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DIABETES, OBESITY AND METABOLISM                                                                  review articleidentify n...
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DIABETES, OBESITY AND METABOLISM                                                                              review artic...
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DIABETES, OBESITY AND METABOLISM                                                                     review articleImplica...
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DIABETES, OBESITY AND METABOLISM                                                                                   review ...
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Farmacoterapia da obesidade

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

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Farmacoterapia da obesidade

  1. 1. review article Diabetes, Obesity and Metabolism 13: 490–497, 2011. © 2011 Blackwell Publishing Ltdarticlereview 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. 2. DIABETES, OBESITY AND METABOLISM review articleidentify novel, safe and efficacious interventions and bring • Bariatric surgery should be performed at high-volume centresthem successfully to market. with experienced surgeons. Table 1 presents the antiobesity drugs that are currentlyLifestyle Modifications and Beyond approved and marketed, as well as the ones previously approved and withdrawn. Table 2 identifies the compounds that are inLifestyle modifications are important first options in treating the current drug pipeline.various disease states. Blood pressure and diabetes mellitusprovide instructive examples. As discussed in the SeventhReport of the Joint National Committee on Prevention, Current Regulatory Landscapes in theDetection, Evaluation and Treatment of High Blood Pressure(JNC 7) [12], the 2010 American Diabetes Association’s United States and EuropeStandards of Medical Care in Diabetes [13] and by the In February 2007, the US Food and Drug AdministrationInternational Diabetes Federation [14], lifestyle modifications, (FDA) issued a draft Guidance for Industry entitled Developingincluding 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) documentematics of calories and weight are simple: if one routinely entitled Guideline on Clinical Evaluation of Medicinal Productsconsumes (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 theseweight 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 approachrate), 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 slightlydescribe 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 placebobehavioural changes are not easy to implement and/or main- . . . . Proportions of responders in the various treatment armstain for the vast majority of individuals and, certainly in could be considered as an alternative primary efficacy criterionwestern settings, there are many cultural reinforcers for eating where response is more than 10% weight loss at the end of aunhealthily 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% andof agents has been proven to reduce the complications of the difference is clinically significant; orthese conditions [12]. However, this luxury of pharmaceutical • The proportion of subjects who lose ≥5% of baseline bodyoptions is not currently available for obesity. weight in the active-product group is at least 35%, is approximately double the proportion in the placebo-treatedPharmaceutical Interventions to Date and group, and the difference is statistically significant.the Current Pipeline Second, while there is no mention of appropriate sampleThe guidelines from the US Preventive Services Task Force sizes in the EMA guideline, the FDA guideline provides thefor 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-offVolume 13 No. 6 June 2011 doi:10.1111/j.1463-1326.2010.01353.x 491
  3. 3. review article DIABETES, OBESITY AND METABOLISMTable 1. Currently available and withdrawn antiobesity drugs.Drug Mechanism of action Date/region approved Date/region withdrawn CommentsCurrently available prescription drugsOrlistat 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 farAmphetamine 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 ActAmphetamine 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 weeksPreviously available drugsRimonabant 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 companiesSibutramine 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 EUMazindol Sympathomimetic amine 1973 FDA Withdrawn from US Withdrawn because of allegations of market in 2001, from increased risk of cardiac valvulopathy UK in 1972Fenfluramine 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 hypertensionAminorex Central norepinephrine Introduced in Germany, Withdrawn in 1972 Withdrawn because of pulmonary release Switzerland and hypertension Austria in 1965Phenylpropanolamine Central norepinephrine 1979 FDA Withdrawn in 2000 Increased risk of haemorrhagic stroke and epinephrine releaseDinitrophenol 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 heatEphedra Sympathomimetic 1947 FDA Banned 2004 FDA Increased risk of cardiovascular and neuropsychiatric adverse eventsEMA, 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. 4. DIABETES, OBESITY AND METABOLISM review articleTable 2. The pipeline of future antiobesity drugs. Table 2. Continued.Drug (manufacturer) Comments Drug (manufacturer) CommentsLorcaserin (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 NDAContrave (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 agreesCetilistat (Norgina Pancreatic lipase inhibitor, phase 3 trials BV/Takeda) in Japan that otherwise healthy adults with a BMI of 30 kg/m2 or moreEmpatic (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 notTesofensine (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 fastingLiraglutide (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 documentNeuropeptide 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 neuropsychiatricMelanin-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,Volume 13 No. 6 June 2011 doi:10.1111/j.1463-1326.2010.01353.x 493
