Broken Trust: the Adulteration of Ranitidine Revealed

Adulterated Ranitidine, and Before that, Valsartan, Irbesartan and Losartan

Another case of drug adulteration has just been made public.  Per the New York Times, Sept 13, 2019,

The Food and Drug Administration said on Friday that it had detected low levels of a cancer-causing contaminant in samples of heartburn medicines containing the drug commonly known as Zantac.

Zantac, the brand-name version of the drug, is sold by Sanofi, but generic versions [ranitidine] are widely sold. The F.D.A. has not identified any specific products that were affected.

The contaminant is one that has been seen before.

The contaminant, a type of nitrosamine called N-nitrosodimethylamine, or NDMA, is the same one that was found in some versions of valsartan, a blood-pressure drug carrying the brand name Diovan.

In the current case, its source is not yet apparent,

NDMA can form during manufacturing if the chemical reactions used to make the drug are not carefully controlled and monitored, the F.D.A. has said.

Jeremy Kahn, an agency spokesman, said Friday that the agency is still investigating contamination of the heartburn drugs, and that it is unclear how many companies’ products are affected and how the problem originated.

Based on the recent case of adulterated valsartan and other angiotensin receptor blocker (ARB) drugs, tt is likely that manufacturing of the drug, at least the "active pharmaceutical ingredient" in it, was outsourced.

The valsartan recalls have renewed questions about the safety of the American drug supply, particularly of generic drugs, composed of raw ingredients that are frequently manufactured in countries like China and where F.D.A. oversight has lagged.

Note that,

The source of the contaminated valsartan was a Chinese manufacturer, Zhejiang Huahai Pharmaceutical Company. Major Pharmaceuticals, Teva Pharmaceutical Industries and Solco Healthcare, which is owned by Huahai Pharmaceutical, sold it in the United States.

The same type of impurities were later found in two other blood-pressure drugs, irbesartan and losartan, in the same [ARB] class as valsartan. Two more nitrosamines — nitrosodiethylamine, or NDEA, and N-Nitroso-N-methyl-4-aminobutyric acid, or NMBA — were found in the drugs. Lists of the affected products are posted on the F.D.A. website. 

Furthermore, the FDA may not yet be on top of the problem with ranitidine:

The agency’s announcement came on the same day that an online pharmacy, Valisure, petitioned the F.D.A. to request a recall of all products containing ranitidine, because it said its own tests had revealed high levels of NDMA, above the F.D.A.’s acceptable daily limit. The Valisure petition speculated that the source of the NDMA was the result of the 'inherent instability' of the ranitidine molecule, which can degrade under certain conditions, such as when it is digested, to create NDMA.

'Our feeling is that this is extremely troublesome,' said David Light, the chief executive of Valisure, which is based in Connecticut. 'We took it off our formulary right away.'

21st Century Cases of Drug Adulteration


Moreover, we should have been warned that these cases were coming.  The cases of adulterated ranitidine and ARBs are not the first important cases of drug adulteration in the 21st century.  In 2008, we wrote aabout the case of toxic adulterated heparin from pigs in China.  We later summarized of that case was:

Baxter International imported the 'active pharmaceutical ingredient' (API) of heparin, that is, in plainer language, the drug itself, from China. That API was then sold, with some minor processing, as a Baxter International product with a Baxter International label. The drug came from a sketchy supply chain that Baxter did not directly supervise, apparently originating in small 'workshops' operating under primitive and unsanitary conditions without any meaningful inspection or supervision by the company, the Chinese government, or the FDA. The heparin proved to have been adulterated with over-sulfated chondroitin sulfate (OSCS), and many patients who received got seriously ill or died. While there have been investigations of how the adulteration adversely affected patients, to date, there have been no publicly reported investigations of how the OSCS got into the heparin, and who should have been responsible for overseeing the purity and safety of the product. Despite the facts that clearly patients died from receiving this adulterated drug, no individual has yet suffered any negative consequence for what amounted to poisoning of patients with a brand-name but adulterated pharmaceutical product.

In 2010, we noted a report by the U.S. China Economic and Security Review Commission on the perils of outsourced drug manufacturing in China.

In 2012 we documented the continuing problems with outsourcing of drug manufacturing.  We noted that at least 70-80% of the "active pharmaceutical ingredients" (APIs) that made up drugs sold in the US were actually manufactured overseas, the majority in China and India.  The regulation of manufacturing in these countries, particularly China, is extremely lax.  In China, APIs are considered chemicals, and the regulation of chemical manufacture is virtually non-existent.  There is evidence that the manufacturing processes in China, particularly at those companies that make the cheapest drugs, are sloppy or worse.  Furthermore, US pharmaceutical companies may buy drugs through brokers, further obscuring who actually made them.


In 2013, we discussed adulteration of  generic drugs made in India by Ranbaxy, a subsidiary of Daiichi Sankyo, and sold in the US.


Summary: Broken Trust

The latest cases of adulterated drugs sold in the US are disgraceful.  Patients ought to be assured that  the medications they take have not been adulterated.  Patients entrust pharmaceutical corporations to  supply pure drugs in the correct dosage.  The purpose of the first major US law to regulate drugs, the US Food and Drug Act of 1906, was to assure that drugs were pure and their dosage was accurate. The presence of adulterated drugs on pharmacy shelves is a major breach of trust, and shows a major failing of the involved pharmaceutical manufacturers and US drug regulation.

If anything, the NYT article understates the problem,

 'I think this is another good example of how our regulations need to change,' said Dinesh Thakur, a drug-safety advocate who exposed widespread quality problems as a former executive at the Indian drug maker Ranbaxy Laboratories. He said the F.D.A.’s testing is too lax. 'Things like this will never get caught, unless somebody is actually actively looking for stuff.'

Since 2008 we have had warnings that outsourced drugs may be dangerous, and that foreign and US regulation is insufficient. Yet, the warning have largely been anechoic and no major action has ensued.  Will the new cases make waves?    Will there be action this time?  Who knows?

For what it's worth, let me resurrect my thoughts from 2016:

In our rush to market fundamentalism, we seem to have deregulated, at least de facto, most aspects of health care.  We now cannot trust the drugs we take to have been made by the companies whose labels they bear, or to be pure.  We now cannot trust that regulators will find that out, or having found that out, will do anything about it in a timely manner. 

To repeatedly reiterate, as long as the leaders of health care organizations are not held accountable for the results of their decisions on health care quality, cost, and access (even in such extreme quality violations as those resulting in multiple patient deaths), we can expect continuing decisions that sacrifice quality, increase costs, and worsen access, but that are in the self-interest of the people making them.

To really reform health care, we must hold health care organizations and their leaders accountable (and not blame all the problems on doctors, other health care professionals, patients, and society at large).

More Than Just Dander

First, a sort of meta-comment in the form of a shout-out to HCRenewal's intrepid editor, Dr. Roy Poses, for his just-published analysis of what we might call "blogging: rise and fall." He sees decline reflected in publications long  devoted to health and health policy, yet now flaking off.

