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.

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

Another Echo of the Case of the Deadly Heparin - A Report on the Perils of Out-Sourcing Drug Production

In 2008, we published multiple posts on how heparin made as an "active pharmaceutical ingredient" 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.

Case Summary

- 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.)

Now, as reported to date only on the PostScript blog, a US government report on problems with active pharmaceutical ingredients made in China has appeared.

A new report (pdf) by the U.S. China Economic and Security Review Commission stresses the safety risks to Americans posed by pharmaceutical ingredients made in China.

According to the report, issued by a group that advises Congress on the economic and trade implications of U.S.-China relations, found that the U.S. is the number one destination for Chinese pharmaceutical raw material exports – a $2.2 billion business each year. The U.S. relies heavily on Chinese products not only for over-the-counter drugs but for active pharmaceutical ingredients (API) found in prescription drugs.

And the report makes clear that China has neither the will nor the systems in place to monitor its exports.

This 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)? 

Post Title → Another Echo of the Case of the Deadly Heparin - A Report on the Perils of Out-Sourcing Drug Production

The Perils of Contract Research Organizations Out-Sourcing Clinical Trials

The St Petersberg Times last week published an investigative series on the out-sourcing of clinical trials to India, which raised important questions about the quality of data they produce.

Mary K. Pendergast, a former FDA deputy commissioner, said identifying a dangerous product is difficult enough. It's considerably trickier to find fraudulent clinical trial data, which could lead to the approval of dangerous drugs years later.

'It's much more time-consuming and extraordinarily tedious,' said Pendergast, who plowed through such data when she was prosecuting doctors doing drug studies in the United States. 'It's especially hard if the trial is taking place in a different country.'

Particularly when that country has a reputation for cutting corners.

The article quoted a number of people familiar with the clinical trials scene in India who suggested that corners indeed were being cut.

Amar Jasani:

In the burgeoning clinical trial business, says Amar Jesani, a doctor and medical ethicist in Mumbai, every layer of oversight is compromised by cash, and independent monitoring is nonexistent. He has resigned from supposedly independent ethics committees that rubber-stamp drug companies' proposals and overrule any objections.

Dr Arun Bhatt:

Dr. Arun Bhatt is president of Clininvent, a contract research organization in Mumbai that is running 11 trials involving 1,000 patients. He worries that Indian doctors ignore patients' reactions to experimental medicines, missing critical clues about a drug's safety.

'Most sites are not used to recognizing serious adverse events, so they are underreported,' he said with an attitude of resignation. 'Either they don't recognize, don't realize or are afraid to report this information.'

Dr Nandini Kuman:

Dr. Nandini Kumar retired in June as deputy director general of the Indian Council of Medical Research, the equivalent of the U.S. National Institutes of Health. She now works as a consultant for the agency in New Delhi, teaching doctors how to run ethical trials. Kumar is stunned by their ignorance of internationally recognized standards for conducting drug studies.

Asked what aspect of good clinical practice most surprised her students, the gray-haired, sari-clad Kumar snapped, 'Everything.'

'There are efforts to put rules in place, but at the same time there are people who just want to get the extra dollars or perks like trips abroad from doing drug trials....'

Dr S P Kalantri:

Dr. S.P. Kalantri has conducted trials for global pharma at the government hospital in Sevagram, a small town in central India. But he said he has pulled back from doing the studies.

'It's difficult to explain the complexities of trials to study participants,' Kalantri said of the hospital's mostly poor, illiterate patients. 'I think many investigators tend to take their patients for a ride. And there's an abysmal lack of know-how about clinical research among investigators.'

Dr C M Gulhati:

Dr. C.M. Gulhati, editor of an Indian medical journal, Monthly Index of Medical Specialties, said authorities cannot cope with the tsunami of trials.

'India's drugs controller general's office is both understaffed and incompetent,' he said, citing a case where the agency claimed it reviewed an 800-page trial protocol in just five days. 'How is that even possible?'

Gulhati, who fights unbridled drug testing from a dim and cluttered office above a busy Delhi shopping plaza, reeled off a litany of troubled trials:

In 2003 in Hyderabad, an unregistered study of a heart attack drug that resulted in six deaths.

In 2004 in Delhi, a first-in-human trial of a new suturing device on 13 patients without regulators' approval.

Last year, India's decision to become the only nation to allow domestic drug maker Sun Pharmaceutical Industries to market the anticancer drug Letrozole for infertility in women despite the drug's originator, Novartis, warning that it may cause fetal harm and should be used only in postmenopausal women.

And in October in Bangalore, the death of a baby during the testing of a new Wyeth vaccine.

But doing trials in India, and other less-developed countries is far cheaper and faster than doing them in developed countries. Contract research organizations (CROs) have figured this out.

Contract research organizations keep tabs on trials with regular audits. Site management organizations put an extra set of eyes in the doctor's office. Both entities dangle promises of FDA-ready studies in half the time, at 30 to 60 percent the cost in the United States. The secret? Cheap help and fast patient recruiting.

Quintiles, the world's largest contract research organization, boasts of enrolling 50 patients with diabetes in one month in India and 204 infants for a vaccine study in three days, far faster than possible in the States. In a brochure, Quintiles sums up India's allure: 'It's practically a paradise for conducting clinical trials.'

In fact, on Quintiles current web-site is an offer related to Phase II and III trials for

Accelerated Start-up and Recruitment worldwide, through a global network of investigators that includes many in nontraditional regions with large clusters of patients and few competing trials.

We have noted before that the limited oversight of CROs, which are responsible for an increasing proportion of industry-funded trials of drugs and devices, makes possible poor quality work, hence unreliable data (see most recent post here and links backward). The threat to data integrity from too hasty, too profit driven clinical research done by CROs is the third of the three major threats to the integrity of the clinical research data base. The other two, which are discussed frequently on Health Care Renewal, are suppression of clinical research, and manipulation of research design, implementation, and analysis and dissemination.

