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European Pharmaceutical Contractor

The Heart of the Matter

As obesity levels continue to rise, the pharmaceutical industry is focusing on developing safe and effective treatments that meet regulatory standards, with some promising new drugs in the pipeline.

Obesity has reached epidemic proportions in the US. The Centers for Disease Control and Prevention (CDC) estimate that at least one-third of adults – over 72 million people – are obese. While many health initiatives focus on prevention, the pipeline of drugs targeting obesity is very active in the hope of finding an effective and safe drug treatment. Over the last few years, the regulatory activities of the US FDA related to drugs intended to treat obesity have been dynamic. In 2010, the organisation’s Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) reviewed three new drug applications (NDAs): naltrexone/bupropion; lorcaserin; and phentermine/ topiramate (PHEN/TPM) (1).

Early in 2012, the FDA held public meetings to consider the lorcaserin and PHEN/TPM applications and address the safety issues brought to light in the previous reviews of data from clinical trials involving obesity drug products. The FDA is also due to convene at an EMDAC meeting in May 2012 to again review lorcaserin as part of the regulatory review process. Advisory committees are an important step in the drug approval process. New information gathered during these meetings contributes scientific and regulatory perspectives that can provide a valuable tool for examining products brought into the approval pipeline.

During the 2010 NDA public meetings, the EMDAC reviewed both safety and efficacy data, with safety issues dominating the discussions. The committee cited cardiovascular (CV) risk profiles as a chief concern, but also highlighted psychiatric events and comorbidities in the target populations as additional concerns. The paucity of data regarding the characterisation of a target subpopulation in the very diverse, high-risk obese and overweight patient population was also carefully considered. Further studies to obtain more results were strongly recommended. In weighing their decisions regarding support for ultimate approval of these drugs, some advisory committee members cited the limited treatment options for obesity, a significant point considering that the outlook for obesity treatments had not changed over the year previous to these meetings.

Of the three products reviewed in 2010, PHEN/TPM (proposed trade name Qnexa) was the first to become the topic of a 2012 public advisory committee meeting. The product is proposed as an adjunct to diet and exercise for weight management in obese or overweight patients with weightrelated comorbidities. The safety issues cited as a concern with Qnexa were in part similar to those seen in the range of drugs targeting obesity and included cognitive, teratogenic, cardiac, and mental health adverse events (AEs). In order to evaluate the increased heart rates observed in study subjects, additional studies were undertaken. The approaches for managing the risks related to this product was a primary topic during the February 2012 meeting, and may serve as a model for other companies with obesity products in the pipeline. New information from each step in the approval process allows the FDA to focus on each product with regard to any unique issues that may present during the process.

Cardiovascular Risk in the Target Population

The primary concern of both the FDA and the expert panel members throughout the review of obesity drugs has been CV risk. This concern is not wholly unexpected, given the potential for high rates of comorbidities in the target population, especially diabetes, which itself carries a high risk of CV morbidity. According to the FDA, only two controlled trials have been conducted to examine the effects of drug-induced weight loss on CV events, and both used the composite endpoint known as major adverse cardiac events (MACE) as primary endpoints, but included slightly different events (see Considerations for Clinical Trials). The hypothesis that drug therapy resulting in weight loss will reduce MACE has only been adequately tested with one weight-loss drug, sibutramine. Another Phase 3 study testing this hypothesis with rimonabant in the EU was prematurely ended (2).

The sibutramine cardiovascular outcomes (SCOUT) trial showed that patients randomised to sibutramine had an increased risk of MACE (11.4 per cent) compared with patients randomised to placebo (10 per cent). The study concluded that subjects with pre-existing CV conditions who received long-term sibutramine treatment had an increased risk of nonfatal myocardial infarction and nonfatal stroke, but not of CV death or death from any other cause. The comprehensive rimonabant evaluation study of cardiovascular endpoints and outcomes (CRESCENDO) trial included almost 19,000 patients who had, or were at increased risk of, vascular disease. Though this trial was discontinued due to psychiatric-related safety issues, analysis resulted in some data on CV risk. At the close of the trial in November 2008, a MACE occurred in 364 (3.9 per cent) patients assigned to rimonabant and 375 (4.0 per cent) assigned to placebo (hazard ratio = 0.97; 95 per cent confidence interval (CI): 0.84-1.12; p-value = 0.68). Both trials provide insight into designing quality CV outcomes trials (CVOTs).

