Showing posts with label China. Show all posts
Showing posts with label China. Show all posts

Saturday, February 22, 2020

Rising Tide of Disinformation about Coronavirus: the Roles of Ideologues, Quacks, Russians, and US Politicians

Introduction: Propaganda and Disinformation in Health Care

We used to write about propaganda and disinformation used to promote health care goods and services (stealth marketing campaigns), and advocate for policies favorable to private health care organizations (stealth health policy advocacy and stealth lobbying).  Some stealth marketing, lobbying and policy advocacy campaigns encompass not just propaganda, but disinformation.  For example, consider the health insurance company campaign to derail the Clinton administration's attempt at health reform as described by Wendell Potter in Deadly Spin (look here).  The tactics employed in that campaign included: use of front groups and third parties (useful idiots?); use of spies; distractions to make important issues anechoic; message discipline; and entrapment (double-think).

In fact, towards the end of its existence, the USSR sponsored a disinformation campaign which spread the notion that HIV was a bio-weapon invented by a US laboratory (look here).  Although false ideas associated with that campaign persisted for years, the risk that health care disinformation would be used by hostile state actors seemed to die off as the cold war ended.

But now we have a new (ab)normal that includes propaganda and disinformation in the service of hostile authoritarian foreign states meant to disrupt more democratic governments, whatever the cost in human health and lives.  For an example look here at  how starting around 2015 Russia was spreading disinformation about measles and measles vaccination over the internet, using new technology like bots.

Now they seem to be doing it again, this time about coronavirus.

Disinformation About Coronavirus

On January 29, 2020, the Washington Post reported on a new disinformation campaign:

As China attempts to contain the spread of a new coronavirus that has left more than 100 people dead, rumors and disinformation have spread amid the scramble for answers.

Some of the speculation has centered on a virology institute in Wuhan, the city where the outbreak began. One fringe theory holds that the disaster could be the accidental result of biological weapons research.

The story started circulating in right-wing media:

The British newspaper Daily Mail was among the first to suggest the possibility of a link between the newly spreading virus and the Wuhan National Biosafety Laboratory, reporting last week that the lab, which opened in 2014 and is part of the Wuhan Institute of Virology, had been the subject of safety concerns in the past.

A separate article published by the Washington Times, a conservative newspaper in Washington, took the theories a step further, suggesting in a headline that the 'Coronavirus may have originated in lab linked to China’s biowarfare program' and pointing to the Wuhan Institute of Virology.

So,

Despite little public evidence, the theory has spread widely on social media, to conspiracy theory websites and in some international news outlets.

Yet there was no good evidence to support this theory.

'Based on the virus genome and properties there is no indication whatsoever that it was an engineered virus,' said Richard Ebright, a professor of chemical biology at Rutgers University.

Also,

Milton Leitenberg, an expert on chemical weapons at the University of Maryland, said he and other analysts around the world had discussed the possibility that weapons development at the Wuhan lab could have led to the coronavirus outbreak in a private email chain but that no one had found convincing evidence to support the theory.

Then the bioweapon theory started appearing on more extreme sites.  BuzzFeed reported on January 31, 2020:

A popular pro-Trump website has released the personal information of a scientist from Wuhan, China, falsely accusing them of creating the coronavirus as a bioweapon, in a plot it said is the real-life version of the video game Resident Evil.

On Wednesday, far-right news site Zero Hedge claimed without evidence that a scientist at the Wuhan Institute of Virology created the strain of the virus that has led the World Health Organization to declare a global health emergency.

Note that

Zero Hedge, which describes itself as a financial blog, has more than 50,000 followers on Facebook and more than 670,000 followers on Twitter and is run by Daniel Ivandjiiski, a Bulgarian-born, US-based, former investment banker, who writes the majority of the posts published by the pseudonym Tyler Durden. The site regularly amplifies conspiracy theories from anonymous message board 4chan and writes frequently about the deep state, doomsday prep, bitcoin speculation, and New Age pseudoscience.