In combination, they threaten the well-intentioned and idealistic goals of evidence-based medicine, to improve clinical care by basing decisions not only on knowledge of biology and the values of patients, but on critical review of the best available clinical evidence. But given that we have become increasingly skeptical, if not outright distrustful of the integrity of the evidence, the alternative ways of making clinical decisions, basing them on theoretical (but possibly incorrect) knowledge of biology, on authority, or on tradition to me are much worse.

Doctors and patients should be vehement about the need for carefully performed clinical trials free of manipulation meant to benefit vested interests, reported honestly even if their results offend vested interests.

Post Title → The Perils of Contract Research Organizations Out-Sourcing Clinical Trials

Cancer Data Collection Outsourced, and Then Manipulated

I have a favorite quote about the impossibly complex bureaucratic structure of the American health care system from Oxymorons by JD Kleinke,(1) (which I used in my "Cautionary Tale" article in the European Journal of Internal Medicine[2]):

Tens of thousands of well-meaning people work throughout the health care system, none of whom ever see a patient or deliver any actual medical care. They preside over an infinity of rules, regulations, forms, processes, contract outsourcing, financial brokering, benefit plan tinkering, analytical processes, incompatible data systems, and dead forests of paperwork. Health care administration in America is a tower of Babel that reaches to the moon....

It seems impossible to keep track of all the administrative, managerial and bureaucratic organizations that now impact health care. All of them, however, seem greatly susceptible to mismanagement, and worse.

Here is the latest example, from the Baltimore Sun,

A state contractor tampered with Maryland's cancer registry, a database used by researchers to track the disease's impact, counting hundreds of patients as having cancer when they did not, according to a legislative audit released yesterday.

The company, Macro International Inc., found in an internal investigation that data were deliberately altered between August 2004 and December of that year. The company fired the employee responsible for the cancer registry. State officials said that Macro employees apparently overreported the incidence of cancer to ensure that the database met standards set by a national certification association, which closely monitors registries to ensure that states have a complete count of cases.

The misinformation led researchers to send an estimated 400 women letters beginning in 2005 asking them to participate in a cervical cancer study when they did not have the disease. About 10 of those women called the state Family Health Administration, part of the state's Department of Health and Mental Hygiene - one of the first indications that the cancer registry was inaccurate.

Guy Garnett, a Macro vice president, declined to comment, citing company policy not to discuss client issues. The company completed the contract term, earning $1.9 million to manage the registry for 18 months through January. The state hired a new vendor, Westat, beginning in February.

In 2003, when Macro submitted the 2001 cancer database to the North American Association of Central Cancer Registries, it did not receive certification as required under its contract. Auditors faulted the state agency for not taking action, such as terminating the contract.

The next year, Macro did receive certification, but the auditors noted that information was later found to be erroneous. Auditors outlined several red flags that were not raised until years later.

First, the state agency did not review the 2002 data until August 2005, when it found they showed a 90 percent increase in cervical cancer cases and a 70 percent increase in melanoma cases from 1998 to 2002. At the time, auditors said, Macro could not provide an adequate explanation for the staggering rise in cancer incidence.

Around the same time, as part of the state health department's study of breast and cervical cancer diagnosis in Maryland women, about 2,300 patients in the cancer registry were asked to participate in the study. The Family Health Administration later worked with Macro to comb through medical histories, comparing original laboratory reports with data in the cancer registry, and determined that 400 of them did not have cancer. The study was suspended.

Then in May 2006, a former Macro employee informed the state agency that data were deliberately altered. Macro's investigation found that more than 13 percent of all cases in 2002 showed signs of tampering, according to the audit. Macro concluded that the changes were 'methodical and were made by one or more persons with broad access to the system,' the audit said.

I am of course familiar with the concept of a state-wide cancer registry. I must say it did not previously occur to (even) me that states would out-source the operation of such registries, and if so, that they would not bother to supervise the companies entrusted with collecting and analyzing the data.

Macro International Inc, is a for-profit, apparently privately held company. (I cannot find it on the Edgar database.) It boasts that its"mission is to deliver high-quality, research-based solutions to complex problems, integrating objective information with the advisory and implementation tasks needed to improve real world performance." That wording is so full of buzz words and management/ bureaucratic-speak that I am not sure what it means. So I cannot accuse Macro International's performance of violating its own mission. But it certainly violated the values of public health and health care research.

So we have yet another example of how health care activities have been transferred from people and organizations which were supposed to be fulfilling a (in this case, public) health mission, to (in this case, for-profit) organizations which do not have an overt commitment to the mission, a governance structure designed to fulfill the mission, or effective oversight or regulation to ensure that they fulfill the mission.

So the result was mismanagement, and fabricated data. The latter had direct impact on health care research, and on individual patients.

To take back the future of health care, we will have to ensure that health care is carried out by people and organizations pledged to uphold its core values, and working transparently and accountably under explicit and enforceable codes of ethics.

References

1. J.D. Kleinke. Oxymorons: the myth of a US health care system, Jossey-Bass, San Francisco (2001).

2. Poses RM. A cautionary tale: the dysfunction of the American health care system. Eur J Int Med 2003; 14: 123-130.

Post Title → Cancer Data Collection Outsourced, and Then Manipulated

Outsourced to Death?

A while back, we posted frequently about the sudden toxicity of what used to be an apparently well understood drug. A summary of the story to date is below (in smaller type.):

- 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.
- Then, 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."
- The parties involved, including the US Congress, the US Food and Drug Administration, its Chinese counterpart, Baxter International, Scientific Protein Laboratories, blamed each other for the problems (see post here).