Methinks, however, despite the usefulness of his overview of recent decades, Dr. P need not fret excessively. Water spilling out of the barrel's lip will slow down once folks come along and punch a whole bunch of little mid-section tweet-holes in it. Information still flows. (Sort of.)  In any case, surely there's overlap between blogs' and tweets' readerships. Surely well-researched and -reasoned long form still has its place. Unfortunately, hard to know for sure: it's hard to measure. Nobody's polling these folks and to my knowledge information scientists haven't published much--a quick search inside Google Scholar bears this out--that's of a quantitative nature.

So we're left with admittedly rather unsatisfactory anecdotal reports on people who need blogs like ours and find their way to it. Congressional staffers you know who you are. Rightly or wrongly, I'm hopeful. Maybe we shade this a little by the suspicion that many younger social media users share with me a short attention span. Hence they come to rely more and more on quick hits. In any case, let's hope this is evolution and diversification, not just entropy and a race to the bottom.

Now to my theme of the day. Yet again the dander hath risen for I've lost count how many times around what ails our health delivery systems. And so is my lunch: the gorge, too, hath risen. The miscreants' very relentlessness is nauseating. More, then, on two of them that keep cropping up here like those small burrowing insectivores in this tedious yet oddly riveting game of Whack-A-Mole.

A. Chicanery at the VA: looking back and looking forward.

On balance, and despite its many flaws, VA health's operation in all its enormity is not itself a miscreant. Different story for those folks trying to destroy it from within, on the dubious premise that lest we privatize it it's irredeemable. Search this blog on "VA Cetona" for detail on such matters.

Why does this even happen? We've described the VA's Shadow Rulers (search here on that as well) in these pages. The SR's fall in the 0.1%. Why do they need or want the headache of trying, in what's fated to be a futile effort, to upend and hollow out the health lifeline extended for nearly a century to patriots returning from the military?

When the left gets power it tries to expand and improve government. (Of course the efforts can unfortunately go awry, viz. Hillarycare in the 1990s, and cast shade on future attempts.) When the right gets power, at least in the two generations since an actor became president in 1980, government is seen as "not the solution but the problem." The response may be to try to rejigger and downsize. "Drown the baby in the bath." Or, perhaps far more likely, something else now happening in the VA and throughout the Trump kakistocracy.

Namely, don't seize power to return it to the people. Seize it in order to use it in a third-dimensional play to drain resources. As for the first two dimensions, don't even try to improve--David Shulkin's mistake (see below)--or eliminate (despite Mick Mulvaney's baby drowning proclivities, hugely unpopular) care provided by the VA. Not when there's a third way: divert those resources. In fact, from the earliest instances of frontier exploitation to the newest frontier we have--our heretofore private personal information--despoliation has been the watchword, the core motive, the secret sauce: don't ameliorate. Don't eliminate. (Honestly: viz., Shrub's expansion of guvmint.) Despoliate.

It is, as Shrub used to say (maybe), one of our country's most basic pieces of strategery.

Such a strategy was discussed (and surely it's as old as the hills) by Times tech reporter Steve Lohr in a recent piece on, of all things, artificial intelligence. ("Elixir of prosperity [or] job killer"?) Lohr makes clear that what's old is new again, linking the asset of private data to all the other assets that've been strip-mined. "In the American model," notes Lohr, "coming from Silicon Valley in California, a handful of Internet companies become big winners and society is treated as a data-generating resource to be strip mined."

As Buffy the Vampire Slayer once said, "can you spell 'duh'?"

Strip mining started with the earliest settlers, and now ... data, the final frontier. Same deal, though. The American model, and economic maldistribution, and so much of our plight is bound up with this baked-in trait, which seems to've seeped into society's DNA. Or else originated there. Find a mine. Strip it. Let others pick up the pieces.

But let's go back to that last credible VA Secretary. How do we know that Shulkin pissed off the strip-miners? Why, just read what he himself wrote in a scholarly publication just a few months ago in the prestigious New England Journal. In a piece entitled "why the VA needs more competition," he and closely-associated Michigan colleague Kyle Sheetz first declared, unequivocally and repetitiously, competition: good!!! Emphasis in the original through repetition. Clever. After reassuring their audience how much they liked competition they let the cat out of the bag in the final paragraph of a long-ish article: "Privatizing the VA by offering unregulated access to private-sector providers is probably not feasible, necessary, or the best way to care for veterans."

That's exactly what the quietly-undermining, unelected Trumpsters pushing for strip-mining veterans' health care didn't want to hear. We know (see below) how that came out.

Similar in emphasis is a piece just out (January 2019) in the equally prestigious Annals of Internal Medicine, by (no pun intended) veteran federal health official Carolyn Clancy and her own VA/AHRQ colleagues. I'm perplexed at the way Clancy herself has hung in there (and yet she persisted) at the federal agencies to which she's contributed greatly over recent decades. I'm perplexed about how, within these agencies,she's been bounced around, most recently landing as the VA's "Deputy Under Secretary for Discovery, Education and Affiliate Networks." (That top's spinning so fast what I just wrote may already be superannuated news.)

In any case Clancy et al. put their shoulders to Shulkin's wheel extolling the May 2018 federal MISSION legislation streamlining VA and non-VA care, and the ostensible role their new Center for Innovation might play in such an effort. They pointed out all the right innovation-cum-research caveats about the need for adequate data: "paying for value could backfire without accurate measurement of costs and outcomes." In this case they were certainly correct: privatizers in this particular world aren't interested in evidence-based anything. They're profiteers. (See: "Department of Education." See: "Department of the Interior." See: Environmental Protection Agency.)

Shulkin's words saw the light of day about a month after the MISSION legislation, in the final days of June, 2018. But here's why I put Shulkin having "liked competition" in the past tense. By the time his NEJM piece appeared Shulkin, also accused of what I still deem to've been truly flimsy ethics violations, was already gone from his organization. By the end of March the Orange Man had already fired him. As a personal fiasco this was unseemly, since the VA secretary was a rare bird who both consented to be a hold-over from early administrations, yet managed early on to be a current POTUS favorite. Surprising? In this White House?

In none of these events was there ever put forward any really compelling justification either for privatizing VA care or for starting with the assumptions that outside "leaders" and outside doctors could do a better job than--what with all their flaws--VA medical staff. Suzanne Gordon, a distinguished journalist and author, admittedly parti pris as a fellow of the Oakland-based 501(c)3 Veterans Healthcare Policy Institute, has just published an American Prospect piece on "Trump’s under-the-radar push to dismantle veterans' health care." Her central thesis is worth quoting in extenso.