The Qnexa sponsor submitted a review of the product’s teratogenic potential as part of the NDA. That review included a CV risk analysis report. Data from the Qnexa clinical programme indicated that cardiac disorders occurred at a higher rate in the Qnexa-treated groups versus placebotreated groups. Cardiac arrhythmia-related AEs occurred with a higher frequency in mid-dose and high-dose Qnexa-treated subjects compared to placebo-treated subjects, though the majority of events were rated as mild in severity. Two subjects in the mid-dose Qnexa group had a serious AE (SAE) related to a cardiac arrhythmia.

Overall, within the ischaemic heart disease subclass, a higher percentage of events occurred in the Qnexa-treated groups (Qnexa 1.1 per cent, placebo 0.4 per cent), the majority of which were rated as severe. No subjects in the placebo group and four subjects in the Qnexa group experienced a nonfatal SAE related to cardiac ischaemia. It is unknown what the clinical significance of CV and metabolic effects will be in a higher-risk CV population with chronic treatment exposure to Qnexa. According to the FDA, only a long-term CVOT can define the effect of Qnexa treatment on risk for MACE in an obese at-risk population.

Abating Risks through Trial Design

A primary tool for controlling risk is a well-designed clinical trial. Post-marketing approaches, such as Phase 4 studies targeting safety outcomes, are often used to further investigate potential risk signals or to monitor populations for potential risks. Most believe that the bestcase scenario includes a clear picture of potential risks, and puts engineering controls in place to mitigate risks prior to approving a product. Where do CV risk trials fit into the mix? In order to uncover potential CV risks in products targeting a population already at-risk, a combination of pre- and post-marketing strategies may pave the way to the approval of more therapeutic drug treatments targeting obesity. To provide insight into the specific issues related to the approval of obesity drug products, the FDA called an EMDAC meeting in March 2012 to draw upon expertise on this topic.

The Qnexa clinical trial data presented in February did not provide clear information regarding CV outcomes. As a result, nearly all committee members encouraged the FDA to mandate a post-approval CVOT, particularly in light of concerns about the large numbers of patients who could be exposed to unknown CV risks. During the March 2012 committee meeting, the members further discussed the role of CV assessment in the pre- and post-approval settings for drugs and biologics developed for the treatment of obesity. According to the FDA, CVOTs should show CV benefit in a superiority-to-placebo design; alternatively, a non-inferiority (NI) design with placebo should rule out an unacceptable increase in CV risk. Demonstration of superiority requires a larger sample size than demonstration of NI, assuming the same true relative risk (less than 1.0) for both analyses. If the objective is NI, the degree of unacceptable CV risk that should be ruled out is a prime consideration. A related issue is whether the NI margin should be the same for all obesity drugs or vary in relation to the specific perceived risks and benefits of individual drugs. Depending on population and endpoint, different estimates of risk may be considered.

To implement CVOTs for obesity drug products, EMDAC members stated that a two-tier process would best suit FDA, sponsor, and patient needs (3). For example, a preapproval assessment might be designed with MACE as the outcome, while a post-approval assessment could use the more difficult MACE-plus (such as coronary revascularisations and hospitalisation). A second tier clinical study would be powered to catch any safety signals missed at the first level. Though the specifics of this tiered system of safety trials were not debated, the panel indicated that this approach would also allow for a better understanding of multiple risks associated with obesity drugs, not just CV outcomes. For CVOTs, the committee concurred with the FDA’s recommendation that pharmaceutical companies should focus on monitoring MACE in Phase 2/3 trials and not on MACE-plus. Data from MACE-plus endpoints could confound the results and change risk evaluation information, especially with the use of NI trials.

There were members on the committee who did not favour requiring CVOTs for drugs with no evidence of CV risk signals, as that could prolong or stagnate obesity drug development. This requirement would be an unacceptable consequence, several EMDAC members stated, given that only one drug is currently FDA-approved for long-term use in obesity patients. Required CVOTs could also provide a false assurance of safety, as they would not detect other common risk factors, such as cancer risk or psychiatric risk.

One needs only to look at some recent FDA guidelines to conclude that the agency appears to be moving toward applying recommendations for CV outcomes data for some product classes. The February 2007 Draft Guidance for Industry: Developing Products for Weight Management notes that some drug classes, depending upon their impact on CV markers, necessitate specific safety evaluation (4). A thorough evaluation of risks and benefits is paramount to providing safe medications for patients, and perhaps such universal recommendations will generate additional and more complete data on CV risk.

