with obesity and its sequelae)
and class III (BMI ≥ 40 kg/m2 ). Although this is still true
and indirect costs (e.g. decreased work productivity, increased
for ethnic and genetic backgrounds other than Asian and
Pacific Island populations, it was recognized that several absenteeism and increased disability payments) are incurred
different ethnic and genetic backgrounds experience the adverse from higher rates of obesity. Although it is difficult to attribute
health effects of excess weight at different levels. Because a specific medical expenditure in the light of its multifactorial
of this the WHO, the International Obesity Task Force physiological effects and host of co-morbidities, it has been
and the International Association for the Study of Obesity estimated that the medical costs associated with obesity account
have proposed lower cut-off points for overweight (BMI = for 9.1% of total US medical expenditures or over $147 billion
23.0 kg/m2 ) and obesity (BMI = 25.0 kg/m2 ) in Asian and annually [7]. Adult obesity accounts for up to 6% of the direct
Pacific Island populations [2]. Furthermore, for children and health costs in the WHO European Region [8].
adolescents, the BMI values that are considered healthy vary With regard to indirect costs, there is a linear relationship
depending on the age. Although the total prevalence of obesity between BMI and the rate, duration and expense of workers’
varies considerably by age, socio-economic status, culture, compensation claims [9]. European studies suggest that obese
gender, race and other characteristics in each country, the WHO workers are absent from the workplace about 10 days more
estimated that in 2005 at least 400 million people globally were on average than their normal weight counterparts [10]. Total
indirect costs may be as high as $65 billion in the United
States [11]. Effective interventions, therefore, would be of
Correspondence to: Dr. Erica Caveney, Quintiles, 5927 South Miami Blvd, Morrisville
27560, USA. considerable advantage to many individuals and organizations,
E-mail: erica.caveney@quintiles.com public and private, including researchers and companies that

2. DIABETES, OBESITY AND METABOLISM review article
identify novel, safe and efficacious interventions and bring • Bariatric surgery should be performed at high-volume centres
them successfully to market. with experienced surgeons.
Table 1 presents the antiobesity drugs that are currently
Lifestyle Modifications and Beyond approved and marketed, as well as the ones previously approved
and withdrawn. Table 2 identifies the compounds that are in
Lifestyle modifications are important first options in treating
the current drug pipeline.
various disease states. Blood pressure and diabetes mellitus
provide instructive examples. As discussed in the Seventh
Report of the Joint National Committee on Prevention, Current Regulatory Landscapes in the
Detection, Evaluation and Treatment of High Blood Pressure
(JNC 7) [12], the 2010 American Diabetes Association’s
United States and Europe
Standards of Medical Care in Diabetes [13] and by the In February 2007, the US Food and Drug Administration
International Diabetes Federation [14], lifestyle modifications, (FDA) issued a draft Guidance for Industry entitled Developing
including improved dietary and physical activity profiles, are Products for Weight Management [17], which is not yet finalized.
first-line therapies for hypertension and diabetes. The European Medicines Agency (currently abbreviated as
They are also important interventions for obesity. The math- EMA, although EMEA was used until early 2010) document
ematics of calories and weight are simple: if one routinely entitled Guideline on Clinical Evaluation of Medicinal Products
consumes (eats and drinks) fewer calories than one expends Used in Weight Control [18] was released in draft form in June
(necessary metabolism to sustain life plus physical activity), 2006 and came into effect in May 2008. A comparison of these
weight loss will ensue. The major components of daily energy guidelines is presented in Table 3.
