Drug Industry Daily - Sept. 20, 2010 Issue

Vol. 9 No. 182

Weldon Plans to Testify Before Congress on J&J Recalls

Johnson & Johnson (J&J) CEO William Weldon plans to testify before a House panel later this month to answer questions on the drugmaker’s recall of consumer healthcare products.

Weldon is slated to testify Sept. 30 before the Committee on Oversight and Government Reform following a written request from committee chair Rep. Edolphus Towns (D-N.Y.), J&J spokeswoman Carol Goodrich told DID Friday.

Although the committee held a hearing on the so-called “phantom” recalls in May, Towns says internal emails have since been uncovered that raise questions on how long the drugmaker was aware of problems with Children’s Tylenol before it was recalled and about the actions of managers at the highest levels of a company.

“The evidence we have uncovered since our first hearing is extremely troubling,” Towns said in letters Thursday to Weldon and Colleen Goggins, head of J&J’s consumer products division, who went before the panel earlier this year.

Goodrich said Goggins’ presence on Sept. 30 is yet to be determined. However, J&J Friday announced that Goggins will retire from the company on March 1, 2011. Goodrich declined to say whether the retirement is related to the recalls.

In emails uncovered by the committee, Lee Lafleur, an executive with a subcontractor who carried out a Motrin phantom recall for J&J, wrote “we are exploring another similar but potentially larger recall for July involving Children’s Tylenol.” He added the recall “would make our Motrin project look small.”

J&J didn’t officially call for a recall of Children’s Tylenol until April 30 of this year, leading to questions of what the drugmaker knew then and why it waited 10 months to act (DID, May 27).

In a second email sent May 27, 2009, Peter Luther, president of J&J subsidiary McNeil Consumer & Specialty Pharmaceuticals, appears to approve the phantom recall of Motrin.

“If true, this raises serious questions about the actions of the managers at the highest levels of a company,” Towns said. He added that the email appears to contradict statements made by Goggins during the May hearing in which she testified she was not aware of the behavior of the contractors who conducted the phantom recall (DID, May 28).

The recalls in question have cost the company $600 million in lost sales and five lawsuits seeking class-action designation also have been filed against the company (DID, July 21).

The letter sent to Weldon, which includes the emails, is available at www.fdanews.com/ext/files/091610JJInvite.pdf. — Virgil Dickson


FDA Investigating Bladder Cancer Risk with Takeda’s Actos

The FDA has initiated a safety review of Takeda Pharmaceuticals’ diabetes drug Actos after preliminary research results showed a potential increased risk of bladder cancer with use of the drug.

Patients with the longest exposure to Actos (pioglitazone) as well as those with the highest cumulative dose of the drug were most at risk, the FDA said Friday.

The findings were based on five-year data from an ongoing, 10-year observational study by Takeda. These early results showed no overall association between Actos exposure and bladder cancer, just an increased risk, the agency said.

Company officials stand behind the drug, pointing out that the interim analysis showed the risk of developing bladder cancer was not statistically significant, Robert Spanheimer, Takeda’s medical director for Actos, told DID Friday.

While a possible association was seen in a subgroup during a post-hoc analysis of patients that were on the drug for a longer period of time, “We need to finish the study to answer the question” about the association, he said.

He said that Takeda was required to conduct the observational study after findings of bladder cancer in some rats in non-clinical trials.

The FDA’s review is ongoing and the agency has not been able to conclude that Actos increases the risk of bladder cancer.
GlaxoSmithKline’s Avandia (rosiglitazone), a diabetes drug in the same class as Actos, has no data linking it to bladder cancer, the FDA says.

Avandia, however, has been associated with cardiovascular risks such as acute myocardial infarction, acute heart failure and death. The FDA is now mulling over whether to pull Avandia off the market or institute risk mitigation strategies (DID, Aug. 26). — Virgil Dickson


FDA Mixes Fear, Enticement in Push for Generic User Fees

As the FDA begins its long-awaited attempt to create a system of user fees for generic drugs, the agency is looking to sell drugmakers on the program while, at the same time, warning of the consequences if it is not established.

“An effective program negotiated between FDA and industry would reduce review times and make funding more flexible,” FDA Commissioner Margaret Hamburg said Friday at the agency’s public meeting on generic user fees in Rockville, Md. “The fact is that no one benefits from a pending application queue of 2,000-plus products.”

Indeed, the ANDA logjam was high on the agency’s agenda at the meeting as Hamburg and other FDA officials sought to downplay fears that the backup was preventing new generic drugs from entering the market.

Calling the situation “not as simple as it first appears,” Hamburg said that a majority of the applications the agency is waiting to review are for products that could not immediately enter the market anyway due to exclusivity on their brand counterparts.

“Although there’s an increase in the number of applications pending, we’re not in a situation where, but for FDA inaction, thousands more generic drugs would currently be on the market in the U.S.,” Hamburg said.