Furthermore,

The new focus on the scientist is the culmination of several conspiracy theories that have gained traction since the beginning of the outbreak early in January. One version of the hoax began in Facebook Groups run by supporters of the pro-Trump QAnon movement and the anti-vax community, where users claimed the outbreak was a population control plot by former Microsoft CEO Bill Gates.

The Zero Hedge take has been propagated widely:

The Zero Hedge article has been posted on Twitter over 10,000 times and shared close 2,000 times on Facebook in the last 24 hours.

And,

The rumors and lies are also being spread across 4chan. A user linked to the Zero Hedge article in a 4chan thread titled, 'All hail [the scientist], creator of Corona-Chan.' In another 4chan thread, users claimed the scientist had created a mutant superbug.

The hoaxes surrounding the coronavirus have become so prevalent that 'uncensored' subreddits about the outbreak are being created for users on Reddit who want to share the theories.

In summary, an unsubstantiated theory about the coronavirus, one that could both increase public anxiety, if not panic, and stir up hostility between China and the US, started circulating in right-wing, including extremist, web-sites and media, and soon bled into the larger social media. But why?  Cui bono? Who could benefit from this?

Using Disinformation and Extreme Ideology to Sell Dubious Products

One answer appear to be people selling quack products.

A New York Times article on February 6, 2020 focused on World Health Organization (WHO) efforts to fight disinformation about coronavirus (see below). It included the opinions of "Andrew Pattison, manager of digital solutions at the W.H.O."  He suggested:

Medical misinformation on the virus has been driven by ideologues who distrust science and proven measures like vaccines, and by profiteers who scare up internet traffic with zany tales and try to capitalize on that traffic by selling 'cures' or other health and wellness products.

'There are self-appointed experts, people working from anecdote, or making up wild claims to get traffic or notoriety,' said Mr. Pattison of the W.H.O.

Furthermore,

Sarah E. Kreps, a professor of government at Cornell University, considers the people deliberately spreading distortions to be practitioners of 'algorithmic capitalism,' in which people scare up traffic and sell against it.

Examples abound. Infowars, the far right website that purveys conspiracy theories and fake news, and others are now banned on several leading social media sites but are still advertising pseudoscientific remedies directly through their own shops. An early distortion of the coronavirus news appeared in an Infowars video on Jan. 22 — claiming that the virus could be part of some man-made plot to thin the population.

'The globalists and the deep state have declared war on humanity,' a host on the video said. 'They hate human life. This is why they kill babies.'

Next to the box in which the video appears is an advertisement for an immune gargle product that, the ad claims, 'is designed to support your immune system like no other,' and that is 'scientifically proven.'

However, the Mayo Clinic reports that the ingredient mentioned in the product, colloidal silver, has not been proved safe or effective in treating disease. And even the Infowars shop where the product is listed reads at the bottom: 'This product is not intended to diagnose, treat, cure or prevent any disease.' 

Whether these disinformationists are primarily cynical businesspeople hiding behind extreme ideology, or extreme ideologists who found a way to profit from these beliefs, or both is not clear.
 
The Russian Connection



 Furthermore, it appears that once again the Russians are involved, demonstrating their updated disinformation techniques that take advantage of the internet and social media.

On February 14, 2020, an article in Foreign Policy discussed Russian involvement in disinformation about coronavirus:

The overarching theme of the stories that appear across the Russian media, from fringe websites to prime-time television, is that the virus is the product of U.S. labs, intended to kneecap China’s economic development. Some articles have flirted with the idea that Bill Gates or Kremlin nemesis George Soros might have had a hand in the outbreak.

Note that:

Right now, the main audience is largely domestic, with a sprinkling of conspiratorial reports across the different language services of Sputnik, the more tabloid of Russia’s international broadcasters. The conspiracy theories haven’t featured prominently on English-language Russian government-backed international broadcasters such as RT and Sputnik, however, according to Bret Schafer, a fellow at the German Marshall Fund’s Alliance for Securing Democracy who studies disinformation. While these channels have historically played around the edges of conspiracy theories, 'they still want that veneer of being a legit international broadcaster,' Schafer said. 

