Novartis Settles, Again

We certainly could not go another week without discussing another settlement of charges of unethical behavior by a major health care organization.  This time, as reported by the Wall Street Journal, it was Swiss pharmaceutical company Novartis:

Novartis AG will pay $72.5 million to settle U.S. Justice Department allegations it submitted false claims for off-label uses of a cystic-fibrosis drug.

The drug, tobramycin or TOBI, joined the Novartis portfolio as part of its 2005 takeover of biotechnology firm Chiron Corp.

In a release Tuesday, the Justice Department said that, between 2001 and 2006, Chiron, and then Novartis, marketed unapproved uses for TOBI, which the Food and Drug Administration approved as an inhaled antibiotic for treating certain cystic-fibrosis patients.

This is not even the first US legal settlement this year for Novartis:

Earlier this year, Novartis said its U.S. subsidiary struck an agreement with the U.S. Attorney's Office in Pennsylvania to settle a criminal investigation of the company's marketing of the epilepsy drug Trileptal. Novartis agreed to plead guilty to violating the U.S. Food, Drug and Cosmetic Act, and to pay a $185 million fine.

We had posted on that previous settlement here.

So the march of legal settlements continues.  It seems that practically every major pharmaceutical corporation has participated in multiple settlements since we started Health Care Renewal.  Yet the process does not seem to deter continuing bad behavior. 

In the current case, like nearly all the others, the corporation will pay what seems to be a huge fine. However, the amount is a pittance compared to the corporation's revenue, and is likely to be viewed as only a small cost of doing a very lucrative business by corporate executives. In very few cases does any individual suffer any negative consequence for approving, ordering or implementing the unethical behavior.  A large fine's impact can be spread among share-holders, employees, and clients/ customers/ patients, and hence poses no threat to executives planning the next bit of unethical behavior.
As I have said before, endlessly, we will not deter unethical behavior by health care organizations until the people who authorize, direct or implement bad behavior fear some meaningfully negative consequences.  Real health care reform needs to make health care leaders accountable, and especially accountable for the bad behavior that helped make them rich.

More Questions, No Answers About the Case of the Deadly Heparin - Some Congressmen Weigh In

In 2008, we started posting on how the "active pharmaceutical ingredient" of heparin made in China under apparently primitive conditions, contaminated accidentally or deliberately, was sold in the US bearing the label of a large American pharmaceutical company. Ultimately, many patients were sickened, or died. A summary of our posts on the topic, in smaller type, is below.

- We have posted several times, recently here and here, about the tragic case of suddenly allergenic heparin. Although heparin, an intravenous biologic anti-coagulant, has been in use for over 70 years, serious allergic reactions to it had heretofore been rare. Starting late last year, hundreds of such reactions, and now 21 deaths were reported in the US after intravenous heparin infusions.All the heparin related to these events in the US was made by Baxter International.

- We then learned that although the heparin carried the Baxter label, it was not really made by Baxter. The company had outsourced production of the active ingredient to a long, and ultimately mysterious supply chain. Baxter got the active ingredient from a US company, Scientific Protein Laboratories LLC, which in turn obtained it from a factory in China operated by Changzhou SPL, which in turn was owned by Scientific Protein Laboratories and by Changzhou Techpool Pharmaceutical Co. Changzhou SPL, in turn, got it from several consolidators or wholesalers, who in turn got it from numerous small, unidentified "workshops," which seemed to produce the product in often primitive and unsanitary conditions. None of the stops in the Chinese supply chain had apparently been inspected by the US Food and Drug Administration nor its Chinese counterpart.

- Most recently, we found out that the Baxter International labelled heparin was contaminated with over-sulfated chondroitin sulfate, a substance not found in nature, but which mimics heparin according to the simple laboratory tests used in the Chinese facilities to check incoming heparin. (See post here.) Further testing revealed that the contamination seemed to have taken place in China prior to the provision of the heparin to Changzhou SPL. (See post here.) It is not clear whether Baxter International or Scientific Protein Laboratories had inspected most of the steps in the supply chain, or even knew what went on there.

- The Baxter and Scientific Protein Laboratories CEOs did not seem aware of where they got the heparin on which the Baxter International label was eventually affixed. But one report in the New York Times alleged that Scientific Protein Laboratories would not pay enough for heparin to satisfy any sources other than the small "workshops."

- Leaders of all organizations involved, Baxter International, Scientific Protein Laboratories, Changzhou SPL, the Chinese government, and the US Food and Drug Administration, and the US Congress assigned blame to each other, but none took individual or organizational responsibility. (See post here.)