But that could soon change if a generic user fee program is not implemented, Hamburg added, noting that the FDA is concerned that without the additional funding the fees would provide, the agency will soon be facing a situation where it is unable to ensure that generic drugs can be distributed to consumers on the first day they can be marketed.

“We’re not in a crisis now, but we may soon be,” Hamburg said

Whether those arguments will spur drugmakers to embrace the program remains to be seen. The Generic Pharmaceutical Association has been generally supportive of the idea but has insisted that the FDA develop a program that provides generic-drug makers with specific agency performance goals (DID, Aug. 9).

The group maintained that position at the meeting Friday, adding that any generic user fee program should also assure predictable review times for ANDAs and establish a single fee for all original applications regardless of their complexity.

Before a user fee program can even be established though, the FDA must first get approval from Congress. While legislation authorizing the FDA to impose the fees has not yet been introduced, negotiations are slowly moving forward and there is a growing sentiment that a bill will be enacted next year, Kurt Karst, an attorney with Hyman, Phelps & McNamara, said last month.

In the meantime, the agency intends to move forward with its proposal and anticipates it could enter into formal negotiations with generic-drug makers by November, Peter Beckerman, a senior policy advisor in the FDA Office of Policy said Friday.

“If it’s ever going to happen the time is now,” Beckerman said. — David Belian


FDA Reviewers Recommend Approval of Boehringer Anticoagulant Pradaxa

FDA reviewers have voiced support for Boehringer Ingelheim’s anticoagulant Pradaxa ahead of a Monday advisory committee meeting, recommending approval of the higher of two doses studied versus warfarin.

The FDA’s Cardiovascular and Renal Drugs Advisory Committee will vote Monday on whether to recommend approval for Pradaxa (dabigatran) to prevent stroke and systemic embolism in patients with atrial fibrillation.

It will also comment on the adequacy of the company’s pivotal trial, a large, randomized, noninferiority study of unblinded warfarin and blinded dabigatran at 110 mg and 150 mg. Members will vote on whether the product label should carry a superiority claim.

FDA reviewers recommend against a superiority claim over warfarin, the generic version of Bristol-Myers Squibb’s Coumadin, according to briefing documents posted online Thursday. They questioned granting the claim based on the results of a single, open-label study. Further, the sponsor set a noninferiority margin at 1.46 despite agency arguments for a margin of 1.38, the documents say.

The FDA will ask the committee whether the trial should have been allowed to proceed given it didn’t meet the margin standard. The committee will also comment on the adequacy of the trial’s conduct and whether the comparison was fair.  

Bleeding was the only important safety concern identified in the trial. Dabigatran 150 mg was not associated with an increased risk of adjudicated major bleeds compared with warfarin, while the 110 mg dose was associated with fewer major bleeding events than warfarin.

However, analyses of dabigatran’s effects on composites of different types of bleeding, stroke and non-central nervous system systemic embolism events suggest the 150 mg dose provides greater net benefit, the FDA says.

REMS Addresses Bleeding Risk

Boehringer has proposed a risk evaluation and mitigation strategy (REMS) to address a bleeding risk with the drug. The REMS includes a medication guide, “Dear healthcare professional” letter and prescriber brochure. Other topics the FDA would like to see addressed include:

  • The importance of patient compliance;
  • The effect of renal function on drug elimination;
  • The risk of gastrointestinal (GI) bleeding;
  • Use with antiplatelet agents; and
  • The performance of available assays in measuring the anticoagulant activity of dabigatran.

More studies may also be needed to address the increased risk of GI bleeding and use of the drug in subjects with marked renal impairment, a population excluded from the pivotal trial.

The trial showed differences in deaths across the three treatment arms, with a numerically smaller number of deaths reported in dabigatran users. However, the rate of myocardial infarction was higher in dabigatran patients compared with warfarin. Boehringer’s Phase III development program in patients with acute coronary syndromes should provide more information on this, the reviewers note.

The committee will also comment on what the drug’s labeling should say about the risk of hepatotoxicity. AstraZeneca’s Exanta (ximelagatran), an oral direct thrombin inhibitor, was associated with hepatotoxicity, raising concern for drug-induced liver injury with dabigatran (DID, Feb. 15, 2006). AstraZeneca subsequently withdrew the Exanta NDA.

If approved, dabigatran may face competition as a replacement for warfarin. Earlier this year, Bristol-Myers Squibb and Pfizer ended early a Phase III study of their anticoagulant apixaban after data showed that the drug prevented stroke among patients with atrial fibrillation (DID, June 14).

Additionally, Bayer and Johnson & Johnson’s anticoagulant Xarelto (rivaroxaban) was effective in a Phase III trial evaluating the drug for the treatment of deep vein thrombosis, and the company plans to submit a complete response to the FDA by year’s end (DID, Aug. 6).  — April Hollis


Lack of Cancer Experts on FDA Panel Torpedoed Lorcaserin, Arena Says

Arena Pharmaceuticals contends that the lack of cancer experts on an advisory panel may have sunk its weight-loss candidate lorcaserin’s chances for approval because members of the panel may have had difficulty understanding the drugmaker’s presentation.