The Russian disinformation did not appear to be focused on the escaped Chinese bio-weapon theory, but that particular theory might not be the point. 
The Russian messaging fits a now well-established pattern in that it doesn’t look to persuade audiences of a single alternative truth. That would take effort, planning, and persuasion. Modern-day Russian propaganda has instead been described by the Rand Corp. as a 'firehose of falsehood,' a steady stream of underdeveloped, sometimes contradictory conspiracy theories intended to exhaust and confuse viewers, making them question the very notion of objective truth itself.

On February 22, 2020, the Guardian provided considerably more detail, and now it is coming from official US State Department sources:

State department officials tasked with combatting Russian disinformation told the AFP false personas were being used on Twitter, Facebook and Instagram to advance Russian talking points in multiple languages.

'Russia’s intent is to sow discord and undermine US institutions and alliances from within, including through covert and coercive malign influence campaigns,' said Philip Reeker, acting assistant secretary of state for Europe and Eurasia.

'By spreading disinformation about coronavirus, Russian malign actors are once again choosing to threaten public safety by distracting from the global health response,' he said.

Some accounts have falsely claimed the US is waging “economic war on China” and that the virus is a biological weapon manufactured by the CIA.

Furthermore,

Several thousand online accounts – previously identified for airing Russian-backed messages on major events such as the war in Syria, the Yellow Vest protests in France and Chile’s mass demonstrations – are posting “near identical” messages about the coronavirus, according to a report prepared for the state department’s Global Engagement Center and seen by the AFP.

The accounts are run by humans, not bots, and post at similar times in English, Spanish, Italian, German and French. They can be linked back to Russian proxies, or carry messages similar to Russian-backed outlets such as RT and Sputnik, the report said.

'In this case, we were able to see their full disinformation ecosystem in effect, including state TV, proxy websites and thousands of false social media personas all pushing the same themes, said Lea Gabrielle, head of the Global Engagement Center, which is tasked with tracking and exposing propaganda and disinformation.

This is now looking like a big-time Russian disinformation effort aimed at further destabilizing the west,

A state official said Russian operatives appeared to have been given 'carte blanche' to attack the US.

'Whether or not a particular theme is being directed at the highest levels doesn’t matter,' the official said. 'It’s the fact that they have freelance ability to operate in this space to do whatever damage they can, which could have seismic implications.'

All from the same folks who are trying to meddle in the upcoming election, in favor of their preferred candidate, President Trump (look here).

A Prominent US Senator Helps Propagate Disinformation


During the early phases of the measles disinformation campaign, we noted that in February, 2015, the New York Times discussed the strange inability of some then Republican candidates for the presidency to discuss the issue clearly.

Now a Senator Tom Cotton (R-AK) is adding to the confusion about coronavirus.  The New York Times reported on February 17, 2020 (updated February 18):

Speaking on Fox News, Senator Tom Cotton, Republican of Arkansas, raised the possibility that the virus had originated in a high-security biochemical lab in Wuhan, the Chinese city at the center of the outbreak.

'We don’t have evidence that this disease originated there,' the senator said, 'but because of China’s duplicity and dishonesty from the beginning, we need to at least ask the question to see what the evidence says, and China right now is not giving evidence on that question at all.'

Note that he raised doubts while suggesting the plausibility of the escaped Chinese bio-weapon theory, but did not dwell on the evidence.  Instead, the Times noted he seemed to complain about the lack of relevant evidence:

Speaking to the Fox News anchor Maria Bartiromo, Mr. Cotton suggested that a dearth of information about the coronavirus’s origins was raising more questions than answers.

'We don’t know where it originated, and we have to get to the bottom of that,' he said on the program 'Sunday Morning Futures.'

