Statement of Anna E. Mazzucco Ph.D. on Anti-Infective Drug Sivextro

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.  Those are the perspectives I bring today.

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 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.

We have concerns about Sivextro 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.  However, Sivextro is already known to share cross-resistance with linezolid-resistant strains with chromosomal mutations, which is the majority.  This is a major shortcoming of this drug.  In non-inferiority trials, it is particularly critical to adequately establish safety and efficacy in critical patient populations.  Otherwise, patients could be treated with a drug that is actually worse than what is already available.  Several placebo-controlled trials have shown that antibiotics are ineffective for abscesses, and 30% of the patients in this trial had abscess, making the non-inferiority design even more problematic.  These infections often among the elderly and those with compromised immune systems — but these patients were NOT represented in the pivotal trials.  In the two phase III trials, only 9% and 13% of the patients treated with Sivextro were 65 or older – that is only 69 patients.  Only 18 patients in both trials together were 75 and older, which is a critical group to test the drug for the proposed indication. 

Similarly, while studies have shown that Hispanic and African-American patients are more likely to contract MRSA, 85% of patients in all the phase III trials were white.   With such a low percentage, any safety or efficacy problems specific to minority patients would be invisible because the small number of African Americans and Hispanics were combined in the analysis with the much larger sample of whites. We know that naturally occurring genetic variations can affect the way certain drugs are metabolized and work in certain racial and ethnic groups.

The percentage of Minority patients would not be important if there were a large enough number of these patients to analyze separately in subgroup analyses.  But, only 77 were African American and only 16 patients were in any other racial or ethnic groups – obviously too small to evaluate safety. And while subgroup analysis was not conducted for secondary endpoints, for the primary clinical endpoint, patients over 65, and the ethnic group labeled “other” had poorer outcomes.

Another problem with the studies is that diabetic patients are particularly susceptible to these infections, but only 4% and 10% of the trial participants had diabetes, which totals only 58 patients  treated with Sivextro in both phase III trials combined.  Again, 58 patients is too few to draw conclusions about, BUT the sponsor should have at least analyzed this group of patients separately to see if the drug is equally effective for them.  They didn’t.

The proposed clinical dose is specified for patients 12 and older, yet the minimum patient age among all the phase III trials was 17.  Kids do a lot of growing during those teenage years, and teens of different ages can metabolize drugs differently than adults.  The drug should not be approved for patients who were not studied. The sponsor did not provide a further breakdown of patient age between 18 and 65 years, so we do not know if there is enough data to justify approval for younger adults either.  Drug metabolism starts to change quite dramatically in middle age.

While there were comparable numbers of men and women in the trial, the sponsor did not separately analyze the safety and efficacy for each group separately.  They should have, to make sure it is safe and effective for men and for women.  The company is asking that this drug, which is primarily for elderly patients and those with compromised immune systems, be approved for millions of patients it wasn’t tested on: teenagers, perhaps young adults, African Americans, Hispanics, diabetics, and the frail elderly.    It is impossible to know if the drug is safe or effective for those patients.  Wishful thinking isn’t good enough.

We appreciate that Sivextro is more convenient than other drugs – it would be taken just once a day and for4 to 8 fewer days than other antibiotics.  But that doesn’t justify approval for a drug that hasn’t been adequately tested for the target indication.

I know that many of you are VERY concerned about options for MRSA, and that can pressure you to consider approving new drugs that haven’t been studied as well as you’d like.  But we all know that sometimes new antibiotics do more harm than good.  For example, years after approving the antibiotic Trovan, the FDA had to warn physicians that it could cause life-threatening hepatotoxicity in certain types of patients.  Before that warning, patients were harmed by Trovan, and many of those patients could have safely taken other drugs instead.  That’s just one example of how patients can be harmed – even killed – by a new drug that wasn’t adequately tested for the patients who were likely to take it. Azithromycin and Levofloxacin are just two other examples, which have both been the subject of recent FDA action because of serious safety problems.

Some of you may think post-market studies will solve the problem of poorly designed research.  But, if Sivextro is approved before additional research is conducted, the company has little incentive to quickly conduct required post-market studies on a more generalizable patient population.  For that reason, we believe that Sivextro should NOT be approved until additional research is conducted.

However, if you disagree, we’d like to suggest a compromise, that could get the drug approved more quickly and still address some of these serious concerns:

Prior to approval, FDA should:

Require a subgroup analysis of the 77 African American patients to check efficacy in the secondary endpoints, including sustained clinical response and pain.  It’s not many patients, but better than nothing.  If there is a signal of possible problems, require more African American patients BEFORE the drug is approved or require the label to explain that Sivextro is not approved for non-whites.

Do a separate analysis for the 58 patients in the studies who have diabetes.  If the results look worrisome, the label should clearly state that the drug is not approved for diabetes patients until more are studied.

The label should clearly warn that Sivextro is not approved for patients under 18 or over 75, since they were not studied.  Depending how many patients were under 25 or 35 (we cannot know from how the data is presented here), it may be necessary to exclude that group as well.  Or, if the sponsor prefers, they should add patients in those age groups to existing clinical trials before the drug is approved.

IN summary, whether Sivextro is approved or not, more research is needed to establish safety and efficacy in the most relevant patient populations, such as among the elderly, diabetic patients, and other ethnic groups.

IN conclusion: we urge you to reject Dalvance until better research is conducted, because of questions about efficacy.

But, if the FDA wants to move forward more quickly, we strongly urge FDA to require subgroup analyses on diabetics, African Americans, and older patients in the Sivextro studies BEFORE an approval decision is made.  Based on the results, the FDA should either require additional patients be studied BEFORE approval, or limit the indication to white patients between 18-65 who are not diabetic until post-market studies provide safety and efficacy data for those groups.