[The Republican] strategy will not only erase what has been the most successful American experiment in government-delivered health care, but will also send veterans out into a private system that is more expensive, less accountable, and unable to meet their particular needs. The key notion underpinning the Mission Act, that the private sector can offer comparable care to the VHA, is deeply flawed. Study after study (after study) has found that the VHA generally outperforms the private sector on key quality metrics, and that private providers are woefully unprepared to treat the often unique and difficult veteran patient population. The most recent evidence came in a Dartmouth College study published in December, which compared performance between VHA and private hospitals in 121 regions across the country. The results: In 14 out of 15 measures, government care fared “significantly better” than private hospitals.

Gordon also has a new book out on this subject, as most supporters of the traditional VA system already know. Worth a look. Meanwhile the Senate and White House and those advising them clearly never really cared about quaint ideas such as "studies," "evidence," or "data." They cherry-pick a few quotes about the brusqueness of some VA care, which often is admittedly more bureaucratic than today's "consumer-facing" and endlessly-polling private-care organizations. You can find those quotes as well as I can--any search engine known to man will do the trick.

Recent events on the larger political canvas make it abundantly clear, in the meantime. It's not about quality. It never was. It's about callously starting with a dismissive attitude toward government workers, then back-solving from there. Having worked for years at the VA, I can vouch for its quality as well as its struggle to assist the really needy patients who depend upon it. In fact, this new study shows quite rigorously that the VA was already dramatically reducing wait-times within multiple VA installations, right down to private-sector levels. So this branch of government has listened and successfully striven to achieve a performance level that's not just high-science but also high-touch, as medicine's "customers" (yechhh) have come to expect.

The present furlough of federal employees proves the point. If you can dismiss someone as human collateral-damage, you don't start first by examining the good things they've done for you. You're an elephant poacher. Take the spoils and leave the carcass to rot.


B. More on the Opiate Eaters Who Eat Very Well.

Speaking of despoliators, Dr. Poses and I both wrote here recently on how, in the world of dangerous narcotics, this single family of mostly physicians, the Sacklers, garnered a much more grand market share than they like to let on. Time to add to that and earlier reporting with a few updates.

When, in a different venue than the VA I was providing front line medical care to privately-insured patients, I noticed an arresting change. I saw more and more folks arrive in my office in shop-till-you-drop mode seeing opiate renewals. Always OxyContin, Percocet or Vicodin. If I didn't provide the "fill" they'd go next door. The demand built and built. The drug makers kept assuring they were safe and effective. At free dinners they paid an army of fellow physicians to regale us with the same message.

Then those patients started to die on me. OD courtesy of "safe" Purdue (and others') product.

Then in the past very few years, and I honestly should've seen it coming but didn't, the crisis spilled over from doctors' exam rooms into the political arena. It's actually something, unlike the VA, that's garnering a certain timid degree of nonpartisan interest in finding practical solutions, call it consensus even, starting with decriminalizing measures. But I find it gorge-raising to see the usual suspects continuously fighting the notion that as a society, we blew it with opiates. We blew it. With their help.

I've spent a fair amount of time looking at similar medico-legal crises, including the far-reaching tobacco and environmental lead poisoning matters, as well as narrower ones such as evolving surgical and pharmacological approaches to certain diseases. In every case our tort system, combined with the deep pockets of those who are (allegedly) truly guilty, conspire to perpetuate Bleak House-style court battles over culpability. Strip miners seem to believe--or want us to swallow whole the absurdist notion--that they leave the world a better place. In the case of Purdue, this false consciousness is undoubtedly propped up by the Sacklers' prowess as culturati: one can hardly turn around, as I recently did at the Met in New York, without finding their name plastered on this gallery or that institution of higher learning. But the motive, be it within the strip miners' organization or that of a cultural organization, comes down to the same thing: "we need the money." Allegedly.

Recent disclosures from "sources," including internal Purdue emails, clarify all this. Fortunately for us it turns out the founder's (Raymond's) son Richard was an early adopter--relatively so--of email. Both were physicians, but Richard was of the first generation to be granted an American MD. Email was barely used at all in 1995 when Microsoft first added a TCP/IP stack to its operating system, with the introduction of Windows 95. Then email really took off, by 2001 having a fair amount of penetration in the business world. So maybe we shouldn't be so surprised that Purdue Pharma was squirreling away some of Richard's pronouncements in an archival time capsule for our delectation nearly a generation later.

According to a new court filing recently revealed in the NY Times, Richard Sackler said some, um, fairly incriminating things to say in these internal emails. Still earning his spurs as head of daddy's (and Uncle Mortimer's) company after a couple of years or so in the saddle, and undoubtedly aware of the dramatic uptick in addiction issues that I saw in my own clinic in those turn-of-the-century years, he allegedly blasted everyone else in sight--except, of course, his own ever-so-cultured family.

"[T]he launch of OxyContin tablets will be followed by a blizzard of prescriptions that will bury the competition. The prescription blizzard will be so deep, dense, and white...." said Sackler fils. Based on no evidence reps were told to claim a “less than one percent" risk of addiction. As for that small subset of patients who did find themselves hopelessly addicted, the claim was to be made that “We have to hammer on abusers in every way possible.... They are the culprits and the problem. They are reckless criminals.”

Now, hot off the press in 2019, the Guardian reports how this overall attitude has been replicated within the lobbyist-influenced government of Messrs. Trump and Azar. Since 2015 (pre-Trump! pre-Azar!) chair of the FDA's own Anesthetic and Analgesic Drug Products Advisory Committee, Kentucky anesthesiology professor Raeford Brown has bravely characterized the rift that now mires down the FDA in tackling this crisis seriously. Admittedly with cover from many in Congress, Brown said this to interviewers.

I think that the FDA has learned nothing. The modus operandi of the agency is that they talk a good game and then nothing happens. Working directly with the agency for the last five years, as I sit and listen to them in meetings, all I can think about is the clock ticking and how many people are dying every moment that they’re not doing anything. The lack of insight that continues to be exhibited by the agency is in many ways a willful blindness that borders on the criminal.

Scott Gottlieb, who's tying your hands? Is it this guy? The FDA seems to be replete with such interlocking-directorate staff, all trying to assure  the "level playing field." And what is that playing field? Who are the players? We can answer this. Talk to the drug reps (I have). Except of course those who wake up and see what they're really doing, burn out and bail out. Talk to the lobbyists and the investors (I have). The watchword is not "safe and effective." It's blame-the-victim and lucrative. Let's get our motives straight here. You can do that just fine without listening to us at Health Care Renewal. Just listen to Richard Sackler in a time capsule from 2001.

Ever wonder why the strip-miners need so much of our patients' loot? Well, take a little trip to Davos, Switzerland, where the rich and rich go to rub shoulders and tell each other how smart they are: YouTube offers a hint here.

B'bye--too much dander, got to go take a bath.

The More Things Stay the Same - More Apparently Adulterated Heparin, This Time from Chinese Ruminants

The story of the contaminated heparin just will not go away.  We first wrote about it in 2008 (see first post here, most related posts here, and the longer summary at the end of this post.)

