Mullen, who is leaving Biogen Idec in June, also predicted biotech companies will face a more difficult regulatory process in the United States. “The environment to launch new products… is going to be tougher, the pricing is going to be tougher, the probability (of drug approvals) is probably going to be more challenging,” he said.

Henri Termeer, chief executive of Genzyme Corp. in Cambridge, said the new law has the potential to boost investment in biotechnology research through a 12-year data exclusivity provision that shields biotech drugs from generic competition. The bill also contains a therapeutic-research tax credit for biotech start-ups.

Unlike past pushes for health care overhaul that failed, “this particular set of discussions didn’t focus on the cost of innovation,” Termeer said. “It focused on the cost of access. In fact, you could say that innovation was somewhat talked about in a kind of benevolent way. There was support for the need to be able to take the risks that are necessary. This (Obama) administration is actually interested in innovation.”

Termeer and Mullen spoke on a panel during the MassBio meeting at the Seaport World Trade Center in South Boston. The discussion was moderated by Deborah Dunshire, chief executive of Millennium Pharmaceuticals, another Cambridge biotechnology company that was bought by Japan’s Takeda Pharmaceutical Co. for $8.8 billion in 2008.

Dunshire described her fellow chief executives as “battle-scarred” biotech veterans and noted that they face pressures from increasingly impatient investors. But during the 60-minute event — which didn’t allow for questions from the audience — Genzyme’s high-profile manufacturing problems at its Allston Landing plant and shareholder activist Carl C. Icahn’s push for seats on the boards of both Genzyme and Biogen Idec weren’t discussed.

Mullen took a parting shot at the US Food and Drug Administration, saying European regulators “frankly seem to be a little more balanced” in approving riskier new drugs. Citing what he said was the reluctance of biopharmaceutical companies to develop new treatments for cardiovascular diseases, the Biogen Idec chief said, “The FDA has made it almost impossible to develop anything in cardiovascular. What they ask for sounds very logical in headlines. It’s just not doable.”

FDA officials didn’t immediately respond to requests for comment.

But it wasn’t always so. In the 1970s and ’80s, companies raced to get out of the vaccine business because of the high manufacturing costs, the high chance of failure, and the threat of lawsuits if patients suffered adverse side effects. But then the federal government passed the Childhood Vaccine Injury Act in 1986, which created a pool of money for patients who experienced adverse effects and shielded companies from lawsuits. Advances in technology have driven manufacturing costs down. “And companies have seen that if a vaccine is on a government program, one doesn’t have to spend money to promote it,” Bogorad said.

The market is dominated by a handful of global players, including U.K.-based GlaxoSmithKline, France’s Sanofi Pasteur, Wyeth, which has now merged with New York-based Pfizer Inc., Switzerland’s Novartis AG and Merck and Co. Inc. of New Jersey. This makes it difficult for smaller players to break in.

But this cadre of vaccine giants relies on an ecosystem of smaller companies to fill its pipeline with preventive therapies. And that pipeline could grow now that the Bill and Melinda Gates Foundation has pledged $10 billion to fund vaccine research.

Bogorad said New England provides a ripe landscape for mergers and acquisitions. Case in point is Acambis. The Cambridge company, which has potential vaccines targeting herpes, influenza, dengue fever and West Nile virus, was bought last year by Sanofi Pasteur for $548 million.

One local vaccine company that has been growing independently is Xcellerex Inc. The Marlborough company was founded in 2004, has 120 employees and is cash-flow positive. Xcellerex provides outsourced manufacturing services and equipment, using a disposable system that eliminates the need for steam sterilization of bioreactors used to make vaccines and other biologics. CEO Joe Zakrzewski said the method cuts down on the chances for contamination of vaccines or other products.

Zakrzewski claims that the process can speed up getting a product to market and that clinical trials using the technology can cost one fourth that of clinical trials using traditional biologics manufacturing methods. Xcellerex’s clients include Cambridge-based Acceleron Pharma Inc., whose lead product is a biotherapeutic designed to increase red blood cell and bone formation and is in Phase 2 clinical trials.

Xcellerex also develops its own therapeutics and has launched a Phase 1 clinical trial for a potential vaccine targeting yellow fever. Bogorad and other analysts say that the travel vaccine market is a small segment of the market, but Zakzrewski said there is still money to be made. “Right now, it’s a $100 million market. But 90 percent of the people who need the yellow-fever vaccine don’t get it, because the risks of the current vaccine are too high. So we love it when people say the market is small. We think it could be $1 billion.”

