FDA’s Center for Drug Evaluation and Research is taking concerns about the potential infection risks of treating both eyes after surgery with a single-bottle ophthalmic agent to its Dermatologic and Ophthalmic Drugs Advisory Committee.

While the committee will be asked to consider issues that impact Ista Pharmaceuticals Inc.’s ongoing bid to secure approval of a larger fill size of its eye inflammation treatment Bromday, FDA’s meeting notice suggests the discussions will not be specific to any one product but will apply broadly across ophthalmic products that are used in the post-operative setting.

In a notice scheduled to appear in the Federal Register Nov. 17, FDA said the advisory committee will meet on Feb. 27 to discuss the “appropriateness of marketing a single bottle of ophthalmic product for use in both eyes for post-surgical indications as it relates to the potential risk for infection.”

The agency seeks advice “on the potential risk and approaches to mitigating that risk, including limits to fill size where appropriate,” the notice states.

Since discussions are not limited to any one product in particular, the panel’s recommendations on risk management measures and bottle size limits could affect a host of products.

The committee also will discuss the appropriate types of clinical evidence for developing anti-inflammatory drugs for treating ocular inflammation and pain after surgery, including the definition and scope of the indication and the types of clinical trials needed to support approval ([A#14111116003]).

Battling Over Bromday

CDER and ISTA have been at odds over the company’s request for a larger fill size for Bromday (bromfenac ophthalmic solution 0.09%) since early 2011.

In February, CDER’s Division of Anti-Infective and Ophthalmology Products (now the Division of Transplant and Ophthalmology Products) issued a “complete response” on ISTA’s sNDA seeking to market a 2.4 mL fill size sufficient to treat both eyes. Bromday was approved in October 2010 in a single fill size of 1.7 mL.

The review division said the data submitted did not justify the need for increasing the fill volume and creating a new trade size, the current fill volume appears to contain sufficient product for a full course of treatment, and a single bottle should not be used to treat more than one eye

CDER officials subsequently told ISTA that use of a single bottle to treat both eyes unacceptably and unnecessarily increases the risk of microbial infection. Although they denied approval of the Bromday sNDA, CDER officials said they were considering whether to present the issue of fill sizes for post-op topical ophthalmic products to an advisory committee.

In an unusual move, ISTA requested the opportunity for a hearing on the sNDA denial, rather than resubmitting or withdrawing the application.

On Aug. 3, FDA published a notice of an opportunity for a hearing. In that notice, the agency suggested it was rethinking prior product approvals given concerns it now has about using a single bottle of an ophthalmic agent in both eyes after surgery Also see "Safety Concerns Over Larger Bottle For ISTA's Bromday Could Impact Other Eye Drugs" - Pink Sheet, 2 August, 2011..

ISTA immediately filed a formal hearing request, followed by a Sept. 30 submission that provided the substantial basis for its arguments.

ISTA asserted that CDER’s rejection of the larger fill size was based on hypothetical risks from a use that is contrary to product labeling. The company cited the lack of adverse event reports of infection transferring from one eye to another for either Bromday’s predecessor product Xibrom or more than a dozen other popular post-operative ophthalmic products.

With its denial of the Bromday sNDA, CDER is treating similarly situated products differently because the regulator has approved, and continues to approve, other post-operative ophthalmic products in fill sizes sufficient to treat both eyes, ISTA said Also see "CDER's Rejection Of Larger Bromday Bottle Rests On Hypothetical Risk, ISTA Says" - Pink Sheet, 24 October, 2011..

FDA Commissioner Margaret Hamburg must decide whether to grant ISTA’s hearing request. FDA confirmed to “The Pink Sheet” that no decision on that request has been made.

When asked whether the advisory committee meeting was going to be held in lieu of ISTA’s requested public hearing, FDA said the two matters are separate. CDER scheduled and selected the topics for the February 2012 advisory committee meeting “but it is up to the commissioner to determine whether to grant a hearing,” the agency said.

A representative for ISTA said the company would not provide its perspective at this time on the advisory committee meeting or the status of its hearing request.

Are Two Bottles Better Than One?

ISTA has found one way to get around FDA’s denial of a larger fill size for Bromday. In the third quarter ISTA launched a twin-pack configuration of Bromday containing two bottles, priced at approximately double the single bottle price.

However, ISTA itself highlighted the potential risk management issues inherent with such a configuration in its Sept. 30 submission to FDA, saying the hypothetical risk of cross-infection would not be mitigated if patients prescribed two bottles used them interchangeably.

Bromday Battle Broadens: Ocular Drug Infection Risks, Fill Size Limits Will Get FDA Cmte. Scrutiny

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