Quick Summary

Baxter International imported the "active pharmaceutical ingredient" (API) of heparin, that is, in plainer language, the drug itself, from China. That API was then sold, with some minor processing, as a Baxter International product with a Baxter International label. The drug came from a sketchy supply chain that Baxter did not directly supervise, apparently originating in small "workshops" operating under primitive and unsanitary conditions without any meaningful inspection or supervision by the company, the Chinese government, or the FDA. The heparin proved to have been adulterated with over-sulfated chondroitin sulfate (OSCS), and many patients who received got seriously ill or died. While there have been investigations of how the adulteration adversely affected patients, to date, there have been no publicly reported investigations of how the OSCS got into the heparin, and who should have been responsible for overseeing the purity and safety of the product. Despite the facts that clearly patients died from receiving this adulterated drug, no individual has yet suffered any negative consequence for what amounted to poisoning of patients with a brand-name but adulterated pharmaceutical product.

Here We Go Again

At the end of March, 2016, per Bloomberg,

Heparin tainted with unauthorized Chinese-made ingredients may be on the market in the U.S. and the Food and Drug Administration hasn’t moved swiftly enough to prevent it, according to a congressional probe nearly a decade after hundreds of deaths were linked to sullied batches of the blood-thinning drug.

This possible contamination is different from the earlier one, when Chinese producers made crude heparin containing a deadly chemical. They may be using cow and sheep intestines to produce the raw material for heparin that is supposed to be derived only from the intestinal membranes of pigs, according to a letter the House Energy and Commerce Committee sent Tuesday to the FDA. The agency has known about the risky practice since 2007, around the time it discovered the chemically enhanced crude heparin, the panel said.

The FDA didn’t react early on 'to credible evidence of non-porcine contamination of the Chinese heparin supply,' according to the letter, only putting out testing guidelines for pharmaceutical companies in 2012. Even after the tragedy of the chemically soiled heparin, the committee said, 'loopholes and exemptions that permit part of the Chinese drug supply chain to operate outside government scrutiny still remain.'

The committee charged that nothing much as changed since the 2008 episode of deadly heparin made from Chinese pigs

The letter from the House committee said the FDA dropped the ball on many fronts and may have allowed unsafe blood thinners to remain on the market longer than necessary. Regulators didn’t properly or widely enough share information and didn’t follow up on leads about tainted heparin from other governments, according to the letter. Agency investigators failed to inform others about dodgy crude heparin makers, the panel said. It also said the FDA didn’t follow up on concerns that heparin with the chemical was recycled after the poison was removed and may have entered the U.S. market. The claims are based on documents that Baxter, Scientific Protein and FDA provided the committee as well as interviews with FDA employees, according to footnotes in the letter.

Also, efforts to investigate the 2008 problem seem to have failed,

The chemical, oversulfated chondroitin sulfate, was connected to 246 deaths and sickened hundreds of people who took the blood-thinning medicine, the FDA said at the time. Regulators never found at what point in the chain in China that the drug, sold in the U.S. by Baxter International Inc., was corrupted. The FDA closed its initial criminal investigation after it became difficult to obtain evidence in China, though it has since re-opened a related inquiry, according to the House committee. Baxter, which recalled its heparin in 2008, hasn’t sold the anticoagulant since. It said at the time it was alarmed that the contamination appeared to have been deliberate, but had no proof of how it happened.

Now the problem appears to be more bovine. It appears that French regulators first noted the problem of imported heparin derived from Chinese cows.

The French National Agency for Medicines and Health Products Safety called non-pig blending a 'critical' violation in an inspection report released in February. France cited China’s Dongying Tiandong Pharmaceutical Co. for making heparin with ruminant DNA, which includes cows and sheep. Dongying is registered with the FDA as a manufacturer of active ingredients and isn’t on the agency’s list of companies banned from importing to the U.S.

Yet, the FDA

considers heparin adulterated if it contains oversulfated chondroitin sulfate or non-pig material, according to an FDA document for the pharmaceutical industry on monitoring heparin quality. Material from cows could pose a risk because of possible contamination with mad cow disease.

Oddly enough, the Bloomberg article did not mention any criticism by the committee of the US based manufacturers who outsourced their heparin production to China.

Outsourcing Continues Unabated


In 2012 we noted that outsourcing by big multinational drug companies based in the US and other developed countries of active pharmaceutical ingredient (API) production to dubious manufacturers based in countries with much less robust regulation was continuing.  I wrote then

To put it more directly, most so called pharmaceutical companies in the US and other developed countries have outsourced the actual manufacturing of drugs. Thus, most companies that appear to be pharmaceutical manufacturing companies are really just pharmaceutical marketing and development companies. (And not so much the latter, look here:  Light DW, Lexchin JR. Pharmaceutical R&D; what do we get for all that money? Brit Med J 2012; 345: 22-25.  Link here.) Pharmaceutical companies appear to be abandoning their core essence, but are content to market drugs  under their logos without telling the patients who take them the real source of these products.  This would appear to be a big scandal, but one that stays curiously anechoic.

In 2016, outsourcing of drugs by big multinational corporations with prestigious names seems to be continuing at a rapid pace.  Per Bloomberg,

The U.S. depends heavily on China for medicine. Along with India, the country is one of the top two producers of base ingredients for drugs in the world, according to the National Academies of Sciences, Engineering, and Medicine.

There is still no clear way for US patients or doctors to identify outsourced medicines, and efforts to better regulate them seem feeble. Thus the danger that patients may be getting ineffective, adulterated, even deadly outsourced medicine in bottles with the logos of big, famous pharmaceutical companies seems to be ongoing.

The More Things Stay the Same

In 2012, we wrote

I have yet to see any discussion with pharmaceutical executives about why their companies hardly make drugs anymore. In the absence of such discussion, I can only speculate that most likely, this is first a product of financialization. Drug company executives, like most organizational leaders, have fallen under the spell that says their only goal should be to increase short-term revenues. It may be cheaper to buy drugs from perhaps dodgy outsourced suppliers rather than manufacturing them them themselves. Continuing stories like those above, and that of the contaminated Chinese heparin suggest that these outsourced drugs are cheap for a reason. It appears that to save money short-term, pharmaceutical executives may be abandoning their most central mission, to provide pure, unadulterated drugs.

The continuing story of outsourced pharmaceutical manufacturing provides yet more evidence that current management dogma may be literally toxic. Once again, I suggest that true health care reform requires leadership of health care organization who put patients' and the public's health ahead of short-term revenue (and the personal enrichment that may result).

It is likely that a number of policy changes will be needed to reduce the threats posed by contaminated or adulterated outsourced pharmaceuticals.  There is one simple step that ought to be taken quickly to at least make the problem more transparent.  In the US, most manufactured products have a label disclosing the country of origin.  In parallel with that, all pharmaceutical containers, and all pharmaceutical labels and marketing materials ought to disclose the country in which the active pharmaceutical ingredient was manufactured, and the name and location of the company responsible for that manufacture.

There seems to be no need to rewrite or update this.