expenditure are resting energy expenditure (resting metabolic Although the guidelines are similar in their overall approach
rate), non-resting energy expenditure (physical activity and by agreeing that the primary efficacy endpoint for weight-
exercise) and the thermal effect of food. It has been reported management products should be weight loss, there are note-
that up to 24% of men and 28% of women in the United States worthy differences. First, the threshold set by the EMA is slightly
describe themselves as trying to lose weight [15]. However, few more stringent than the FDA’s. The EMA requires ‘demonstra-
are able to sustain the behavioural and psychological modifica- tion of a clinically significant degree of weight loss of at least 10%
tions to achieve medically relevant weight loss. Many significant of baseline weight, which is also at least 5% greater than placebo
behavioural changes are not easy to implement and/or main- . . . . Proportions of responders in the various treatment arms
tain for the vast majority of individuals and, certainly in could be considered as an alternative primary efficacy criterion
western settings, there are many cultural reinforcers for eating where response is more than 10% weight loss at the end of a
unhealthily and doing less physical activity. Therefore, prag- 12 month period’ [18]. The FDA guideline notes that, in gen-
matic considerations argue for the need for alternate/additional eral, a product can be considered effective for weight manage-
interventions that have a greater chance of success at the public ment if, after 1 year of treatment, either of the following occurs:
health level. For conditions such as hypertension and hyper- • The difference in mean weight loss between the active-
lipidaemia, pharmacological intervention with a wide variety product and the placebo-treated groups is at least 5% and
of agents has been proven to reduce the complications of the difference is clinically significant; or
these conditions [12]. However, this luxury of pharmaceutical • The proportion of subjects who lose ≥5% of baseline body
options is not currently available for obesity. weight in the active-product group is at least 35%, is
approximately double the proportion in the placebo-treated
Pharmaceutical Interventions to Date and group, and the difference is statistically significant.
the Current Pipeline Second, while there is no mention of appropriate sample
The guidelines from the US Preventive Services Task Force sizes in the EMA guideline, the FDA guideline provides the
for Screening for Obesity in Adults give five recommenda- following recommendations:
tions [16]:
A reasonable estimation of the safety of a
• Counsel all patients with obesity (BMI ≥ 30 kg/m2 ) on diet, weight-management product upon which to base
lifestyle and goals for weight loss. approval generally can be made when a total of
• Pharmacological therapy may be offered to those who have approximately 3000 subjects are randomized to
failed to achieve weight loss goals through diet and exercise active doses of the product and no fewer than 1500
alone. subjects are randomized to placebo for 1 year of
• Pharmacological options include sibutramine, orlistat, treatment.
phentermine, diethylpropion and two drugs that are not
approved for obesity treatment, fluoxetine and bupropion. Third, there are slight differences in the populations sought to
• Bariatric surgery should be considered for patients with enrol in clinical trials to test new antiobesity drugs. The FDA
BMI ≥ 40 kg/m2 who have failed diet and exercise (with document advises that ‘patients included in the early phase effi-
or without drug therapy) and who have obesity-related cacy and safety studies generally should have BMIs ≥ 30 kg/m2
co-morbidities (hypertension, impaired glucose tolerance, or BMI ≥ 27 kg/m2 if accompanied by co-morbidities’. It goes
diabetes mellitus, dyslipidaemia and sleep apnoea). on to state that these figures should also serve as BMI cut-off
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3. review article DIABETES, OBESITY AND METABOLISM
Table 1. Currently available and withdrawn antiobesity drugs.
Drug Mechanism of action Date/region approved Date/region withdrawn Comments
Currently available prescription drugs
Orlistat Pancreatic lipase inhibitor 1999 FDA Drug still in market Gastrointestinal side effects, such as faecal
Certain preparations incontinence and steatorrhoea, which may
approved by FDA limit compliance.
(2006) and EMA Between 1999 and October 2008, 32 reports
(2009) for sale without of serious liver injury, including six cases
prescription of liver failure, were submitted to FDA’s
Adverse Event Reporting System. In
March 2010, FDA has approved a revised
label for orlistat to include new safety
information about cases of severe liver
injury, although no causal relationship has
been established so far
Amphetamine Central noradrenaline Weight loss properties Available High abuse and addiction potential. Can
release were first shown in cause elevation of cardiac output and
1938 blood pressure. Currently, very rarely used
for obesity management. In the US
amphetamine is a schedule II drug under
the Federal Controlled Substances Act
Amphetamine Central norepinephrine FDA Available All are scheduled drugs under the US Federal
derivatives and dopamine release • Benzphetamine 1960 Controlled Substances Act:
• Benzphetamine • Phendimetrazine, benzphetamine and phendimetrazine are
• Phendimetrazine diethylpropion, schedule II drugs, diethylpropion and
• Diethylpropion phentermine 1959 phentermine are schedule IV drugs. They
• Phentermine are approved for short treatment periods
of up to 12 weeks
Previously available drugs
Rimonabant Selective cannabinoid Never approved in the In November 2008, The drug was associated with severe
receptor (CB1) United States Sanofi-Aventis halted psychiatric side effects, such as depression,
antagonist any further research anxiety and suicidal ideation.
