Pfizer, on Wednesday, agreed to pay $2.3 billion to end a US Department of Justice investigation citing the company for illegal off-label marketing tactics related to a number of products. It represents the largest single settlement of its type for a pharmaceutical company, topping Lilly’s $1.4 billion Zyprexa settlement reached in January of this year.

Pfizer was accused by company sales representatives of encouraging promotion of the painkiller Bextra in doses beyond what the arthritis drug was sanctioned for, and at levels for which FDA specifically denied approval due to health concerns. Pharmacia & Upjohn Co., a subsidiary of Pfizer, also pled guilty to a felony count of fraudulent marketing.

Whistleblowers claimed that the drug company fully sanctioned off-label promotions on a number of drugs, even after warning letters were issued. One rep accused Pfizer of placating FDA after receiving a warning letter for Zyvox, yet the firm continued to allow reps to make claims to physicians that the drug was better than its far cheaper generic equivalent. 

The bulk of the money—$1.3 billion—will be used to settle criminal charges involving Pfizer’s promotional tactics, which the company pulled from the market in 2005. However, the DOJ ordered Pfizer to pay $503 million to settle civil charges of shady promotional activities. The breakdown is as follows: $301 million for Geodon, $98 million for Zyvox, and $50 million for Lyrica, as well as a $48 million in civil damages for payments given directly to physicians.

“This historic settlement will return nearly $1 billion to Medicare, Medicaid, and other government insurance programs, securing their future for the Americans who depend on these programs,” stated Kathleen Sebelius, Secretary of the Department of Health and Human Services.

Pfizer stated adamantly that it denies all of the civil allegations, with the exception of “certain improper actions” surrounding marketing strategies for Zyvox.

“These agreements bring final closure to significant legal matters,” stated Amy Schulman, senior vice president and general counsel for Pfizer.  “We regret certain actions taken in the past, but are proud of the action we’ve taken to strengthen our internal controls. We will continue to take appropriate actions to further enhance our compliance practices and strengthen public trust in our company.”

The $2.3 billion expense was accounted for in the company’s Q4 2008 earnings.

J&J received a violation letter in response to a journal ad for its topical anti-inflammatory cream Ertaczo, emblazoned with the words “Crush. Kill. Destroy,” in large, orange letters. FDA states that the company is way off-base in touting total annihilation of athlete’s foot, rather that a decrease and potential for cure.

“Although [trial] results show modest effectiveness, they clearly do not support the claims that Ertaczo ‘wipes out’ or crushes, kills, and destroys tinea infections,” DDMAC wrote in the letter.

FDA also took issue with the suggested claims that Erataczo is approved for all patients. In fact, the drug is not approved for patients less than 12 years old.

Allergen got an even harsher letter, stating that its journal advertisement for the acne gel Aczone is a complete misrepresentation of the results of a clinical study, and that the ad “grossly overstates the efficacy of the drug by presenting only the most favorable result for Aczone.”

The ad stated that patients could see a reduction in acne by as much as 24 percent in two weeks. The study FDA is referring to showed that at two weeks, patients showed only a 2 percent decrease in inflammatory lesions.

Finally, Galderma received a warning letter regarding professional visual aids for its skin discoloration cream Tri-Luma. According to DDMAC, the ads “suggest uses for Tri-Luma that have not been approved by FDA, and thus create new  ‘intended uses’ for the drug for which the product lacks adequate directions, broaden indication for Tri-Luma, and omit and minimize important risk information for the drug.”

FDA officials have been promising stiffer enforcement of manufacturing and marketing requirements for several months, and commissioner Margaret Hamburg is moving full-speed ahead to fulfill those predictions. Last month, FDA announced it will issue warning letters quickly when it finds violations and will require manufacturers to respond promptly. Too many serious violations “have gone unaddressed for far too long,” including failings with product quality, adulteration and false and misleading labeling and advertising, Hamburg commented at a meeting sponsored by the Food and Drug Law Institute. The commissioner wants to limit all the back-and-forth wrangling with regulated companies that delays compliance. And if there’s a situation that raises serious health and safety issues, FDA may launch a recall or seizure before even issuing a warning letter, she warned.

Under the new program, manufacturers will have 15 working days after receiving an inspection report to respond to any cited violations. If FDA doesn’t receive a sufficient response in that timeframe, the agency will issue a warning letter. The 15-day policy was described in an Aug.10 Federal Register notice and will apply to violation notices issued after Sept. 15.

On its part, FDA will try to promptly reinspect or investigate a company’s efforts to correct violations. If the problems are not corrected, though, the agency won’t just issue another warning letter, but will look at penalties, seizure, closures or other action.

