FDA drug reviewers’ rejection of a larger fill size for ISTA Pharmaceuticals’ ocular agent Bromday (bromfenac ophthalmic solution 0.09%) was based on a hypothetical risk from a use that is contrary to product labeling, the company says.

The Center for Drug Evaluation and Research’s conclusion that a fill size large enough to treat both eyes creates an infection risk also is not supported by adverse event reports involving bromfenac or more than a dozen other ophthalmic agents, ISTA says in a Sept. 30 submission to the agency.

ISTA has formally requested a hearing on CDER’s rejection of a larger fill size for Bromday.

ISTA’s filing contains data and arguments supporting its request for a public hearing on CDER’s proposed refusal to approve a supplemental NDA for a larger fill size for Bromday, an ocular pain and inflammation treatment used after cataract surgery.

Risk Of Transferring Infection Cited

The company requested approval of a larger bottle size to provide enough drug for dosing in both eyes. However, CDER issued a “complete response” letter on the sNDA in February.

In the letter, CDER said the submitted data did not justify the need for increasing the fill volume and creating a new trade size. The current fill volume is sufficient to provide one full course of treatment, and a single bottle should not be used to treat more than one eye in the post-operative setting, CDER said.

The regulator subsequently told ISTA that use of the same bottle to treat both eyes increases the risk that an infection will be transferred from one eye to another through the dropper tip.

In an unusual move, ISTA decided to request an opportunity for a hearing on the rejected application, rather than resubmitting or withdrawing the sNDA (Also see "ISTA To Challenge FDA’s Refusal To Approve Bromday sNDA, Testing Little-Used Hearing Process" - Pink Sheet, 8 August, 2011.).

On Aug. 3 CDER published a notice of an opportunity for a hearing, giving ISTA 30 days in which to request a hearing. ISTA immediately filed a formal hearing request, followed by its Sept. 30 submission providing the substantial basis for its arguments.

FDA Commissioner Margaret Hamburg must decide whether to grant a hearing. Under the governing statute and FDA’s regulations, if Hamburg grants ISTA’s request for a hearing, it must begin within 90 days after expiration of the initial 30-day period ISTA had for requesting the hearing, which was Sept. 2, unless the parties otherwise agree.

The public hearing pathway is an infrequently used process, particularly for non-approval, as opposed to withdrawal, decisions.

Genentech Inc. and CDER did battle in a two-day hearing in June over the regulator’s proposal to withdraw accelerated approval of Avastin’s (bevacizumab) metastatic breast cancer claim. Hamburg has not yet issued her decision on the indication’s fate (Also see "Avastin’s Breast Cancer Claim: Will FDA’s Hamburg Take A Middle Road?" - Pink Sheet, 4 July, 2011.).

Shire’s request for a hearing on CDER’s proposal to withdraw accelerated approval of the hypotension drug ProAmatine (midodrine) has been pending for more than a year. The commissioner’s office recently announced a timetable for additional submissions by CDER and Shire before deciding whether a hearing should be granted (see related story, Also see "Shire’s Request For ProAmatine Hearing Will Go Unanswered Until 2012" - Pink Sheet, 24 October, 2011.).

Hypothesizing Risks Not Allowed

In the submission supporting its hearing request, ISTA says CDER’s rejection is unlawful because the Food, Drug and Cosmetic Act requires it to evaluate a drug’s safety “under the conditions of use prescribed, recommended or suggested” in labeling.

The law does not permit FDA to “merely hypothesize conditions of use contrary to a drug’s labeling, and then require a sponsor to disprove hypothetical safety issues that might arise under such conditions of use,” ISTA says.

Bromday’s labeling instructs physicians to advise patients against touching the dropper tip to any surface. “Because the ‘conditions of use … suggested’ in the drug’s proposed labeling include not touching the dropper tip to the eye, FDA must assess the safety of the proposed supplement based on those conditions,” the company says.

Even if CDER were allowed to speculate about potential misuse of a product, it lacks actual evidence of risk, according to ISTA.

The company marketed bromfenac as Xibrom, a twice-daily formulation, for more than five years in a fill size sufficient to treat both eyes before the product was replaced with the once-daily dosing formulation of Bromday.