in the compound. Suspension of rimonabant resulted in
Withdrawn from EU termination of the clinical development of
in 2009 other cannabinoid CB1 receptor
antagonists from other pharmaceutical
companies
Sibutramine Serotonin and 1997 FDA January 2010: withdrawn In the SCOUT study, cardiovascular events
norepinephrine from UK and EU occurred in 11.4% of patients using
reuptake inhibitor October 2010: removed sibutramine compared with 10% using a
from the United States placebo. These results led to the
withdrawal of the drug from the United
States and the EU
Mazindol Sympathomimetic amine 1973 FDA Withdrawn from US Withdrawn because of allegations of
market in 2001, from increased risk of cardiac valvulopathy
UK in 1972
Fenfluramine Serotonin reuptake 1973 FDA Withdrawn from the Withdrawn after reports of valvular heart
inhibition and United States 1997 damage (caused by selective stimulation of
serotonin release from and other countries 5-HT2B receptors on human cardiac
vesicular storage followed valves) and primary pulmonary
hypertension
Aminorex Central norepinephrine Introduced in Germany, Withdrawn in 1972 Withdrawn because of pulmonary
release Switzerland and hypertension
Austria in 1965
Phenylpropanolamine Central norepinephrine 1979 FDA Withdrawn in 2000 Increased risk of haemorrhagic stroke
and epinephrine release
Dinitrophenol Uncouples oxidative Introduced in the United Withdrawn from the Withdrawn because of cases of fatal
phosphorylation from States in 1933 United Sates in 1938 hyperthermia, rashes and cataract. Still
the production of ATP, used in the bodybuilding and athlete
leading to calorie loss community
as heat
Ephedra Sympathomimetic 1947 FDA Banned 2004 FDA Increased risk of cardiovascular and
neuropsychiatric adverse events
EMA, European Medicines Agency; EU, European Union; FDA, Food and Drug Administration; SCOUT, Sibutramine Cardiovascular OUTcomes.
492 Caveney et al. Volume 13 No. 6 June 2011

4. DIABETES, OBESITY AND METABOLISM review article
Table 2. The pipeline of future antiobesity drugs. Table 2. Continued.
Drug (manufacturer) Comments Drug (manufacturer) Comments
Lorcaserin (Arena) Selective 5-HT2C receptor agonist Beta-3 adrenergic receptor Phase 2
NDA was submitted to FDA in agonists
December 2009, FDA Advisory • LY377604 (Eli Lilly)
committee in September 2010, Methionine aminopeptidase Phase 1
PDUFA in October 2010 2 (MetAP2) inhibition
On 16 September 2010, a federal ZGN-433 (Zafgen)
advisory committee voted against SGLT2 inhibition Phase 1
recommending approval for • PF04971729 (Pfizer)
lorcaserin, amidst concerns about Diglyceride Acyltransferase Phase 1
the safety of the drug, particularly 1(DGAT1) inhibition
the findings of tumours in • PF-04620110 (Pfizer)
rats Dopamine (D3) receptor Phase 1
On 23 October 2010, FDA rejected the antagonists
NDA • GSK598809 (GSK)
Qnexa (Vivus) Combination of phentermine and Mu-opioid receptor Phase 1
topiramate antagonists
An NDA was submitted to the FDA in • GSK1521498 (GSK)
December 2009 Vabicaserin (Wyeth) Antipsychotic; currently in preclinical
The FDA Advisory Committee in July evaluation for obesity
2010 voted 10-6 against drug approval, Melanocortin-4 receptor Preclinical data
because of potential increased risk of (MC4R) agonists
psychiatric and cognitive adverse 5-HT6 receptor ligands Preclinical data
events, the lack of data regarding
cardiovascular safety and the potential FDA, Food and Drug Administration; GLP-1, glucagon-like peptide-1;
risk of birth defects NDA, new drug application; PDUFA, Prescription Drug User Fee Act.
