FDA’s Approval of Aspartame Under Scrutiny

June 24, 1987

By Tamlin Carlisle

The Globe and Mail

A revolutionary low-calorie sweetener has brought stellar fortunes to its U.S. manufacturer, but critics say it should never have been approved.

NutraSweet, a household word in more than 50 countries, is a brand name for aspartame, the sweetener sold by NutraSweet Co. of Skokie, Ill. Last year, the company had record revenue of $711-million (U.S.).

But documents released by U.S. Senator Howard Metzenbaum (D, Ohio) and by Adrian Gross, a scientist formerly with the U.S. Food and Drug Administration , reveal serious irregularities in the FDA’s approval of aspartame.

The senator’s office is conducting an investigation. A date will soon be set for a Senate hearing on aspartame-related health concerns, a staff member said.

The convoluted sequence of botched laboratory tests, squelched grand jury investigations, and revolving-door relationships between government and industry employees, began in 1965, when a pharmaceutical company, G. D. Searle & Co. of Skokie, accidentally discovered the sweetener.

In 1970, the company obtained a patent for aspartame. Later that year, an internal memo urged company management to get FDA officials into the “habit of saying yes” and to foster in them a “subconscious spirit of participation.”

In 1974, the FDA approved aspartame’s commercial use, over objections by one of its scientists. But lawyer James Turner and medical reseacher John Olney immediately filed a complaint that floored Searle’s marketing plans.

Dr. Olney had found an elevated incidence of brain tumors in aspartame- fed rats. He also argued that aspartame and monosodium glutamate could together cause brain damage in children.

Seven years later, the FDA ruled that aspartame would not cause brain damage or cancer in humans, but both issues are still debated.

Dr. Olney has described the FDA’s approval of aspartame as arbitrary and irresponsible. Anthony Miller, formerly of the National Cancer Institute of Canada, said concerns that the sweetener may cause brain tumors and neurological damage have not been laid to rest.

The FDA said Dr. Olney’s study showed human consumers would risk cancer only by ingesting impossibly large amounts of the chemical. Arthur Hayes, FDA commissioner in 1981, added that Searle’s tests failed to support Dr. Olney’s findings.

But Dr. Gross reviewed Searle’s data and concluded that one test “established beyond any reasonable doubt that aspartame is capable of inducing brain tumors in experimental animals.”

In another test, rats fed normal diets developed cancer at the same rate as rats given an aspartame breakdown product, but Dr. Olney and Dr. Gross said the tumor incidence in both groups was abnormally high.

A 1980 Public Board of Inquiry described the result as “bizarre,” but the FDA turned down requests for more studies, claiming Dr. Olney had overestimated the natural incidence of brain tumors in laboratory rats.

Dr. Gross pointed out that Dr. Olney’s calculations were based on a huge sample of almost 60,000 rats.

In a 1985 letter to Mr. Metzenbaum’s legislative assistant, Dr. Gross asserted the FDA could not legally disregard Dr. Olney’s findings.

U.S. law requires any company proposing a new food additive to prove that it does not cause cancer. There is no comparable law in Canada.

Another setback for Searle occurred when an FDA scientist noticed discrepancies in a test report on a drug the company was developing. Follow-up investigations led to an investigation of Searle’s laboratory operations.

In 1975, FDA commissioner Alexander Schmidt appointed a special task force to examine 25 Searle tests, including 11 on aspartame. It discovered major shortcomings.

“We have uncovered serious deficiencies in Searle’s operations and practices which undermine the basis for reliance on Searle’s integrity in conducting high-quality animal research to accurately determine or characterize the toxic potential of its products,” the investigators wrote in their final report.

In July, 1976, Dr. Schmidt testified at a U.S. Senate hearing that he agreed with the task force’s conclusions. In 1977, the FDA appointed a second task force that re-examined three of Searle’s aspartame tests.

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FDA Investigating Weight Loss Drug for Heart Attacks and Stroke

Novemver 25, 2009

Atlanta Weight Loss Examiner

By Dave Chism

The Food and Drug Administration is investigating the possibility that the weight loss drug, Meridia, may increase the risks of cardiovascular events. The cardiovascular events include heart attack and stroke.

The official name of the study is a mouthful – Sibutramine Cardiovascular Morbidity/Mortality Outcomes in Overweight or Obese Subjects at Risk of a Cardiovascular Event – or SCOUT for short. It was started in 2002 with 10,000 participants that were over 55 years-old, obese, and had a history of cardiovascular events or diabetes. Some of the participants were given Sibutramine (Meridia) and the rest were given a sugar pill placebo.