Carrot for Compliance
In addition to waving a bigger stick, FDA wants to encourage pharma companies to quickly address violations by establishing a formal process for resolving enforcement actions. After determining that problems cited in a warning letter have been corrected, beginning this month the agency will state that compliance in a formal close-out letter and post the information on its website. This gives companies an official statement to show investors and customers that they’re back in FDA’s good graces, and that a facility or product is no longer tainted.

Another important change is to end the extra legal review of warning letters before they are sent out. The Bush administration revised procedures so that the FDA chief counsel examined all warning letters, a policy that was criticized for delaying and reducing agency enforcement actions against industry. “This created very cumbersome practices without a lot of benefit,” Hamburg commented. Now each FDA center will review and identify those warning letters should go to the chief counsel because they raise “novel, complex and sensitive issues,” such as an activity involved in a lawsuit or recently established by legislation.

Hamburg hopes that these policies will spur speedy corrective efforts by cited companies and encourage broader compliance throughout industry. Publicizing agency enforcement actions, she said, will increase public confidence in the agency and better educate patients and consumer about potential risks in medical products.

Faster review of violations and follow-up to corrective actions will require more resources, which Hamburg says are now available due to FDA budget increases. The food safety legislation before Congress also will give the agency some additional enforcement tools.

Hamburg expects an initial increase in warning letters but hopes that the volume will level off over the long run as industry recognizes that a strong compliance program is good for business and for consumers. FDA’s success in spurring compliance “should be measured not by the number of warning letters or injunctions or seizures,” she said, but by “our impact on the health and welfare of the public.” Failure to meet FDA standards means that a company is “putting the public at risk” and also “jeopardizing the public’s confidence in your industry.”

FDA, this morning, walked media through its proposed regulations requiring that pharma companies submit post-market adverse event reports through an electronic format. This is being done to help eliminate time and cost wasted on paper submissions.

“This change will enhance FDA’s ability to rapidly identify new safety concerns and share safety information with the public,” said Gerald Dal Pan, director, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, FDA.

Currently, FDA accepts reports in both paper and digital formats. Since 2000, CDER has allowed drug companies to submit forms electronically via a pilot program. Electronic reports are entered into a database almost immediately if logged through the FDA’s Web gateway, and take a bit longer if submitted on a CD or DVD.

“The proposed rule does not propose any changes to the requirement for what information must be reported to FDA,” Del Pan said in a press conference. “It proposes that the information be submitted electronically rather than on paper.”

Today, FDA laid out two options for electronic submissions. Manufacturers can submit via international electronic standards or through a Web based safety-reporting portal currently under development. According to Del Pan, the Web-based portal is intended for companies with small numbers of reports and for consumers to report side effects directly.

FDA said that the new regulations will improve the overall efficiency of the adverse event reporting process, and that it will cost less to input forms that come in digitally. However, the agency would not disclose the cost of upgrading to the new electronic system.

“A lot of companies are doing this already,” Del Pan said. “We currently receive between 400,000 and 500,000 reports a year, and about 80 percent of those are already coming in electronically, based on the pilot program started in 2000.”

Lilly, on Wednesday, announced that it would not seek regulatory approval for its osteoporosis treatment arzoxifene, because the drug failed to meet certain end points in Phase III clinical trials.

The good news is that the drug was successful in meeting the primary end point of the trial, dubbed “GENERATIONS.” According to a press release, arzoxifene met the primary end point by “significantly reducing the risk of vertebral fracture and invasive breast cancer in postmenopausal women.” However, the drug did not meet specific secondary end points, and patients receiving the drug reported more side effects than those taking a placebo.

Lilly compared the treatment to its current osteoporosis products, and chose not to submit the drug for FDA review. The results of the five-year study will be released some time in 2010.

“At Lilly, our goal is to provide innovative therapies that result in better patient outcomes,” stated M. Johnston Erwin, global brand development leader for the musculoskeletal platform at Lilly. “While arzoxifene met its primary efficacy objectives in this study, we are disappointed that the GENERATIONS data did not convincingly demonstrate that arzoxifene would represent a meaningful advancement in the treatment of osteoporosis.”

Lilly was banking on the success of the drug to boost its pipeline, but the company’s CEO commented in the release by pointing out that Lilly has more than 60 molecules in development.

“It’s not that serious a problem” for Lilly, Natixis Bleichroeder analyst Jon LeCroy told Bloomberg. “Osteoporosis is a very tough category right now, and there is tough competition with generics.”

If approved, the drug would have been fighting it out with GSK, Merck, and Teva—all of which either have competing treatments in the osteoporosis market, or are looking to launch a product in that category in the near future.

Now Lilly must reach out to the trial locations currently treating patients with arzoxifene, and discontinue all medication.