On 28 October 2010, FDA rejected the
NDA
Contrave (Orexigen) Combination of naltrexone and points for phase 3 studies. When it discusses phase 3 trials, the
bupropion. An NDA was submitted to FDA provides the following examples of co-morbidities: type 2
the FDA in March 2010 diabetes mellitus (T2DM), hypertension, dyslipidaemia, sleep
FDA review in December 2010
apnoea and cardiovascular disease. The EMA document agrees
Cetilistat (Norgina Pancreatic lipase inhibitor, phase 3 trials
BV/Takeda) in Japan
that otherwise healthy adults with a BMI of 30 kg/m2 or more
Empatic (Orexigen) Combination of bupropion and may be appropriate patients in these clinical trials. However,
zonisamide, phase 3 the EMA notes that subjects with a BMI > 25 kg/m2 (and not
Tesofensine (NeuroSearch) Triple reuptake inhibitor (serotonin, 27 kg/m2 as the FDA suggests) plus associated or secondary
norepinephrine and dopamine), soon effects of obesity (such as hypertension, hyperlipidaemia, dia-
to start phase 3 trials betes mellitus or impaired glucose tolerance/impaired fasting
Liraglutide (NovoNordisk) GLP-1 analogue, approved for type 2
glucose and cardiovascular disease) should be considered for
diabetes mellitus, in phase 3 studies for
obesity
such studies.
Peptide YY (PYY), pancreatic Obinepitide is a synthetic analogue of The EMA guideline also notes that effects on morbidity
polypeptide (PP) PYY and PP currently in phase 2 and mortality may be measured directly as efficacy variables,
• Obinepitide (Nastech) studies. TM30339 targets the PP Y4 but can be properly evaluated only in large clinical trials. It
• TM30339 (Nastech) receptor, currently in phase 2 studies. states ‘in view of the goals of treatment of obesity, drugs
• PP1420 (Wellcome Trust) PP1420 is a PP analogue, currently in used to treat it should be shown to have no deleterious
phase 1 studies
effects on cardiovascular factors’ [18]. The EMA document
Neuropeptide Y (NPY) NPY Y5 receptor antagonist with two
modulation phase 2 clinical trials completed in the also singles out neuropsychiatric effects as an area where special
• Velneperit (Shionogi United States in 2009 efforts should be made to assess potential adverse effects. The
Research Laboratories) FDA guidelines also direct the assessment of neuropsychiatric
Melanin-concentrating Phase 2 function for centrally acting compounds and the evaluation
hormone-1 receptors of the immunogenic potential of therapeutic proteins and
antagonists study abuse liability in centrally acting weight-management
• BMS-830216 (Bristol Myers
Squibb)
products.
Pramlintide plus Metreleptin Pramlintide is a synthetic analogue To ensure that any weight loss attributed to a new drug is
(Amylin) of amylin, metreleptin is an also associated with a beneficial health profile, both agen-
analogue of human leptin, phase 2 cies include various secondary endpoints to better assess
studies efficacy in their guidelines. These include blood pressure,
AgRP antagonists Phase 2 pulse rate, lipids, fasting glucose and insulin. Additionally,
• TTP435 (TransTech)
the EMA’s guideline contains ultrasensitive C-reactive protein,
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5. review article DIABETES, OBESITY AND METABOLISM
Table 3. Comparison of the FDA and EMA regulatory guidelines for development of medicinal products for weight management.