But there is nothing to suggest that he used his position as a US Senator to learn more about what facts are currently known, and what public health experts currently think.  Surely organizations like the CDC and WHO could have helped him with that before he jumped into the discussion.  It would also have been possible for him to access the US State Department's information about the Russian  coronavirus disinformation campaign and about the possible malign effects of further spreading disinformation about this new disease.  But no, Sen Cotton appeared to be attending to other sources, like these mentioned in the Times article:

Last month, Mr. [Steve] Bannon [former Trump campaign manager in his 2016 campaign, former owner of Breitbart News]  invited Bill Gertz, a Washington Times reporter, to be a guest on the inaugural episode of his radio show 'War Room: Pandemic,' a spinoff of his 'War Room: Impeachment,' which defended Mr. Trump during the Senate impeachment trial.

'Bill Gertz had an amazing piece in The Washington Times about the biological labs that happen to be in Wuhan,' Mr. Bannon said on his Jan. 25 show. Mr. Gertz appeared on another show several days later to continue putting forward the bioweapons theory.

Fox News has also dabbled in the theory, in one article drawing a connection between a 1980s thriller by Dean Koontz that 'predicted coronavirus.' The book is about a Chinese military lab that creates a biological weapon.

In addition, although the NYT article suggested that Sen Cotton then attempted to "walk back" his original statements, on January 19, 2020, Fox News reported he had reiterated it:

Sen. Tom Cotton, R-Ark. stood by his earlier suggestion that the deadly coronavirus may have originated in a high-security biochemical lab in Wuhan, China, telling 'The Story' Tuesday that we 'need to be open to all possibilities' in exploring the origins of the outbreak that has sickened more than 75,000 people around the world.

When host Martha MacCallum pressed the Senator on his startling and unverified claim, Cotton cited a study published by Chinese scientists in The Lancet, which he called a 'respected international science journal.'

'I'm suggesting we need to be open to all possibilities and we need to demand that China open up and be transparent so a team of international experts can figure out exactly where this virus originated,' Cotton said.

He also brought up the 'questions' surrounding the biosafety level 4 'super laboratory' in Wuhan, the city where the virus is believed to have originated.

In epidemiology, it may be wise not to dismiss even theories that appear far-fetched, at least in the initial phases of an investigation, but there should be some effort to assess the plausibility of the competing hypotheses.  Again, notice that a US Senator with no obvious public health or epidemiological expertise was continuing to talk off-the-cuff about a major public health issue, sans any reference to the sorts of expertise and evidence he could easily access.


Discussion

The problem of disinformation about medicine, health care, and public health only seems to be getting worse. It appears to be fueled in part by the good old fashioned profit motive, but often focused on the profits from useless, possibly harmful pseudo-remedies.  It may be justified, or actually generated by extreme ideologies, all of which so far seem to be on the far-right end of the political spectrum.   Particularly disquieting is the proclivity, at least in the US, for politicians of a certain stripe to not merely downplay it, but aid in its dissemination, meanwhile ignoring all the possible resources available to them that could supply some evidence and rational assessment of same.

One small cause for hope are the growing efforts to combat it.  For example, as discussed in the New York Times, the WHO is now actively trying to combat the "infodemic" of coronavirus disinformation.

Clearly, health care professionals should be doing their part in fighting disinformation and active measures that seek to distort medicine, health care and public health.  National and local health departments, and agencies such as the CDC and FDA in the US all should be joining the WHO and the US State Department in fighting current disinformation campaigns, and preparing for future ones.  Needless to say, politicians regardless of political philosophy should be supporting these efforts, should base their remarks on evidence and logic, and certainly should not be helping the spread of disinformation.

Yet, as Chris Cilllizza wrote for CNN re Sen Cotton's dissemination of coronavirus disinformation, we are living

in a sort of post-truth world, one if not created, then pushed by President Donald Trump. Trump's candidacy was born in a conspiracy theory (former President Barack Obama wasn't actually born in the United States) and he has embraced any number of conspiracy theories in his days as President. (Millions of illegal votes were cast in the 2016 election, Obama ordered the phones at Trump Tower wiretapped, etc.)

Trump has mainstreamed conspiracy theories and convinced lots and lots of people they are true with much the same tactic Cotton used on Sunday, which amounts to this: I am not saying this is true, I am just saying people are talking about it and we owe it to ourselves to ask the question. But simply because Trump has made this sort of stuff commonplace doesn't mean it's OK. It isn't. After all, there's a difference between a random post on some Reddit message board and a US senator spinning conspiracy theories on national TV. Or at least, there should be.