Since the beginning of May, the story has become surprisingly anechoic. Just recently, however, a brief, grim reminder appeared (e.g., by Bloomberg News, via the Boston Globe):

The blood thinner heparin has been linked to 149 US deaths in people who had allergic reactions after taking it, US regulators said.

The new tally, posted yesterday on the Food and Drug Administration's website, expands the toll of people who took the drug and suffered allergic reactions. The agency said in April it knew of 81 people who died after suffering allergic reactions from the drug, made from pig intestines.

But since early May, no more seems to be known about where the contaminant was introduced in the supply chain, who introduced it, or whether faulty oversight on the part of Baxter International or Scientific Protein Laboratories allowed the contamination to go undetected.

The mounting death toll from contaminated heparin suggests that the outsourcing of core functions of health care organizations may need to be rethought.

Thus, the recent discussion on the Managed Care Matters Blog, by Joe Paduda about the perils of brain-dead outsourcing seems particularly relevant. He first noted:

In the old days, companies tried to control as much of their raw materials - and the refining and transportation of those raw materials - as possible. In addition to auto plants Ford owned iron mines, steel mills, glass factories, rubber plantations, ships, and railroad cars. Nowadays Ford outsources some of its vehicles' key components (engines, transmissions, steering linkages) to other companies, concentrating on designing, assembling and marketing instead.

Over the last couple of decades, manufacturers found themselves increasingly relying on other companies for critical processes and components - if all worked well, profits zoomed, and if not, heads rolled.

But often this sort of outsourcing often breaks down

and when it does disaster often ensues

He had plenty of examples,

Sony buys LCD panels not on clarity and brightness but on cost, thinking hey, they are cheap so more folks can afford them - don't worry if the picture is lousy and colors muddy - in fact don't even look at the picture before you select a vendor.

Paduda cited the example of Compaq, once one of the major US makers of personal computers (and the first maker of a practical "lugable" computer.) Based on an interview with "disruptive technology" guru, Clayton Christensen, Paduda summarized how Compaq first outsourced some of the circuit boards in the computer, and saved money in the process. Then they outsourced the mother board, the main computer circuit board. Then they outsourced the design of the computer. As Christensen said, Compaq managers agreed, "our core competency is really our brand. We can fire all the engineers...." The result was, "the supplier in the Third World starts to eat their way up inside the customer, and every step forward they take progressively trivializes the remaining value Compaq adds, until in the end they're providing almost no value and the company vaporizes."

The key lesson here, which was not stated by Paduda or Christensen, is confusion about what an organization's core really is. The rationale for a company to outsource is that an outside organization may be able to provide non-core functions at a lower cost. Real problems arise, however, when managers seem to progressively decide that less and less of the organization's functions are core.

It may be that many managers seem to think that what they do is the only real core part of the organization, that is, that they, the managers, are the only indispensable part of the organization. It may be that many managers, trained as super-generalists, believe only they have the brilliance to manage any organization, even if they do not understand the context in which it operates, or the technical or scientific rationale of its products. Scientists, engineers, professionals, assembly line workers, service specialists to such managers are all superfluous. Of course, it may actually be harder to find specialized technical workers or professionals, or to set up complex manufacturing processes, than to find a few more self-proclaimed genius MBAs.

In my humble opinion, this kind of thinking has infected many health care managers. It may have contributed to the death of 149 people from out-sourced, contaminated heparin. More disasters are likely to ensue, and will keep happening until we reaffirm what the core of health care organizations really is.

It is dedicated health care professionals sworn to put patients' interests first. It is scientists who mean to discover the truth about biology and disease. It is the complex, often highly technical infrastructure that allows good care to happen for particular patients at the time it is needed, and the particularly qualified people who staff that infrastructure.

It is not managers who do not understand health care, medicine, or biology. It is not marketing. It is not accounting. It is not legal services. Maybe we have the outsourcing in health care all backwards.

Post Title → Outsourced to Death?

Contaminated Heparin: Where is the Outrage?

We have posted frequently on the case of the contaminated heparin. A summary to date 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."

Although this case has been extensively covered by some major newspapers, with kudos going to the Chicago Tribune, New York Times, and Wall Street Journal (in alphabetical order), the story has inspired, in my humble opinion, very little commentary, and that commentary has been remarkably reticent. This week, though, some interesting points were raised in the blogsphere.

On the PharmaLot blog, Ed Silverman interviewed personal injury attorney Eric Turkewitz, who undoubtedly had some of his own axes to grind. Nonetheless, he made some points that others have not.

• Baxter International could be in serious legal trouble - "Assuming the reports are true. Baxter sold a counterfeit drug, which is in violation of federal law. We lawyers like to call it ‘negligence per se.’ They had an obligation to verify the goods they sold are bona fide. But it appears that Baxter sold something different." Furthermore, "They have an obligation to make sure the stuff they’re selling is what they say it is. They’re the ones selling the product."
• Baxter International executives ought to have known that deliberate counterfeiting was a potential source of contamination - "I think it’s impossible for anybody to say, with a straight face, that they’re taken by surprise by what’s happened. The dangers of counterfeiting, because of the vast sums of money at stake, are well known in the pharmaceutical industry. And one aspect of that problem is counterfeit ingredients in the production process as opposed to a counterfeit finished product that enters the supply chain in the US and is mixed in with a legitimate shipment or sold as a substitute. This is the issue with the production in China. It’s called foreseeable risk. For Baxter, I don’t know if (the sourcing) was a decision to save money or they had to look for another supplier. But whatever the reason they used this supplier, they can’t excuse it. I can’t think of any excuse (Baxter) can come up with that will hold water."

