Drug Industry Daily - Nov. 4, 2010 Issue

Vol. 9 No. 215

FDA Likely to Come Under More Scrutiny Following Election

Congressional oversight of the FDA is likely to increase dramatically following Republican gains in Tuesday’s election, according to a former FDA deputy commissioner and healthcare lawyer.

Scott Gottlieb, a resident fellow at the American Enterprise Institute and former FDA deputy commissioner, told DID the House Energy and Commerce Committee is likely to hold hearings that focus on the FDA’s performance and the impact its focus on risk aversion is having on the consistency and performance of the review process.

“You have seen a single story line for the last few years … that drugs aren’t safe, industry can’t be trusted, and the FDA needs more resources and authorities,” he said. “Now the FDA privately admits they have more slots than they can hire and they have vast new authorities that they are going to need years to figure out how to fully implement.”

Gottlieb says this is being translated into higher development costs, delayed approvals and a heightened degree of uncertainty around interactions with the agency. “I would expect to see some discussion of these issues.”

The FDA “will be squarely in the crosshairs of Congress,” John Manthei, partner and global co-chair of Latham & Watkins’ healthcare and life sciences practice, said on a media call Wednesday.

“Oversight can be time consuming for leadership at the agency,” he said, adding that the agency will likely have to answer to a different set of oversight inquiries, a change from the past two years, when oversight “was done almost in collaboration with the FDA.”

For example, previous oversight has highlighted perceived budget shortfalls at the FDA and potential statutory changes that could be made to further Democrat priorities, he said. When the new Congress comes in, should the FDA seek changes, they will need to be done administratively instead of as broader legislative reforms.

The GOP will probably focus on what it views as a too-aggressive postmarket stance and unnecessary slowing down of reviews, Manthei said.

Manthei also said the agency will also find itself in a challenging appropriations setting, and requests for funds are going to be reviewed carefully. “Each proposal is going to be analyzed for its price tag on industry and its impact on creating jobs in the United States,” he said.

Although the Senate did not change hands, it is going to be a dramatically more conservative institution, Manthei noted. “I think any proposal for the FDA that isn’t budget-neutral is going to be met with extreme skepticism.”

He also discussed the upcoming Prescription Drug User Fee Act (PDUFA) reauthorization, noting industry is pushing for a “clean PDUFA,” which should lower chances for inclusion of a recent drug safety bill giving the FDA broader powers and bringing the agency’s inspections of foreign plants in line with U.S.-based facilities (DID, Sept. 22).

But Manthei said the agency remains likely to increase harmonization efforts with other global regulatory authorities. “There’s been some recognition in the last few years that it can’t go it alone” and that it should work to recognize other regulatory organizations’ inspections.

Although industry groups PhRMA and the Biotechnology Industry Organization (BIO) did not comment on specific expectations from the new Congress, the organizations said they would continue to work with legislators.

“Our biggest priority is working on PDUFA,” PhRMA Senior Vice President Wes Metheny told DID Wednesday. “We’ve worked with both sides of the aisle and we’ll continue to do so.”

That sentiment was echoed by BIO President Jim Greenwood.

“We will continue to seek bipartisan — and even nonpartisan — approaches to ensure a policy environment that promotes continued U.S. leadership in biotech innovation and helps our industry foster domestic economic growth,” Greenwood said.

Leerink Swann analyst John Sullivan says changes in the already passed healthcare reform law are not expected, as there are not enough votes for a veto-proof repeal in the Senate or for significant offsetting legislation. “Until and if the White House changes parties, healthcare reform is the law of the land.” — April Hollis


Researcher Nabbed for Insider Trading Has Consulted for Many Drugmakers

The clinical researcher facing 25 years in prison for unlawfully tipping off a hedge fund manager about negative trial results is listed as an investigator for at least one ongoing clinical trial by Novo Nordisk and has consulted for many drug companies.

French national Yves Benhamou is listed as a principal investigator for a diabetes trial with Novo Nordisk, according to ClinicalTrials.gov. Company spokeswoman Lori Moore declined comment.

