March 31, 2014
My name is Dr. Anna Mazzucco. Thank you for the opportunity to speak today on behalf of the National Research Center for Women and Families. After completing my Ph.D. at Harvard Medical School, I conducted research at the National Institutes of Health. Since last year, I have been using those skills and perspectives to analyze the safety and efficacy of prescription drugs that the FDA is considering for approval
Our research center conducts research, analyzes data in the research literature, and then explains the evidence of risks and benefits to providers, policymakers, and consumers. Our president is on the Board of Directors of the Alliance for a Stronger FDA, which is a nonprofit dedicated to increasing the scientific resources that the FDA needs to do its job. Our organization does not accept funding from pharmaceutical companies, and therefore I have no conflicts of interest.
Like you, I have been scrutinizing the risks and benefits of Dalvance for the treatment of adult patients with acute bacterial skin and skin structure infections.
The main goal in antibiotic drug development is finding new drugs to target strains that are resistant to currently available drugs. Unfortunately, most vancomycin resistant organisms are resistant to dalbavancin as well through van A mechanism.
A careful analysis of the data calls into question the efficacy of Dalvance. In the DUR001-301 trial, 19% of patients who initially responded at the first time point later failed to achieve complete resolution of all local symptoms of infection, versus 11% in the comparator arm. Of patients with bacteremia due to Gram-positive aerobes at baseline, 25% of patients receiving Dalvance were initially non-responders at the first time point, compared to 12% in the comparator arm. Both those statistics indicate Dalbavandin patients are approximately twice as likely to have worse clinical outcomes compared to patients taking the comparison drug, vancomycin. The FDA also concluded that while there was inconsistency between the two phase III trials, sensitivity analyses showed that Dalbavandin performed less favorably at end-of-treatment in both trials when stricter criteria were used for judging success based on erythema. Why should the FDA approve a drug with such poor results when more effective options are already available?
Of course, the outcome patients most care about is getting well of surviving. But another clinical endpoint that is important to patients is pain, because that is a common symptom of these infections. And yet, there was no clinical endpoint to assess pain, which is a key symptom.
In addition to concerns that this drug isn’t very effective, it has serious risks. There was a significant hepatotoxicity signal in this trial which could not be attributed to anything other than the drug. Specifically, 6 patients who took Dalvance had alanine aminotransferase (ALT) elevation of more than 5 times the upper limit of normal. This could cause serious liver damage, especially in patients with compromised liver function. None of the comparison group patients had such a severe reaction .
There is no logical explanation for this liver toxicity, other than the drug. The patients assigned to Dalvance were comparable to the comparator patients in terms of relevant co-morbidities and elevated ALT at baseline.
We agree with the sponsor, which concluded that based on these findings, “it is likely that Dalvance may cause elevations of liver enzymes especially in patients with pre-existing liver dysfunction”.
This is a major risk for patients, because patients with chronic liver disease are more susceptible to MRSA due to impaired neutrophil function. Bottomline: thousands of patients could be at risk of serious liver damage if given this drug, and yet the drug is not even as effective as other alternatives already on the market.
And while studies have shown that Hispanic and African-American patients are more likely to contract MRSA, 9 out of 10 patients in both phase III trials were white. We know that naturally occurring genetic variations can affect the way certain drugs are metabolized and work in certain racial and ethnic groups.
And yet, only 28 patients were African American, and we cannot even determine the number of Hispanics from the data as it is presented. Although the sponsor states that they observed similar safety and efficacy results in all patient ethnic groups, there are too few patients to be confident that would be true of the general population.
Based on the weaker efficacy compared to other drugs, the lack of any safety or efficacy data for African Americans or Hispanics, and the extremely serious risk of liver damage, Dalvance seems inferior compared to other antibiotics. If the sponsor does additional research that includes subgroup analysis of African Americans and Hispanics, measures pain as an outcome, and determines which patients are most likely to benefit, then FDA should consider this drug at that time. But today, speaking not on behalf of any company but instead on behalf of our nation’s public health and the patients who rely on safe and effective antibiotics, we strongly urge the panel to REJECT approval of Dalvance at this time.
I want to emphasize: more research is needed BEFORE approval. Sometimes Advisory Committees recommend approval based on their hopes for a drug and ask the FDA to require post-market studies for more conclusive data. The companies are more focused on selling the new drug than studying it, so research shows that it takes about 10 years for the company to complete and analyze a post-market study. The risks of Dalvance are too great to allow sales now and then wait that long for better data. The company should be required to add a more diverse population and one that consists of patients who are immunocompromised BEFORE this drug can be approved.
In 2009, FDA withdrew the antibiotic Tequin from the market due to fatal blood-sugar events that were particularly dangerous for diabetic patients. As diabetic patients are at higher risk for MRSA, this drug must be adequately tested for safety and efficacy in this group. The FDA has also recently put out warnings for doripenem and tigecycline ,citing increased mortality risks. In fact, more than 40% of antibiotics approved since 1980 have subsequently been withdrawn, highlighting the risks of approving drugs based on insufficient data.