The preliminary findings revealed that those taking Meridia encountered cardiovascular events at a rate of 11.4 percent compared to 10 percent of the participants taking the placebo. The FDA did note that warnings with the drug do state that it should not be taken by people with a history of heard disease, stroke, heart rhythm problems, or congestive heart failure.

A spokesman for Abbott, the maker of Meridia, told Dow Jones that the drug wouldn’t be prescribed for almost 90% of the participants in the study. “Abbott’s assessment is that the data do not indicate a change in the safety profile of [Meridia] when used in the approved patient population,” he said.

Sibutramine first gained FDA approval in 1997 as a prescription drug to aid in weight management. Clinical trials have shown that it significantly effects total weight loss and weight loss maintenance.

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Drug Industry Wants More Online Advertising

November 11, 2009Associated Press

by Matthew Perrone

As federal regulators take their first tentative steps toward policing the wild west of medical information online, pharmaceutical companies are pressing their case to market drugs via Google, Twitter and other Web sites.

The Food and Drug Administration will convene a two-day meeting beginning Thursday to hear the drug industry’s position on Internet marketing. The agency has agreed to consider developing rules for online advertising after companies complained that the current guidelines for traditional media — which require a detailed list of possible side effects — have left them hamstrung on the Web.

An estimated 83 percent of Internet users search for health information online, according to a recent survey from the Pew Research Center.

A few drugmakers have begun trying to reach patients via social networking sites like Facebook and YouTube. But overall the industry’s online presence trails other sectors, including retail, financial services and computer makers.

In the first half of 2009, pharmaceutical companies represented just 4 percent of the $10.9 billion spent on online advertising, according to a report from PricewaterhouseCoopers.

Industry observers say companies have largely steered clear of the Web for fear of running afoul of FDA regulators, who have not defined the rules of operating online.

In a public statement announcing the meeting, the FDA acknowledged that “emerging technologies may require the agency to provide additional guidance.” But some industry experts worry the FDA’s rule development process — which often takes years — cannot keep pace with online innovation.

“What’s happening is these new media are emerging at an increasingly rapid rate, and are being regulated by an agency that moves very slowly,” said attorney Mark Senak, who advises drug companies as a consultant for communications firm Fleishman-Hillard. “In essence, you have a regulatory communication crisis developing.”

The vast majority of the pharmaceutical industry’s roughly $4.5 billion in annual marketing is still spent on traditional TV and magazine advertising, where the rules are clear: all ads that mention a drug must provide a balanced picture of its risks and benefits.

The requirement to disclose risk information demands those long lists of side effects heard during TV and radio spots, as well as the large blocks of small print seen in magazine ads.

When drug companies have tried to adapt such ads to the abbreviated language of Google and Yahoo, they’ve run into trouble. In April, the FDA fired off warning letters to Pfizer Inc., GlaxoSmithKline PLC and a dozen other drugmakers for search engine ads that did not mention drug risks.

The ads — called sponsored links — appear on the screen margins of sites like Google when users search for certain key words. With a maximum of just 25 words, the links did not include information about potential side effects, making them illegal, according to the FDA.

On Thursday, the Pharmaceutical Research and Manufacturers of America group will argue that the FDA should relax its standards to accommodate new online approaches to marketing.

In documents released ahead of the meeting, PhRMA suggests the agency develop a logo that could be used in place of hundreds of words about drug risks. The logo would link viewers to the drug’s full risk information, allowing manufacturers to send messages about their drugs on sites like Twitter, which has a 140-character limit.

But industry observers say the online marketing environment is not as restrictive to drugmakers as some suggest. Pharma Marketing News publisher John Mack says drug companies already are free to post abbreviated ads about diseases and treatments — provided they don’t mention a specific product.

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Cereal Claims Immunity Boost

November 2,2009

USA Today

by Bruce Horovitz

 
Kellogg, the nation’s largest cereal maker, is being called to task by critics who object to the swine flu-conscious claim now bannered in bold lettering on the front of Cocoa Krispies cereal boxes: “Now helps support your child’s IMMUNITY.”
Of all claims on cereal boxes, “this one belongs in the hall of fame,” says Kelly Brownell, director of Yale University’s Rudd Center for Food Policy and Obesity. “By their logic, you can spray vitamins on a pile of leaves, and it will boost immunity.”