- Researchers (who turned out to have financial ties to a company which is developing an anti-coagulant drug that could compete with the heparin made by Baxter International) investigated the biological mechanisms by which the contamination of the heparin lead to adverse effects, but no one investigated further how the contamination occurred, or who was responsible.  (See post here.)

- Hundreds of lawsuits against Baxter have now been filed, so far without resolution.  (See post here.)

- A recent government report which attracted little attention warned of the dangers of pharmaceutical ingredients made in China and subject to virtually no oversight. (See post here.)

Last week, minority (Republican) members of a committee of the US House of Representatives sent a letter to the Commissioner of the US Food and Drug Administration (FDA) raising a number of concerns of its investigation of contaminated heparin from China.  The letter was summarized in http://www.theheart.org/ (here), but so far has not been noticed by any main-stream media outlets.  The main concerns raised in the letter were:

1. The FDA has not adequately followed up specific and credible information linking Chinese heparin firms to counterfeit heparin or contaminated heparin in several different supply chains.
2. The FDA inspected several Chinese heparin firms in 2008 and 2009 for regulatory compliance issues but did not conduct these inspections consistently and adequately for determining the source of the heparin contamination.
3. The FDA has not adequately followed up with the Chinese government about the heparin contamination-source investigation.

Curiously, though, most of the letter detailed concerns about an FDA inspection of a company called Chongqing Imperial Bio-Chem Co, Ltd, which appears to be separate from any of the firms mentioned above which seemed to be involved with the heparin ultimately sold in the US under the Baxter label.  In fact, I have not seen to date any report on the contamination of that heparin, supposedly whose active ingredient Baxter obtained from  a US company, Scientific Protein Laboratories LLC, which in turn obtained it from a factory in China operated by Changzhou SPL, which in turn was owned by Scientific Protein Laboratories and by Changzhou Techpool Pharmaceutical Co. Changzhou SPL, in turn, got it from several consolidators or wholesalers, who in turn got it from numerous small, unidentified "workshops," which seemed to produce the product in often primitive and unsanitary conditions.  Nor have I seen any report on the responsibility of any of these parties for the purity and safety of the heparin.  In particular, given that the heparin was sold in containers with the Baxter International label, and hence given that the doctors, nurses and pharmacists involved in its administration likely thought that it was actually made by Baxter, I have not seen any further discussion of that company's responsibility to provide a pure, safe, unadulterated product to its US patients. 

And all this still begs the question that most of the coverage of the deadly heparin also begged. Are American pharmaceutical companies so besotted with the need for cost-savings that they are willing to buy active pharmaceutical ingredients with unknown provenance overseas as if they were a pig in a poke? If so, why do we allow company leadership to potentially sacrifice quality, and sell adulterated drugs just to enrich their bottom lines (and their executives' salaries)?

As a postscript, a report last week in a New York Times blog reminds us of the monetary stakes here:

A drug harvested from pigs’ intestines has made a low-profile Chinese couple the nation’s wealthiest overnight. Husband and wife Li Li and Li Tan’s Shenzhen Hepalink Pharmaceutical sold 10 percent of its shares this week in an I.P.O. that values their stake at about $6.2 billion, The Financial Times reported.

The I.P.O. also earned Goldman Sachs a near 200-fold profit on its original $5 million investment.

According to the newspaper, analysts say Hepalink’s high valuation is a result of the company being the only one in China that is accredited by the U.S. Food and Drug Administration [presumably after the above case of the deadly heparin] to export the 'active pharmaceutical ingredient' heparin after it has been harvested.

This amount of money sloshing around suggests that the reason this case remains so persistently anechoic is fear of offending those who have been getting very rich from the products of pigs' intestines.

I hope that more investigators with intestinal fortitude step in to investigate the out-sourcing of drug production to dubious suppliers before more patients are poisoned.

Traditional Preparation Methods Improve Grains' Nutritive Value

Soaking or Germinating Grains

The most basic method of preparing grains is prolonged soaking in water, followed by cooking. This combination reduces the level of water-soluble and heat-sensitive toxins and anti-nutrients such as tannins, saponins, digestive enzyme inhibitors and lectins, as well as flatulence factors. It also partially degrades phytic acid, which is a potent inhibitor of mineral absorption, an inhibitor of the digestive enzyme trypsin and an enemy of dental health (1). This improves the digestibility and nutritional value of grains as well as legumes.

I prefer to soak all grains and legumes for at least 12 hours in a warm location, preferably 24. This includes foods that most people don't soak, such as lentils. Soaking does not reduce phytic acid at all in grains that have been heat-treated, such as oats and kasha (technically not a grain), because they no longer contain the phytic acid-degrading enzyme phytase. Cooking without soaking first also does not have much effect on phytic acid.