However Trump, and maybe Cotton too, seem to benefit from the barrage of disinformation and active measures emanating from Russia. We just heard that the US intelligence community says Russia is once again using active measures to influence the upcoming US election - on behalf of Trump (look here). It is also hard to ignore that Sen Cotton is a big fan of US President Donald Trump (look  here) as is Trump of him.

So, it may be too much to expect them to change their ways. Instead, we may need to change our political leadership, and charge our political operating system to make it less vulnerable to hacking by hostile foreign nations, like Russia.


Saturday, September 14, 2019

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).


Wednesday, April 13, 2016

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).

Monday, December 22, 2014

Guest Post: Scholarly Mad Libs and Peer-less Reviews

Health Care Renewal presents a guest post by Marjorie Lazoff, MD, a Board certified internist with a clinical background in academic emergency medicine.  She is currently a full time freelance editor and independent consultant specializing in evidence-based clinical content and medical informatics.

On December 17, 2014, Scientific American published an investigative report by journalist Charles Seife documenting a new and curious form of scholarly publication fraud, For Sale: “Your Name Here” in a Prestigious Science Journal. As an editor and supporter of evidence-based medicine I am both appalled by, and sympathetic to, how such widespread fraud could take place unnoticed.

Seife describes how he discovered the doctored writings:

The dubious papers aren't easy to spot. Taken individually each research article seems legitimate. But in an investigation by Scientific American that analyzed the language used in more than 100 scientific articles we found evidence of some worrisome patterns—signs of what appears to be an attempt to game the peer-review system on an industrial scale…

…This is not a simple case of plagiarism. Many seemingly independent research teams have been plagiarizing the same passage. An article in PLOS ONE may eventually lead to 'our better, comprehensive understanding' of the association between mutations in the XRCC1 gene and thyroid cancer risk. Another in the International Journal of Cancer (published by Wiley) might eventually lead to 'our better, comprehensive understanding' of the association between mutations in the XPA gene and cancer risk—and so on. Sometimes there are minor variations in the wording but in more than a dozen articles we found almost identical language with different genes and diseases seemingly plunked into the paragraph, like an esoteric version of Mad Libs, the parlor game in which participants fill in missing words in a passage.

Another example virtually eliminates the likelihood of coincidence:

There is no such thing as a 'Beggers funnel plot'…the proliferation of 'Begger's' tests [were discovered] by accident. While looking for trends in medical journal articles, papers [were found] that had almost identical titles, similar choices in graphics and the same quirky errors, such as 'Begger's funnel plot.'

Seife’s investigative reporting revealed that China was the source of most of his “fill-in-the-blanks” research. Further,

Much of the funding for these suspect papers comes from the Chinese government. Of the first 100 papers identified by Scientific American [and listed at the close of his article], 24 had received funding from the National Natural Science Foundation of China (NSFC), a governmental funding agency roughly equivalent to the U.S.'s National Science Foundation. Another 17 acknowledged grants from other government sources.

Seife suspects that most research probably began as legitimate work without intent to deceive, but somewhere an author or service was added to help ensure publication through the necessarily arduous manuscript review process.

The culprit?

A quick Internet search uncovers outfits that offer to arrange, for a fee, authorship of papers to be published in peer-reviewed outlets. They seem to cater to researchers looking for a quick and dirty way of getting a publication in a prestigious international scientific journal.

Seife’s investigation goes undercover, 60 Minutes style:

In November Scientific American asked a Chinese-speaking reporter to contact MedChina, which offers dozens of scientific 'topics for sale' and scientific journal 'article transfer' agreements. Posing as a person shopping for a scientific authorship, the reporter spoke with a MedChina representative who explained that the papers were already more or less accepted to peer-reviewed journals; apparently, all that was needed was a little editing and revising. The price depends, in part, on the impact factor of the target journal and whether the paper is experimental or meta-analytic. In this case, the MedChina rep offered authorship of a meta-analysis linking a protein to papillary thyroid cancer slated to be published in a journal with an impact factor of 3.353. The cost: 93,000 RMB—about $15,000.