An FDA director has come under fire by a generics firm claiming that the director of the Center for Drug Evaluation and Research favored a competitor in a wanton act of conflict of interest. The Wall Street Journal this morning broke the story that Janet Woodcock is under investigation by FDA officials, and that an official ethics complaint has been filed against the director.

The generic firm leading the charge, Amphastar, submitted an application in 2003 for approval of a generic version of the blood-thinner Levenox. In 2007, FDA rejected the drug due to potential immunogenicity concerns.  After sifting through public records, Amphastar discovered a conflict of interest between Woodcock and Momenta Pharmaceuticals—a rival firm that filed for a similar blood thinner two years after Levenox.

“It appeared [that] one of the founders of Momenta and the vice president of Sandoz, in February of 2007, were working together to define the immunogenicity standards at MIT,” Amphastar spokesperson Dan Dichner told Pharm Exec. “They sent these emails to Janet Woodcock urging FDA not to approve a generic equivalent hastily.”

Additionally, Amphastar claims that during the heparin crisis Woodcock turned to Momenta to identify the contaminant instead of using its own internal labs. Both companies’ blood thinners include Heparin, but neither firm was found to have the tainted heparin in its drugs.

The clincher was that Woodcock penned journal articles for two publications in tandem with Momenta scientists, which, according to Amphastar, caused Momenta’s stock to spike 17 percent.

“We just summarized public information, and asked Woodcock to recuse herself from the review process based on this information,” Dichner said. “The ball’s in [FDA’s] court. We’ve done everything they’ve asked. We’ve been inspected 12 times in the last year, which is unbelievable. The correspondence with the new leadership has been positive. They claim that they don’t encourage these types of industry relationships, and we hope that that’s true.”

FDA did not respond to comment by deadline.

Score another win for Genentech and its cancer treatment Avastin (bevacizumab). On Monday, the biotech giant, now owned entirely by Roche, announced that FDA has approved the drug for kidney cancer.

Avastin blocks new blood vessels from forming and supplying tumors with the nutrients they need to grow and spread to other parts of the body.

Since it was first approved in 2004, Genentech has expanded Avastin’s uses to colorectal cancer, breast cancer, and non-small cell lung cancer. According to Roche, the treatment is being tested for treatment in more than 30 tumor types.

“We hope that researchers some day find a cure for kidney cancer,” stated William P. Bro, chief executive of the Kidney Cancer Association, in a release.  “Until then, each new medicine, like Avastin, offers patients an opportunity to find the treatment best suited for them.”

FDA approved this indication of Avastin after reviewing data from a study that documented a 67 percent increase in progression-free survival of patients receiving Avastin for previously untreated metastatic renal cell carcinoma. Additionally, 30 percent of patients taking Avastin with interferon alpha saw a drop in tumor size, compared to 12 percent in patients not taking Avastin.

According to Roche, the study was conceived to show an increase in overall survival in patients with this type of cancer. The company didn’t succeed in that regard, stating that there was no improvement in overall survival. However, the endpoints that were reached were more than enough to satisfy FDA’s approval process.

Avastin now enters a very crowded kidney cancer market with competition from Pfizer, Wyeth, and Bayer. However, CNN reports that many physicians have been using the drug off-label for kidney cancer, which could boost market penetration.

In an effort to boost its sales force without hiring more sales reps, Amgen announced on Tuesday that it has signed a deal with GlaxoSmithKline to co-market its osteoporosis treatment denosumab—currently pending FDA approval.

GSK will paying $120 million up front (along with royalties) to mutually market denosumab, or DMab, in regions where Amgen currently doesn’t have a strong sales force, such as China, India, and Brazil. The companies will tag team commercialization in Europe, Australia, New Zealand, and Mexico. Meanwhile, Amgen will handle all marketing in the United States and Canada.

“Our collaboration with GlaxoSmithKline will help Amgen bring the promise of denosumab to patients in Europe and other parts of the world more effectively than if we commercialized the drug globally on our own,” stated Amgen CEO Kevin Sharer in a release. “Amgen and GlaxoSmithKline together are uniquely positioned to help medical providers and patients understand the clinical promise and economic value of denosumab.”

Amgen is banking on denosumab being a blockbuster treatment, with analysts speculating that the drug could fetch $2 billion by 2018. The twice yearly injectible will go up against Merck’s daily osteo pill Fosamax, which went generic in 2007.

Typical of new administrations, FDA commissioner Margaret Hamburg is moving around some staff functions and bringing in new faces, but holding off on major reorganizational changes at the agency. There will be a new “food czar”—a deputy commissioner of food—but not a comparable official in charge of drugs, biologics and medical devices. Hamburg also is looking for a politically savvy health expert to head up a new Center for Tobacco Products, plus other newcomers to direct revised operations for managing policy, budget, science and communications functions in the FDA commissioner’s office.

