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Weighing Up the Decision

Three new drug applications for weight management products were filed in 2010 with the US FDA, but to date none have been approved. In addition to the drug being promising, the safety profiles must fulfil certain criteria in order to pass the test.

Over the last few years, the US Food and Drug Administration’s (FDA) regulatory activities related to drugs for obesity have been dynamic. In 2010 alone, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) reviewed three new drug applications (NDAs) for: naltrexone/bupropion; lorcaserin; and phentermine/topiramate (PHEN/TPM).These products have so far gone unapproved. Another significant regulatory action occurred in September 2010 when the FDA held a public meeting to review data from clinical trials for the approved weight loss drug Meridia (sibutramine).The EMDAC members responded critically to the results of the Sibutramine Cardiovascular Outcomes (SCOUT) trial, with half the committee members voting to support the removal of the drug from the US market. Within two months of this meeting, the sibutramine sponsor, Abbott Laboratories, voluntarily withdrew the product from the US market.

In all of their meetings last year, members of the EMDAC reviewed both safety and efficacy data; however, safety issues, particularly cardiovascular risk profiles,were a specific focus. All the trials submitted as the basis for gaining FDA approval were randomised and placebo-controlled.When examining the committee’s comments during the public meetings, several commonalities emerge, despite the differences in the chemical formulations of the products. Similar concerns were highlighted years before at a 2007 public meeting on the weight loss drug rimonabant (Sanofi-aventis). At that time, the advisory committee unanimously refused to support approval of the product, mostly due to the lack of available safety data on the drug, and the committee highlighted some trial design issues, namely long-term data.

Approved, But With a Catch

The regulatory processes relating to the safety evaluation of sibutramine also highlighted particular safety and efficacy concerns that have emerged as primary considerations in the approval of obesity drugs. Sibutramine was approved as Meridia in 1997 for the management of obesity, including weight loss and weight loss maintenance, when combined with a reduced-calorie diet.This indication is very similar to those named in the NDAs reviewed in 2010.

At the sibutramine public meeting in 2010, EMDAC members reviewed data from the SCOUT trial. SCOUT was part of a postapproval commitment between the European Medicines Agency (EMA) and the manufacturer. Begun in 2002, SCOUT was designed to show that weight loss with sibutramine and standard care was more effective in reducing the number of cardiovascular events when compared to weight loss from a placebo and standard care.

Following their evaluation of data from SCOUT, the EMDAC voted to support the removal of sibutramine, citing its modest efficacy for weight loss and evidence of cardiovascular risks.The committee also stressed that the SCOUT data offered no evidence that weight loss achieved by use of the drug results in any of the health benefits associated with weight loss achieved through diet and exercise (for example, reduction in diabetes or sleep apnea). In addition, the data failed to identify a particular subgroup of patients benefitting from sibutramine that would justify keeping the drug on the market.

Committee members who supported continued marketing of the drug with revised labelling and boxed warnings stated that the failure of the data to show health benefits was due to the trial’s design. They stressed that consumers should not lose access to a drug due to researchers’ failure to design a trial that identified health benefits, and indicated that combined with an effective risk evaluation and mitigation strategy (REMS), the drug could remain on the market safely.

EMDAC members stated repeatedly they were unable to respond to FDA questions about sibutramine due to lack of data.The agency had asked whether the risk for major adverse cardiac events (MACE) could be mitigated through the monitoring of body weight, blood pressure and pulse.While a patient’s pulse is an important factor when analysing MACE risk, there were no data presented at the meeting to support that monitoring of pulse would help to mitigate the cardiovascular risks associated with sibutramine.Panel members stipulated that if the drug were to remain on the market, tools would be needed to help identify patients at risk before the drug was prescribed.

Back to the Drawing Board

In all EMDAC obesity drug meetings, cardiovascular risk has been a prevailing discussion prior to and after the review of sibutramine.This is reflected in the statements made by committee members regarding PHEN/TPM (proposed trade name Qnexa), the first obesity drug reviewed in 2010 as part of an NDA.This product was sponsored by Vivus, Inc and proposed as an adjunct to diet and exercise for weight management. However, several other common safety and efficacy issues begin to appear when the discussions were compared.

While the committee generally supported the efficacy of PHEN/TPM, their concerns regarding the cardiovascular implications, as well as the potential for cognitive and teratogenic adverse effects, resulted in a negative recommendation. All panel members agreed on the need for long-term data given the trend of those who lost weight gaining it back within a few years following discontinuation of therapy. The trials did not include adequate numbers of participants with comorbid conditions and the committee recommended modifications to trial design to account for this deficiency.



More Information Needed

The next product reviewed in 2010 was lorcaserin (proposed trade name Lorquess), a new molecular entity (NME) proposed as a weight management treatment for obese patients when combined with diet and exercise. In their review of this product, several EMDAC members called the drug promising, however, overall the committee concluded that the data presented did not provide enough convincing evidence of efficacy and safety to merit approval. Population-related deficiencies in the pivotal clinical trials were again seen as an issue.