ISTA is not aware of any reports of cross-infection resulting from use of a single bottle of Xibrom on two eyes. Furthermore, a search of FDA’s AERS database for more than a dozen other popular post-operative ophthalmic products over a 13-year span found no reports of an infection in one eye transferring to the opposing eye.

“CDER does not point to any adverse event data illustrating the risk – for ISTA’s product, or other products marketed with fill sizes sufficient to treat two eyes – and it does not identify any studies demonstrating a risk of cross-infection in ophthalmic NSAID products,” the company says.

Misplaced Reliance On Observational Data

CDER’s notice of an opportunity for a hearing cites an observational study published in the British Journal of Ophthalmology in 2007 as support for its view that patients may accidentally touch the dropper tip to the eye or skin, causing contamination that could spread to the other eye.

The study authors reported that 8% of ophthalmic solutions used in a long-term care facility were contaminated with bacteria. In light of frequent contamination during reuse of certain steroid-containing products, single-use solutions might be preferred for some ocular drugs, the authors suggested.

ISTA, however, said the article’s authors also found that the manufacturing process may be a source of contamination for steroid-containing products, and they did not study whether the observed contamination was linked to an increased infection risk.

“CDER’s conclusion that the fill size proposed in [the Bromday sNDA] poses a risk of infection is thus several steps removed from the conclusions of this study,” ISTA says.

Since CDER’s concern about transfer of infection from one eye to another is entirely hypothetical, other hypotheses with potentially negative consequences also should be considered, the company said.

The hypothetical risk of cross-infection would not be mitigated if patients prescribed two bottles of Bromday used them interchangeably, ISTA said.

“It is possible, for example, that patients who have undergone two eye surgeries would forego obtaining a second bottle of Bromday due to the inconvenience of making a second trip (while recovering from the first surgery) to the pharmacist. This could lead to underutilization of the drug and have negative implications for patient care,” ISTA says.

“It is also possible that patients prescribed two bottles of the product will use them interchangeably, meaning the risk of cross-infection (if it existed) would not be mitigated.”

Dissimilar Treatment Of Similar Products

The company further argued that CDER, through its rejection of the Bromday sNDA, arbitrarily is treating similarly situated products differently.

“CDER has proposed to deny ISTA’s supplement, yet it has approved numerous other products with fill sizes sufficient to treat two eyes, and CDER continues to approve products that raise the same concerns that supposedly warrant denial” of the Bromday sNDA, the company says.

For example, in April 2011 CDER approved Bausch & Lomb’s Lotemax (loteprednol etabonate ophthalmic ointment 0.5%), a corticosteroid for post-operative inflammation and pain. Labeling directs users to apply a small amount “in the conjunctival sac(s) four times daily” and states patients should be advised not to touch the eyelid or surrounding areas with the tip of the tube.

“The Lotemax labeling contains an almost identical warning as Bromday regarding touching the tip of the tube to the eye lids and surrounding areas due to risk of contamination, yet [CDER’s Division of Anti-Infective and Ophthalmology Products] apparently concluded that the warning was sufficient to eliminate the purported risk associated with using a single tube on both eyes,” ISTA said.

ISTA said it recognizes that FDA is not bound to continue to follow its precedents even when past approvals have established a general policy of approving a particular type of product or presentation.

“But where FDA intends to change such an established policy, it must do so as a matter of general application and not arbitrarily on some but not all similarly situated applications,” ISTA says. “Moreover, it must do so through a guidance document after giving the public an opportunity to comment.”

Unless the commissioner decides to summarily reverse CDER’s proposed denial of the sNDA, the law requires that the company’s hearing request be granted, ISTA said.

ISTA is represented by Covington & Burling, the same law firm that counseled Genentech through the Avastin hearing.

“At the hearing, ISTA will present testimony of witnesses regarding the rationale for providing a fill size sufficient to treat two eyes, the proven safety of this fill size option, the legal ramifications of CDER’s proposal to deny [the sNDA], and the policy implication of CDER’s proposed action.”

ISTA’s submission was filed by Gerald Masoudi and Christopher Pruitt of Covington & Burling. Masoudi is a former FDA chief counsel. The same law firm, through different attorneys, represents Genentech in its challenge on the Avastin MBC claim.

By Sue Sutter

CDER's Rejection Of Larger Bromday Bottle Rests On Hypothetical Risk, ISTA Says

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