Letter to Dr. Woodcock, FDA Director for the Center for Drug Evaluation and Research on the approval of Qnexa, a weight-loss drug

April 16, 2012

Janet Woodcock, M.D.
Director
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave
Silver Spring, MD 20993-0002

Re: Pending Application for Qnexa

Dear Dr. Woodcock,

We are writing to urge the FDA’s Center for Drug Evaluation and Research (CDER) not to approve Vivus’ New Drug Application for Qnexa (phentermine/topiramate) because of serious unresolved safety concerns about its potential to cause cardiovascular harm and birth defects.

The agency previously rejected this drug in 2010 due to these same unanswered safety questions, and Vivus’ new submission fails to answer those questions. As you know, on February 22, 2012, the Endocrinologic and Metabolic Drugs Advisory Committee voted to recommend approval of Qnexa. However, we believe it’s critically important that in making its decision about Qnexa, CDER consider the full context of the committee’s discussion rather than simply the results of that vote.  Specifically, we would draw your attention to committee members’ comments demonstrating that the questions raised about the rejected Qnexa application in 2010 remain unanswered and to the concerns expressed about the potential for approval to expose millions of people – mostly women – to serious cardiovascular threats.

We recognize that there is an unmet demand for safe and effective treatment options for obesity and obesity-related health conditions. At the same time, we believe that anyone taking a weight loss drug should have the FDA’s assurance that the benefits outweigh the risks, and that there is evidence that it will meaningfully improve physical or mental health, not simply reduce the number on the scale. Obesity is associated with serious and life-threatening diseases and conditions – such as diabetes, hypertension, and heart disease – but the sponsor has not established that Qnexa improves those outcomes. In addition, although weight loss can improve other symptoms and quality of life, the value of those improvements is clearly limited if the weight loss cannot be sustained, and the Qnexa data indicate limited success in maintaining weight loss.  While some women and men may seek, and be satisfied, with weight loss alone, they still want assurance that the drug will help them achieve and maintain a lower weight without compromising their health, and the FDA cannot provide this assurance about Qnexa.

Vivus failed to answer the FDA’s questions about Qnexa’s cardiovascular safety

After having its application for approval of Qnexa rejected in 2010, Vivus resubmitted its application barely a year later without providing additional data that is adequate to resolve the safety concerns previously raised about this drug. The analyses of the cardiovascular effect of the drug provided by the sponsor with this resubmission were deficient in several ways, noted below.

  • Despite the fact that cardiovascular risk was the primary reason given for Qnexa’s rejection, the sponsor did not provide any new cardiovascular outcomes data to answer the agency’s outstanding questions from 2010 – not additional short-term data specifically evaluating cardiovascular risk, nor valid longer-term data assessing cardiovascular risk over time. Instead, the sponsor did a cardiovascular risk analysis report of its original clinical trial data even though those studies were only conducted for one year and weren’t designed to assess cardiovascular risks and benefits. Several committee members noted this and questioned the validity of the data provided.  One stated that the cardiovascular risk data was so insufficient that it could not be extrapolated to provide an accurate benefit/risk profile of Qnexa.
  • The sponsor used inappropriate cardiovascular risk indices in its risk analysis report, given that the population enrolled in the trial was predominantly female. The measurement tools used by the sponsor have only been proven to work with men, leaving women without any meaningful information about the cardiac risk this drug might pose to them. For example, the Cooper Clinic Mortality Risk Index was derived and validated in men ages 20-69 with no history of coronary heart disease, stroke or cancer, who were predominantly white college graduates. This measure has never been validated as a measure for women or people of color. The FDA’s clinical reviewer raised these same concerns stating that “the clinical implication of these tools is unclear, especially for women.”
  • Increased heart rate, a predictor of heart attack and other life-threatening cardiovascular events, was one of the specific risks identified in the original Qnexa application. The FDA rejected that application in part because the sponsor provided no data that could be used to evaluate the impact of the increased heart rate over time. But with this application, Vivus once again failed to provide data to address this concern. Because the bulk of the original data was only one-year data, and because Vivus did not collect long-term cardiovascular data to support its new application, the cardiovascular risk analysis report submitted with this second application did not and could not address the FDA’s original questions about what happens over time to people whose heart rate increases while taking Qnexa. One of the current committee members noted concern about this side effect, specifically in light of the fact that increased heart rate was also a known side effect of Avandia, a drug which later proved to cause serious cardiovascular harm to many patients.
  • Finally, the FDA medical reviewers found several serious methodological problems with the cardiovascular risk analyses that the sponsor provided. The cardiovascular risk analysis report pooled data across the sponsor’s Phase III trials, which casts doubt on the scientific integrity of all of the conclusions drawn from this report. One committee member raised concerns about the validity of the pooled data because the trials had different populations with varying co-morbidities, used different doses, and one trial wasn’t even randomized.  Her conclusion was that the pooled data weren’t reliable. Similar critical comments about the methodology used by the sponsor were echoed by several other committee members as well.