  5. 5. review article DIABETES, OBESITY AND METABOLISMTable 3. Comparison of the FDA and EMA regulatory guidelines for development of medicinal products for weight management. FDA EMAPrimary 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 significantSample 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 diseaseEfficacy 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 productsPotential 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 aspectsVisceral fat measurement: Waist circumference should not serve as a surrogate for Waist circumference, waist-to-hip ratio, magneticBoth guidances direct that visceral fat content resonance imaging, computed tomography can be measurement in body mass used to assess abdominal fat content composition be doneEMA, 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-raysecondary 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 ofological 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 shouldabdominal adiposity, is a significant independent risk factor not serve as a surrogate for visceral fat content when measuredfor metabolic abnormalities and cardiovascular disease [19,20]. in a clinical trial investigating the efficacy of a product for weightOn the basis of this, both guidances direct that a study’s design loss, thus implying the need for more accurate assessment ofensures that the drug- or biologic-induced weight loss is caused changes in body composition. In contrast, the EMA statesprimarily 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 maymeasuring 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. 6. DIABETES, OBESITY AND METABOLISM review articleImplications of Current Regulatory Favourable Benefit–risk Profiles and theDocuments and Evolving Regulatory Mitigation of RiskLandscapes By definition, all regulatory decisions are made at the publicIt can be reasonably argued that regulatory agencies are becom- health level. The ultimate question of concern is Does thising more cautious in their marketing approval assessments, product have a favourable benefit–risk profile from a publicgiven the increased attention to safety considerations. Clear health perspective? This contrasts with decisions made byexamples are the relatively recent FDA and EMA guidances prescribing physicians and their patients, which are made ataddressing the prospective exclusion of unacceptable cardio- the individual level on a patient-by-patient basis. The conceptvascular 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 toT2DM. These guidances, which have a noble goal at heart, define drug safety operationally is to measure adverse eventscould lead to less than the desirable availability of antidiabetic and adverse drug reactions (i.e. harm) and define safety asdrugs 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 andthe 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 requiredmake 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 isregulatory requirements be less stringent for the approval for one that has acceptable risks, given the magnitudenew drug therapies. The rationale for this is that, as we have of benefit expected in a specific population anda 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, asencourage safe innovation in this area by having a lower bar much as possible must be done to mitigate the risks. Therefor the approval for antiobesity drugs. If this stance were are several tools available to regulators to mitigate risks atadopted, the regulatory agencies would be broadcasting that the public health level, including traditional label warningsthey believe treating obesity is not a cosmetic decision, but one and the more recent strategies provided by the Food andthat is imperative for the health of overweight and obese people Drug Administration Amendments Act of 2007 [26]. Subtitleglobally. If the agencies allow the perfect to get in the way of the A, Title IX, Section 901 introduced the Risk Evaluation andpossible for antiobesity drugs, they will send a message about Mitigation Strategies (REMS). A REMS is not a general ‘howhow 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 premarketingbe expected that patients will take antiobesity medicines for approval or subsequent postmarketing surveillance [27]. Ayears, 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 carethat 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’, whichthe 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 particulardrug 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 dispensedrugs 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 careunderscored 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 otherone of the reasons some members voted against approval documentation of safe use conditions, such as laboratory testfor 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 tocause birth defects and cardiovascular problems. However, Therefore, strategies to minimize risk at the public healthQnexa 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 nodosumapproves 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 consideredpresence of other risk factors such as hypertension, diabetes a cosmetic condition, but, also like obesity, can have seriousmellitus 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. 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. wereconcerning 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 AdvisoryCommittee. Required elements include the provision of com- Referencesplete risk information to the patient, administration of the 1. World Health Organization. Available from URL: http://www.who.int/compound to specific patient populations and enrolment of topics/obesity/en. Accessed 18 July 2010.physician/patient/pharmacist to special registries [29,30]. 2. World Health Organization/International Obesity Task Force. The Asia- In contrast, based on the same data and announced on the Pacific Perspective: Redefining Obesity and its Treatment. Australia: Healthsame day as the FDA’s decision, the EMA’s Committee for Communications Australia Pty Limited, 2000.Medicinal Products for Human Use voted to remove the drug 3. World Health Organization. Obesity and Overweight. Fact Sheet Numberfrom the European markets: the European Commission will 311. 