The fact that this problem has been known for 2008 year, but not clearly addressed, shows the pitiful state of American health care dysfunction.  But those with vested interests in preserving the current system remain fat and happy, like the pigs of China.

 Appendix - Heparin Case Summary

- We have posted several times, 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 in 2007, hundreds of such reactions, and 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. (See posts here and here.)

- 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.)  Note that SPL was recently bought out and taken private, making its current leadership even less transparent (see post here).  A 2010 inspection of an SPL facility by the FDA revealed ongoing manufacturing problems (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.)  Efforts to make documents to be used in these cases public so far have not succeeded (see post here).

- A 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.)

-  Despite requests from the US, the Chinese government did not investigate the production of the heparin that lead to the deaths (see post here.)

-  In February, 2011, a congressional investigation of the case was announced, but results were unavailable until now (see above)

-  In June, 2011, a jury returned the first verdict in a civil case about the contaminated heparin, awarding money from Baxter International and Scientific Protein Laboratories to the estate of a man who apparently died due to tainted heparin (see post here).

Six Years Later, Ranbaxy - Oops, Daiichi Sankyo - Pleads Guilty to Adulteration, Pays $500 Million

It only took until 2013, but the US Food and Drug Administration finally secured guilty pleas and fines.  The basics are in an Associated Press story (via the Washington Post):

 A subsidiary of India’s largest pharmaceutical company has agreed to pay a record $500 million in fines and penalties for selling adulterated drugs and lying to federal regulators in a case that is part of an ongoing crackdown on the quality of generic drugs flowing into the U.S.

Federal prosecutors say the guilty plea by Ranbaxy USA Inc. represents the largest financial penalty against a generic drug company for violations of the Federal Food, Drug and Cosmetic Act, which prohibits the sale of impure drugs.

Note that the company pleaded guilty to criminal charges.

 The subsidiary of Ranbaxy Laboratories Limited pleaded guilty to federal criminal charges and the company separately agreed to resolve civil claims with all 50 states and the District of Columbia. The company had earlier set aside $500 million to cover potential criminal and civil liability stemming from the Justice Department investigation.

It admitted as part of the deal that it sold adulterated batches of drugs — including an antibiotic and generic versions of medications used to treat severe acne, epilepsy and nerve pain — that were developed at two manufacturing sites in India. 

Ironies

Note that this resolution has certain ironies.

Lateness

There is a saying that justice delayed is justice denied.  Note that it took six years to obtain the guilty pleas.  As noted by the AP,

 The problems were largely revealed by a whistleblower in a federal lawsuit filed in Maryland in 2007. 

Ambiguities about Responsibility

First, note that while all the headlines are about Ranbaxy, Ranbaxy is not really an independent company.  As reported by Reuters (and only by Reuters so far as I can tell at this time),

Ranbaxy ... [is] majority-owned by Japan's Daiichi Sankyo.

Second, as per the AP, see the comment made by the Ranbaxy CEO,

'While we are disappointed by the conduct of the past that led to this investigation, we strongly believe that settling this matter now is in the best interest of all of Ranbaxy’s stakeholders; the conclusion of the DOJ investigation does not materially impact our current financial situation or performance,' Ranbaxy CEO and managing director Arun Sawhney said in a statement.

Maybe there was something lost in translation, but the CEO certainly spoke as if someone else was responsible for the "conduct of the past."  Incidentally, it does not appear that so far any journalist has even sought comment from the people really in charge, at Daiichi Sankyo.

Third, just like many other cases we have reported before, no individual, especially anyone who authorized, directed, or implemented the bad behavior, was held legally responsible.  The cost of the fines will no doubt be spread among the corporate structures involved.  Since a company pleaded guilty, no individual pays a fine, much less goes to jail.

It does appear that when the settlement was first announced in 2011, a cut in compensation for top executives of Daiichi Sankyo was announced, but the cuts were temporary, and apparently in response to the immediate financial consequences of the settlement, not any larger implications.  See Bloomberg's report:

 Chief Executive Officer Joji Nakayama and board members will receive 5 percent to 30 percent less compensation for six months in response to the cut in the earnings forecast, Daiichi Sankyo said today. The company has lost about half its market value since agreeing to buy a majority stake in Ranbaxy, India's largest drugmaker, in June 2008. 

 The Contrast with the Case of the Adulterated Heparin

Note that in this case, there have been no allegations that patients were harmed by the admitted adulteration,  Per the AP:

 It’s not known whether the problems with the drugs led to any health issues.... The government’s allegations against the company make no claims that the drugs, whose strength, purity or quality differed from the specifications, harmed anyone.

In 2008, we began blogging about how  US patients started to get sick and die after being infused with heparin, the common anti-coagulant drug. As we have discussed repeatedly  (look here, and see the summary at the end of the post), Baxter International was selling contaminated heparin under its label which was made in unregulated workshops in China, and then transmitted through a complex chain of Chinese and US companies.

The AP article stated,

 The case comes as federal regulators and prosecutors focus attention on the quality of ingredients of generics and other drugs manufactured overseas, said Allan Coukell, an expert on drug safety at The Pew Charitable Trusts. He said the 2008 deaths linked to tainted batches of the blood-thinner heparin that were imported from China served as a 'wake up call' about just how much of the nation’s drug supply comes from overseas.

So perhaps this wake up call helped propel the current case against Ranbaxy, that is, Daiichi Sankyo.  However, since 2008, if there has been a criminal investigation of the tainted heparin, which appears to have been much more consequential, sometimes fatally so, to patients, the results have not been made public.  A cynic might note that the contaminated heparin was sold by a US based manufacturer of branded pharmaceuticals, not a foreign based manufacturer of generic drugs.

Summary

The most fundamental obligation of a drug company is to produce pure, unadulterated drugs.  The first attempts to regulate the drug industry in the US were meant to ensure that these companies fulfilled this obligation.  Yet now there is increasing evidence that the contemporary pharmaceutical industry has trouble with this most basic responsibility. 

As we discussed here, the managers of pharmaceutical companies have been swept up in a dominant business management fad, outsourcing, as a means to cut costs to the bone.  (It seems that most health care managers are also caught up in the larger rage for financialization, to emphasize short term revenue over all other concerns, including patients' and the public's health.)  As the New York Times reported  re the Ranbaxy case,

Others say the company’s problems highlight how little oversight federal drug safety officials have of overseas plants. Studies that have shown the F.D.A. inspects foreign generic manufacturing plants about once every seven to 13 years, compared with once every two years for domestic manufacturers. A law passed last year will eventually require the F.D.A. to apply the same standards when inspecting all manufacturing plants, regardless of location. But some worry that federal budget cuts are slowing the adoption of that law. 

'They just happened to stumble across the Ranbaxy problem at those two plants in India,' said Joe Graedon, a pharmacologist who runs a consumer Web site, the People’s Pharmacy, which has raised questions about the safety of generic drugs. 'Ranbaxy was the biggest and one of the best in India. What about all the smaller ones? What does that say about them?'

