Drug Industry Daily - May 23, 2011 Issue

Vol. 10 No. 101

Hamburg: FDA Must Better Collaborate Adverse Event Reporting Across Agency

FDA Commissioner Margaret Hamburg acknowledged the agency needs to do a better job at integrating all of the many postmarket monitoring safety tools at the agency.

Her remarks followed a report to the FDA’s Science Board that highlighted the inadequacies of pharmacovigilance programs at the agency.

Hamburg spoke to one of the more troubling findings about the lack of coordination between FDA centers and adverse event reporting systems and said the agency needs to address the issue. 

Overall, the 22-page report from an 8-member subcommittee that reviewed pharmacovigilance efforts found the FDA needs to be more proactive in its efforts to improve adverse event reporting (DID, May 19). The report called for a more collaborative approach across the many adverse event reporting systems.

Stephen Spielberg, subcommittee chair and director of the Center for Personalized Medicine and Therapeutic Innovation at Children’s Mercy Hospital in Kansas City, Mo., called the current Adverse Event Reporting System “outdated,” adding the FDA’s current IT infrastructure limited full capacity.  

The Science Board subcommittee was unable to review the new FDA Adverse Event Reporting System (FAERS), which has yet to be implemented.

CDER Director Janet Woodcock said FAERS would still have limitations but would make integral improvements over its current system.

“I believe there are still serious issues in our ability to execute large IT projects,” Woodcock added.

The subcommittee report also recommends better mining data from increasingly popular electronic medical records to more easily file adverse event reports.

Speaking to that, Woodcock said the FDA is working with vendors of electronic medical records to better pool data from patient charts with the agency’s adverse event reporting systems.

Like Hamburg, Woodcock acknowledged the difficulty in producing reports from hospital or physician data.

The report was critical of the 36-minute average time it takes for a clinician to file an adverse event report with the FDA.

The subcommittee’s report is available at  www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ScienceBoardtotheFoodandDrugAdministration/UCM255723.pdf. — David Pittman


FDA Approves J&J HIV Treatment Edurant, Setting the Scene for Btripla

The FDA has approved Johnson & Johnson’s (J&J) HIV infection treatment drug, paving the way for approval of the combination HIV treatment Btripla.

Edurant (rilpivirine), previously referred to as TMC278, is a non-nucleoside reverse transcriptase inhibitor that blocks HIV viral replication.

Developed by J&J subsidiary Tibotec, rilpivirine is a once-daily pill taken with food that should be used as part of an antiretroviral therapy regimen to suppress HIV in the blood (viral load), the FDA says. Edurant is indicated for use in combination with other antiretroviral drugs for adults who are treatment naïve.

The drug should be available to wholesalers in the first half of June, Tibotec spokeswoman Pam Van Houten told DID.

Edurant’s approval was based on two Phase III clinical trials. Treatment-naive patients were randomized to Edurant or Bristol-Myers Squibb’s Sustiva (efavirenz). Both drugs were dosed in combination with other antiretroviral drugs.

Edurant was as effective as Sustiva at lowering viral load. However, patients with a higher viral load at study baseline were more likely not to respond to rilpivirine than patients with a lower viral load (DID, July 23, 2010).

Additionally, patients who failed therapy with Edurant developed more drug resistance than patients who failed Sustiva, the FDA says.

“This could impact TMC278’s commercial potential and future placement in HIV treatment guidelines,” warned Wells Fargo analysts Larry Biegelsen and Brian Abrahams in a Friday note

The most common side effects for patients taking Edurant were depression, difficulty sleeping, headache and rash. Fewer patients receiving rilpivirine stopped treatment because of side effects compared to patients taking Sustiva, according to the FDA.

Tibotec developed Edurant and will commercialize the product in the U.S. Regulatory applications have been filed in the EU, Canada, Switzerland and Australia, said Van Houten.


The company is collaborating with Gilead Sciences to develop and commercialize a once-daily fixed-dose combination of Edurant and Gilead’s Truvada (emtricitabine/tenofovir disoproxil fumarate) called Btripla. The companies refiled Btripla’s NDA in February after receiving a refuse-to-file letter from the FDA last year (DID, Feb. 14).