The next level of grain preparation is germination. After soaking, rinse the grains twice per day for an additional day or two. This activates the grains' sprouting program and further increases their digestibility and vitamin content. When combined with cooking, it reduces phytic acid, although modestly. Therefore, most of the minerals in sprouted whole grains will continue to be inaccessible. Many raw sprouted grains and legumes are edible, but I wouldn't use them as a staple food because they retain most of their phytic acid as well as some heat-sensitive anti-nutrients (2).

Grinding and Fermenting Grains

Many cultures around the world have independently discovered fermentation as a way to greatly improve the digestibility and nutritive value of grains (3). Typically, grains are soaked, ground, and allowed to sour ferment for times ranging from 12 hours to several days. In some cases, a portion of the bran is removed before or after grinding.

In addition to the reduction in toxins and anti-nutrients afforded by soaking and cooking, grinding and fermentation goes much further. Grinding greatly increases the surface area of the grains and breaks up their cellular structure, releasing enzymes which are important for the transformation to come. Under the right conditions, which are easy to achieve, lactic acid bacteria rapidly acidify the batter. These bacteria are naturally present on grains, but adding a starter makes the process more efficient and reliable.

Due to some quirk of nature, grain phytase is maximally active at a pH of between 4.5 and 5.5, which is mildly acidic. This is why the Weston Price foundation recommends soaking grains in an acidic medium before cooking. The combination of grinding and sour fermentation causes grains to efficiently degrade their own phytic acid (as long as they haven't been heat treated first), making minerals much more available for absorption (4, 5, 6, 7). This transforms whole grains from a poor source of minerals into a good source.

The degree of phytic acid degradation depends on the starting amount of phytase in the grain. Corn, rice, oats and millet don't contain much phytase activity, so they require either a longer fermentation time, or the addition of high-phytase grains to the batter (8). Whole raw buckwheat, wheat, and particularly rye contain a large amount of phytase (9), although I feel wheat is problematic for other reasons.

As fermentation proceeds, bacteria secrete enzymes that begin digesting the protein, starch and other substances in the batter. Fermentation reduces lectin levels substantially, which are reduced further by cooking (10). Lectins are toxins that can interfere with digestion and may be involved in autoimmune disease, an idea championed by Dr. Loren Cordain. Grain lectins are generally heat-sensitive, but one notable exception is the nasty lectin wheat germ agglutinin (WGA). As its name suggests, WGA is found in wheat germ, and thus is mostly absent in white flour. WGA may have been another reason why DART participants who increased their wheat fiber intake had significantly more heart attacks than those who didn't. I don't know if fermentation degrades WGA.

One of the problems with grains is their poor protein quality. Besides containing a fairly low concentration of protein to begin with, they also don't contain a good balance of essential amino acids. This prevents their efficient use by the body, unless a separate source of certain amino acids is eaten along with them. The main limiting amino acid in grains is lysine. Legumes are rich in lysine, which is why cultures around the world pair them with grains. Bacterial fermentation produces lysine, often increasing its concentration by many fold and making grains nearly a "complete protein", i.e. one that contains the ideal balance of essential amino acids as do animal proteins (11, scroll down to see graph). Not very many plant foods can make that claim. Fermentation also increases the concentration of the amino acid methionine and certain vitamins.

Another problem with grain protein is it's poorly digested relative to animal protein. This means that a portion of it escapes digestion, leading to a lower nutritive value and a higher risk of allergy due to undigested protein hanging around in the digestive tract. Fermentation followed by cooking increases the digestibility of grain protein, bringing it nearly to the same level as meat (12, 13, 14, 15). This may relate to the destruction of protease inhibitors (trypsin inhibitors, phytic acid) and the partial pre-digestion of grain proteins by bacteria.

Once you delve into the research on traditional grain preparation methods, you begin to see why grain-eating cultures throughout the world have favored certain techniques. Proper grain processing transforms them from toxic to nutritious, from health-degrading to health-giving. Modern industrial grain processing has largely eschewed these time-honored techniques, replacing them with low-extraction milling, extrusion and quick-rise yeast strains.

Many people will not be willing to go through the trouble of grinding and fermentation to prepare grains. I can sympathize, although if you have the right tools, once you establish a routine it really isn't that much work. It just requires a bit of organization. In fact, it can even be downright convenient. I often keep a bowl of fermented dosa or buckwheat batter in the fridge, ready to make a tasty "pancake" at a moment's notice. In the next post, I'll describe a few recipes from different parts of the world.

