Greed Greed everywhere: off label marketing, drug contamination and death

It hasn't been a good week for big Pharma. But it also hasn't been a good week for many who suffer as collateral damage due to the greedy and conscienceless. Someone finally plead guilty to the crime of marketing a prescription drug for doing what it was neither designed nor tested for doing.

Pharmaceutical employees plead guilty to violating Food, Drug and Cosmetic Act

Four people pleaded guilty Thursday to breaking federal law by marketing the drug Loprox to Kansas doctors as a diaper-rash treatment, the U.S. Attorney's Office said.
Loprox has been approved to treat infections only for patients older than 10.

These people that were arrested and fined in the Laprox case are small potatoes sales reps, not the big boys in the office. The big boys decide where their drugs are manufactured, while their pals in the FDA tell you which big boy product is best. The FDA also works hard to discourage you from getting cheaper drugs from Canada or Mexico. They say the cheaper drugs may be of inferior quality; and so, it is best to get your medicine from the American big boys. Guess what? Even the American pharmaceuticals (can we even call them that, aren't they multi nationals now?) are also made in foreign countries, and are of poor quality. In some cases, they have resulted in resulted in death.

Heparin Contamination Fiasco Reveals Dirty Secret of Drug Industry: Their Pills are Made in China!

But hold on: The FDA actually used to run full-page magazine ads warning consumers about the dangers of drugs being contaminated if they were bought from Mexico, Canada or -- God forbid -- the Internet! Those drugs were dangerous, the FDA warned us, because they were not subjected to rigorous quality control requirements. The implication in that warning, of course, is that brand-name pharmaceuticals sold in the U.S. at U.S. pharmacies must therefore NOT be contaminated.

Enter the blood-thinning drug Heparin. This blood-thinning drug, made by Baxter International, was recently discovered by consumers to have been manufactured in China. Worse yet, the quality controls in China were so low that this FDA approved, brand-name prescription drug was apparently deliberately contaminated with an adulterated chemical that has now resulted in the death of dozens of consumers in the United States

So far, then, there are three astonishing facts that have come out of this recent news about Heparin:

Fact #1: Most U.S. prescription drugs aren't even made in the U.S.

Fact #2: Many U.S. prescription drugs are made in China, a country widely known to have the lowest quality control standards in the world.

Fact #3: U.S. drug companies don't even run quality control checks on the drugs they import from China!

Secret medical studies and increased risk for death

Based on results from several clinical trials of blood substitutes, people were 30% more likely to die from using these products. I can't believe this data isn't being shouted from the loudest rooftops. The way some of these studies were conducted was appalling.

There have also been allegations where the manufacturers tried to hide the data. Then there are also issues with participants not having informed consent. The FDA allows this in some trials. This was the case with the blood substitute
polyheme. In some areas, whether people knew it or not, they were automatically participants in the blood substitute study, should they ever need blood in an emergency situation.

Paramedics are testing an experimental blood substitute on severely injured patients without their consent in an unusual study under way or proposed at 20 hospitals around the country.

The study was launched last month in Denver and follows similar research that was halted in 1998, when more than 20 patients died after getting a different experimental blood substitute.

Unless, a person was lucky enough to notice that biomedical studies were being conducted in which they could unwittingly be recruited, and they completed an opt form, they were participants period. In the bat of an eye, an accident happens, they need blood and it's polyheme, or some other product to the rescue. Only it increases the risk of death by some 30%.

Then there were all the protocol violations, reports of data witholding and god knows what else. A lot of this stuff was coming out in 2004, 2006 and a few university medical centers pulled out of the study, now in 2008 we are learning of how risky this polyheme product is while many have known this for a while now.

Apparently it wasn't just the US. Greed knows no borders and people die for it.

Patients endangered in 'secret science' trials of risky blood substitutes: Study

TORONTO — U.S. and Canadian regulatory rules allowed companies to conduct "secret science" that jeopardized the lives and health of hundreds of people who took part in clinical trials for a human blood substitute, even though earlier tests had shown the existing products were dangerous, researchers reported Monday.

A review of data from 16 clinical trials showed people who got blood substitutes were 30 per cent more likely to die than those who did not. And the risk of heart attack in patients who received the products was nearly three times higher, according to the study.

The authors and others suggested rules should be changed to require companies to publish study data promptly, especially negative findings that might red flag future such studies by other groups. And if they won't do so, critics say, regulatory agencies like the U.S. Food and Drug Administration or Health Canada should.

"If the research isn't published or otherwise made public, someone knows that the proposed therapy may be harmful, but that somebody won't tell anybody else," said Dr. Joel Lexchin, a York University researcher who closely monitors regulation of the pharmaceutical industry.

"So you have research ethics boards approving studies where the therapy may be dangerous. You have patients enrolling. You have the doctors who are running the trials undertaking them. . . . You've got all these people participating in something which is inherently unethical."

Both the FDA and Health Canada said data provided to them by drug makers is proprietary information and cannot be released without the consent of the submitting company.

