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.

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.

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)? 

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)? 

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.

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.

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.