GAO Report Criticizes FDA on Antibiotic Labeling; Finds No Evidence of Encouraged Innovation

By Kurt R. Karst –      

A new report released by the Government Accountability Office (“GAO”), titled “Antibiotics: FDA Needs to Do More to Ensure That Drug Labels Contain Up-to-Date Information,” says that since the September 27, 2007 enactment of the FDA Amendments Act (“FDAAA”) FDA has not taken sufficient steps to ensure that antibiotic labels contain up-to-date information, and that certain FDAAA provisions relating to antiobotic innovation have not resulted in the submission of marketing applications for antibiotics. 

The GAO report focuses on three FDAAA provisions:

(1) Section 1111, titled “Identification of clinically susceptible concentrations of antimicrobials,” which required FDA to identify “antibiotic breakpoints” “where such information is reasonably available,” to periodically update them, and to make these up-to-date breakpoints publicly available within 30 days of identifying or updating them.  (A “breakpoint” included on an antibiotic’s label reflects the concentrations at which bacteria are categorized as susceptible to treatment with a given antibiotic drug and can change over time.  An outdated breakpoint can result in the unknowing selecting ineffective treatments, which can also contribute to antibiotic resistance.);

(2) Section 1112, titled “Orphan antibiotic drugs,” which authorized funding for grants and contracts under the Orphan Drug Act and required FDA to convene a public meeting to discuss incentives, such as those included in the Orphan Drug Act, to develop or otherwise obtain marketing exclusivity for antibiotics that treat serious and life-threatening infectious diseases; and

(3) Section 1113, titled “Exclusivity of certain drugs containing single enantiomers,” which is not specific to antibiotic drug development, allows a sponsor of an enantiomer of a previously aproved racemate to elect to have its drug considered a New Chemical Entity (“NCE”) eligible for a period of 5-year NCE exclusivity (instead of 3-year exclusivity for enantiomers of previously approved racemates) provided certain statutory conditions are met.

Antibiotic Labeling Breakpoint Updates.  In 2008, FDA sent letters to application holders requesting that they inform the Agency as to whether or not their product included up-to-date breakpoints.  In June 2009, FDA issued final guidance on compliance with FDAAA § 1111 and discussing a sponsor’s responsibility to maintain up-to-date breakpoints on their antibiotics drug labels.  According to the GAO report, although FDA has taken these initial steps to update breakpoint information on antibiotic labels, the Agency “has not confirmed that the information is up to date for most reference-listed antibiotics.”  Indeed, as of November 2011:

over 3.5 years after FDA sent its letters, 146, or 70 percent, of the 210 antibiotics are still labeled with breakpoints that have not been updated or confirmed to be up to date. For 78 of the 146 antibiotics, FDA has not yet received a submission regarding the currency of the breakpoints; for 12 of the antibiotics, the sponsors’ submissions are pending FDA review; and for 56 of the antibiotics, FDA determined that the sponsors’ submission was inaccurate or incomplete and therefore requested a revision or additional information. Thus far, FDA has determined that 64, or 30 percent, of the 210 antibiotics have up-to-date breakpoints.

There are two reasons so many antibiotics still have breakpoints that FDA has not confirmed to be up to date, according to the GAO: (1) “many sponsors have not fulfilled the responsibilities outlined in FDA’s 2008 letters;” and (2) “FDA faced difficulty in keeping up with the workload that resulted from sponsors’ breakpoint submissions.”

The GAO recommends that FDA Commissioner Hamburg take several actions to help ensure the accurate labeling of antibiotics, including “expeditiously review sponsors’ submissions regarding the breakpoints on their antibiotics’ labels,” taking “steps to obtain breakpoint information from sponsors that have not yet submitted breakpoint information in response to the 2008 letters sent by the agency;” and establishing “a process to track sponsors’ submissions of breakpoint information included in their annual reports to ensure that such information is submitted to FDA and reviewed by the agency in a timely manner,”

Enhanced Incentives.  The two FDAAA provisions (Sections 1112 and 1113) applicable to antiobotic drug sponsors (although only generally in the case of FDAAA § 1113) that provide for enhanced incentives have apparently not encouraged the development or approval of new antibiotics.  According to the GAO:

To date, drug sponsors, including those we received comments from, have not submitted any NDAs for antibiotics as a result of the FDAAA provision granting additional market exclusivity for new drugs containing single enantiomers of previously approved racemic drugs.  According to FDA officials, they have received very few inquiries regarding this provision and as of November 2011, no NDAs for antibiotics have been submitted that would qualify for this exclusivity. . . .

The lack of NDAs for antibiotics submitted in response to this FDAAA provision is consistent with the overall trend in the approval of innovative antibiotic NDAs.  The number of annual approvals of antibiotic NMEs from 2001 through 2010 has not changed significantly since the passage of FDAAA. Specifically, the annual number of antibiotic NME approvals was two or less for the years prior to, and one or less for the years following, the enactment of FDAAA. 

FDAAA § 1113 amended the FDC Act to add § 505(u), which is scheduled to sunset this year unless reauthorized by Congress.  Although there are public reports of companies that have expressed interest in developing drug products that might qualify for the 5-year NCE exclusivity election, we are not aware of any NDA (antibiotic or otherwise) that has been approved and granted exclusivity under this provision.  Another exclusivity provision originally included in FDAAA, but removed and later enacted as part of the QI Act, that is targeted to so-called “old” antibiotics (i.e., FDC Act § 505(v)) is not discussed in the GAO’s report, presumably because of the limited scope of the GAO report.

On the orphan drug front (FDAAA § 1112), FDA held a public meeting on April 28, 2008 (Docket No. FDA-2008-N-0225) to, among other things, explore whether and how existing incentives and potential new incentives could be applied to promote the development of antibiotics as well as to discuss whether infectious diseases may qualify for grants or other incentives that may promote innovation.  While potential new incentives and tinkering with current ones were suggested at the public meeting, the GAO says that “many of these suggestions – such as tax incentives and extended market exclusivities – would require a statutory change.”

The GAO also examined orphan drug designation data and found that it is relatively uncommon for FDA’s Office of Orphan Products Development to designate an antibiotic an as orphan drug.  According to the GAO, its examination of odphan drug designations showed:

that the annual number of antibiotics that received an orphan drug designation from 2001 to 2007 – when FDAAA was enacted – was three drugs or fewer each year.  The number of antibiotics that received orphan drug designation following FDAAA’s enactment in 2007 has remained constant at this rate through 2010.  Additionally, not all antibiotics that have been awarded orphan drug designation have been or will apply to be approved for marketing.  Of the 15 antibiotics that received an orphan drug designation from 2001 through 2010, only 1 was approved for marketing as of November 2011.

To give you a sense of how small the figure 15 is, we tallied the number of orphan drug designation between 2001 and 2010 and came up with 1,262.  So, a mere 1.19% of those designations represent antibiotics.