Again, all pharmaceutical companies, not just generic drug manufacturers, have seen fit to outsource much, if not most of their production.

In our rush to market fundamentalism, we seem to have deregulated, at least de facto, most aspects of health care.  We now cannot trust the drugs we take to have been made by the companies whose labels they bear, or to be pure.  We now cannot trust that regulators will find that out, or having found that out, will do anything about it in a timely manner. 

To repeatedly reiterate, as long as the leaders of health care organizations are not held accountable for the results of their decisions on health care quality, cost, and access (even in such extreme quality violations as those resulting in multiple patient deaths), we can expect continuing decisions that sacrifice quality, increase costs, and worsen access, but that are in the self-interest of the people making them.

To really reform health care, we must hold health care organizations and their leaders accountable (and not blame all the problems on doctors, other health care professionals, patients, and society at large).

- Roy M. Poses MD for Health Care Renewal 


Appendix - Heparin Case Summary

- We have posted several times, 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 in 2007, hundreds of such reactions, and 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. (See posts here and here.)

- 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.)  Note that SPL was recently bought out and taken private, making its current leadership even less transparent (see post here).  A 2010 inspection of an SPL facility by the FDA revealed ongoing manufacturing problems (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.)  Efforts to make documents to be used in these cases public so far have not succeeded (see post here).

- A 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.)

-  Despite requests from the US, the Chinese government did not investigate the production of the heparin that lead to the deaths (see post here.)

-  In February, 2011, a congressional investigation of the case was announced, but results are so far unavailable (see post here.)

-  In June, 2011, a jury returned the first verdict in a civil case about the contaminated heparin, awarding money from Baxter International and Scientific Protein Laboratories to the estate of a man who apparently died due to tainted heparin (see post here).

-  If there was a criminal investigation of the case, its results have not yet appeared. 

Who Really Makes Brand-Name Pharmaceuticals?

A striking illustration of the hazards to patients' and the public's health from health care organizational leaders using fashionable management techniques to maximize short-term revenue appeared in Reuters. 

Background: The Contaminated Heparin from China

The particular issue got public notice after US patients started to get sick and die after being infused with heparin, the common anti-coagulant drug. As we have discussed repeatedly starting in 2008 (look here, and see the summary at the end of the post), Baxter International was selling contaminated heparin under its label which was made in unregulated workshops in China, and then transmitted through a complex chain of Chinese and US companies.  What helped to further obscure the problem was what Baxter was buying was called the active pharmaceutical ingredient (API), which actualy means it was buying the active drug from poorly documented foreign sources.  In other words, it had entirely outsourced the manufacturing of a drug it sold as if it had been made by Baxter in the US.

Continued Outsourcing to Questionable Drug Manufacturers

Reuters reported on a new investigation of outsourcing of drug manufacturing to China.  The main point was:

Four years ago, Beijing promised to clean up its act following the deaths of at least 149 Americans who received contaminated Chinese supplies of the blood-thinner heparin. But an examination by Reuters has found that unregulated Chinese chemical companies making active pharmaceutical ingredients (API) are still selling their products on the open market with few or no checks.

Interviews with more than a dozen API producers and brokers indicate drug ingredients are entering the global supply chain after being made with no oversight from China's State Food and Drug Administration (SFDA), and with no Good Manufacturing Practice (GMP) certification, an internationally recognized standard of quality assurance.

'There is falsification of APIs going on, we know it,' said Lembit Rago, coordinator for Quality Assurance and Safety in Medicines with the World Health Organisation (WHO).

In fact, the article made the point that the majority of drugs sold worldwide are the product of outsourced, often unregulated, and potentially contaminated and adulterated manufacturing:

'Illegal ingredients in bulk are a big problem, but nobody talks about it,' said Guy Villax, chief executive of Hovione, an API supplier based in Portugal with factories there and in China, the United States and Ireland.

About 70 to 80 percent of all active drug ingredients - the biologically active component in medicines - originate in China and India, estimate industry experts, with China accounting for the lion's share. Its export market in these products is worth $22 billion in annual sales, according to the China Chamber of Commerce for Import and Export of Medicines and Health Products.

'If China for some reason decided to stop exporting APIs, within three months all our pharmacies would be empty,' said Villax.

How Dodgy Manufacturers Continue to Operate

Apparently, a particular problem in China is that APIs, that is, the particular drugs in question, can be made by chemical as opposed to officially designated "pharmaceutical" companies, and these chemical companies are not regulated,

A key regulatory weakness in China is the distinction between pharmaceutical and chemical companies. While the former are regulated by the SFDA, the latter, making everything from sweeteners to solvents, are not. Yet many chemical companies also churn out drug ingredients, exploiting a loophole by describing the products as chemicals, which they are, rather than the more specific designation of APIs.

For example, the article recounted how an unregulated chemical company was apparently a source for a well-known branded pharmaceutical sold by two big pharmaceutical companies headquartered in developed countries,

[A]company, Jinan Hongfangde Pharmatech (JHP), of Jinan city in Shandong province, had a product list showing at least five patented products for sale. They included tiotropium bromide, a blockbuster lung drug co-promoted by Boehringer-Ingelheim and Pfizer Inc and sold under the name Spiriva,...

Both Boehringer-Ingelheim and Pfizer spokespeople claimed that they only bought drugs from known sources, but then it would be pointless for Jinan Hongfangde Pharmatech to manufacture tiotropium bromide.

The Use of Brokers

More questions were raised by the pharmaceutical company's apparently common practice of buying drugs through brokers,

The rise of the Internet has facilitated exports of drug ingredients. An online search brings up websites offering hundreds of Chinese API sellers. Those not GMP-certified or SFDA-registered are not necessarily substandard, but buyers lack independent quality assurance.

The pervasive presence of brokers in the supply line is another risk. Pharmaceutical companies looking to source APIs in China typically hire middlemen to help them navigate the language, red tape and protocol. That system helps Chinese companies making substandard APIs avoid detection.

The reason corporate executives choose to buy drugs in China rather than having their companies manufacture them themselves seems to be to reduce costs. A post on the In-Pharma blog quoted Lembit Rago, the same WHO official quoted by Reuters, thus,

There are Chinese manufacturers supplying APIs of high quality to multinational companies, but there are also companies producing APIs of poor or not defined quality.

So,

As long as there are customers for substandard APIs they will be produced and sold.

The cheapest Chinese drugs, of course, come from the most questionable manufacturers, and that may not be apparent to companies who use brokers to facilitate purchases.

'Any number of foreign pharmaceutical companies go no further than looking for API suppliers at CPhI (an international pharmaceutical fair) based only on price,' [manaing director of Samsara Biopharma Consulting Robert] Walsh said.

Reuters spoke to brokers who said an API made by an unregulated chemical company would cost less than one from a company that had a GMP certificate.

'Different (API) grades have different prices. Sometimes we accept an order sheet and we happen to find a factory that can do it cheaper than our factory, we will outsource to them and make a bigger margin,' said one broker based in China who sources for a South African outsourcing firm.