Also, Nancy Reyes, described as a retired physician living in the rural Philippines, made some points on the Blogger News Network about what commentary there has been about the case.

• The commentary seemed to assume that the problem was due to accidental contamination, not deliberate counterfeiting - "The problem is that too many American newspapers are writing editorials as if this was merely a quality control problem that FDA inspections would eliminate." However, "The drug was deliberately diluted with a drug that would pass routine drug testing.
• The suggested solution, more inspections, could be evaded by people who deliberately seek to sell counterfeit drugs - "Inspections won’t work. You need a full time watchdog…one who won’t accept a bribe…" Furthermore, inspections "assume honesty. But would an honest man go out of their way to find a drug that is cheap and would pass routine tests? Obviously not. And if they cheat in big things, what makes you think that the labels and paper work would be honest?" In summary, "To think that simple inspections will find the hidden corruption that allows such deliberate contamination is naive. The criminals will merely find another way to outwit the inspectors to make money. If there is to be inspections, could I suggest that the ones to do such inspections should include FBI agents familiar with organized crime?"

It seems to me that the public discourse about this case has been strangely reticent. After all, after getting intravenous heparin, patients died, and many patients got very sick. So where is the outrage? Instead, the problem seems to be discussed as if it were a natural disaster or an innocent accident, which could not have been prevented, and for which no one was to blame.

What criticism there has been was of the US Food and Drug Administration for its inadequate inspections of outsourced drug suppliers. With the exception of the interview above, there has been little criticism of the US companies who sold drugs without paying much attention to how they were produced.

Finally, almost nothing has been heard from physicians (with the recent exception of Dr Reyes). In my extensive file on this case, I have found no other commentaries written by physicians, in newspapers, and certainly not in medical journals. Maybe it just takes a long time for such things to get published.

Yet, physicians' prime obligation is to put their patients' interests first. Presumably many well-meaning physicians gave heparin to their patients assuming it was safe, pure, and more likely to do more good than harm, only to see some of them sicken, and a few die. One would think physicians would be hopping mad to find out the drug they trusted was not really made by the venerable drug company whose label adorned it, that it was really made in unknown Chinese "workshops," and was apparently deliberately contaminated long before it got to the US.

Maybe physicians are so deep into a state of learned helplessness, or so fearful of company lawyers waving SLAPPs that they can't or won't express outrage. But if we don't get mad when bad things happen, more and more bad things will happen. It is our role as physicians to stand up for our patients. So the least we can do is express our outrage when the drugs we prescribe for them turn out to be contaminated and counterfeit.

So let me say it: This case is outrageous. It demands not only a scientific, but a criminal investigation. Any people identified as responsible for contaminating the heparin, and responsible for selling the contaminated heparin without making adequate attempts to assure its purity, should be prosecuted. The negative incentives for counterfeiting drugs, and for selling drugs likely to be contaminated without adequately assessing their purity should be so strong that no one in their right mind would dare to do this again.

Post Title → Contaminated Heparin: Where is the Outrage?

Who Was Responsible for the Purity of Baxter International's Heparin?

We have posted several times, most 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 was made by Baxter International. We then learned that although the heparin carried the Baxter label, it was not really made by Baxter. In fact, 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.)

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."

By the end of this week, it became clear that the counterfeit ingredient was added to the heparin in China. Per Bloomberg,

The contamination was present in the powdered raw heparin purchased by Scientific Protein's plant in China, said Robert Rhoades, a pharmaceutical consultant with Becker & Associates in Washington, speaking for Scientific Protein. The company was unaware of the contamination at the time because it wasn't detected in tests Scientific Protein conducted on the powder provided by suppliers, he said.

Scientific Protein purchased raw heparin from consolidators and refined it further before sending it to Baxter, which uses the ingredient to make the finished drug, Rhoades said. The consolidators obtained the ingredients from workshops in China, he said.

The contaminant 'was very likely introduced at the workshop or consolidator level,' Norbert Riedel, Baxter's corporate vice president and chief scientific officer, has said.

Nonetheless, a number of experts suggested that there was reason not be complacent about drugs made in China. A Washington Post article noted that it was well known that Chinese manufacturers were liable to supply dodgy drugs,

Although the contaminated heparin is the largest and highest-profile instance of tainted prescription drugs made in China, it is not the first. In the late 1990s, a spike in deaths associated with the intravenous antibiotic gentamicin was linked to China-based Long March Pharmaceuticals. Although no definitive link was ever established, tests by German researchers later found a wide range in quality and effectiveness in what were supposed to be uniform dosages of the drug, leading them to write that 'it was assumed' the deaths 'were related to faulty manufacture.'

The Post quoted former US Food and Drug Administration (FDA) official William Hubbard,

The history of some of these developing countries in terms of substituting or counterfeiting concerns is a long and well-documented one....

USA Today quoted former FDA Commissioner David Kessler saying that

the news shouldn't come as a surprise: China is 'as close to an unregulated environment as you can get.' In fact, it's a lot like the USA was in 1906, he says —'that's why we developed an FDA.'

Furthermore, one expert argued that Baxter International was ultimately responsible for the drug that it sold, per the Chicago Tribune,

The presence of a foreign ingredient raises new questions about Baxter's oversight because a lack of record-keeping at the China plant makes it more difficult for Baxter and government inspectors to trace the origin of the raw material for Baxter's product.

'Where are the controls here? What is the process here?' asked Carl Nielsen, who was the FDA's director of import operations and policy before leaving the agency to form a consulting firm in 2005.

'Ultimately, Baxter is the most responsible' for monitoring the quality of products that move through the company's pipeline, Nielsen said.