"There are very distinct limitations to the FDA's ability to share information which is identified as confidential or trade secret," Dr. Jay Epstein, director of the office of blood research and review, said in a briefing for journalists.

"And that sort of information would not be made public under current laws and regulations."

A spokesperson for Health Canada said the drug regulator is looking at ways to try to increase transparency of clinical trials.

"Health Canada is currently exploring the development of a regulatory requirement for the registration of clinical trials and disclosure of results," Stephane Shank said via e-mail.

"While this work proceeds, Health Canada encourages sponsors and manufacturers to register their clinical trials of therapeutic products within 21 days of the trial's onset" in one of two international clinical trial registries.

The study was published Monday by the Journal of the American Medical Association in advance of a two-day FDA hearing on blood substitutes that will be held in Bethesda, Md., beginning Tuesday.

A safe substitute for human blood would be enormously useful, especially in theatres of war and in remote settings.

Researchers in the U.S. military and a number of biotech companies have been working for years to devise such products, aiming for something that would have a long shelf-life, wouldn't require refrigeration, would eliminate the risk of transmission of HIV or other blood-borne infections and could be given to anyone, regardless of their blood type.

But the products devised so far - called hemoglobin-based oxygen carriers or HBOCs - have been a disappointment. Despite numerous trials in a variety of different patient populations, they have failed to show benefit and, this new study reveals, have shown significant risk. Only one country, South Africa, has approved a blood substitute product.

The researchers, from the U.S. National Institutes of Health and the Washington-based consumer advocacy group Public Citizen, pooled data from 13 published studies, and three more for which results were either disclosed in a press release or in an FDA review. They made several attempts to get additional data from companies that had conducted studies but the requests were either ignored or rebuffed.

The authors were critical of the FDA for not requiring the companies to publish their findings, and for allowing additional trials to be conducted after the risk should have been apparent.

"At some point, somebody should have realized that we've tried it in trauma patients, we've tried it in surgical patients, we've tried it in stroke patients, we've tried many different formulations and we keep finding the same result," said Dr. Charles Natanson, lead author of the meta-analysis, a technique in which data from a number of trials are combined and re-analyzed.

"At some point, and we sort of argue in the paper that may have been the year 2000 . . . it was time to put a halt" to additional trials, Natanson said.

Canadian patients were also exposed to the risks in clinical trials of a product called Hemolink, which was made by a now defunct company called Hemosol Inc. The company conducted at least three trials of the product, though data from only two were included in the JAMA analysis.

Natanson, who is an advocate for patient safety in clinical trials, was paid $10,000 to review the data from a third trial when Hemosol was trying to decide whether to push on with the research. The company later went into receivership.

The company never published the findings and Natanson cannot comment on what he saw or recommended.

An editorial accompanying the review points out further studies of these products are underway or planned in a number of countries around the globe.

The authors, from the Ottawa Health Research Institute, argue future work on blood substitute products should not be allowed in humans until it's clear from animal studies that the products are likely to be safer.

Lead author Dean Fergusson, a clinical trials expert, said the withholding of the negative results meant ethics boards and trial participants could not accurately weigh the risks and benefits of the research.

"How can patients or their decision makers make truly involved consent without all this information? I think that's a huge message," said Fergusson, who reported he was paid a one-time fee of $500 for attending a Hemosol advisory board meeting.

The lack of disclosure suggests company stock prices were placed at a higher priority than the safety of people being asked to go into clinical trials, experts suggest.

"They didn't think beyond the four walls of their corporation, I think, quite frankly," Fergusson said of the companies.

Lexchin was more critical of Health Canada for treating unpublished studies as confidential information. "They're calling this business information, not health information," he said.

Epstein said the FDA's own analysis of the accumulating experience with the blood substitutes led it to conclude there were safety risks associated with the entire class of drugs. "It's because of FDA's safety concerns that there currently are no ongoing studies of HBOCs in the United States trials and no approved HBOC products."

But he challenged the Natanson article's contention that the risk should have been apparent by 2000, saying the FDA had access to information Natanson and his colleagues have not seen that suggested there might be benefits in some situations.

"Basically even though aware of certain safety signals, our reviewers determined that there were enough differences between products and their intended uses to support a careful weighing of individual clinical trial proposals, only some of which were allowed to proceed," Epstein said.

Vaccine problems at big Pharma

You bet Merck wanted to hide the report to as they say prevent "unwanted panic", more like unwanted loss of sales.



FDA report shows problems at Merck vaccine plant

Federal inspectors documented unwanted "fibers" on the stoppers of vaccine vials at Merck & Co. Inc.'s vast vaccine plant in Montgomery County.

They also found instances of contaminated children's vaccines and complaints that were not always investigated at the West Point plant.

Inspectors from the U.S. Food and Drug Administration spent 30 days at the plant between November and January and cited 49 areas of concern, including a failure to follow good manufacturing practices.

The findings are detailed in an unpublished 21-page FDA report obtained by The Inquirer under the federal Freedom of Information Act.