Btripla’s user fee action goal date is Aug. 10.

Investors may be more focused on the approval and launch of Btripla, Biegelsen and Abrahams wrote. “We do not necessarily see Btripla as a huge growth driver for Gilead compared to Atripla, Truvada or the Quad regimen [but] Btripla does offer an opportunity for diversification/life cycle management of Gilead’s HIV franchise.”

Btripla is expected to be a key aspect of Gilead’s product pipeline and a successor to its blockbuster Atripla, which combines Truvada with Sustiva.

Quad is a fixed-dose, single-tablet HIV treatment developed by Gilead that includes corbicistat, a pharmacoenhancing agent, and Truvada.

The analysts forecast worldwide Edurant sales, including sales to Gilead, at $35 million this year, $231 million next year and $870 million in 2015. “TMC278 represents a modest opportunity, we view it as one of J&J’s four major pharmaceutical launches in 2011 that should help accelerate the pharma division’s and J&J’s overall growth rate.”

The wholesale acquisition cost of Edurant is $21 per tablet, Van Houten said. Actual retail prescription prices will vary.

Tibotec will set Edurant’s price, which will then dictate the price for Btripla, the analysts agreed. “We currently model pricing at parity to Sustiva, $6,630 per year, and our Btripla list price estimate of $19,520 per year (before discounts),” the analysts said. “It is possible that given the tolerability advantages J&J could price ‘278 at a premium to Sustiva, although a significantly higher price could dissuade Btripla usage in the context of the virologic failure concerns.”

The FDA stresses Edurant does not cure HIV infection and patients must stay on continuous treatment to control the infection and decrease related illnesses. — Molly Cohen


FDA Asked Pfizer to Resubmit Chantix Adverse Event Reports

The FDA last year asked Pfizer to resubmit thousands of adverse event reports associated with its smoking cessation drug Chantix (varenicline) because they were not filed in a way that would enable a thorough evaluation, a statement issued by the agency says.

Pfizer initially submitted the adverse event reports in periodic safety summary reports, rather than via the FDA’s electronic Adverse Event Report System (AERS), the FDA says. The problem is not isolated to Pfizer or Chantix, the agency says, adding that it has since clarified its instructions to all drugmakers on how to make AERS submissions.

Approved in 2006, Chantix has been associated with serious neuropsychiatric events, including suicidal ideation, suicide and aggressive behavior.

In addition to resubmitting the adverse event reports, the FDA required Pfizer to conduct a large, comparative postmarket clinical trial comparing Chantix safety with that of other smoking-cessation drugs, according to the agency.

The FDA has initiated two other observational safety studies of Chantix, with the Veterans Administration and Department of Defense.

Pfizer must complete the postmarket trial by Aug. 23, 2016 and submit a final study report to the FDA within the following 12 months, FDA spokesman Jeff Ventura told DID.

The FDA issued the statement to quell any concerns that might have been sparked by a report in the May issue of QuarterWatch that draws attention to 150 Chantix-related suicides that were not made known to the agency until 2010. The report asks the FDA to investigate Pfizer’s handling of the suicides, some of which date to 2007, as well as numerous suicide attempts and other serious neuropsychiatric events.

According to the article, Pfizer’s failure to submit the reports through the agency’s Adverse Event Reporting System (AERS) “meant that until July 2010 FDA safety analysts were not aware of more than half of the reported suicide cases in which varenicline was the primary suspect drug, and did not have available hundreds of other reported cases of serious psychiatric side effects.”

In its response, the FDA says it “takes seriously the adverse events associated with all drugs, including Chantix … [and] continues to monitor for serious and unexpected events associated with Chantix.” The agency stressed that there are “no new safety concerns” with Chantix.

In 2008, the FDA required Pfizer to include a mandatory medication guide for patients describing the risk of neuropsychiatric events (DID, Feb. 4, 2008). The following year, at FDA’s request, Pfizer added a boxed warning on the Chantix label highlighting the risks (DID, July 2, 2009).