Benhamou has consulted for other companies including Abbott, Novartis, Roche and Vertex, according to disclosure statements from several medical journals.

A complaint filed Tuesday with the U.S. District Court for the Southern District of New York accused Benhamou of using his role as an adviser for Human Genome Science’s (HGS) hepatitis C drug candidate Albuferon (albinterferon alfa-2b) to provide nonpublic information about the drug trial’s progress prior to a company announcement. At the same time, the complaint further alleges, he was working as a private, paid consultant to an unnamed hedge fund.

Calls made to Frontpoint Partners, named in several reports as the hedge fund to which Benhamou provided the insider information, were not answered.

In addition to the criminal charges, Benhamou has been charged by the SEC with violating antifraud provisions of federal securities laws. The agency is seeking a permanent injunction against Benhamou, disgorgement of any ill-gotten gains and a civil penalty.

“We cooperated fully with the investigation and have no comment beyond that,” said HGS spokesman Jerry Parrott, who confirmed that Benhamou is no longer a consultant with the company.

The SEC complaint said Benhamou, a member of the steering committee overseeing the clinical trial of Albuferon, later known as Zalbin, tipped off the portfolio manager about issues uncovered in a Phase III trial.

Benhamou learned about two serious adverse events, including one death and one case of lung disease, a possible side effect of a higher dose of the drug in one arm of the study.

HGS decided to reduce the dosage for the patients in that arm and publicly announced the changes on Jan. 23, 2008, according to the complaint. The company’s stock plunged 44 percent at the end of that trading day.

A hedge fund manager ordered the sale of the firm’s entire position of HGS stock held by six healthcare-related funds that he co-managed, about six million shares, during the six-and-a-half weeks preceding the January 2008 announcement. The sales saved the hedge funds at least $30 million, according to the SEC.

Benhamou, 50, of Neuilly-sur-Seine, France, was arrested Monday in Boston, where the annual meeting of the American Association for the Study of Liver Diseases was being held.

HGS and its partner, Novartis, decided to halt development of albinterferon alfa-2b, known in Europe as Joulferon, last month. The biologic was pending before U.S. and EU regulatory authorities. The decision followed an FDA complete response letter which expressed concerns regarding its risk-benefit assessment (DID, Oct. 6). — LaCrisha Butler


Brand Companies Strike Back Against Calls for Flexible Biosimilars Regulations

Brand-drug makers are putting up a unified front in their efforts to ensure strict limits on the development of biosimilars, telling the FDA that regulation of the drugs should be much tighter than that being sought by generic manufacturers.

Speaking at the second day of the FDA’s public meeting on the topic Wednesday, representatives from brand-drug makers including Johnson & Johnson (J&J), Merck and Roche told the agency that policies proposed by generics companies, such as granting approval to multiple indications of a drug that have the same mechanism of action without requiring further testing, would be potentially unsafe.

“We would assert that the same mechanism of action is necessary, but not sufficient,” Jay Siegal, global head of regulatory affairs for J&J’s pharmaceuticals group, said. “Two highly similar products with similar clinical effects in one indication may have different effects in another indication.”

That stance was in contrast to the position put forth Tuesday by Teva, the world’s largest generic-drug maker, which told the FDA that once a product is proven to be biosimilar, additional indications should not require additional trials (DID, Nov. 3).

Other brand-drug makers speaking at the meeting echoed J&J’s stance.

“Extrapolation of safety and efficacy across indications should not be supported without adequate clinical studies,” Michael Wenger, clinical science leader for Roche, said.

Such extrapolation should only occur under “stringent conditions” that would include an open-label study, added Nikhil Mehta, vice president of biologics regulatory affairs for Merck.

The brand manufacturers’ call for strict regulations also extended to the initial process of proving a product to be biosimilar, with Wenger saying that proposals from generic companies to require only a noninferiority study were “not acceptable.”

“An equivalence trial is not going to be substantially larger [than a noninferiority trial] and provides greater assurance that the product is biosimilar,” added Mehta.