In China there are few legal repercussions for broker firms who relabel or misrepresent products, and tracing counterfeit and substandard APIs is extremely difficult.

'There are a lot of brokers who are relabeling (APIs) which means you can't trace where the API comes from and that adds to the risk,' said the WHO's quality assurance expert Rago.

Andre, the Belgian drug detective, estimates he has uncovered fraud or misrepresentations in as many as 25 percent of cases where he has been hired to audit factories all over China. 'If you can substitute an API that is expensive to make and manufactured at a high level with something that costs much less, then that can happen,' Andre said. 'It's impossible to give an exact number, but it's not rare. It's a minority, but not tiny minority.'

Use of Substandard Raw Materials

Meanwhile, a post on PharmaLot suggested that the supposedly regulated Chinese "pharmaceutical" companies may implement questionable manufacturing practices,

A subsidiary of the Joincare Pharmaceutical Group reportedly used reprocessed cooking oil – otherwise known as ‘gutter’ oil – to make a widely used antibiotic in China. If the term gutter oil is unfamiliar, this refers to reprocessed oil made from kitchen waste dredged from gutters behind restaurants. The State Food and Drug Administration is now investigating the charge after media reports over the past several days, China Daily reports.

Why might gutter oil be purchased to produce antibiotics? The oil is cheaper than the more expensive soybean oil used to make 7-aminocephalosporinic acid, or 7-ACA, a chemical for produce cephalosporins. Joincare produces 25 percent of the total amount of the chemical, although up to a dozen other drugmakers may have purchased gutter oil from various suppliers, according to various Chinese media reports. For its part, Joincare reportedly denied using gutter oil.

The companies reportedly bought the recycled cooking oil from a company called Huikang Grease Co., which is facing prosecution over its alleged processing and selling of thousands of tons of gutter oil in 2010 and 2011. The Shanghai Daily reported that Huikang received around $22.5 million for roughly 14,700 tons of gutter oil sold to Jiaozuo Joincare Biological Product, a unit of Joincare.

Summary

There is increasing evidence that a substantial proportion, probably the majority of drugs sold by big pharmaceutical companies based in developed countries were actually made by often poorly regulated firms based elsewhere, often China or India. To put it more directly, most so called pharmaceutical companies in the US and other developed countries have outsourced the actual manufacturing of drugs. Thus, most companies that appear to be pharmaceutical manufacturing companies are really just pharmaceutical marketing and development companies. (And not so much the latter, look here:  Light DW, Lexchin JR. Pharmaceutical R&D; what do we get for all that money? Brit Med J 2012; 345: 22-25.  Link here.) Pharmaceutical companies appear to be abandoning their core essence, but are content to market drugs  under their logos without telling the patients who take them the real source of these products.  This would appear to be a big scandal, but one that stays curiously anechoic.

I have yet to see any discussion with pharmaceutical executives about why their companies hardly make drugs anymore. In the absence of such discussion, I can only speculate that most likely, this is first a product of financialization. Drug company executives, like most organizational leaders, have fallen under the spell that says their only goal should be to increase short-term revenues. It may be cheaper to buy drugs from perhaps dodgy outsourced suppliers rather than manufacturing them them themselves. Continuing stories like those above, and that of the contaminated Chinese heparin suggest that these outsourced drugs are cheap for a reason. It appears that to save money short-term, pharmaceutical executives may be abandoning their most central mission, to provide pure, unadulterated drugs.

The continuing story of outsourced pharmaceutical manufacturing provides yet more evidence that current management dogma may be literally toxic. Once again, I suggest that true health care reform requires leadership of health care organization who put patients' and the public's health ahead of short-term revenue (and the personal enrichment that may result).

It is likely that a number of policy changes will be needed to reduce the threats posed by contaminated or adulterated outsourced pharmaceuticals.  There is one simple step that ought to be taken quickly to at least make the problem more transparent.  In the US, most manufactured products have a label disclosing the country of origin.  In parallel with that, all pharmaceutical containers, and all pharmaceutical labels and marketing materials ought to disclose the country in which the active pharmaceutical ingredient was manufactured, and the name and location of the company responsible for that manufacture. 


Appendix - Heparin Case Summary

- We have posted several times, 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 in 2007, hundreds of such reactions, and 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. (See posts here and here.)

- 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.)  Note that SPL was recently bought out and taken private, making its current leadership even less transparent (see post here).  A 2010 inspection of an SPL facility by the FDA revealed ongoing manufacturing problems (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.)  Efforts to make documents to be used in these cases public so far have not succeeded (see post here).

- A 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.)

-  Despite requests from the US, the Chinese government did not investigate the production of the heparin that lead to the deaths (see post here.)

-  In February, 2011, a congressional investigation of the case was announced, but results are so far unavailable (see post here.)

-  In June, 2011, a jury returned the first verdict in a civil case about the contaminated heparin, awarding money from Baxter International and Scientific Protein Laboratories to the estate of a man who apparently died due to tainted heparin (see post here).

Just Business - Employee Control Fraud, Gresham's Dynamic, and the Race to the Bottom in Health Care

Since Enthoven called for the break up of the physicians' "guild," and handing over its supposed power to managers, (see post here) managers have taken over from physicians and other health care professionals as leaders of health care organizations.  Unfortunately, most of these managers are generic, often lacking knowledge and experience in health care, and understanding of its core values.  Instead, such generic managers may rely on the current management dogma.  The perils of doing so are illustrated by an analysis of the recent expose of conditions at Apple manufacturing plants in China.

The Apple Expose

The New York Times summarized in a landmark article how bad it is to work in factories building Apple products under contract in China.  Workers endure harsh conditions, toiling up to six days a week, 12 hours a day.  Meanwhile, banners remind them to "work hard on the job today or work hard to find a job tomorrow."  Workers may be exposed to hazardous, even poisonous materials (like n-hexane used to clean components).  Workers have died in explosions due to inadequate control of combustible dust. Over 18 workers at one factory attempted or committed suicide within two years.

The article suggested that while Apple managers may be well-intentioned, and "want to improve conditions in factories," the bottom line is more important:

that dedication falters when it conflicts with crucial supplier relationships or the fast delivery of new products.

In fact, because of its rigid insistence on cost control, its suppliers are sorely tempted to push their workers too hard:

Apple typically asks suppliers to specify how much every part costs, how many workers are needed and the size of their salaries. Executives want to know every financial detail. Afterward, Apple calculates how much it will pay for a part. Most suppliers are allowed only the slimmest of profits.

So suppliers often try to cut corners, replace expensive chemicals with less costly alternatives, or push their employees to work faster and longer, according to people at those companies.

'The only way you make money working for Apple is figuring out how to do things more efficiently or cheaper,' said an executive at one company that helped bring the iPad to market. 'And then they’ll come back the next year, and force a 10 percent price cut.'