The QuarterWatch report also maintains that Pfizer should have reported the suicides within 15 days because of the seriousness of the events. However, Ventura pointed out, Pfizer wasn’t in the wrong on the 15-day rule because it applies to “serious and unexpected” adverse events, and suicide is included as a possible risk in the boxed label warning.

Last year, worldwide revenues for Chantix were $755 million — up 8 percent from 2009, but 17 percent lower than the $846 million in revenues in 2008, according to Pfizer’s 2010 annual report. The company noted a drop in sales following the changes to the product label, mainly in the U.S.

FDA’s statement on Chantix can be accessed at www.fda.gov/Drugs/DrugSafety/ucm255918.htm.

The QuarterWatch article is available at www.ismp.org/QuarterWatch/2010Q3.pdf. — Meg Bryant


Senate Committee Approves Legislation Banning Secret Settlements

A Senate committee has approved bipartisan legislation to prevent secret court settlements that can keep dangerous products on the market.

The Sunshine in Litigation Act of 2011 (S. 623), sponsored by Herb Kohl (D-Wis.), Lindsey Graham (R- S.C.) and Patrick Leahy (D- Vt.), prohibits secret court settlements that keep the government and consumer groups from learning about defective products so they can stay on the market unchallenged.

The Senate Judiciary Committee approved the legislation in a 12 to 6 vote Thursday.

The legislation requires judges to consider public health and safety before granting a protective order, sealing court records or approving settlement agreements. Judges are also given the opportunity to grant or deny secrecy based on a balancing test that vacillates between potential public health effects and legitimate interests in secrecy.

Kohl proposed the act in response to court cases regarding products that represent hazards and threats to public health. These dangers were undisclosed in court settlements, resulting in serious injuries, illnesses and fatalities.

While the legislation will affect numerous industries, the health sector is a major area of focus.

“We are all familiar with cases where protective orders and secret settlements prevented the public from learning about the dangers of silicone breast implants, IUDs, a prescription pain killer … defective heart valves … and most recently prescription drugs,” Kohl said. “Had information about these harmful products not been sealed by court orders, injuries could have been prevented and lives could have been saved.”

Kohl pointed to two recent court-endorsed secrecy agreements as prime examples of what the legislation will prevent.

A federal judge is currently deciding whether AstraZeneca can keep clinical trials that reveal harmful side effects of its antipsychotic drug Seroquel (quetiapine fumarate) under seal. While some documents in question have been opened by the court, requests to release all AstraZeneca submissions to foreign regulators and sales representatives’ notes on doctors’ meetings have been denied. The company recently paid $200 million to settle lawsuits for failing to disclose the risks (DID, Aug. 10, 2010).

“This is exactly the sort of case where judges should consider public health and safety when deciding whether to allow a secrecy order,” Kohl said.

Kohl also points to 8,000 cases Eli Lilly settled in relation to its schizophrenia and bipolar disorder treatment Zyprexa (olanzapine). According to the cases, Lilly failed to disclose known harmful side effects including unusual weight gain and dangerously high blood sugar levels that could result in diabetes. The company was also accused of promoting off-label use of the drug (DID, June 10, 2009). The settlements required plaintiffs to refrain from communicating or publishing statements regarding the circumstances of the settlements. It took two years for the public to learn about Zyprexa’s side effects, according to Kohl. In 2009, the company paid West Virginia $22.5 million to settle (DID, Aug. 24, 2009).

Kohl has long been pushing for his “sunshine” provisions to protect public health. He recently urged HHS Secretary Kathleen Sebelius to implement new transparency regulations signed into law last year (DID, Nov. 12, 2010).  — Molly Cohen


Shire Receives Paragraph IV Letter from Sandoz for ADHD Drug Vyvanse

More generic-drug makers are attacking the exclusivity of Shire’s attention deficit hyperactivity disorder (ADHD) drug franchise as Sandoz has filed an ANDA for Vyvanse.