As the H1N1 virus worries parents and threatens children, the claim of supporting immunity is compelling to many. But it comes at a time foodmakers are being held more accountable for claims. The industry’s self-created “Smart Choices” nutrition-labeling program was voluntarily halted recently after federal regulators expressed concern that such programs may be misleading.
Last week, San Francisco sent a letter to Kellogg and to the Food and Drug Administration asking Kellogg to prove its claim. “I am concerned the prominent use of the immunity claims to advertise a sugar-laden chocolate cereal like Cocoa Krispies may mislead and deceive parents of young children,” said Dennis Herrera, the city attorney.
Kellogg says the critics are wrong. Development of the line started more than a year ago, and it was rolled out in May 2009. “It was not created to capitalize on the current H1N1 flu situation,” spokeswoman Susanne Norwitz says. “Kellogg developed this product in response to consumers expressing a need for more positive nutrition.”
Since studies showed that antioxidant vitamins A, C and E play an important role in the immune system, Kellogg increased its amount in the line — which includes Rice Krispies — from 10% daily value to 25% daily value, Norwitz says.
“The idea that eating Cocoa Krispies will keep a kid from getting swine flu, or from catching a cold, doesn’t make sense,” says Marion Nestle, nutrition professor at New York University. “Yes, these nutrients are involved in immunity, but I can’t think of a nutrient that isn’t involved in the immune system.” Nestle saw the claims at a grocery store in August and sent a letter to the FDA. She hasn’t heard back.
The FDA has jurisdiction over false or misleading labeling. FDA officials are not permitted to discuss specific cases under consideration and declined to comment on this one.

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Pfizer to Pay Record $2.3B Penalty Over Promotions

September 2, 2009

Associated Press

By Devlin Barrett

Pfizer Inc., the world’s largest drug maker, will pay a record $2.3 billion civil and criminal penalty over unlawful prescription drug promotions, the Justice Department announced Wednesday.

The department said the $2.3 billion settlement included a $1.2 billion criminal fine, the largest criminal fine in U.S. history. The agreement also included a criminal forfeiture of $105 million.

“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.

Click here for the full report from the Associated Press

Makers of Swine Flu Vaccine Can’t Be Sued

July 18, 2009

Associated Press

by Mike Stobbe

ATLANTA — The last time the government embarked on a major vaccine campaign against a new swine flu, thousands of people filed claims contending they suffered side effects from the shots. This time, the government has already taken steps to prevent that.

Vaccine makers and federal officials will be immune from lawsuits that result from any new swine flu vaccine, under a document signed by Secretary of Health and Human Services Kathleen Sebelius, government health officials said Friday.

Since the 1980s, the government has protected vaccine makers against lawsuits over the use of childhood vaccines. Instead, a federal court handles claims and decides who will be paid from a special fund.

The document signed by Sebelius last month grants immunity to those making a swine flu vaccine, under the provisions of a 2006 law for public-health emergencies. It allows for a compensation fund, if needed.

The government takes such steps to encourage drug companies to make vaccines, and it has worked. Federal officials have contracted with five manufacturers to make a swine flu vaccine. First identified in April, swine flu has so far caused about 263 deaths, according to numbers released by the Centers for Disease Control and Prevention on Friday.

The CDC said more than 40,000 Americans have had confirmed or probable cases, but those are people who sought health care. It’s likely that more than 1 million Americans have been sickened by the flu, many with mild cases.

The virus hits younger people harder than seasonal flu, but so far hasn’t been much more deadly than the strains seen every fall and winter. But health officials say the virus could mutate to a more dangerous form, or at least contribute to a potentially heavier flu season than usual.

“We do expect there to be an increase in influenza this fall,” with a bump in cases perhaps beginning earlier than normal, said Dr. Anne Schuchat, director of the CDC’s National Center for Immunization and Respiratory Diseases.

On Friday, the Food and Drug Administration approved the regular winter flu vaccine, a final step before shipments to clinics and other vaccination sites could begin.

The last time the government faced a new swine flu virus was in 1976. Cases of swine flu in soldiers at Fort Dix, N.J., including one death, made health officials worried they might be facing a deadly pandemic like the one that killed millions around the world in 1918 and 1919.

Federal officials vaccinated 40 million Americans during a national campaign. A pandemic never materialized, but thousands who got the shots filed injury claims, saying they suffered a paralyzing condition called Guillain-Barre Syndrome or other side effects.

“The government paid out quite a bit of money,” said Stephen Sugarman, a law professor who specializes in product liability at the University of California at Berkeley.