Where PHEN/TPM had included a population representative of comorbidities seen in the target population, lorcaserin did not meet this prerequisite. A frequent criticism made by EMDAC experts was the lack of diversity in the Phase 3 trial population leading to the conclusion that such a narrow population might result in efficacy of the drug being overstated, while any potential safety risks were understated. It was noted that while lorcaserin data did meet FDA efficacy criteria minimally, the merits of that evidence were tempered by the lack of realworld information on patients with significant comorbid conditions (such as diabetes, hyperlipidaemia and cardiovascular disease). As with PHEN/TPM, the committee recommended studies with a broader population and, due to concerns about the risk to cognitive function, also recommended further studies that included subjects with major depression and other mood disorders, prior to approval.

There was concern over lack of data on the interaction of lorcaserin with other drugs, as weight loss drugs are frequently used in combination with other agents.This was particularly the case regarding concomitant use with drugs that are known, or suspected, to carry risks for valvular heart disease (VHD). Another safety consideration was that animal data on cancer risk were not well-correlated with that potential in humans.

Panel Divided

Unique among the other NDAs for obesity drugs reviewed by EMDAC, the naltrexone/bupropion product (proposed trade name Contrave) from Orexigen Therapeutics, Inc, earned considerable support by the committee members. The limited treatment options for the current indication was noted by several members in the justification of their decision, a significant point considering that the outlook for obesity treatments had not changed over the year prior to this meeting. Panelists who did not favour the risk-benefit profile stated that the efficacy findings were inadequate and long-term data (beyond one year of treatment) were lacking.

Panelists on both sides of the vote strongly supported the need for further characterisation of the agent in an additional randomised clinical trial to provide a thorough assessment of its cardiovascular risk profile, and agreement on at least a study protocol prior to the approval of Contrave.Differences were seen when discussing when those studies should occur. Members who favoured a post-approval clinical outcomes trial expressed concern that it would require a considerable amount of time and resources to conduct trials pre-approval and thus delay a much-needed drug.

One of the safety issues of interest in the Contrave review was the various outcomes observed in the clinical programme related to blood pressure, pulse and major cardiovascular events including death,myocardial infarction (MI), and cerebrovascular accident (CVA). It was because of data indicating an increased risk of MI and stroke that the FDA requested the voluntary removal of sibutramine from the US market.Yet, the Phase 3 trials using the same cardiovascular outcomes for Contrave were deemed adequate by some committee members to allow for postmarket qualification. With sibutramine, significant concern was noted in the inability to isolate a population for which the drug was safe, tipping the balance of risk overshadowing benefit. Without defining the population at risk, there is no way to mitigate the risk.

The minority of EMDAC members in favour of clinical characterisation of cardiovascular safety of Contrave prior to approval noted that drug effects on interim or surrogate markers, such as blood pressure and pulse,may not translate into clinically significant outcomes from treatment (such as reduction in morbidity and mortality from obesity). The inclusion of higher risk populations, such as ethnic minorities, individuals with comorbidities, and those on multiple medications in additional studies,were recommended. All of these issues were noted in previous NDA reviews. The review of panel discussions on Contrave highlights the differences in committee opinions for this product when compared to those from previous drug reviews.

The undefined population and cardiovascular risk noted in other product reviews were seen as deficiencies that warranted study prior to approval.The reasons for differences in the committee’s ultimate recommendation for Contrave compared to other products are not easily determined. However, the comparison of voting patterns indicates only a slight margin in favour of Contrave while the previous NDA reviews from 2010 had only a slight margin against supporting approval.



Conclusion

Regardless of the particular issues related to voting patterns by individual committee members, the fact remains that similar issues have emerged during public meetings on NDAs for weight management products. A simple comparison of issues raised by committee members may explain the ultimate recommendation for approval for these products (see Figure 1 and Table 1, page 84).

In addition to cardiovascular risk, psychiatric events and comorbidities in the target populations were chief among the concerns. It may be the number as well as the types of risks associated with the product that lead a committee to a certain conclusion. In all of the products reviewed, not only was cardiovascular risk considered, but also the paucity of data regarding the characterisation of a target subpopulation in the very diverse, high-risk obese and overweight patient population. In each review, the committee recommended further studies to meet this end. In the case of Contrave, the overall safety profile combined with the lack of therapeutic alternatives in the wake of the sibutramine withdrawal may have weighed in on the ultimate decision. It remains to be seen if the committee’s opinion figures into the final regulatory actions made by the FDA.


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Regina M Ballinger has been with Thomson Reuters for eight years specialising in pharmaceutical regulatory affairs. She is currently the Senior Manager of Regulatory Intelligence and directs US regulatory content for the IDRAC database and publication of IDRAC’s AdComm Bulletin. She has been working in the healthcare industry for over 15 years. Email: regina.ballinger@thomsonreuters.com
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