Further reading:

How to Eat Grains
A Few Thoughts on Minerals, Milling, Grains and Tubers
Dietary Fiber and Mineral Availability
A New Way to Soak Brown Rice

Traditional Preparation Methods Improve Grains' Nutritive Value

Soaking or Germinating Grains

The most basic method of preparing grains is prolonged soaking in water, followed by cooking. This combination reduces the level of water-soluble and heat-sensitive toxins and anti-nutrients such as tannins, saponins, digestive enzyme inhibitors and lectins, as well as flatulence factors. It also partially degrades phytic acid, which is a potent inhibitor of mineral absorption, an inhibitor of the digestive enzyme trypsin and an enemy of dental health (1). This improves the digestibility and nutritional value of grains as well as legumes.

I prefer to soak all grains and legumes for at least 12 hours in a warm location, preferably 24. This includes foods that most people don't soak, such as lentils. Soaking does not reduce phytic acid at all in grains that have been heat-treated, such as oats and kasha (technically not a grain), because they no longer contain the phytic acid-degrading enzyme phytase. Cooking without soaking first also does not have much effect on phytic acid.

The next level of grain preparation is germination. After soaking, rinse the grains twice per day for an additional day or two. This activates the grains' sprouting program and further increases their digestibility and vitamin content. When combined with cooking, it reduces phytic acid, although modestly. Therefore, most of the minerals in sprouted whole grains will continue to be inaccessible. Many raw sprouted grains and legumes are edible, but I wouldn't use them as a staple food because they retain most of their phytic acid as well as some heat-sensitive anti-nutrients (2).

Grinding and Fermenting Grains

Many cultures around the world have independently discovered fermentation as a way to greatly improve the digestibility and nutritive value of grains (3). Typically, grains are soaked, ground, and allowed to sour ferment for times ranging from 12 hours to several days. In some cases, a portion of the bran is removed before or after grinding.

In addition to the reduction in toxins and anti-nutrients afforded by soaking and cooking, grinding and fermentation goes much further. Grinding greatly increases the surface area of the grains and breaks up their cellular structure, releasing enzymes which are important for the transformation to come. Under the right conditions, which are easy to achieve, lactic acid bacteria rapidly acidify the batter. These bacteria are naturally present on grains, but adding a starter makes the process more efficient and reliable.

Due to some quirk of nature, grain phytase is maximally active at a pH of between 4.5 and 5.5, which is mildly acidic. This is why the Weston Price foundation recommends soaking grains in an acidic medium before cooking. The combination of grinding and sour fermentation causes grains to efficiently degrade their own phytic acid (as long as they haven't been heat treated first), making minerals much more available for absorption (4, 5, 6, 7). This transforms whole grains from a poor source of minerals into a good source.

The degree of phytic acid degradation depends on the starting amount of phytase in the grain. Corn, rice, oats and millet don't contain much phytase activity, so they require either a longer fermentation time, or the addition of high-phytase grains to the batter (8). Whole raw buckwheat, wheat, and particularly rye contain a large amount of phytase (9), although I feel wheat is problematic for other reasons.

As fermentation proceeds, bacteria secrete enzymes that begin digesting the protein, starch and other substances in the batter. Fermentation reduces lectin levels substantially, which are reduced further by cooking (10). Lectins are toxins that can interfere with digestion and may be involved in autoimmune disease, an idea championed by Dr. Loren Cordain. Grain lectins are generally heat-sensitive, but one notable exception is the nasty lectin wheat germ agglutinin (WGA). As its name suggests, WGA is found in wheat germ, and thus is mostly absent in white flour. WGA may have been another reason why DART participants who increased their wheat fiber intake had significantly more heart attacks than those who didn't. I don't know if fermentation degrades WGA.

One of the problems with grains is their poor protein quality. Besides containing a fairly low concentration of protein to begin with, they also don't contain a good balance of essential amino acids. This prevents their efficient use by the body, unless a separate source of certain amino acids is eaten along with them. The main limiting amino acid in grains is lysine. Legumes are rich in lysine, which is why cultures around the world pair them with grains. Bacterial fermentation produces lysine, often increasing its concentration by many fold and making grains nearly a "complete protein", i.e. one that contains the ideal balance of essential amino acids as do animal proteins (11, scroll down to see graph). Not very many plant foods can make that claim. Fermentation also increases the concentration of the amino acid methionine and certain vitamins.