Xcellerex officials say that their vaccine candidate is fundamentally different from current vaccines because it uses a dead virus rather than a live one. Xcellerex has partnered with other companies on manufacturing four or five vaccines in the past. In October, the company announced it would partner with Rockville, Md.-based Novavax to ramp up large-scale manufacturing for its H1N1 vaccine.

The perils of this high-stakes business can be seen across New England. Protein Sciences Corp., in Meridien, Conn., received a blow when the U.S. Food and Drug Administration rejected its potential flu vaccine this fall, because the agency wanted more safety data. Analysts and public health officials had been watching the progress of the potential vaccine because it would represent a novel breakthrough. While current vaccines for influenza are made from fertilized chicken eggs, which is slow and expensive, the Protein Sciences target aims to produce flu cells in caterpillars.

Antigenics Inc., in Lexington, also faced a regulatory setback this fall when European authorities rejected its potential cancer vaccine, called Oncophage. Cancer vaccines have been an elusive target so far, but officials in area companies say that is going to change.

“We (in the industry) are starting to learn from our mistakes. It’s not a matter of if, but when,” said Eric Von Hofe, CEO of Antigen Express Inc. The Worcester-based vaccine developer is working on targets using synthetic peptides, which are protein fragments, that Von Hofe says can be manufactured more quickly than the traditional chicken-egg method. Von Hofe is reporting positive interim results for a Phase 2 vaccine study targeting breast cancer. But so far, no synthetic vaccines have been approved by the FDA. 

“Combating health care fraud is one of this administration’s top priorities,” Associate Attorney General Thomas Perelli said in announcing the settlement. He said it illustrates ways the department “can help the American public at a time when budgets are tight and health care costs are rising.” 

The overall settlement is the largest ever paid by a drug company for alleged violations of federal drug rules.

The government said the company promoted four prescription drugs, including the pain killer Bextra, as treatments for medical conditions different than those the drugs had been approved for by federal regulators.  Use of drugs for so-called “off-label” medical conditions is not uncommon, but drug manufacturers are prohibited from marketing drugs for uses that have not been approved by the Food and Drug Administration.  A Pfizer subsidiary, Pharmacia and Upjohn Inc., which was acquired in 2003, has entered an agreement to plead guilty to one count of felony misbranding. “These agreements bring final closure to significant legal matters and help to enhance our focus on what we do best — discovering, developing and delivering innovative medicines to treat patients dealing with some of the world’s most debilitating diseases,” said Amy W. Schulman, senior vice president and general counsel of Pfizer.

Authorities said Pfizer’s salesmen and women created phony doctor requests for medical information in order to send unsolicited information to doctors about unapproved uses and dosages.

Justice officials discussed details of the deal at a news conference with FBI, federal prosecutors, and Health and Human Services Department officials.

In financial filings in January, the company had indicated that it would pay $2.3 billion over allegations it had marketed the pain reliever Bextra an possibly other drugs for medical conditions different than their approved use. The settlement announced Wednesday also covered Pfizer’s promotions of three other drugs: Geodon, an anti-psychotic, Zyvox, an antibiotic, and Lyrica, an anti-epileptic.

Under terms of the settlement, Pfizer must pay $1 billion to compensate Medicaid, Medicare, and other federal healthcare programs. Some of that money will be shared among the states: New York, for example, will receive $66 million, according to the state’s attorney general, Andrew Cuomo.

“Pfizer ripped off New Yorkers and taxpayers across the country to pad its bottom line,” Cuomo said. “Pfizer’s corrupt practices went so far as sending physicians on exotic junkets as well as wining and dining health care professionals to persuade them to prescribe the company’s drugs for patients in taxpayer-funded programs.”

Pfizer spokesman Chris Loder confirmed Wednesday that the $2.3 billion charge to the company’s earnings had been taken in the fourth quarter of 2008.

“No additional charge to the company’s earnings will be recorded in connection with this settlement,” he said.

In her statement, Schulman said: “We regret certain actions taken in the past, but are proud of the action we’ve taken to strengthen our internal controls and pioneer new procedures so that we not only comply with state and federal laws, but also meet the high standards that patients, physicians and the public expect from a leading worldwide company dedicated to healing and better health.”

“Corporate integrity is an absolute priority for Pfizer,” she said, “and we will continue to take appropriate actions to further enhance our compliance practices and strengthen public trust in our company.”

When Pfizer originally disclosed the settlement figure, it also announced plans to acquire rival Wyeth for $68 billion. That deal, which would bolster Pfizer’s position as the world’s top drug maker by revenue, is expected to close before year’s end.