Yet Baxter International executives have not exactly been jumping forward to claim responsibility. In a letter, again to the Chicago Tribune, Peter J Arduini, President, Medication Delivery, for Baxter International seemed to be deflecting responsibility towards Scientific Protein Laboratories and the FDA, while asserting Baxter did all it could do.

Regarding the issue of active pharmaceutical ingredient that originated in China, Baxter's API supplier for heparin is in fact a Wisconsin-based company, Scientific Protein Laboratories, with whom Baxter and its predecessor in this business has worked for more than 30 years. SPL had been procuring heparin raw material from China for more than 10 years and opened a location in Changzhou, China, in 2004. Baxter worked with the U.S. Food and Drug Administration to obtain the appropriate approvals to work with this facility. For the API we receive from SPL, and for the API we receive from all our suppliers, Baxter performs quality testing of all incoming materials above and beyond what's required, to ensure that incoming API is what our suppliers claim it to be. Unfortunately, as the FDA has said, the problematic heparin API could not have been detected by the testing required of and done by any heparin manufacturer.

Previously Baxter International's CEO, Robert L Parkinson Jr, had dodged responsibility for the supply chain that provided the heparin to Scientific Protein Research's Changzhou facility, as we posted here, and as originally reported in the Chicago Tribune,

Baxter International Inc. does not monitor its supply chain to the extent that it would know that a supplier in China was never inspected before it began shipment of the blood-thinning drug heparin, which is linked to more than 300 illnesses in the U.S., the company's chief executive said Wednesday.

Baxter contracted with a Wisconsin supplier, Scientific Protein Laboratories, and not with that company's Chinese affiliate, Baxter CEO Robert Parkinson said Wednesday in his first interview since the heparin problems surfaced.

'It's not unusual for us not to know that the FDA hasn't inspected a supplier to a supplier,' Parkinson said.

Yet if Baxter International is not responsible for the production of drugs that carry its name, who is? If Baxter International's executives are not responsible for how the drugs it sells are manufactured, who should be?

In an ironic juxtaposition, a small and little noticed news item last week declared that Robert Parkinson received $16,600,000 in compensation in 2007, a 30.5% increase from 2006. In fact, the company's 2008 proxy statement suggests even greater total compensation in 2007, $17,580,718. And Mr Arduini's 2007 compensation was reported to be $2,438,642.

The usual justification for compensation at this level is the brilliance of and great responsibilities borne by the executives who receive it. But, if Baxter International's executives will not take responsibility for their products and how they are made, what again is the justification for paying them the big bucks?

So the case of the contaminated heparin becomes another reason to question the imperial nature of the current leadership of health care organizations.

Post Title → Who Was Responsible for the Purity of Baxter International's Heparin?

Fake Heparin, then Sick and Dead Patients

We have posted several times, most recently 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 was made by Baxter International.

We then learned that although the heparin carried the Baxter label, it was not really made by Baxter. In fact, 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.

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."

Now the US FDA just reported it identified a contaminant in the heparin that may be responsible for the adverse reactions. This has already been reported today by many media outlets, but I will quote Bloomberg since its article makes the main points most concisely,

Baxter International Inc.'s blood thinner heparin, linked to deaths and allergic reactions, was contaminated with a less-expensive ingredient derived from animal cartilage, U.S. regulators said.

The contaminant, over-sulfated chondroitin sulfate, isn't approved for use in medicine, said Janet Woodcock, the head of the Food and Drug Administration's drug division, in a conference call today with reporters. Regulators are investigating whether the substance was intentionally or accidentally added to raw heparin from China.

'It does not appear to have come straight from the pig,' Woodcock said of the contaminant. 'It doesn't appear to be a natural contaminant that got in there. We don't know how it was introduced or why.'

Adding the contaminant to raw heparin, the active ingredient in the finished product, would have been cheaper than using pure raw heparin, according to the FDA. The agency didn't know how much money would be saved by its use, Woodcock said.

Chondroitin sulfate is taken orally as a dietary supplement to treat joint pain. The over-sulfated version found in the heparin was chemically modified to act like heparin, Woodcock said.

Over-sulfated chondroitin sulfate is generated in laboratories for experimental purposes, said Siobhan DeLancey, an FDA spokeswoman, in an interview. It is chemically altered to add additional sulfates, she said.

Two percent to 50 percent of the contaminated raw heparin samples tested by the FDA were made up of over-sulfated chondroitin sulfate, Woodcock said.

So it now appears, although it is not yet proven that the adverse reactions and deaths were caused not by a trace contaminant derived from a sloppy, primitive, and unsanitary manufacturing process, but from a bulk counterfeit ingredient deliberately introduced because it was cheaper than heparin, yet would fool purchasers into thinking it was heparin.

Thus we see what happens when US health care leaders were happy to put their prestigious logo on a drug whose source was unknown to them, presumably just to save some money. By obviously failing to exert rigorous oversight over how the drug which carried their company's name was produced, they not only allowed sloppy, primitive and unsanitary manufacturing practices, but apparently were easily snookered by counterfeiters who substituted a likely toxic ingredient for the real thing.

This was putting profits before patients. And the results were very bad for patients.

Baxter claims to apply

its expertise in medical devices, pharmaceuticals and biotechnology to make a meaningful difference in patients' lives.

However, rather than its expertise, its sloppy and uncaring leadership seemed to leave some of its patients' lives meaningfully worse.

This case is a glaring demonstration of why we need a new set of leaders of our health care organizations, and a new corporate culture within these organizations. Otherwise, failing to understand the health care context, and failing to put patients before profits will yield more sick and dead patients.