The departure of the remaining top staffers under the previous administration—chief of staff Susan Winckler, policy chief Randall Lutter and chief of operations John Dyer—facilitates these changes. Budget development will shift to the policy office to better meet demands from Congress for more detailed information on how FDA will spend all the added money it’s seeking. An office of external affairs will handle FDA’s relations with the media, health professionals and interest groups, and a new Office of Special Medical Programs is slated to absorb a number of cross-cutting programs—bioresearch monitoring, combination products, orphan drugs and pediatrics.

That will leave chief scientist Jesse Goodman to focus on innovation and counter-terrorism, in charge of FDA’s Critical Path Initiative and pandemic response. Goodman also will head up a new office of scientific integrity that will resolve scientific disputes within the agency, and share oversight of the Center for Toxicological Research in Arkansas.

But Hamburg’s main focus clearly is on improving food safety and oversight. The commissioner proposed these changes to the secretary of Health and Human Services (HHS) in June, just as the Obama administration rolled out new proposals from its food safety working group to better control food-borne illness. As part of the initiative, FDA issued a long-awaited final rule for reducing salmonella contamination in eggs and promised new guidance on ways to prevent E.coli contamination of tomatoes, melons and leafy greens.

At the same time, Hamburg announced the return of former FDA official and food regulatory expert, Michael Taylor, as a special advisor on foods. The expectation is that Taylor will be new food czar, overseeing the Center for Food Safety and Nutrition (CFSAN) and the Center for Veterinary Medicine (CVM), along with extensive food-related oversight provided by FDA’s field force. Taylor comes to FDA with the benefit of experience as administrator of the Department of Agriculture’s Food Safety and Inspection Services (FSIS) as well as FDA deputy commissioner for policy in the early 1990s. As an academic for the last 10 years, Taylor has been involved in food safety research and policy. He has backed proposals to create a single federal agency governing food safety, but says that’s off the table for now.

Bigger Budget

Hamburg will have support for reorganization and expansion in the form of a $3 billion budget for the coming year. House and Senate spending bills provide FDA with $2.3 billion in appropriated funds plus some $600 million in user fees. The legislators specify increases in funds for generic drug approvals and instruct FDA to use much of the added money to increase inspections of food and drug operators, examine more imports, upgrade lab equipment and improve information technology.

There are special earmarks for research on food-borne contaminants, neuroblastoma, dietary guidelines and the impact of Risk Evaluation and Mitigation Strategies for drugs. The Senate bill earmarks $18 million for the Critical Path Initiative, along with research on tropical diseases, tuberculosis treatment, antibiotics and the bioequivalence of anti-epileptic drugs.

Differences in the specifics will be ironed out this fall, with an eye to approving final agency funding before the new fiscal year begins Oct. 1 – a major accomplishment after years of missed funding deadlines.

Using the social networking tool, Kimball openly talks about what it’s like to live with Type 1 diabetes and tweets about using Novo Nordisk’s Levemir (insulin detemir) to treat the disease.

Twitter, for those not in the know, is a mini-blog system that allows users to post short-form blurbs for their followers to read. A tweet is slang for the actual post. Novo Nordisk and its agency Biosector 2 did not work with Twitter to establish the site. The account was created for free just like any other Twitter account and updated directly from Kimball’s iPhone.

Online Gamble
Pharma companies have been reluctant to embrace social media tools such as Twitter due to the newness of the technology and to FDA’s reluctance to release clear and concise guidelines as to how pharma can use sites like Twitter.

A few months back, FDA issues 14 warning letter to pharma companies that were improperly posting online text ads. According to FDA, pharma can either create a branded ad and not state the disease state, or create an informational ad with no mention of the brand—not even in the URL.

Novo Nordisk trained Kimball to never write about the brand in the same tweet as the disease state.  Besides that direction, Kimball has free reign to write about anything he wants. The Twitter account was publically announced last week, but the account has been active for about a month so the pharma company could work out any kinks.

“Part of the reason this site works is because we have Charlie,” Ambre Morley, associate director of product communications at Novo Nordisk. “He has become the face of our brand and we are very transparent that the site is sponsored by Novo Nordisk.”

The Twitter page has prescribing information in the top left corner and any tweet that mentions the brand name has a link to the risk/benefit summary. The company said that its constantly working on the site, and currently Kimball is not accepting any friends (or following anyone).

“All companies, by and large, are looking at new media,” Morley said. “We’re kicking the tires, but I think every company is going to have to find a way to do new media effectively and make sure that it we stay within the regulatory requirements.”

Related articles by Zemanta

• FDA Issues Public Health Advisory Regarding Levemir Insulin (fda.gov)
• New study first ever to directly compare once-daily Levemir with another basal insulin analogue (worldpharmanews.com)
• Charlie Kimball: Can I Drive Your Car? (sixuntilme.com)