So,

'You can set all the rules you want, but they’re meaningless if you don’t give suppliers enough profit to treat workers well,' said one former Apple executive with firsthand knowledge of the supplier responsibility group. 'If you squeeze margins, you’re forcing them to cut safety.'

William Black's Analysis: Employee Control Fraud and the Race to the Bottom

Writing in the Huffington Post, William K Black showed how Apple executives' relentless focus on cost could drive a race to the bottom. He began by analyzing Apple executives' explanation for out-sourcing their production:

'We shouldn't be criticized for using Chinese workers,' a current Apple executive said. 'The U.S. has stopped producing people with the skills we need.'

He noted that it is absurd to suggest that the US does not have workers with the technical skills necessary to build Apple products. He suggests, however, that these are not the skills that matter.

The suppliers want engineers and managers who will selectively apply their substantive skills. American engineers and managers cannot be counted on to provide the necessary selectivity. Apple's suppliers' often seek managers willing to order their workers to exceed the lawful workweek, to refuse to pay them for significant portions of the wages they have earned, to unlawfully employ child labor, and even to coerce abortions.

So, in the n-hexane example,

The engineer did not order the workers to use the nerve poison because he hated the workers. It was 'just business.' The nerve poison reduced cleaning time, so an engineer knowingly ordered the workers to use it and scores of other engineers did nothing to prevent the usage.

Note that Black calls this employee control fraud, deceiving the employee that he or she is working in a reasonably safe environment, and that employee health and safety is a concern, when in truth the only concern is the bottom line.

So what Apple executives, and by analogy, other multi-national corporate executives want are underlings, particularly middle and line managers who will do anything, anything to cut costs and improve the bottom line. This will produce the race to the bottom:

What we are observing is the essence of a Gresham's dynamic in which bad ethics drives good ethics out of the market.

Two aspects of this Gresham's dynamic are obscene, and both are produced by neoclassical economics dogma. Calling this process 'creative destruction' is baseless and dishonest. It is the fraudulent destruction of honest businesses, professions, and labor.

Black concluded:

firms that are anti-employee control frauds are likely to commit other forms of control fraud. Apple and its Western counterparts have driven the creation of an Asian network of fraudulent firms that has distorted international trade, hollowed out U.S. manufacturing, and created a bizarre hybrid: quasi-communist crony capitalism. It boggles the mind that theoclassical economists celebrate the corrupt result as the essence of creative destruction. The network is corrupt. It will not play by the rules. Firms like Apple help create the perverse incentives that encourage the network to cheat. Surviving U.S. manufacturing firms are whipsawed by the powerful Gresham's dynamic that the frauds produce. U.S. firms and workers are constantly pressured to reduce wages and workforce to try to compete with the foreign frauds. This is the 'Road to Bangladesh' strategy that has caused U.S. working class wages to stall for decades. Europe is retreating along this same road at an even more rapid rate. The Gresham's dynamic tilts the world in favor of fraudulent firms operating in fraud-friendly nations.

The Race to the Bottom in Health Care
Note that we have written about numerous examples of executives of US health care organizations putting revenue ahead of the health care mission, ahead of workers' morale, ahead of patients' and the public's health. Some of these examples involve executives of nominally non-profit organizations that are supposed to have charitable purposes. (Look under our heading of mission-hostile management.)

In fact, just yesterday, Dr Carl Elliott, writing for the Chronicle of Higher Education, summarized how pharmaceutical companies have out-sourced clinical research. The resulting commercial clinical research have generated conditions as bad for the research subjects as those endured by the Chinese electronics workers above:

If the past decade had an emblematic moment for clinical research, it was probably November 12, 2005, the day when Bloomberg Markets published its cover story, “Big Pharma’s Shameful Secret.” In that issue, Bloomberg reporters laid out the story of SFBC International, a contract research organization in Miami that was paying undocumented immigrants to test the safety of new drugs in a seedy motel. The SFBC owners had converted the lobby into a large waiting area with plastic chairs, and they were housing their research subjects six to a room. The medical director of the research site was unlicensed to practice medicine; the Institutional Review Board that approved many of the studies was owned by the wife of the company vice-president; and the converted motel, which had been cited for fire and safety violations, was eventually demolished. Nonetheless, SFBC had become an astonishingly successful enterprise. Just a few years before the Bloomberg Markets report, Forbes had named SFBC one of the most admired small businesses in America. Virtually every major pharmaceutical company had tested drugs with the company. In fact, with 675 beds, the converted motel was the largest research facility in North America.

Note: see our relevant posts here on SFBC International, and on contract research organizations.

Moreover, such out-sourcing has produced the sort of race to the bottom described by Black, but this time involving one of the US most important health care institutions, academic health care:

the more important reason is money. In medical schools, faculty members are often expected to generate their own salaries, either by seeing patients or getting grants and contracts. Likewise, academic departments are often expected to be financially self-sufficient, with as little support as possible from central administration. 'Eat what you kill' is the phrase used, without irony, by medical school deans and department heads. And if you are not killing it with NIH grants, you probably need to be killing it with AstraZeneca or Pfizer.

This system has not been good for human subjects, but it has not been good for academic physicians either. According to a recent study of over 5,000 faculty members at U.S. medical schools, 51 percent of respondents said that the administration is only interested in me for the revenue I generate.' Thirty-one percent said that their institution discourages altruism; 27 percent said that it does not reward clinical excellence; and over half said that it does not value teaching. Nearly half of respondents were considering leaving their current jobs; almost a third were considering leaving academic medicine altogether. Asked if their values lined up with the medical schools where they worked, over half said no. And just in case you are wondering why these physicians are not standing outside the building with picket signs, protesting the injustice of the system, the survey offers another clue. Thirty percent of respondents agreed with the statement, 'I am reluctant to express my opinion for fear of negative consequences.' [This was from an abstract by Pololi L et al.  See our relevant post here.]

Of course, this survey does does not exactly match up with the happy propaganda disseminated by the media-relations offices at most medical schools. Instead, it offers a picture of alienated, demoralized physicians, unhappy in their jobs, pressed to work according to values that repel them in order to prop up an institution that views them primarily as instruments to generate profit. In this environment, contract research makes perfect sense. It may not require much intellectual work, but it pays the bills and keeps the authorities happy. And if medical schools don’t really value intellectual work anyway, that may well be enough.

So the pressures on medical school faculty are little different from those on corporate middle management.  Their only role is to make money, mainly so that the top leaders can become multi-millionaires, and woe unto them if they object.
Summary

What is missing in all this is any organized opposition to the race to the bottom. As long as top executives can make nearly unlimited money, as long as they can do so by making their subordinates put revenue ahead of all else, as long as there are no countervailing forces, the race to the bottom will continue.

To stop it, we need some combination of efforts by honest government regulators, professional and trade organizations, civil society organizations including non-profit organizations and NGOs that really care about patients' and the public's health, and finally an activated, and properly outraged public.

As long as we think that a laissez faire policy allowing continual market dysfunction to continue, the good times for executives will keep rolling, over all of the rest of us.