Post Title → Fake Heparin, then Sick and Dead Patients

Heparin in an Era of Hogwash

Two weeks ago we first posted about an emerging scandal about the production of the drug heparin, a biologic that has been in use for over 70 years. First, we posted about the sudden increase in the frequency and severity of adverse effects due to heparin that carried the Baxter International label. However, its "active ingredient," that is, the heparin itself, was purchased from 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. Furthermore, it turns out that the factory was never inspected by either the US Food and Drug Administration (FDA) or its Chinese counterpart.

Last week, we posted about how the CEOs of Baxter International and Scientific Protein Laboratories did not seem aware of the origin of the heparin for which they were ostensibly responsible. Furthermore, it turns out its origin was not just Changzhou SPL, but a series of small, unregulated Chinese factories.

Since then, the plot has continued to thicken.

A congressional investigation is starting. Per the Wall Street Journal,

congressmen asked whether Baxter had known the Chinese plant hadn't been inspected and suggested the company might therefore be distributing an unapproved drug.

In a separate letter to HHS Secretary Michael O. Leavitt, the lawmakers asked for records relating to the FDA's preapproval inspection policy. They also sought an explanation of the agency's interpretation of the legal status of drugs shipped into 'United States commerce by a drug company that knew or should have known that FDA had not performed a preapproval inspection, as is alleged in the Heparin case.'

Chinese regulators dodged any responsibility. Again, per the Wall Street Journal,

China's drug-safety agency, responding to questions about oversight of an exported blood-thinning compound, said checks of pharmaceutical ingredients made in China are ultimately the responsibility of countries that buy them.

The State Food and Drug Administration said it works with foreign counterparts to monitor drug-ingredient production. But it said that based on international practice, 'safeguarding the legality, quality and safety of active pharmaceutical ingredients' is up to importing countries.

The supply chain of heparin in China appears to be even more difficult to trace than previously reported. An investigative report published in the NY Times, first quoted the CEO of Scientific Protein Laboratories, Mr David Stunce, "we have a collection chain in place, and we stick with that." However,

But interviews with dozens of heparin producers and traders in several Chinese provinces, as well as a visit to a village near here dominated by tiny family workshops that process crude heparin from pig intestines, show the difficulties confronting investigators as they seek to trace the supply chain. The picture that emerges is of a chain more complex, and less orderly, than the one Mr. Strunce laid out.

The Chinese heparin market has become increasingly unsettled over the last year, as pig disease has swept through the country, depleting stocks, leading some farmers to sell sick pigs into the market and forcing heparin producers to scramble for new sources of raw material. Traders and industry experts say even big companies have been turning more often to the small village workshops, which are unregulated and often unsanitary.

One of the wholesalers named by Scientific Protein Laboratories, Ruihua Biochemical in Hangzhou, said it provided a mix of crude heparin that it manufactured and some that it bought 'from small factories nearby in several villages.' The owner, Hua Ruihua, said he never inspected the small factories. 'We are not the government,' he said in a telephone interview. 'We have no right to inspect their pigs or intestines or facilities.'

The owner of one of those workshops, Fan Yinan, said, I sold to Ruihua several times before, but since last September I have had no intestines.' He confirmed that 'no one from Ruihua inspected my pigs or intestines.'

Strunce's response was this non-denial denial, "we have no information to suggest your information is true."

Some heparin is produced in primitive and unsanitary conditions. The Times reporters also visited some small factories, whose operations do not exactly inspire confidence in the safety and purity of their products.

Some experts say as much as 70 percent of China’s crude heparin — for domestic use and for export — comes from small factories in poor villages. One of the biggest areas for these workshops is here in coastal Jiangsu Province, north of Shanghai, where entire villages have become heparin production centers.

In a village called Xinwangzhuang, nearly every house along a narrow street doubles as a tiny heparin operation, where teams of four to eight women wearing aprons and white boots wash, splice, separate and process pig intestines into sausage casings and crude heparin.

The floors had large puddles and drainage channels; the workshops were dilapidated and unheated; and steam from the production process fogged up the windows and soaked the walls. There were large ovens to cook ingredients and halls lined with barrels to store enzymes, resins, intestines and wastewater.

'This is our family-style workshop,' said Zhu Jinlan, the owner of one heparin operation, who stopped sorting pig intestines and invited visitors to a back room, where she lives with her husband and child. 'We’ve been doing this about 10 years.'

Experts say the small, unregulated factories could pose dangers because they do not have the same controls and rules as large slaughterhouses, which also produce crude heparin.

'If you don’t control the incoming source, it’s very hard to get rid of the contaminants,' says Liu Jian, a heparin expert at the University of North Carolina.

Mr. Strunce of S.P.L. says his company never buys directly from the crude-heparin producers, only through its wholesalers, which he called 'consolidators' — Changzhou Techpool, its Chinese joint venture partner, and Ruihua. His company, he said, has records documenting all the transactions.

But here in Rugao, producers of crude heparin tell a somewhat different story. A sales manager for a major supplier, Nantong Koulong, said he sells directly to S.P.L. without going through either of the two wholesalers. 'We provided crude heparin to Changzhou SPL,' said the sales manager, Chen Jianjun. Some of Koulong’s stock comes from the unregulated workshops, he said.

The owner of one such workshop, Ms. Zhu in Xinwangzhuang, said she sold to S.P.L. two years ago. She also sells to Koulong. 'We are really a traditional family-style plant,' she said. 'We have no certificate.'

S.P.L. said it never bought directly or indirectly from Koulong.

The large companies cared more about getting heparin cheap than about where it came from. Again, according to the NY Times,

After an outbreak of blue ear pig disease swept through 25 of China’s 31 provinces and regions last year, prices soared, and many drug suppliers had to look to the small workshops. The epidemic, said Cui Huifei, a heparin expert at the Shandong University School of Medicine, 'made those biotech companies inevitably purchase from the family-style plants, for cheaper prices'

A sales manager for another large slaughterhouse in Shandong Province, north of Jiangsu, said he was approached late last year by a buyer for S.P.L. offering what he described as rock-bottom prices for crude heparin.

