ISTA To Challenge FDA’s Refusal To Approve Bromday sNDA, Testing Little-Used Hearing Process

An unusual regulatory situation involving ISTA Pharmaceuticals’ ophthalmic drug Bromday could put FDA in the position of testing an infrequently used procedure for refusing to approve an application.

This comes just months after FDA confronted another untested regulatory process in trying to rescind the accelerated approval for Genentech's breast cancer drug Avastin. Both actions involve moving to a public hearing after the sponsor objects to FDA’s decision.

FDA is offering ISTA an opportunity to request a hearing on the Center for Drug Evaluation and Research’s proposed refusal to approve a supplemental NDA for a larger fill size of Bromday (bromfenac ophthalmic solution 0.09%), an ocular pain and inflammation treatment used after cataract surgery. The company requests a larger bottle size to provide enough drug for dosing in both eyes. However, this is unsupported and would increase the risk of microbial contamination, CDER says in a notice published in the Federal Register on Aug. 3.

CDER issued a “complete response” letter on the sNDA, instructing the company that it must resubmit the application, withdraw it or request an opportunity for a hearing. ISTA decided to request an opportunity for a hearing.

Such a decision by a sponsor is unusual. Following the publication of the notice of opportunity for a hearing, if ISTA formally requests a hearing by the Sept. 2 deadline and the agency grants the request, both FDA and the sponsor would find themselves navigating a little-used regulatory route that generally has been limited to market withdrawal proceedings.

Responding To “Complete Response” Letters

FDA’s regulations governing “complete response” letters (21 CFR Section 314.110) state that recipient applicants must either resubmit the application and address the identified deficiencies, withdraw the application or request an opportunity for a hearing.

With regard to the latter option, the regulations state: “Ask the agency to provide the applicant an opportunity for a hearing on the question of whether there are grounds for denying approval of the application or abbreviated application under section 505(d) or (j)(4) of the [FD&C] act, respectively. The applicant must submit the request to the Associate Director for Policy …. Within 60 days of the date of the request for an opportunity for a hearing, or within a different time period to which FDA and the applicant agree, the agency will either approve the application or abbreviated application under Sec. 314.105, or refuse to approve the application under Sec. 314.125 or abbreviated application under Sec. 314.127 and give the applicant written notice of an opportunity for a hearing under Sec. 314.200 and section 505(c)(1)(B) or (j)(5)(c) of the act on the question of whether there are grounds for denying approval of the application ….”

Going Down The Public Hearing Path

Under the agency's drug approval regulations, sponsors may request an opportunity for a hearing as to whether grounds exist for denying approval of a drug application under the Food, Drug and Cosmetic Act. The sponsor must submit a request for a hearing within 30 days of publication of a notice of opportunity for a hearing, with a supporting data package due 60 days after publication. In ISTA’s case, these deadlines are Sept. 2 and Oct. 3, respectively.

A similar, albeit more expedited, process was used for the June 28-29 hearing on CDER’s proposal to revoke accelerated approval of the metastatic breast cancer claim for Genentech's Avastin (bevacizumab).

Under the accelerated approval regs, Genentech had to submit a request for a hearing within 15 days of publication of the notice of opportunity for a hearing, and the data package had to be submitted within 30 days of the notice ('How The Avastin Appeal Will Proceed,' 'The Pink Sheet,' Dec. 20, 2010).

Granting A Hearing

FDA’s regulations governing hearing procedures for new drugs (21 CFR Section 314.200) state that the FDA commissioner will grant a hearing “if there exists a genuine and substantial issue of fact or if the commissioner concludes that a hearing would otherwise be in the public interest.”

If the request is granted, the hearing “will begin within 90 days after the expiration of the time for requesting the hearing unless the parties otherwise agree in the case of denial of approval, and as soon as practicable in the case of withdrawal of approval.”

The accelerated approval regs require that a hearing be conducted in the presence of an advisory committee – a requirement that does not appear to apply to products considered for regular approval, as is the case with Bromday.

Avastin marked the first time that a sponsor of an accelerated approval drug had refused the agency’s request to withdraw a product or indication, opting instead for a public hearing. The process was a bumpy one for all involved.

The agency could be headed for another hearing under the accelerated approval regs if Commissioner Margaret Hamburg grants Shire’s request to publicly challenge CDER’s proposed withdrawal of the hypotension drug ProAmatine (see related story, (Also see "Amid Avastin Noise, Shire Quietly Awaits Word On ProAmatine Public Hearing" - Pink Sheet, 8 Aug, 2011.)).

Historically, the hearing process laid out in the Bromday notice appears to have been used primarily by sponsors objecting to an agency proposal to withdraw a drug. For example, several generic companies requested a hearing on CDER’s proposed withdrawal of ANDAs referencing prescription Miralax (polyethylene glycol), a laxative that was approved for over-the-counter sale in 2008. Those requests are still pending.

The hearing process laid out in the Bromday notice appears to have been used largely by sponsors objecting to a withdrawal proposal, rather than a refusal to approve.

Several drug regulatory attorneys told “The Pink Sheet” they could not recall a situation in recent years where a notice of opportunity for a hearing had been published, and a hearing granted, in connection with FDA’s refusal to approve a drug application.

FDA confirmed it is rare for an applicant receiving a “complete response” letter to request an opportunity for a hearing. “While there have been notices of opportunity for hearing and actual hearings on refusals to approve applications in the past, there have not been any recently,” the agency said in an e-mailed response.