Another problem with grain protein is it's poorly digested relative to animal protein. This means that a portion of it escapes digestion, leading to a lower nutritive value and a higher risk of allergy due to undigested protein hanging around in the digestive tract. Fermentation followed by cooking increases the digestibility of grain protein, bringing it nearly to the same level as meat (12, 13, 14, 15). This may relate to the destruction of protease inhibitors (trypsin inhibitors, phytic acid) and the partial pre-digestion of grain proteins by bacteria.

Once you delve into the research on traditional grain preparation methods, you begin to see why grain-eating cultures throughout the world have favored certain techniques. Proper grain processing transforms them from toxic to nutritious, from health-degrading to health-giving. Modern industrial grain processing has largely eschewed these time-honored techniques, replacing them with low-extraction milling, extrusion and quick-rise yeast strains.

Many people will not be willing to go through the trouble of grinding and fermentation to prepare grains. I can sympathize, although if you have the right tools, once you establish a routine it really isn't that much work. It just requires a bit of organization. In fact, it can even be downright convenient. I often keep a bowl of fermented dosa or buckwheat batter in the fridge, ready to make a tasty "pancake" at a moment's notice. In the next post, I'll describe a few recipes from different parts of the world.

Further reading:

How to Eat Grains
A Few Thoughts on Minerals, Milling, Grains and Tubers
Dietary Fiber and Mineral Availability
A New Way to Soak Brown Rice

David Blumenthal on health IT safety: nothing to see here, move along

At "FDA on Health IT Adverse Consequences: 44 Reported Injuries And 6 Deaths In Two Years, Probably Just Tip of Iceberg" I wrote about a meeting of the HIT Policy Committee, Adoption/Certification Workgroup on February 25, 2010. The topic was "HIT safety." The agenda, presenters and presentations are available at this link.

At this meeting FDA testimony was given by Jeffrey Shuren, Director of FDA’s Center for Devices and Radiological Health. Dr. Shuren noted several categories of health IT-induced adverse consequences known by FDA. This information was striking.

He wrote:

... In the past two years, we have received 260 reports of HIT-related malfunctions with the potential for patient harm – including 44 reported injuries and 6 reported deaths. Because these reports are purely voluntary, they may represent only the tip of the iceberg in terms of the HIT-related problems that exist.

Well, there's absolutely nothing to worry about, according to the Office of the National Coordinator and Dr. David Blumenthal. Nothing to see here. Move on.

Blumenthal has just reportedly stated that:

http://www.massdevice.com/news/blumenthal-evidence-adverse-events-with-emrs-anecdotal-and-fragmented

... [Blumenthal's] department is confident that its mission remains unchanged in trying to push all healthcare establishments to adopt EMRs as a standard practice. "The [ONC] committee [investigating FDA reports of HIT endangement] said that nothing it had found would give them any pause that a policy of introducing EMR's could impede patient safety," he said.

I ask a simple question:

• Are these the words to be reasonably expected from an academic physician/scientist?

Perhaps I'm a bit behind these postmodern times, but I once believed the perhaps now old-fashioned and obsolete view that a scientist would not base a conclusion of medical safety in national dissemination of drug, device, or whatever on some analysis of anecdotal data, whether 'preliminary' or final.

Due to reasons such as the lack of knowledge of FDA as a place to report HIT problems, as well as fear by clinicians in reporting HIT problems at all, the cited FDA data (260 HIT-related adverse events over two years, including 44 reported injuries and six deaths) is most certainly anecdotal and incomplete, and potentially (per FDA's Jeff Shuren, MD, JD) the "tip of the iceberg."

I would not take the FDA data to be anything but a possible red flag, not a source of truth, one way or the other.

For example, the scant reports of health IT bugs and defects -- many of which admittedly could cause medical error -- in another database, MAUDE, voluntarily submitted by just a tiny fraction of the HIT vendors, should give a scientist pause. They are a sentinel. (See my Oct. 2009 post "Our Policy Is To Always Have Unabashed Faith In The Computer ... Except When It Screws Up, And Then It's The Doctor's Fault" for several MAUDE database examples).

(Feb. 2011 addendum - see my more recent post about MAUDE health IT defects reports at this link.)

Obviously, the unreported, unrecognized (and therefore uncorrected) bugs and defects have the same potential. Those MAUDE reports alone should provide an impetus to call for full, rigorous, scientific, uncensored investigations on HIT safety, not make pronouncements on safety to a national audience.

Proof by lack of evidence is not what I was taught in medical school.

Blumenthal appears to be speaking not as a scientist, but as a marketer and (of course) politician.

This is quite disappointing.

However, as the man said, nothing to see here, move along.

By the way, I am assuming the "analysis" will be open to public scrutiny.

-- SS