The agency continued to question presenters on how it could allow for biologics approved by the European Medicines Agency to be used as reference products for biosimilars in the U.S., an idea suggested by generic manufacturers.

That issue is especially relevant for companies such as Indian generic-drug maker Dr. Reddy’s, which already has several biosimilars on the market in Europe.

“Clinical costs represent by far the largest proportion of the overall cost of biosimilar development,” Anshuman Patwardhan, a senior director for Dr. Reddy’s, said. “The burden of having to repeat clinical studies for every major market is guaranteed to be a major entry barrier for a majority of biosimilar manufacturers.”

Momenta Pharmaceuticals, which earlier this year received a major boost when the FDA approved its generic version of Sanofi-Aventis’ complex blood thinner Lovenox (enoxaparin sodium) without requiring clinical trials, urged the agency to proceed with caution.

“If the rules [the FDA develops] establish burdensome limitations on [developers of biosimilars], the goals of the legislation will be undermined,” James Roach, Momenta’s chief medical officer, said. — David Belian


$1 Billion Worth of Government Research Grants, Tax Credits Awarded

An infusion of $1 billion in tax credits and grants will help nearly 3,000 small biotechs develop new therapies to treat cancer and other illnesses with unmet medical needs, help make firms more competitive and create and sustain jobs in the U.S., federal officials said Wednesday.

Companies from 47 states and the District of Columbia qualified for up to $1 million per project each under the Qualifying Therapeutic Discovery Project program, part of the healthcare reform package that passed earlier this year. The largest award to any one company was $2.9 million.

Treasury Secretary Timothy Geithner said the capacity of the U.S. to grow as a country and its ability to generate future job growth will depend on its ability to “keep America at the frontier of innovation.”

“With this funding, they will be able to hire more staff, improve facilities and move forward with research projects that otherwise would have been put on hold,” HHS Secretary Kathleen Sebelius said. “This work is too important to slow down or be stopped by a lack of funds or opportunity.”

NIH Director Francis Collins, whose agency reviewed 5,600 applications, hailed the grants and credits as a shining example of translation medicine at work. NIH moved 4,606 applications forward, representing 2,923 companies, some for multiple projects.

The grants and credits, combined with NIH’s Cures Acceleration Network, will focus on the research necessary to developing promising treatments, he said, adding, “It is a nice demonstration of government working together.”

To be eligible for the program, projects had to demonstrate reasonable potential to treat areas of unmet medical need, prevent, detect or treat chronic or acute disease and conditions, reduce long-term healthcare costs or significantly advance the goal of curing cancer within a 30-year period

Only companies with fewer than 250 people could apply for the credit, which could be accepted as a grant — for startups — or tax credit.

The complete list of grants and tax credits awarded is available at www.irs.gov/businesses/small/article/0,,id=228690,00.html. — LaCrisha Butler


FDA Approves Cadence’s Ofirmev as First IV Acetaminophen

The FDA has approved Cadence’s Ofirmev as the first intravenous formulation of the pain reliever acetaminophen.

The FDA approved the drug Tuesday to treat mild-to-moderate pain, moderate-to-severe pain with opioids and to reduce fever for adults and children two years and older.

Cadence said the drug would be available in the first quarter of 2011.

In a study of 101 orthopedic patients undergoing hip or knee replacements, Ofirmev 1,000 mg given every six hours proved superior to placebo for the reduction of pain intensity with less morphine.

Another study of 244 abdominal surgery patients showed treated patients had significantly less pain intensity compared with placebo after receiving Ofirmev 1,000 mg every six hours or 650 mg every four hours.

Study results showed Ofirmev’s safety profile was similar to oral acetaminophens, as Ofirmev is also contraindicated in patients with severe hepatic impairment and liver disease. The drug does not have a risk evaluation and mitigation strategy.

The most common adverse reactions were nausea, vomiting, headache and insomnia for adult patients. Pediatric patients reported nausea, vomiting, constipation, pruritus, agitation and atelectasis.