FDA EMA
Primary efficacy endpoint Weight loss: Weight loss:
Threshold After 1 year of treatment the difference in mean weight Demonstration of a clinically significant degree of
loss between the active-product and placebo-treated weight loss of at least 10% of baseline weight, which is
groups is: also at least 5% greater than placebo after a 12-month
• at least 5% period
• the difference is clinically significant;
or
the proportion of subjects
who lose ≥5% of baseline
body weight in the
active-product group is:
• at least 35%
• approximately double the proportion in the placebo-
treated group
• the difference is statistically significant
Sample size Specified Not specified
Population Subject’s body mass index (BMI) should be ≥30 kg/m2 Otherwise healthy adults with a BMI ≥ 30 kg/m2 or
or ≥27 kg/m2 if accompanied by co-morbidities, such BMI ≥ 25 kg/m2 plus associated or secondary effects
as type 2 diabetes mellitus, hypertension, of obesity, such as hypertension, hyperlipidaemia,
dyslipidaemia, sleep apnoea and cardiovascular diabetes mellitus or impaired glucose
disease tolerance/impaired fasting glucose or cardiovascular
disease
Efficacy variables Centrally acting drugs: must evaluate neuropsychiatric No deleterious effects on the cardiovascular system
function Centrally acting drugs:
Assessment of the immunogenic potential of therapeutic must evaluate
proteins neuropsychiatric
Abuse liability in centrally acting weight-management function
products
Potential secondary Blood pressure Blood pressure
endpoints Pulse rate Pulse rate
Lipids Lipids
Fasting glucose Fasting glucose
Insulin Insulin
Ultrasensitive C-reactive
protein sleep apnoea
episodes
Mechanical joint distress
infertility
Psychosocial aspects
Visceral fat measurement: Waist circumference should not serve as a surrogate for Waist circumference, waist-to-hip ratio, magnetic
Both guidances direct that visceral fat content resonance imaging, computed tomography can be
measurement in body mass used to assess abdominal fat content
composition be done
EMA, European Medicines Agency; FDA, Food and Drug Administration.
sleep apnoea episodes, mechanical joint distress, infertility and content can be accurately measured with computed tomog-
psychosocial aspects (measured as quality of life) as potential raphy, magnetic resonance imaging and dual-energy x-ray
secondary efficacy endpoints. absorptiometry. Less costly measurements, such as measur-
Both guidances acknowledge the fact that several epidemi- ing skin-fold thickness, waist circumference and the ratio of
ological studies have shown that the regional distribution of waist/hip circumference, are routinely used in clinical prac-
tice.
body fat, specifically an increased level of visceral or intra-
The FDA guidance directs that waist circumference should
abdominal adiposity, is a significant independent risk factor
not serve as a surrogate for visceral fat content when measured
for metabolic abnormalities and cardiovascular disease [19,20].
in a clinical trial investigating the efficacy of a product for weight
On the basis of this, both guidances direct that a study’s design loss, thus implying the need for more accurate assessment of
ensures that the drug- or biologic-induced weight loss is caused changes in body composition. In contrast, the EMA states
primarily by a reduction in fat content, and not lean body that ‘methods such as waist circumference, waist-to-hip ratio,
mass or body water, and they ask that this be shown by magnetic resonance imaging and computed tomography may
measuring changes in body mass composition. Visceral fat be used to assess abdominal fat content’ [18].
494 Caveney et al. Volume 13 No. 6 June 2011

6. DIABETES, OBESITY AND METABOLISM review article
Implications of Current Regulatory Favourable Benefit–risk Profiles and the
Documents and Evolving Regulatory Mitigation of Risk
Landscapes By definition, all regulatory decisions are made at the public
It can be reasonably argued that regulatory agencies are becom- health level. The ultimate question of concern is Does this
ing more cautious in their marketing approval assessments, product have a favourable benefit–risk profile from a public
given the increased attention to safety considerations. Clear health perspective? This contrasts with decisions made by
examples are the relatively recent FDA and EMA guidances prescribing physicians and their patients, which are made at
addressing the prospective exclusion of unacceptable cardio- the individual level on a patient-by-patient basis. The concept
vascular risk of new antidiabetic drugs for the treatment of of the benefit–risk profile is particularly useful because the
definition of ‘drug safety’ is not clear. One simple way to
T2DM. These guidances, which have a noble goal at heart,
define drug safety operationally is to measure adverse events
could lead to less than the desirable availability of antidiabetic
and adverse drug reactions (i.e. harm) and define safety as
drugs in coming years [21,22].
its inverse: the less the harm, the greater the safety [24]. The
At the American Diabetes Association 2010 Scientific session,
FDA’s Sentinel Initiative provides a more sophisticated and
the current state of obesity treatment was compared with the
useful definition [25].
state of diabetes treatment 30 years ago, when there was a large-
scale medical need with few treatment options available. To Although marketed medical products are required
make researchers and companies more interested and invested by federal law to be safe for their intended use,
in developing antiobesity treatments, it was suggested that safety does not mean zero risk. A safe product is
regulatory requirements be less stringent for the approval for one that has acceptable risks, given the magnitude
new drug therapies. The rationale for this is that, as we have of benefit expected in a specific population and
a global epidemic that increases morbidity and mortality with within the context of alternatives available.
