I am Dr. Jennifer Yttri, and I have a PhD in immunology from Washington University in St Louis. Thank you for the opportunity to speak today on behalf of the National Research Center for Women & Families. Our organization is a nonprofit research center that does not accept funding from pharmaceutical companies, so I do not have any conflict of interest.
The FDA has denied approval of VIBATIV for treatment of hospital associated pneumonia on 2 separate occasions. After reviewing the required additional data, there is not sufficient evidence to support telavancin as a safe and effective treatment for nosocomial pneumonia.
Instead, the new data raise more questions about a high mortality rate associated with telavancin, especially in the intent-to-treat population. Differences in mortality cannot simply be explained by pre-existing medical conditions. In each randomized trial, the telavancin and vancomycin groups are similar in pre-existing medical conditions. Without additional trials, it cannot be determined if the observed increased day 28 mortality is associated with the drug alone or with the combination of telavancin and pre-existing renal impairment. It would be completely inappropriate to combine the two randomized trials to mask the mortality difference.
There is no way to determine if telavancin is non-inferior given the lack of clarity in study design, especially the outcomes chosen by the sponsor. We agree with the FDA reviewers who diplomatically stated that “the interpretation of results based on clinical response is limited. To be more blunt: clinical response is a poorly defined endpoint that does not reliably measure patient benefit. Consider the “large number of patients who were considered clinical cures at the [test of cure] assessment but subsequently died by Day 28.” Using the company’s definition of “clinical response”, which is an unclear combination of laboratory tests and clinician judgment, there is no way to evaluate any actual benefit or comparison with other antibiotics.
When looking at the data for the population with pneumonia, every parameter tested trends in favor of vancomycin over telavancin. If pneumonia wasn’t a serious, life threatening, and contagious disease, a slightly lower effectiveness might be acceptable for a drug with a better safety profile. Telavancin has numerous adverse effects, including nephrotoxicity, complications with renal insufficiency and pregnancy, and potentially higher mortality. Any loss of effectiveness does not balance this risk. Your job is to review the science, not reward the company for perseverance in their efforts to get this drug approved. Based on the data, VIBATIV must be denied approval for nosocomial pneumonia.
Doctors like to have choices when they select treatments for patients, but we do patients and their doctors no favors by approving new drugs that are less safe and no more effective than drugs that are already available. If this drug is more effective in some subgroup of patients, perhaps those with MRSA, then the drug should be studied in and used only in that patient population. Today’s study uses a non-inferiority trial with patients that may or may not have pneumonia. Benefits of drugs should not be assumed in groups that have not been studied.
To provide solid evidence supporting telavancin as a safe and effective drug, the FDA should require a superiority study using the 28 day mortality endpoint. The study must be conducted in the appropriate patient population, who have limited treatment options, not patients who already have safer and more effective options. Not only would such a study require fewer patients, it will provide clear data to address any benefits of telavancin given the documented adverse effects, including renal failure and death.
Our ability to fight against common, severe infections depends on drugs that are as safe and effective as possible. Patients are counting on you. Please consider whether you would prescribe this drug to a loved one, knowing that safer and equally effective treatments are available.
Unfortunately, warnings on labels would not be adequate protection to patients. The sponsor today admitted that only 20-27% of doctors remember current warnings when prescribing telavancin for skin infection. The only way to help doctors save their patients is by keeping this drug off the market.
Update: FDA approved Vibativ in June 2013 for use against ventillator and hospital acquired pneumonia when other treatments are not appropriate. Unfortunately, the restriction is unlikely to be enforced and therefore many patients will be exposed to unnecessary harm from this antibiotic.