As part of the approval, Cadence will conduct post-marketing efficacy studies of Ofirmev in infants and neonates. The company plans to commence the studies in 2011.

Ofirmev will fill an unmet medical need in the hospital setting company officials said during a late Tuesday conference call, since it is a nonopioid and nonsteroidal anti-inflammatory drug (NSAID).

“Ofirmev has the opportunity to help patients deliver better pain management while at the same time reducing narcotic use,” noted CEO Theodore Schroeder. The company’s chief medical officer, James Breitmeyer, added that opioids and NSAIDs are “often limited by their significant side effects and risks.”

“The fact that acetaminophen [is in a different class], has a very, very well understood safety profile that differentiates it from NSAIDs, in particular, we think that it’s going to occupy a very separate and secure space on most hospital formularies,” Scott Byrd, chief commercial officer, said.

On the marketing side, Cadence plans to hire 150 sales reps to target 80 percent of its market opportunity, which it pegs at about 1,800 hospitals.
Byrd expects the U.S. market to be similar to that of the EU, noting that 90 million vials of intravenous acetaminophen were sold in Europe in 2008. He added 291 million units of intravenous NSAIDs and opioids were sold in the U.S. the same year.

Intravenous acetaminophen has been available in Europe since 2002, where it is marketed by Bristol-Myers Squibb (BMS) as Perfalgan. Cadence acquired the exclusive rights to Ofirmev in the U.S. and Canada from BMS in 2006. With the approval, Cadence will now pay BMS a $15 million milestone payment.

Canaccord Genuity analyst Adam Cutler notes that in 2008, Perfalgan had a 20 percent unit share of the entire injectable analgesic market and 90 million units were sold, which translated into $250 million in product sales. “If Ofirmev wins similar market share in the U.S. to what Perfalgan has garnered in Europe, Ofirmev would be at least a several hundred million dollar drug,” he says, adding peak sales could reach $500 million.

However, Ladenburg Thalmann analyst Juan Sanchez is skeptical of Ofirmev’s potential, since the drug lacks efficacy data beyond several hours after surgery and physicians may not necessarily embrace the drug for post-surgery patients.

Ofirmev’s approval follows a Feb. 10 complete response letter to Cadence in which the FDA stated issues with its manufacturing facility in Cleveland, Miss. (DID, Feb. 12). The plant in question was a Baxter facility that was later reinspected.

Cadence resubmitted its NDA for Ofirmev in early May, following a mid-April meeting with the FDA to discuss the deficiencies noted at the Baxter facility (DID, May 6). — Molly Cohen


BMS’ Ipilimumab Gets Three-Month Review Extension

The FDA is delaying by three months a decision on Bristol-Myers Squibb’s (BMS) melanoma biologic, ipilimumab.

The new user fee action date is March 26, 2011, the company said late Tuesday.

Ipilimumab was granted priority review in August as a second-line treatment for advanced melanoma (DID, Aug. 19). BMS was previously expecting an FDA decision by Dec. 25.

The biologic will go before the Oncologic Drugs Advisory Committee meeting on Dec. 2.

Ipilimumab works by blocking the activity of CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), a protein that plays an important role in regulating natural immune responses. By suppressing CTLA-4, ipilimumab can help sustain an immune response attack on cancer cells.

Results from ipilimumab’s Phase III trial showed that overall survival was significantly extended in patients with previously-treated metastatic melanoma who received ipilimumab.

After one year, between 44 and 46 percent of patients treated with ipilimumab were alive, compared with 25 percent of patients treated with gp100 peptide cancer vaccine alone. At two years, between 22 and 24 percent of patients treated with ipilimumab were alive, compared with 14 percent of patients treated with gp100 alone.

The most common adverse events reported during the Phase III trial were immune-related and most often affected the gastrointestinal, skin, liver or endocrine systems.

BMS submitted an application for ipilimumab to the European Medicines Agency at the end of June, the same time as the U.S. submission. The biologic is also under investigation for nonsmall cell lung cancer. — Molly Cohen

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

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