Shares of Pfizer were up 9 cents at $16.47 in early trading Wednesday.

The agency also approved a one-dose version of the product called Plan B One-Step that will also be available over the counter to women age 17 and older. Both products are sold by Duramed Pharmaceuticals, a unit of Teva Pharmaceuticals Industries Ltd.

Duramed loses market exclusivity on the traditional Plan B pill—which is taken in two steps—next month, allowing generic versions to be made available. Teva said the Plan B One-Step would be available in pharmacies next month.

In March a federal court ordered the FDA to lower the age requirement set by the Bush administration for Plan B to be sold over the counter, to 17 from 18.

In 2006, the FDA agreed to make Plan B available without a prescription to women over 18 and required the product to be placed behind the pharmacy counter. In 2004, the FDA rejected an application to make Plan B available without a prescription even though an advisory panel of outside medical experts voted to support the switch from prescription to nonprescription status.

Plan B was approved as a prescription “emergency” contraceptive in 1999. It is made of the hormone progestin, and is designed to prevent pregnancy if taken within 72 hours of unprotected sexual intercourse. The original Plan B pill is designed to be taken in two doses, 12 hours apart.

The pills are similar to birth-control pills but contain higher doses of progestin to block a potentially fertilized egg from becoming implanted in a woman’s uterus.

The court ruling came in response to a lawsuit filed in 2005 by the Center for Reproductive Rights, a women’s health advocacy group.

-Jennifer Corbett Dooren

It’s no surprise that these pain relievers are considered dangerous. They contain powerful, habit-forming narcotics like oxycodone and hydrocodone. But that’s not the issue. Percocet and Vicodin also contain acetaminophen — you know, Tylenol, that “harmless” over-the-counter pain reliever we pop like candy at the least sign of a headache, sore throat or general malaise.

It turns out that Tylenol isn’t all that harmless. Overdoses kill more than 400 people each year and send 42,000 to the emergency room with acute liver failure. And so-called “combination pain killers” account for most of those overdoseIf the FDA follows the panel’s recommendation, and it usually does, will the result be another manifestation of the “nanny state”? Will sick people be unjustly deprived of an effective drug like Vicodin because some idiots don’t bother to read the directions?

A bad combination

I put that question to Dr. Scott Fishman, the chief of pain medicine at the University of California-Davis School of Medicine. He’s an advocate for pain management, so I expected he’d say the panel overreacted.

But Fishman is fine with getting rid of drugs that combine opium-based drugs with acetaminophen.

“The FDA panel is not saying the drugs in Vicodin are bad,” he said. “They are saying that tying those drugs together is wrong.”

By adding acetaminophen to narcotics, combination drugs provide better pain relief with lower levels of narcotic. They are great for short-term use, such as after surgery.

Patients who take these drugs for chronic pain, however, build up a tolerance to the narcotic. As they take more and more, they also take more acetaminophen, and are at risk of liver damage.

Instead, Fishman said, doctors should prescribe the narcotics and acetaminophen separately. More trouble, but a safer option.

A pill for everything

Whatever the FDA decides, the panel has identified a problem that I fear can’t be solved by taking a few drugs off the market.

We are a nation of pill-poppers. Stomach upset? Don’t give up those hot peppers, just reach for Pepcid AC. Got a cold? Don’t suffer. DayQuil and NyQuil will get you through. No matter what ails us, from high cholesterol to low libido, we expect relief in a pill bottle.

But do we really know what we’re taking?

Like millions of Americans, I have a bottle of Extra-Strength Tylenol in my medicine cabinet, another in the kitchen, and a little vial in my purse for emergencies. I know not to exceed the recommended daily dose of eight tablets a day. So when I saw the statistics about overdoses, I couldn’t believe how careless some people are. How hard is it to count to eight?

Then I looked in my medicine cabinet to see how much acetaminophen was lurking. A bottle of NyQuil, 500 milligrams per dose. A few individually wrapped (and impossible to open without the Jaws of Life) DayQuil capsules, 325 milligrams each. And a box of TheraFlu with whoa! 1,000 milligrams per packet.

I imagine some coughing, sneezing, fuzzy-headed person, desperate for relief, finding that packet of TheraFlu and not thinking about the Tylenol she already has taken. She squints at the directions on the label but can’t make out the fine print without a microscope. Oh, what the heck. Down the hatch.

Just thinking about that poor woman’s liver is giving me a headache. Hmm. Where’s that bottle of Tylenol?

-Patty Fisher

The article, by several Duke University researchers, suggests an ethical quagmire when drugs intended for wealthy nations are tested on people in developing countries. The authors suggest that human volunteers in foreign countries may be unduly influenced with the promise of financial compensation or free medical care to participate in clinical trials.