Independent experts who reviewed the report say it documents serious concerns in one of the country's premier vaccine plants. They suggested the problems could be a symptom of Merck's cost cutting in the face of rapid growth of its vaccine business.

"I would fault the management for not providing enough resources to do the work that needs to be done," said Scott M. Wheelwright, a biotech manufacturing expert and chief executive officer of the biotech consulting firm Strategic Manufacturing Worldwide, of Saratoga, Calif.

John T. McCubbins, who heads Merck's Global Vaccine Manufacturing and West Point Operations, disputed that assessment. He maintained that the division's employment had kept pace with vaccine production. He stressed that no contamination was found in finished vaccines and that Merck was addressing all the problems.

McCubbins stressed that Merck's own technicians - not FDA inspectors - had detected and reported most of the problems, which were found in the manufacturing process, not in vaccines themselves.

"We are absolutely confident in the quality of the product," McCubbins said.

The plant continues to operate, and the FDA has not ordered Merck to stop production or to recall any products.

The report comes as demand for Merck's vaccines is surging. The company began selling four new vaccines in 2005 and 2006, pushing up total vaccine sales from $1.1 billion in 2005 to $4.3 billion in 2007.

The West Point plant, where Merck makes most of its vaccines, has had issues before. Bulk production of varicella-related vaccine for chicken pox has been down for many months, leading to shortages. The supply of Vaqta for hepatitis A also has been disrupted.

In June 2006, the company paid $20 million in a consent decree with authorities after a chemical spill shut down recreation on the Wissahickon Creek and closed water-intake pipes on the Schuylkill.

In December 2007, the company voluntarily withdrew 1.2 million doses of the childhood vaccines PEDVAXHIB and COMVAX because executives said they could not guarantee the products' sterility.

In contrast to pills, vaccines are harder to make because they are produced by living organisms that must be grown under precise conditions and kept from contamination.

In their report, FDA inspectors criticized the company for making a manufacturing change involving the withdrawn vaccines in mid-2006 and later reversing course and citing the change as the cause for the withdrawal.

McCubbins said the recall showed the company's quality-control systems were effective. All the recent problems reflect the inherent difficulty of working with living organisms to make vaccines, he said.

"The primary driver when we get here is the quality of the products we produce," McCubbins said. Merck will resolve the agency's concerns, he said.

FDA inspectors spent a total of 30 days at the West Point plant between Nov. 26, 2007, and Jan. 17, 2008. The agency could go on to issue a warning letter and take other actions if its concerns are not addressed. The FDA declined repeated requests to comment.

The report cites cases where bulk lots of PEDVAX and ProQuad were contaminated. Unwanted "fibers" were found on the vial stoppers of MMR, the measles, mumps and rubella vaccine, among others. They were caused by "lesser quality" supplies from a vendor, the FDA report said.

The report noted defective vials had to be rejected twice to be discarded, and that one internal quality investigation went on for more than a year.

Several experts said no single finding was horrendous but that the overall pattern was troubling. "It's the sum of many small things that puts the whole operation in question," said consultant Wheelwright.

Merck is a fabled name in vaccines. It was at Merck that microbiologist Maurice Hilleman developed many of the most common childhood vaccines, which are credited with saving millions of lives.

Richard T. Clark, Merck's current chief executive, started as a quality inspector in 1972 and held several key manufacturing positions at West Point before his rise to the top.

That Merck would be having problems with FDA inspectors surprised several longtime company observers.

Sammie Young, a retired FDA deputy director, inspected the West Point plant early in his career and for many years oversaw vaccine-plant inspections for the entire agency.

"There are a lot of violations there [in the report]," Young said, after reading the report. "I'm surprised."

He said vaccine-makers were supposed to investigate vaccine lots if their use was associated with a death or a life-threatening event.

Merck failed to investigate two such cases, the FDA report said. A patient treated with the pneumococcal vaccine Pneumovax developed a half-dollar-size abscess and needed intravenous antibiotics to contain the infection. A pregnant woman who took the HPV vaccine Gardasil lost her baby, the FDA report noted. The Gardasil packaging warns against its use for pregnant women.

"I am concerned about the adverse-event reporting system," Young said. "It looks like the people didn't know when they were supposed to report. I find that hard to believe."

Wheelwright, a consultant with 25 years' experience in vaccine manufacturing, suspects that the workload could be overwhelming.

"I would not judge the plant as being out of control," he wrote in an e-mail. "There are numerous issues where they failed to comply with their own documentation and SOP [standard operating procedure] requirements. This suggests insufficient staff. There are other instances where the validation was insufficient. This also looks to me like overwork of the available crew. Sometimes in a plant where everyone feels overburdened . . . they give up trying to do everything and just try to keep their heads above water."

McCubbins disputed the criticism, saying the staff follows its procedures and investigates complaints. "There's always a level of interpretation," he said.

McCubbins said he feared the FDA report could create unwarranted "panic" about the firm's vaccines.

The plant would make changes, he said, "where we believe that the agency may have a point and often they do. Nobody's perfect."