Vaccines aren’t as profitable as other drugs for manufacturers, and without protection against lawsuits “they’re saying, ‘Do we need this?’” Sugarman said.

The move to protect makers of a swine flu didn’t go over well with Paul Pennock, a prominent New York plaintiffs attorney on medical liability cases. The government will probably call on millions of Americans to get the vaccinations to prevent the disease from spreading, he noted.

“If you’re going to ask people to do this for the common good, then let’s make sure for the common good that these people will be taken care of if something goes wrong,” Pennock said.

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GAO: FDA Can’t Estimate Its Own Budget Needs

July 20, 2009

Associated Press

by Matthew Perrone

The Food and Drug Administration — which has struggled to fulfill its mission of regulating food, drugs and other consumer goods that make up nearly a quarter of the U.S. economy — does not have the expertise to forecast its own budget needs, according to congressional investigators.

While many lawmakers and consumer advocates have long complained that the agency lacks the staff and equipment to accomplish its mission, the Government Accountability Office says the agency doesn’t even have “the data to develop a complete and reliable estimate of the resources it needs.”

The GAO places some of the blame on the FDA’s lopsided budget — which dedicates significant resources to approving new products, but far less to tracking their safety once they’ve reached the market.

FDA officials acknowledged the problems uncovered by the GAO, saying they are working to get a better picture of the agency’s spending and how much additional funding it needs.

“We have to be able to talk about the funds we need, and how we’re using the money, with more detail than FDA has in the past,” said Dr. Joshua Sharfstein, the agency’s deputy commissioner.

The GAO report, released Monday, is the latest in a series to document the problems facing the agency. The FDA has spent the last few years careening from one public health crisis to the next. They have included the recall of the painkiller Vioxx — which was linked to heart attacks, contaminated blood thinners imported from China, and an investigation into a salmonella outbreak that dragged on for weeks before peppers were identified as the culprit.

The agency’s product review program is largely funded by user fees from drug and medical device companies, while the company’s safety inspections are funded by taxpayer dollars. Over the last 10 years, funding from private companies increased nearly 270 percent, while funds from the U.S. government grew less than 70 percent.

Currently, the federal government pays for just over 30 percent of the FDA’s medical products budget. As a result, the FDA is approving more new products but is spending far less to make sure they are being used safely.

“The approval of new products has increasingly become the beneficiary of the agency’s budget,” according to the GAO report.

Between 2004 and 2008 the agency failed to inspect all U.S. drug manufacturing plants every two years, as required by law. In other areas, such as reviewing reports of negative drug side effects, the FDA could not even say how much money and manpower it spent.

Investigators recommended the FDA conduct a comprehensive assessment of its current workload and use that to develop future budget requests.

Sens. Ted Kennedy, D-Mass., and Charles Grassley, R-Iowa, and Rep. Henry Waxman, D-Calif., requested the GAO probe.

“This report makes it clear that the FDA has to get a handle on its own resource requirements and how to use resources more effectively,” Grassley said in a statement.

Under the Bush administration, FDA officials often insisted the agency had sufficient funding, even when its own advisers said it desperately needed more. In 2007, the agency’s independent group of science advisers said the FDA was in danger of failing in its mission due to a lack of expertise and resources.

“American lives are at risk,” the group concluded.

Sharfstein said President Barack Obama is aware of the agency’s funding woes and is working to boost its budget for safety and inspection activities. The administration’s fiscal year 2010 budget proposal would increase FDA’s federal funding by more than 14 percent, to $2.35 billion from $2.06 billion. The spending bill passed the House earlier this month and is moving through the Senate.

Obama tapped Sharfstein to fill the FDA’s No. 2 position in March. A pediatrician and former Baltimore Health Commissioner, he reports to FDA Commissioner Margaret Hamburg, who was confirmed by the Senate in May.

FDA officials already are working to keep better track of how the agency uses its funding.

“We’ve actually been working on this since we started here, but it’s a big agency and it’s going to take some work to get to the level of detail people want,” Sharfstein said.

Click here for the full report from the Associate Press.

U.S. to Spend Another $1 Billion on Flu Vaccine

July 12, 2009

Reuters

The United States will spend another $1 billion on ingredients for an H1N1 vaccine, U.S. Health and Human Services Secretary Kathleen Sebelius said on Sunday.

“There’ll be another $1 billion worth of orders placed to get the bulk ingredients for an H1N1 vaccination. Congress has agreed with the president that this is the number one priority, keeping Americans safe and secure,” Sebelius said on CNN.