2006.make the final decision that will be legally binding the 27- 4. Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends inmember countries in the European Union. This difference in obesity among US adults, 1999–2008. JAMA 2010; 303: 235–241.regulatory action, however, is not the result of widely diverging 5. World Health Organization Europe. 10 things you need to know aboutassessments of the available data [29]. Rather, it reflects that obesity. November 2006.the FDA has a useful tool, the REMS, at its disposal that 6. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass indexcan be used to facilitate the continued availability and the and incidence of cancer: a systematic review and meta-analysis ofuse of rosiglitazone by a select group of patients for whom prospective observational studies. Lancet 2008; 371: 569–578.its benefit–risk balance is favourable. As the EMA has no 7. Finkelstein EA, Trogdon JG, Cohen JW, Dietz W. Annual medical spendingequivalent tool, its recommendation must be a blanket removal attributable to obesity: payer and service-specific estimates. Health Afffrom the market, therefore depriving an important subgroup 2009; 28: w822–w831.of patients for whom the drug’s benefit–risk profile would have 8. Muller-Riemenschneider F, Reinhold T, Berghofer A, Willich SN. Health-been favourable. economic burden of obesity in Europe. Eur J Epidemiol 2008; 23: 499–509. 9. Ostbye T, Dement JM, Krause KM. Obesity and workers’ compensation:Concluding Comments results from the Duke Health and Safety Surveillance System. Arch InternAs the regulatory agencies chart the way forward, they have Med 2007; 167: 766–773.lessons learned from the past to help guide their future. In 10. Neovius K, Johansson K, Kark M, Neovius M. Obesity status and sick leave:the past decade, there have been some important and well- a systematic review. Obes Rev 2008; 10: 17–27.publicized medicines that have been implicated in causing more 11. Trogdon JG, Finkelstein EA, Hylans T, Dellea PS, Kamal-Bahl SJ. Indirectrisks than benefits in certain instances. 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Avail-gering, there are many promising pharmaceutical treatments able from URL: http://www.idf.org/webdata/docs/GGT2D%2005%20in the current drug pipeline (Table 2). United States and Euro- Lifestyle%20management.pdf. Accessed 26 July 2010.pean regulatory agencies have similar but slightly different 15. Kruger J, Galuska DA, Serdula MK, Jones DA. Attempting to lose weight:expectations to show clinical efficacy and safety, requiring Specific practices among U.S. adults. Am J Prev Med 2004; 26: 402–406.researchers to design clinical trial protocols strategically to 16. The U.S. Preventive Services Task Force, Screening for Obesity in Adults,measure decreases in body fat as well as long-term health con- Recommendations and Rationale. Available from URL: http://www.ussequences. Hopefully, several compounds in development will preventiveservicestaskforce.org/3rduspstf/obesity/obesrr.htm. Accessed 5 November 2010.become widely available safe and effective tools for cliniciansto decrease the health risks of obesity in their patients. 17. FDA. Guidance for Industry: Developing Products for Weight Management. Available from URL: http://www.fda.gov/downloads/Drugs/Guidance ComplianceRegulatoryInformation/Guidances/ucm071612.pdf. Accessed 18 July 2010.Conflict of Interest 18. EMA. Guideline on Clinical Evaluation of Medicinal Products Used inE. C., L. G., R. S. and J. R. T. have disclosed that they Weight Control. Available from URL: http://www.ema.europa.eu/docs/work for Quintiles, a commercial vendor of drug development en_GB/document_library/Scientific_guideline/2009/09/WC500003264.consulting and clinical trial services. B. J. C. works at Duke pdf. Accessed 18 July 2010.496 Caveney et al. Volume 13 No. 6 June 2011
  8. 8. DIABETES, OBESITY AND METABOLISM review article19. Canoy D. Coronary heart disease and body fat distribution. Curr Atheroscler 26. 110th US Congress. Food and Drug Administration Amendments Act; Rep 2010; 12: 125–133. September 2007. Available from URL: http://www.fda.gov/ Regulatory20. Phillips LK, Prins JB. The link between abdominal obesity and the metabolic Information/Legislation/FederalFoodDrugandCosmeticActFDCAct/Signific syndrome. Curr Hypertens Rep 2008; 10: 156–164. antAmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsA ctof2007/FullTextofFDAAALaw/default.htm. Accessed 18 July 2010.21. Caveney E, Turner JR. Regulatory landscapes for future antidiabetic drug development (Part I): FDA guidance on assessment of cardiovascular risks. 27. Faich G. Evaluation of REMS. Presentation given at the FDAnews/United J Clin Stud 2010; January Issue: 34–36. BioSource Corporation/Center for Medicine in the Public Interest ‘Drug Management and Drug Safety Summit’. Washington, DC: National Press22. Turner JR, Caveney E. Regulatory landscapes for future antidiabetic drug Club, 29 October 2008. development (Part II): EMA guidance on assessment of cardiovascular risks. J Clin Stud 2010; March Issue: 38–40. 28. Turner JR. Drug safety, medication safety, patient safety: an overview of recent FDA Guidances and initiatives. Regulatory Rapporteur 2009; 6: 4–8.23. McCaughan M, Helbling L. The RPM Report 2010; 4: 1–11. 29. Sutter S, Davis J. FDA, EMA decisions on Avandia reflect the power of24. Durham TA, Turner JR. Introduction to Statistics in Pharmaceutical Clinical REMS. ‘‘The Pink Sheet:’’ Prescription Pharmaceuticals and Biotechnology. Trials. London: Pharmaceutical Press, 2008. 27 September 2010; 1 and 4–6.25. Food and Drug Administration, 2008. The Sentinel Initiative: National 30. Turner JR. Integrated drug safety: benefit-risk assessments in drug Strategy for Monitoring Medical Product Safety. Available from URL: development and use. Appl Clin Trials, in press. http://www.fda.gov/downloads/Safety/FDAsSentinelInitiative/UCM124 701.pdf. Accessed 24 October 2010.Volume 13 No. 6 June 2011 doi:10.1111/j.1463-1326.2010.01353.x 497

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