'It was impossible,' said the sales manager, Wang Shengfu, who works for Shandong Jinluo Group, a major producer of crude heparin. 'Only small factory-style farms could accept that low price.'

The deal was never consummated.

Wherever it gets its heparin, there were problems in the Changzhou SPL Plant. US Food and Drug Administration (FDA) inspectors finally got to the Changzhou SPL plant, and here is what they found, according to the Wall Street Journal,

Food and Drug Administration inspectors found problems at a Chinese plant that made most of the active ingredient for Baxter International Inc.'s blood thinner heparin, but the agency still hasn't pinpointed a cause for hundreds of bad reactions in people who took the drug.

Among other findings, the FDA said investigators found lapses in the Changzhou, China, manufacturer's quality-control procedures and the way it assessed its own efforts to remove impurities from raw materials.

The FDA also said yesterday it was seeking to examine upstream consolidators and small workshops that supplied raw material to the Changzhou factory. FDA inspectors found in its inspection report that some heparin sold in the U.S. included 'material from an unacceptable workshop vendor.'

Baxter International has recalled nearly all its extant heparin products, as reported in the WSJ article above.

Finally, the toll of serious adverse events linked to heparin has increased to 448, possibly including as many as 21 deaths. (See the same article.)

Health Care Renewal has documented numerous cases of financial mismanagement by leaders of health care organizations. We have discussed misleading marketing by drug, biotechnology and device companies, and by hospitals, academic medical centers, and health insurance companies. We have noted how medical education has been twisted into marketing, and clinical science has been manipulated, aided by pervasive conflicts of interest affecting physicians, academics, and various not-for-profit organizations.

But through all that, even I thought that the purity of the drug supply remained sacrosanct. Even I thought that no US or major multinational pharmaceutical or biotechnology company would sacrifice the purity and quality of the drugs they sold to cut their costs.

I may have thought that over-the-top marketing and shoddy research had inflated the benefit/ harm ratio of many drugs and devices. Up to now, however, I never doubted the purity of an FDA approved drug sold in the US with the logo of a reputable drug or biotechnology company.

In my previous academic life in which I spent a fair chunk of my time as an academic hospitalist, I often oversaw the use of parenteral heparin. I never would have suspected that the raw material in a vial of Baxter heparin came from some primitive, unsanitary, uninspected "family style" workshop in China.

We have reached a new low in US health care. The system is now mired in muck. We need a new generation of muck-rakers to clean it out. We need a total overhaul of the management of US health care organizations. We need managers who once again put patients before profits, and before lining their own pockets. Until things change, more people will die, and we will all eventually drown in the hogwash.

Post Title → Heparin in an Era of Hogwash

Heparin Made Out of Pigs from Elsewhere

Last week, we discussed what was known about the sudden increase in the frequency and severity of adverse effects due to heparin, an anti-clotting drug that has been in use for more than 7o years. The heparin all carried the Baxter International label, but its "active ingredient," that is, the heparin itself, was purchased from 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. Furthermore, it turns out that the factory was never inspected by either the US Food and Drug Administration (FDA) or its Chinese counterpart.

First, the Wall Street Journal reported how heparin is made in China.

In a small, damp factory here [in Yuanlou, China], blood-smeared men wring pulp from pig intestines, then heat it in concrete vats.

The activity at Yuan Intestine & Casing Factory is the first step in the poorly regulated process of making raw heparin, the main ingredient in a type of blood-thinning medicine that in recent days has come under suspicion in the deaths of four Americans.

More than half the world's heparin comes from China. The chemical is often extracted from pig entrails in small factories -- many as rudimentary as this one, which also manufactures sausage casings from intestines.

Heparin goes through extensive processing in its journey from abattoir to IV bag. Nevertheless, because some of it originates in tiny Chinese factories like these, if there's a problem with the final medication, it can be nearly impossible to trace the raw heparin back to the source, the pigs whose tissue was used to make it.

Heparin makers in China readily acknowledge the lack of oversight. Yuan Changkun, the owner of the small factory here, says health regulators don't visit his plant. Mr. Yuan doesn't keep records of where he acquires the intestines he uses. Nor is he sure who the end customers are.

The raw heparin made by China's myriad small producers ends up in the hands of about 50 export companies, which sell to customers overseas. In the first half of last year, more than 85% of these heparin exports went to the U.S., Austria, France, Italy and Germany, according to an industry trade group.

In fact, although Scientific Protein Laboratory did not get the heparin it sold to Baxter International from Yuan Changkun, it appears that the management of SPL did not know much about the heparin it supplied.

David Strunce, the president of Scientific Protein Laboratories, Baxter's main supplier of heparin, says that the Yuan Intestine & Casing Factory isn't in his company's supply chain. He says Scientific Protein can't trace its supplies in China in as much detail as it can in the U.S. 'We're all dealing with the China collection system,' Mr. Strunce says.

In fact, Changzhou SPL actually was not the source of the heparin that eventually got the Baxter International label. Changzhou SPL, in turn, got the heparin from a number of wholesalers who in turn, got it from a number of smaller, unnamed factories.

Scientific Protein's Mr. Strunce says his company's China venture, Changzhou SPL, gets raw heparin from two wholesalers who gather it from 'six to 12' workshops. 'You can have better, or less good, workshops, Mr. Strunce says.