Sebelius has said plans were on track for a mid-October vaccination program, although it was not certain Americans would be offered the vaccine for the so-called swine flu.

“We are aggressively working on, first of all, testing the virus strains to get a vaccination ready. It needs to be safe so testing and clinical trials will start this month. We’ll know a lot more by the end of the summer and it needs to be effective,” she said.

The World Health Organization may issue guidance as soon as Monday on whether an H1N1 swine flu vaccine will be offered alongside the seasonal flu vaccine.

Vaccine makers Sanofi-Aventis, Novartis, Baxter, GlaxoSmithKline, Solvay and AstraZeneca’s MedImmune subsidiary have finished making seasonal flu vaccines for this year.

The U.S. Food and Drug Administration has scheduled a July 23 advisory panel meeting to discuss clinical trials of the vaccines against the H1N1 influenza virus and the U.S. Advisory Committee on Immunization Practice wills meet July 29.

“FDA is working with the scientists at NIH (National Institutes of Health) to make sure that we have a safe and effective strain and then we’re getting ready to make sure that we have a vaccination program,” Sebelius said.

Health experts estimate at least 1 million people have been infected with H1N1 in the United States, and the U.S. Centers for Disease Control and Prevention has confirmed 211 deaths. It often takes weeks or months to collect data on flu deaths.

About 36,000 people die each year from the seasonal flu in the United States alone, and 250,000 to 500,000 die globally.

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US FDA Staff Question J&J, Zeltia Cancer Drug Data

July 13, 2009

Reuters

By Lisa Richwine

U.S. drug reviewers will ask outside advisers if a Johnson & Johnson and Zeltia drug provides enough benefit to justify its approval for women with ovarian cancer, a memo released on Monday said.

Shares of Spanish biotechnology company Zeltia dropped 19 percent to 4.47 euros in Madrid trading.

Food and Drug Administration staff said discrepancies in radiology readings raised the question of whether patients’ status was reliably measured in the main study of the drug, Yondelis. The study examined the time it took the cancer to worsen when patients were treated with a combination of Yondelis and another J&J cancer drug, Doxil.

Doxil is already approved for treating cancer, while Yondelis is not currently sold in the United States.

FDA staff said they would ask an advisory panel that meets Wednesday if the results “are reliable, are clinically significant, and are associated with an acceptable benefit:risk ratio.”

The study found patients had about six more weeks without their cancer getting worse if they were treated with Doxil. FDA staff said they would ask the advisory panel if the extra six weeks “at a cost of additional toxicity is sufficient benefit for approval.”

The main side effects included a decrease in white blood cells that can make patients vulnerable to infections, the FDA reviewers said. Cardiac problems also were higher in patients who received Yondelis.

CM Capital Markets equity analyst Flemming Barton said the staff review “casts doubts over Zeltia’s flagship drug.”

“This is bad news … There was a lot of expectation that the FDA would give the green light right away,” Barton said.

“But the stock has had a very good run, outperforming the broad market ahead of the FDA decision, so it’s not so surprising there are sell orders in there now,” he added.

The FDA staff said they would ask the panel if the agency should wait for a final analysis of patients’ survival before deciding whether to approve Yondelis for sale, the drug reviewers said in a memo prepared for the panel. The drug’s generic name is trabectedin.

Johnson & Johnson, in a separate summary prepared for the panel, said the Yondelis and Doxil combination offered a safe and effective option, especially for women with relapsed ovarian cancer who cannot take other platinum-based regimens.

A Zeltia spokesman said the balance of benefits and risks for Yondelis was “positive.”

J&J also is seeking approval in a separate application for wider use of Doxil in breast cancer patients. FDA reviewers said they had concerns about the company’s proposed regimen of adding Doxil to another drug, docetaxel, as a first-choice therapy.

The combination produced “modest improvement” in the time before cancer started growing but no improvement in overall survival, FDA reviewers said. The regimen was “poorly tolerated” and 34 percent of patients stopped taking Doxil due to side effects.

J&J said Doxil “offers an effective treatment option, without increased risk of cardiac toxicity” seen with other drugs.

The FDA will consider the advisory panel’s input before deciding whether to approve Yondelis and the new use for Doxil. The agency usually follows panel recommendations.

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Suicide Warnings for 2 Anti-Smoking Drugs

July 2, 2009

New York Times

by Gardiner Harris & Duff Wilson

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