A Phase IV study will not adequately ensure patient safety

The Advisory Committee linked its recommendation that the FDA approve Qnexa with a requirement that the sponsor conduct a large, post-market cardiovascular outcomes trial as quickly as possible. The committee’s recognition of the need for this trial demonstrates that its members believe the safety questions that led to Qnexa’s rejection in 2010 have not yet been answered and are still critically important for evaluating the safety of the drug.  We agree that these questions remain unanswered, and we urge you not to approve Qnexa without first getting answers.

A Phase IV study, such as the one proposed in the committee’s recommendation will not adequately ensure patient safety. First of all, one committee member noted serious questions about the sponsor’s ability to conduct and complete a large post-market cardiovascular outcomes study. Moreover, a post-market trial will not be completed until after this drug has been used by millions of people. Additionally, another committee member pointed out that the pool of people who are likely to consider this drug includes not only the more than 75 million obese adults in the United States, but also millions more who are trying to lose weight.  She noted that this is a vast pool of patients who may potentially be harmed if the safety signals evident in the currently available data on Qnexa turn out to be predictors that the drug significantly increases a patient’s risk for serious cardiovascular harm. This relates to Fen-Phen, a weight-loss drug regimen that was removed from the market due to its very dangerous cardiovascular side effects.  One-third of Fen-Phen users were not obese, and some of those seriously harmed were not even overweight. With the millions of lives potentially at risk, and the clear consensus that the safety questions still need to be answered, we believe the only responsible course of action is for the FDA to require the sponsor to conduct an additional Phase III trial before final a decision is made regarding approval.

Data on birth defects caused by fetal exposure are inadequate to support informed use

Lastly, we are concerned about the outstanding questions regarding Qnexa’s risk of causing birth defects. We do not believe the FDA should limit women’s access to an effective medication because of their reproductive capacity. Nonetheless, given the high rates of pregnancy experienced by women even under the controlled circumstances of the clinical trials, it is clear that if Qnexa were approved there would be a substantial number of pregnancies among women using the drug and therefore the teratogenic effects of the drug must be addressed.  We believe that when a drug is known to be associated with an increased risk for birth defects, it is important to ensure that women get the information necessary to understand the risks so they can make an informed decision about whether to use the drug and how to protect against pregnancy during use.

Based on the available data, the committee concluded that there is between a two- and five-fold increased risk of birth defects, including cleft lip and palate, for women who become pregnant while taking the drug.  Several committee members raised concerns, however, that the data submitted by the sponsor were insufficient to fully characterize the risk of birth defects associated with fetal exposure to Qnexa. Until researchers have a better understanding of the birth defect risks associated with fetal exposure to Qnexa, we do not believe that clinicians will be able to provide the millions of reproductive age women who may take this drug with the complete and accurate information needed to support an informed decision about use.

In conclusion, we recognize that obesity is a very serious health problem and that people wanting to lose weight are looking for more options. However, consumers depend on the FDA to ensure that drugs are safe and effective before they are approved. Vivus has failed to provide adequate evidence to demonstrate that Qnexa meets this standard because it did not submit data that can answer the safety questions raised by the committee and the agency in 2010. According to news reports, Vivus has submitted a new risk management plan to address outstanding safety concerns. While the public has not had the opportunity to review this new plan, we strongly believe that without additional data, no risk management plan will be adequate to ensure patient safety.

The available evidence to date shows that the risks of Qnexa outweigh its benefits. Consequently, we strongly urge the FDA to stand by its previous decision and reject Qnexa again.

Sincerely,

National Research Center for Women & Families/Cancer Prevention and Treatment Fund

National Women’s Health Network

WomenHeart: The National Coalition for Women with Heart Disease

Cc:       Eric Colman, M.D., Deputy Director, Division of Metabolism and Endocrinology Products, OND, CDER, FDA