During the obesity meetings, reference was made to the December 2008 FDA Guidance for Industry: Diabetes Mellitus – Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes (5). In the guidance, the FDA notes that new diabetes therapies should be developed so as not to result in an unacceptable increase in CV risk for patients. The considerable overlap of disease in the diabetes and obesity populations cannot be overlooked. To that end, the FDA intends to use its experience with the 2008 document to determine guidance for obesity drugs regarding clinical trial design to limit CV risk. Several recommendations to be considered include: 

  • The use of an independent CV endpoints committee to prospectively adjudicate, in a blinded fashion, CV events during all Phase 2 and Phase 3 trials
  • A comparison of the incidence of MACE associated with the investigational agent to the incidence of the same types of events occurring with the control group, showing that the upper bound of the two-sided 95 per cent CI for the estimated risk ratio is less than 1.8, with a reassuring point estimate
  • If the pre-marketing data show that this upper bound is <1.3, and the overall risk-benefit analysis supports approval, a postmarketing CV trial may not be necessary

Other general design recommendations are made by the FDA in its 2007 weight management guidance. Sponsors should include at least 3,000 patients in investigational drug therapy trials, and at least 1,500 patients in oneyear Phase 3 trials. During the March 2012 meeting, the FDA acknowledged that a 50 per cent withdrawal rate for patients before one year of treatment is typically anticipated for Phase 3 clinical trials of obesity drugs. This impact requires that sponsors carefully consider in the statistical plan the impact of patients who prematurely withdraw from clinical trials. The FDA suggests that an on-treatment population provides more information regarding true CV efficacy and safety of obesity drugs, due to historically high rates of premature subject withdrawal in long-term obesity drug trials. In the briefing materials for the February meeting on Qnexa, an FDA statistician stated that statistical significance of clinical results would be greatly improved if studies could achieve a dropout rate of 20 per cent or less.

An intention-to-treat (ITT), or an on-treatment and off-treatment population, takes into account data from subjects who have dropped out of the trial, and is generally considered the most appropriate population for primary efficacy analyses. Sponsors should be proactive in attracting high retention rates for study subjects, and follow up with patients even after a drug is discontinued or a patient stops treatment. The FDA encourages sponsors to obtain body weight measurements in all subjects who prematurely withdraw from clinical trials near the calendar date at which they were scheduled to complete the trial. A sensitivity analysis should be conducted that considers subjects who are treated, drop out, and do not have complete post-baseline data as treatment failures.

In addition, the weight-loss efficacy for many obesity drugs is usually greatest at six to nine months following therapy initiation, and often wanes thereafter. A drug’s CV efficacy/safety profile also can change over time. Thus, the timing of an interim analysis, the results of which may provide the basis for regulatory approval of an obesity drug, needs to be determined carefully. Panellists acknowledged that the target population for obesity drugs is generally middle-aged women, who typically are at lower risk for CV complications. Despite this, they encouraged the FDA to consider enriching clinical trials with patients who are at higher CV risk and who are generally older and suffering from comorbidities. Such enrichment, they stated, is in keeping with good clinical trial design and could provide the event rate needed for clinically significant results.

With the potential for mass exposure to obesity drugs comes the potential for a major public health impact. This point has been noted at the Qnexa meeting in February 2012, the March 2012 trial design meeting, and at the majority of meetings in 2010. The subsequent review of data submitted in support of the Qnexa NDA garnered solid support in favour of approving the product. Panel members cited the drug’s positive potential in light of the strong efficacy data paired with a large, unmet need for pharmacologic options to treat obesity. The lack of effective treatment continues to weigh heavily in arguments for approving new obesity products. In April, the FDA extended its review timeline for Qnexa with a decision on approval slated for July 17, 2012 (6).

Central to the decisions on Qnexa, and on some previously considered products targeting obesity, was the existence of a rigorous Risk Evaluation and Mitigation Strategy (REMS) designed to address the gamut of risks. Regarding the specific concerns for CV risk, all panel members encouraged a swift Phase 4 study to address unanswered questions. CV risk associated with drug treatments for obesity remains a primary concern. Long-term study and evaluation of data for immediate implications, as well as lessons on epidemiologic and pharmacologic trends, will contribute to enhancing the pipeline for needed products targeting America’s epidemic – obesity.


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Regina M Ballinger has been with Thomson Reuters for nine 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 employed in the healthcare industry for over 15 years.
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