few treatment options available, the regulatory agencies should Once it is determined that the benefit-risk is favorable, as
encourage safe innovation in this area by having a lower bar much as possible must be done to mitigate the risks. There
for the approval for antiobesity drugs. If this stance were are several tools available to regulators to mitigate risks at
adopted, the regulatory agencies would be broadcasting that the public health level, including traditional label warnings
they believe treating obesity is not a cosmetic decision, but one and the more recent strategies provided by the Food and
that is imperative for the health of overweight and obese people Drug Administration Amendments Act of 2007 [26]. Subtitle
globally. If the agencies allow the perfect to get in the way of the A, Title IX, Section 901 introduced the Risk Evaluation and
possible for antiobesity drugs, they will send a message about Mitigation Strategies (REMS). A REMS is not a general ‘how
how they view the consequences of obesity. to use the drug’ document, but addresses a specific potential
However, because obesity is typically a chronic state, it can risk indicated by a specific safety signal seen in premarketing
be expected that patients will take antiobesity medicines for approval or subsequent postmarketing surveillance [27]. A
years, decades or even indefinitely. Twelve months of clinical REMS can include elements such as a medication guide,
trial data cannot supply the regulators with the knowledge a package insert and a communication plan to health care
that the drug is safe and effective for longer time periods. An providers.
example of this is highlighted by the fact that, in October 2010, It can also contain ‘Elements to Assure Safe Use’, which
the FDA decided against the approval for lorcaserin because include [28]:
of breast tumours in rats during the preclinical studies of the • Health care providers who prescribe the drug have particular
drug and the potential relevance of this finding for human training or experience or are specially certified.
subjects. Furthermore, the target population for these types of • Pharmacies, practitioners or health care settings that dispense
drugs will often be of childbearing potential, requiring close the drug are specially certified.
analysis during studies. The importance placed on this fact was • The drug is dispensed to patients only in certain health care
underscored at a July 2010 FDA Advisory Committee meeting settings, such as hospitals.
on the fate of Qnexa (phentermine/topiramate), citing this as • The drug is dispensed to patients with evidence or other
one of the reasons some members voted against approval documentation of safe use conditions, such as laboratory test
for the drug [23]. Perhaps not unexpectedly, in October results.
2010 the FDA rejected the Qnexa New Drug Application, • Each patient using the drug is subject to certain monitoring.
• Each patient using the drug is enrolled in a registry.
requesting a thorough evaluation of the drug’s potential to
cause birth defects and cardiovascular problems. However, Therefore, strategies to minimize risk at the public health
Qnexa comprises doses of phentermine and topiramate, which level, and also the individual patient level, are available.
are substantially less than the doses currently approved for the Examples where special precautions are taken include thalido-
treatment of other diseases; in addition, the FDA currently mide (indicated in the United States for erythema nodosum
approves phentermine for short-term use (up to 12 weeks) in leprosum and multiple myeloma) and isotretinoin (Accutane,
obese adults with a BMI ≥ 30 kg/m2 or BMI ≥ 27 kg/m2 in the indicated for acne, which, like obesity, can be considered
presence of other risk factors such as hypertension, diabetes a cosmetic condition, but, also like obesity, can have serious
mellitus and/or dyslipidaemia or a high waist circumference. psychological consequences for individuals with the condition).
Volume 13 No. 6 June 2011 doi:10.1111/j.1463-1326.2010.01353.x 495

7. review article DIABETES, OBESITY AND METABOLISM
An instructive example here is provided by respective University Medical Center. E. C., L. G., B. J. C. and R. S.
decisions made by the FDA and EMA in September 2010 designed the study. E. C., L. G., B. J. C. and J. R. T. were
concerning the thiazolidinedione rosiglitazone (Avandia). The involved in conduct/data collection. E. C., L. G., B. J. C., J. R.
FDA required a postmarketing REMS for the drug follow- T. and R. S. analysed the data. E. C., J. R. T., L. G. and B. J. C.
ing recommendations made at a July 2010 joint meeting were involved in writing the manuscript.
of its Endocrinologic and Metabolic Drugs Advisory Com-
mittee and its Drug Safety and Risk Management Advisory
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