The report, “Ethical and Scientific Implications of the Globalization of Clinical Research,” also asks whether drug research conducted in developing countries is relevant to the treatment of American patients.

“We don’t want to imagine that lower-income countries are the clinical trial mill for higher-income countries,” Dr. Kevin A. Schulman, the lead author of the article, said in a phone interview last week. Dr. Schulman is a professor of medicine at the Fuqua School of Business at Duke, in Durham, N.C.

But some critics say the authors used overly simplistic data mining to raise an alarm, without presenting hard evidence of widespread ethical or scientific problems.

“More places outside the United States are participating in research — is that a bad thing?” said Dr. Ezekiel J. Emanuel, the chairman of bioethics at the Clinical Center of the National Institutes of Health in Bethesda, Md., after reading an abstract of the article sent to him by a reporter.

Dr. Emanuel cited a clinical trial of the Merck drug Gardasil, a vaccine against the human papilloma virus, that was conducted in Costa Rica, where there is a high incidence of the disease. “This is the kind of case where it is a good thing.”

Whatever the interpretations, the use of offshore clinical trials is growing. In the last 10 years, the proportion of United States-based researchers who direct clinical trials registered with the federal Food and Drug Administration has declined significantly, while the percentage of F.D.A.-registered researchers outside the United States has significantly increased, according to a report in January by the Tufts Center for the Study of Drug Development in Boston.

In 1997, about 86 percent of F.D.A.-registered principal investigators were based in the United States, the Tufts study said. By 2007, only about 54 percent of about 26,000 F.D.A.-regulated chief scientists who conducted clinical trials that year were based in the United States.

Kenneth A. Getz, a senior research fellow at the Tufts center, said drug companies were looking abroad because it was often less expensive to conduct clinical trials outside the United States, and it was easier to find a large group of study subjects who had never been treated with medications.

Critics of the Duke article take issue with its methodology. The authors, for example, compare the locations of 300 clinical trials published in three leading medical journals in 1995 and 2005, concluding that the number of countries participating in studies more than doubled over that decade.

But critics question that comparison, because about 40 percent of the published clinical trials from 1995 did not indicate where the studies were conducted.

One of the authors, Dr. Seth W. Glickman, a senior scholar at the Fuqua School of Business at Duke, said he did not know how omitting those studies might have skewed the analysis.

And although the article uses the country statistics to raise concerns about the increased globalization of clinical research, the Tufts study shows that the majority of F.D.A.-regulated drug researchers are still in the United States. Offshore researchers, moreover, are represented largely by Western Europe and middle-income countries in Eastern Europe and Latin America, according to the Tufts data.

The Duke authors also write that drug research in developing countries — where certain populations may metabolize medications differently because of environmental factors or genetic mutations — might not be relevant for American patients. “There are issues with the interpretability of the findings,” Dr. Glickman said.

Dr. Emanuel of the N.I.H. agreed that it was possible that some offshore drug research might not be applicable to American patients. But he faulted the report for seeming to treat all foreign countries alike. Research conducted in some places outside the United States — like Canada and Sweden — might be perfectly relevant to American patients, he said.

“It’s not a sufficiently nuanced concern to give it credibility,” said Dr. Emanuel.

The plan for permanent outposts marks a break from the agency’s current practice of sending inspectors abroad on individual assignments. The safety of imported food and drugs has become a growing concern as domestic manufacturers shift operations overseas and foreign producers make inroads here. Over the past year, the FDA has been criticized for failing to prevent a string of safety problems, including contaminated blood thinners manufactured in China and salmonella-tainted peppers imported from Mexico.

“We are sending a very clear message to producers: if you want to have access to our market you need to make products that meet our standards of quality,” Health and Human Services Secretary Michael Leavitt told reporters. Mr. Leavitt oversees the FDA and other federal health agencies.

FDA officials said the plan would cost about $30 million in its first year, primarily to set up the offices and hire new staffers, including foreign nationals who would report to the agency.

Mr. Leavitt and Dr. von Eschenbach acknowledged that several dozen additional staffers wouldn’t be able to visit the thousands of plants across the globe that fall under FDA’s responsibility. They said the U.S. government would need to outsource some inspections to foreign governments and companies, who would verify that plants meet U.S. standards.

Officials said the FDA doesn’t have the authority to accredit third-party inspectors and would have to seek Congress’s approval to do so.

Copyright © 2008 Associated Press http://online.wsj.com/article/SB122418628228041817.html