At Press Time

Panel Won't Approve Single-bottle Bromday

Study may be needed to validate postop bilateral use.

By Samantha Stahl, Assistant Editor

■ A recent meeting of the FDA's Dermatologic and Ophthalmic Drugs Advisory Committee voted against the idea of labeling a single bottle of NSAID drops for use in both eyes after cataract surgery.

The FDA's Center for Drug Evaluation and Research (CDER) was asked to approve an increased fill size of topical NSAID drops to allow patients going through two cataract surgeries to treat both eyes with a single bottle. The request came from Ista Pharmaceuticals regarding the company's Bromday (bromfenac ophthalmic solution 0.09%) drops. Ista sought to increase the fill size from 1.8 mL to 2.4 mL, a size still smaller than most topical NSAIDs, due to Bromday's once-a-day indication for postop pain and inflammation.

Wiley Chambers, MD, deputy director of the division of transplant and ophthalmology products for the CDER, requested the panel discussion to review postoperative drop use in more than one eye, since the issue had not previously been considered by the CDER.

The panel was asked to vote on whether it is “appropriate to use a single bottle of anti-inflammatory ophthalmic drops to treat both eyes postoperatively.” Five panel members voted yes, four voted no and two abstained.

To clarify confusion about the wording of the question, the panel was also asked: “Is it appropriate to label a single bottle of anti-inflammatory ophthalmic drops to treat both eyes postoperatively?” Only one member voted yes, 10 voted no and none abstained. Lack of evidence to support the safety of a single bottle for both eyes was cited as the chief reason for voting against the labeling.

Mark Packer, MD, of Eugene, Ore., who testified at the hearing on behalf of ASCRS, said the increase in fill size would have benefits to both patients and doctors. “I felt like the FDA was being penny-wise and pound-foolish,” he said. “A larger fill size would account for missed drops, and could eliminate the need for an extra refill, which is just a waste of time and money for patients.”

He explained that to officially change the label, a postop study would likely need to be completed that reassures the safety of using one bottle for both eyes. Currently, there is no data that has confirmed what he calls the “phantom risk” for spreading infection from one eye to another with a bottle.

“There was a broad level of support for the utility of a larger fill size in line with current standards of practice,” said an Ista Pharmaceuticals spokesperson. While there was no official vote, only discussion, the panel “also supported creating additional language for packaging that advises patients to avoid contact with the top of the bottle and to wash hands before using as a way of further mitigating the potential risk of contamination and infection.”

Ista will now wait on the FDA's final decision concerning Bromday's labeling. In the meantime, the company will continue to offer the drug in a twin pack with a smaller bottle size. Ista says it will also take the panel's discussion into consideration as it files its NDA submission for Prolensa (bromfenac ophthalmic solution), for which it hopes to have a larger fill size approved.

Criteria for Drug Approvals

Critic: Safety best basis for FDA decisions.

By René Luthe, Senior Associate Editor

■ The FDA approval process is so slow and outdated, says a former agency commissioner, that the United States is in real danger of losing its pre-eminence in the global biomedical market. In a recent op-ed piece in the Wall Street Journal, Andrew von Eschenbach, who served at the FDA from 2005-2009, recommends a policy of approving drugs based on proof of concept and safety testing, leaving demonstration of efficacy for post-market studies.

Due to some well-publicized cases of unanticipated side effects of drugs such as Vioxx, the FDA has required more data and longer clinical trials from manufacturers to identify rare side effects. Mr. von Eschenbach cites The Tufts Center for the Study of Drug Development report that clinical trials from 2003-2006 were nearly 70% longer than those from 1999-2002. The result is “skyrocketing” drug development costs that crowd out investments in new therapies for such significant health threats as diabetes, obesity and heart disease. He also cites macular degeneration as a disease where new concepts such as stem cell therapy should be allowed to move ahead more quickly.

An additional danger the FDA's current modus operandi poses, says Mr. von Eschenbach, is of an economic nature: “The US biomedical industry of the American economy. It employs 1.2 million people directly and over five million throughout its supply chain, with a total output of $519 million,” he says, citing a 2011 Milken Report claiming that from 2001 to 2010, US-based companies produced approximately 60% of the new medications globally. “But US firms won't continue to lead unless the FDA retains its role as the world's ‘gold standard’ for evaluating new medical products.” Israel, China and Singapore are among the countries poised to “leapfrog” US leadership in the life-sciences industry, he warns.

In a reader comment posted by Allan May, chairman of Life Science Angels, a company that tracks venture capital investments in healthcare, Mr. May notes that the FDA's slow pace is “rapidly forcing the off-shoring of the US's vaunted medical device and biotech industries. This is not a future threat; it is a present reality.” He notes that the system advocated by Mr. Eschenbach, of products approved after they demonstrate safety, followed by efficacy studies once they are on the market, is the system already used in Europe — a continent for whose residents numerous studies have shown life expectancy and quality of life at least equal to those of patients in the United States.

Mucin-killing Bacteria

A cause of serious eye infections?

■ Scientists from the Schepens Eye Research Institute have found for the first time that a bacterial pathogen can literally mow down protective mucins found on mucus membranes to enter and infect a part of the body. Their landmark study on the phenomenon, published recently in the journal PLoS ONE, describes how they discovered that an “epidemic” strain of the bacterium Streptococcus pneumoniae, which causes conjunctivitis, secretes an enzyme to damage mucins and breach the mucosal membrane to infect and inflame the eye.

“We are excited about this finding,” says Ilene Gipson, PhD, the study's principal investigator and a senior scientist at the Schepens. “Our discovery may ultimately lead to new ways of diagnosing, treating and preventing bacterial infections originating not only in the eye but in other parts of the body as well.”

Until the current PLoS ONE study, little has been known about how epidemic infection-causing bacteria are able to cross through the mucin barrier. Experts in the study of mucins determined to find a piece of this puzzle, the Schepens scientists hypothesized that “epidemic” bacteria must somehow remove the mucins themselves.

To test their hypothesis, the team grew “epidemic” conjunctivitis bacteria (a strain of Streptococcus pneumoniae) in a culture. This bacteria causes an inflammation of the conjunctiva. They then applied the fluid that the bacteria were cultured in to cell lines that mimicked the eye's surface, including presence of intact mucins, and found that the membrane-anchored mucins were cut off and released from the surface of the cells. Removal of the mucins allowed the bacteria to enter the cells.

Using mass spectrometry, the researchers were then able to identify the enzyme ZmpC as the culprit. They confirmed their findings by knocking out the gene in the bacteria that produced this enzyme and demonstrated that the bacterium could no longer remove the mucins from the membrane.

According to Dr. Gipson, “This discovery is a major breakthrough in this long unsolved puzzle about how ‘epidemic’ bacteria enter the body and has given us a new target for drugs that could even be used preventatively.”

The next step in the research, according to Dr. Gipson, will be to determine if the method of enzymatically removing the surface mucins to gain entrance is used by other disease-causing bacteria.