Shire announced Thursday it had received Paragraph IV notice from Sandoz signaling the generic-drug maker’s intention to market a Vyvanse (lisdexamfetamine dimesylate) generic before patents expired.

The letter from Sandoz, a subsidiary of Novartis, cites all of Shire’s 16 Orange Book-listed patents for Vyvanse, which run to 2023. Shire has 45 days to file a patent infringement lawsuit to block an FDA decision for either 30 months or until the outcome of a legal decision, whichever comes first.

Vyvanse’s exclusivity expires Feb. 23, 2012, according to Shire.

But if Sandoz’s letter is the first received for Vyvanse as Shire says, Sandoz would have 180 days of marketing exclusivity for a generic version of the drug.

Vyvanse garnered $634 million in revenue last year, a 26 percent jump from 2009, according to Shire’s annual report. It also earned 15 percent of the market share for ADHD drugs, Shire says.

The drug is approved for the treatment of ADHD in children ages six and up through adulthood (DID, Nov. 16, 2010).

Shire’s ADHD franchise also includes Intuniv (guanfacine) and Adderall XR (mixed amphetamine salts). Intuniv is already under siege by generic-drug makers (DID, April 25).

Sandoz’s filing isn’t the first time a generic-drug maker has tried to shake Vyvanse’s exclusivity.

Actavis Elizabeth claimed Shire didn’t deserve exclusivity for the drug because Vyvanse’s active ingredient lisdexamfetamine converted to dextroamphetamine once inside the body. An appeals court sided with Shire (DID, Nov. 12, 2010).

Earlier this month, Vyvanse received a warning letter for promotional magnetic business card holders after the drug’s risk information was hidden by the same business cards it held (DID, May 18). — David Pittman


Apotex Receives Closeout Letter, Will Resume Shipping to US

Canadian generic-drug maker Apotex has received a closeout letter from the FDA, lifting an import alert for Apotex’s Etobicoke, Ontario facility, and paving the way for Apotex to resume exports to the U.S.

The FDA placed two Apotex facilities — in Etobicoke and Toronto, Ontario — under an import alert in 2009, following a warning letter that cited serious good manufacturing practice (GMP) deficiencies at the company’s Etobicoke plant (DID, Sept. 9, 2009).

The FDA’s June 25, 2009, warning letter cited “multiple, serious deficiencies,” including noting that the company’s out-of-specification investigations “illustrate problems in the quality control unit’s ability to conduct thorough investigations,” according to the FDA (DID, July 16, 2009).

Subsequent to the FDA’s import alert, Apotex voluntarily recalled lots of three drugs on the Canadian market while Health Canada carried out GMP investigations of its own (DID, Sept. 21, 2009).

It appears that Apotex has since made the necessary GMP corrections. “Based on our evaluation, it appears you have addressed the violation(s) contained in this warning letter,” the FDA says in a May closeout letter, recently posted online.

However, the closeout letter does not relieve Apotex of the “responsibility of taking all necessary steps to assure sustained compliance,” and will not preclude future regulatory action should inspections reveal other violations, the FDA says.

The company has said it will “soon resume shipments of its oral solid dose products to the U.S. market,” but did not specify a specific date when shipments would begin. Apotex did not respond to a request for further clarification by press time.

In addition, the FDA’s closeout letter only applies to Apotex’s Etobicoke location. The FDA has not said whether it has taken any action regarding the Toronto facility.

Apotex is the largest generic-drug maker in Canada, and sells a portfolio of approximately 300 drugs to 115 countries around the world, according to the company’s website.

The FDA has been slow to issue closeout letters to companies who have received warnings. As of Nov. 5, 2010, only 4 percent of drugmakers that had received a warning letter since the FDA’s new enforcement policy went into effect on Sept. 1, 2009 had received a closeout letter (DID, Nov. 29, 2010). — Kevin O’Rourke

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Reporters: Virgil Dickson, Molly Cohen, David Pittman, Kevin O'Rourke, Sarah Karlin

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