So to recap so far, Baxter International got the heparin that it sold under its label from SPL, which got the heparin from Changzhou SPL in China, which got the heparin from several wholesalers, which got the heparin from numerous, unnamed small factories. Apparently at none of the steps along the way in China was the heparin subject to any inspection or regulation by the US FDA or its Chinese counterpart.

Then, the Chicago Tribune reported,

Baxter International Inc. does not monitor its supply chain to the extent that it would know that a supplier in China was never inspected before it began shipment of the blood-thinning drug heparin, which is linked to more than 300 illnesses in the U.S., the company's chief executive said Wednesday.

Baxter contracted with a Wisconsin supplier, Scientific Protein Laboratories, and not with that company's Chinese affiliate, Baxter CEO Robert Parkinson said Wednesday in his first interview since the heparin problems surfaced.

"It's not unusual for us not to know that the FDA hasn't inspected a supplier to a supplier," Parkinson said.

Parkinson noted that Baxter's auditors had inspected the facility in the last six months, but he declined to speculate on whether they may have missed something.

'It is both premature and inappropriate to go down that path,' he said.

So, to summarize, a commonly used drug which carried the label of a formerly respected US pharmaceutical company actually came down a torturous supply chain that began in several small factories in China. The factories, and the entirety of the supply chain was never subject to FDA inspection. The respected US company and its CEO did not seem aware of who was actually making the drug it sold under its name, and under what circumstances it was made. The US company that was the proximate source of the active drug to the pharmaceutical company, and its CEO did not seem aware of who was actually making the drug it supplied, and under what circumstances it was made.

Most US corporate CEOs receive extremely generous compensation. For example, Robert L Parkinson, the CEO of Baxter International, was recently reported as getting $3.16 million a year in total compensation. One common explanation for such compensation that to some borders on the outrageous is that the CEOs have to make the tough decisions and take ultimate responsibility for what their companies do. Yet Mr Parker did not seem aware of company practices critical to the health and safety of the patients who were using Baxter International products.

More importantly, patients and physicians used to have some reason to trust the quality of drugs made by US pharmaceutical companies. But now, big US pharmaceutical companies seem willing to outsource the drugs that doctors and patients thought the companies themselves made. Big US pharmaceutical companies do not always seem to know where and how these drugs are made.

In addition, patients and physicians used to have some reason to trust that the FDA was assuring the quality and purity of drugs. My dim recollection of the history is that the FDA was founded to assure the purity and quality of US pharmaceuticals. But now, the FDA no longer seems to be keeping track of an increasing proportion of drugs marketed by US companies, but actually made somewhere else.

So tell me again why US patients and physicians should trust these companies to provide them with pure drugs which are as safe as their labels purport them to be, and why they should accept the high prices these companies charge for their heavily marketed products.

Reckless outsourcing of drug production, failure of US pharmaceutical companies to control and be responsible for how and where the drugs they market were made, and the FDA's failure to monitor drugs sold with US company labels but made somewhere else threaten a crisis of confidence that could have dire consequences for US health care.

ADDENDUM (22 February, 2008) - Also see comments on Effect Measure blog.

Post Title → Heparin Made Out of Pigs from Elsewhere

BLOGSCAN - "Lawyerly Parsing" the Manufacturing Outsourcing Story

On PharmaLot, Ed Silverman follows up on the story that AstraZeneca plans to outsource its pharmaceutical production, mainly to India and China. (See previous post here.) Apparently, the publicity garnered by the first version of the story put the company into a bit of a tizzy. Silverman concluded first, " the AZ effort to disavow Smith’s remarks appears disingenous and resembles the worst kind of lawyerly parsing." His final conclusion would seem familiar to Health Care Renewal readers, "If AZ wants public trust in its products, the drugmaker must also instill trust in its words."

Post Title → BLOGSCAN - "Lawyerly Parsing" the Manufacturing Outsourcing Story

Outsourcing Health Care

A post by guest blogger Robert Wachter....

I wrote a couple of pieces in last month's (2/16) issue of the NEJM on the future of medical outsourcing. I had an epiphany after reading Friedman's "The World is Flat" this summer - namely, medicine has been uniquely insulated from globalization because of the physicality of the enterprise (we need to be in the room to examine the patient, read a paper chart, and, in the old days, look at a "film" (remember films). Now with digitalization, all that will rapidly change, as the computers de-tether us and make all kinds of things possible without physical presence.

The two camel's nose examples are international teleradiology (tonite, about 200 hospitals will have their ER CT scans read by radiologists sitting in another country) and e-ICUs (in which intensivists sit in front of monitors, watch patients on closed circuit televisions, follow streams of physiologic data, and sometimes even enter orders into the hospital's CPOE system). Today, the e-ICUs use domestic providers, but you can bet there will ultimately be international entrants to this market as well.

These are just the start - think robotic and laparoscopic surgery. I tried to depict the possible advantages and disadvantages of this model - it'l be your call how well I did. Like all kinds of globalization, the concerns center around ensuring quality (in addition to the domestic job loss); some of these concerns will be quite legitimate, and some will be protectionism in the garb of QA. In the accompanying podcast, the interviewer asked me several times, "how can we ensure quality when the docs are 5000 miles away?" My answer: "how can I ensure quality when my mom sees her doc in Boca Raton?"

Increasingly, quality assessment will be web enabled and involve real-time assessment of practice. Once this happens (and I don' minimize the challenges here), ensuring the quality of the provider in Bangalore may not be fundamentally more complex than doing the same for the one in Bangor.

One thing for sure: fasten your seat belts.

The Journal has made the articles freely available, even for non-subscribers: http://content.nejm.org/cgi/content/full/354/7/661
http://content.nejm.org/cgi/content/full/354/7/662
And the podcast: http://content.nejm.org/cgi/content/full/354/7/662/DC1

Post Title → Outsourcing Health Care