Other Sponsors Will See Trickle-Down Effect

Whether or not the Bromday matter reaches the hearing stage, the dispute between CDER and ISTA is expected to affect other ophthalmic product sponsors, who could face regulatory action over approved package sizes that CDER now believes pose safety concerns (Also see "Safety Concerns Over Larger Bottle For ISTA's Bromday Could Impact Other Eye Drugs" - Pink Sheet, 2 Aug, 2011.).

Bromday is the follow-on product to ISTA's Xibrom, containing the same active ingredient but with a different dosing schedule.

Xibrom was approved in March 2005 in 2.5 mL and 5 mL fill sizes. It is applied to the affected eye twice daily for two weeks. In October 2010, FDA approved the once-daily dose formulation, under the trade name Bromday, in a single fill size of 1.7 mL. Xibrom was discontinued several months after Bromday's approval.

ISTA’s sNDA seeks to market a 2.4 mL fill size, intended to provide enough product to treat both eyes for a full, two-week course of therapy.

In a February 2011 “complete response” letter, CDER's Division of Anti-Infective and Ophthalmology Products (now the Division of Transplant and Ophthalmology Products) determined the sNDA could not be approved. CDER said the data submitted do 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.

On May 12, ISTA submitted a request for an opportunity for a hearing. During a June 22 teleconference, CDER officials told ISTA that use of a single bottle to treat two eyes "unacceptably and unnecessarily increases the risk of microbial infection," the Federal Register notice states. CDER officials said they intended to deny approval of the sNDA but were considering whether to present the issue of fill sizes for post-operative topical ophthalmic products to an advisory committee.

CDER told “The Pink Sheet” it has not reached a final decision on whether to take the issue to a panel.

The agency is, however, rethinking prior product approvals given the concerns it now has about using a single bottle of an ophthalmic agent in both eyes following surgery. "We note that although we did not consider this safety issue at the time of initial approval of Xibrom and certain other products for which this issue may be relevant, as this issue develops we also intend to take appropriate steps with respect to other products that raise the issue," the notice states.

ISTA believes making Bromday available in a multiple bottle configuration would not require FDA approval.

ISTA told "The Pink Sheet" it is examining multiple pathways for making available a larger fill presentation of Bromday. While one way would be a larger bottle size, "another example would be a multiple bottle configuration (of the approved bottle size), which we believe does not require FDA approval," the firm said.

Fighting FDA On Generics, Too

Although ISTA is protesting the basis for CDER’s refusal to approve its sNDA, it is simultaneously trying to leverage those same safety concerns to its advantage in a lawsuit challenging FDA’s approval of generic bromfenac.

In March, ISTA filed a citizen petition requesting FDA refrain from approving any bromfenac ANDA that references Xibrom labeling or omits the section of Bromday labeling related to once-daily dosing. On May 11, CDER denied the company's 2011 petition, although it granted some relief requested in an earlier petition filed by ISTA.

Concurrent with the petition denial, the agency determined that Xibrom was not withdrawn from the market for reasons of safety and effectiveness – a necessary determination for generic submissions –- contrary to ISTA's assertion that Xibrom had been discontinued for safety reasons. The agency also approved Coastal Pharmaceuticals' ANDA for twice-daily bromfenac ophthalmic solution 0.09%. Coastal's generic is marketed by Mylan.

Two days later, ISTA sued FDA in U.S. District Court for the District of Columbia, challenging the agency's approval of Coastal's generic and denial of the 2011 citizen petition.

In an amended complaint filed July 18, ISTA notes that Coastal’s generic bromfenac was approved in a 5 mL fill size, enough to treat both eyes. The filing cites the June 22 teleconference with CDER, in which the agency stated “for the first time” that it believed safety problems existed with post-surgical use of a single bottle of eye drops for both eyes.

The agency asked ISTA to voluntarily modify the Xibrom label to remove the 5 mL fill size capable of treating both eyes and change the directions for use to clarify that the drug should be applied only to a single eye, according to the complaint.

“To the extent that FDA has made a finding or otherwise asserted that there are safety issues with Xibrom or a generic that references Xibrom’s label, in approving Coastal’s ANDA, FDA has violated its statutory mandate of ensuring that all drug products sold in interstate commerce are safe and effective for use,” the complaint states.

Product Franchise Revenues On The Line

The fact that ISTA is fighting on multiple fronts to protect its Xibrom/Bromday franchise is unsurprising given that the product line accounted for about half of the company’s revenues during the first half of 2011.

Xibrom/Bromday sales during the first six months were $36.6 million, down 12% from the year-ago period, the company reported in its most recent 10-Q filing with the Securities and Exchange Commission.

ISTA said that despite 10.5% growth in new prescriptions, Xibrom/Bromday net revenues decreased because of three factors: a lower average price per Bromday prescription compared to Xibrom due to marketing only one bottle size; a marginally lower refill rate for Bromday; and the entry of generic bromfenac in May.

While the SEC filing touts the company’s success in switching patients from Xibrom to Bromday, ISTA has run into FDA trouble with its promotional campaign for the newer product. On July 13, the Division of Drug Marketing, Advertising and Communications issued a warning letter citing the company's failure to adequately reflect risk information in a flyer (“Catching DDMAC's Eye: Leaving Out Risk Information Proves Risky Practice For ISTA,” “The Pink Sheet” DAILY, July 28, 2011).

By Sue Sutter