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 9–5 against lorcaserin’s approval Thursday, saying the drug’s potential risks outweighed the modest weight loss seen (DID, Sept. 16).

Concerns about lorcaserin’s modest weight loss, a limited study population and a possible cancer risk seen in animal studies contributed to the negative vote, members of the panel said. Some panel members encouraged the company to submit additional data if the FDA opts not to approve lorcaserin.

The agency is scheduled to make a decision on lorcaserin, which has the tentative trade name Lorqess, by Oct. 22.

“We believe that lorcaserin does not pose a cancer risk to humans at the recommended therapeutic dose,” Arena CEO Jack Lief said during a Friday conference call. “It’s a shame that there were no carcinogenicity experts on the panel,” he added.

In its presentation, Arena said that mouse tumors were due to the toxicity of an increased preclinical dose and rodent-specific physiological mechanisms.

In presentations to the panel Thursday, FDA reviewers said that lorcaserin produced multiple tumor types in rats, including brain and breast tumors. The carcinogenic mechanism of action remains unknown, they explained.

However, in its Friday conference call, Arena officials emphasized that all of the tumors were limited to one strain of rodent, primarily males, at a toxic dose. “We also have mechanisms for a number of the tumors,” Chief Medical Officer Bill Shanahan said. “So, we showed that all of these were related to toxicity and/or we had mechanisms to explain them all.”

“We may be able to address this [issue] in other ways,” Shanahan noted. But the most important thing now, he said, is to “have discussions with the FDA.” — LaCrisha Butler


Future of R&D Tax Credit Stalls in Congress

An effort to permanently extend the Research and Development (R&D) tax credit as part of legislation aimed at providing assistance to small businesses has been denied.

In a bid to permanently extend the credit, Sen. Orrin Hatch (R-Utah) attempted to get his fellow lawmakers to suspend consideration of H.R. 5297, the Small Business Jobs and Credit Act of 2010, until the Senate Finance Committee includes the provision in the bill.

“We need to keep in mind that one of the best things we can do to retain and create good jobs in the U.S. is to incentivize research activities,” Hatch said.

However, Committee Chairman Max Baucus (D-Mont.) viewed the motion as disingenuous, a method to again delay the small business bill, which has been only temporarily renewed.

“These motions are the way that folks score points,” Baucus said.  “These motions are the way that folks try to embarrass other people.  These motions, quite frankly, are stunts.”

The bill passed 61–38 Thursday without the R&D provision. Baucus, however, did not rule out permanently extending the R&D tax credit, which expired at the end of 2009, in a separate piece of legislation.

“One way or another, Congress will address these expiring provisions,” he said.

Prior to Hatch’s motion, President Barack Obama had announced earlier this month that he planned to reach out to lawmakers to extend the credit permanently, and released a detailed plan of how it would be structured.

Although drugmakers have been pushing to get the R&D tax credit made permanent for several years, they did not immediately throw their support behind Obama’s proposal, saying they needed time to study the details.

“We haven’t taken a position yet on the president’s tax credit plan,” PhRMA spokeswoman Kate Michael told DID. “America’s biopharmaceutical research companies look forward to working with the Administration and Congress on finding long-term policy solutions that can help ensure that America keeps its innovative edge.”

Others questioned the proposals’ overall impact.

“The credit is not refundable and most of our companies have no taxable income,” Ellen Dadisman, a spokeswoman for Biotechnology Industry Organization (BIO), told DID. “However, we fully support making the credit permanent since it does have an overall positive effect on investment in the work our members do.”

The president’s proposal would expand the R&D credit by about 20 percent, making it  the largest increase since the credit was created in 1981, according to White House briefing documents.

“Instead of tax loopholes that incentivize investment in overseas jobs, I’m proposing a more generous, permanent extension of the tax credit that goes to companies for all the research and innovation they do right here,” Obama said during a speech outlining his plan earlier this month.

In total, the expanded credit would devote about $100 billion over the next 10 years to leverage additional R&D investment. Like previous credits, it would apply only to eligible research and experimentation conducted in the U.S.

Part of the administration’s proposal is to simplify the credit. In the past, businesses chose one of two formulas to calculate their credit. If they used the complex formula, they could get a 20 percent credit for investments over a certain base.

But “the complex formula is, in fact, so outdated that it takes into account the amount of a business’ R&D expenses from 1984 to 1988,” the White House says.

If drugmakers use the simpler formula, they could get a 14 percent credit in excess of a base amount. The administration proposes increasing that rate to 17 percent to make it more attractive for businesses.

Simplifying the credit in this manner would increase its impact by encouraging investment in research in the U.S., the White House says.

The R&D credit has been extended 13 times over the past 30 years, with some extensions lasting just six months. — Virgil Dickson

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Reporters: David Belian, April Hollis, Virgil Dickson, LaCrisha Butler, Wilson Peden

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