Finally, the corrosive effect of this particular fraud on scientific and medical publication is real:

Publishers at the moment are fighting an uphill battle. 'Without insider information it's very difficult to police this,' Clinical Endocrinology's Bevan says. CE and its publisher, Wiley, are trying to close loopholes in the editorial process to flag suspicious late changes in authorship and other irregularities. 'You have to accept that people are submitting things in good faith and honesty,' Bevan says.

That is the essential threat. Now that a number of companies have figured out how to make money off of scientific misconduct, that presumption of honesty is in danger of becoming an anachronism.

Were this the only threat currently facing research journals today! Last month, Retraction Watch published an article describing a known and partially-related problem: fake peer reviews, in this case involving 50 BioMed Central papers. In the above-described article, Seife referred to this BioMed Central discovery; he was able to examine 6 of these titles and found that all were from Chinese authors, and shared style and subject matter to other “paper mill-written” meta-analyses.

Retraction Watch agrees:

It would seem that a third party, perhaps marketing services helping authors have papers accepted, was involved.

Problems with peer review are longstanding editorial fodder. For a description of another recent peer review scam, this one involving authors hijacking researchers’ identities, see the article also written by Retraction Watch editors and published last month in Nature.

On Friday, in response to requests by several publishers, The Committee on Publication Ethics (COPE) posted a statement on inappropriate manipulation of peer review processes 

While there are a number of well-established reputable agencies offering manuscript-preparation services to authors, investigations at several journals suggests that some agencies are selling services, ranging from authorship of pre-written manuscripts to providing fabricated contact details for peer reviewers during the submission process and then supplying reviews from these fabricated addresses. Some of these peer reviewer accounts have the names of seemingly real researchers but with email addresses that differ from those from their institutions or associated with their previous publications, others appear to be completely fictitious.

COPE recommends, among other things, the retraction of articles based solely on fraudulent reviews. Retraction Watch’s announcement earlier today of a MacArthur Foundation grant to help fund a comprehensive and freely available database of retractions could not have come at a better time!

Seife and Retraction Watch have documented new forms of published research fraud among third world researchers. Certainly the solution is not for editors and readers to suspect all papers from specific countries; there are ample instances of research fraud emanating from English-speaking researchers and top U.S. institutions. Research from around the world is critically important, particularly although not exclusively in the basic sciences, emerging infectious disease, and public health/epidemiology. Now that it has been identified, a common screening procedure for manuscripts at a journal can be adjusted to filter out this new form of plagiarism.

Sadly, it seems to me that fraudulent research of all types can flourish within a perfect storm of circumstances and factors: the globalization of science and medicine encourages non-or-limited English-speaking researchers to publish (or perish) in the highest impact English language journals; the proliferation of open-access wannabes, hybrids of every color and degree of sincerity, and other money-over-science journals and companies that rip off desperate and naïve researchers; a complicated, time-consuming and often author-unfriendly manuscript submission process; and journal editors who struggle with limited staffing and resources, necessarily arduous editorial processes, and the pressure of increasing numbers of worthy manuscripts deserving to reach the scientific and medical communities in near-real time. Research fraud is particularly destructive given traditional publishing’s ongoing struggle to survive the transformational Electronic Age; the pervasive if not perverse marketing of pharma, medical device companies, and self-promoting individuals and institutions using “unbiased” research; and today’s bizarrely anti-science culture.

Health Care Renewal is wonderful at calling out intentionally perpetrated health care events whose importance and implications can be debated, depending on one’s perspective and personal values. Here, I think, we have the reverse: there is near unanimity over the need to prevent fraudulent papers of any type from contaminating our research databases, as best as is humanly and technologically possible. There is also near unanimity among quality medical journals throughout the world, and internationally respected editor and publisher groups, to confront and solve these problems. The enemy identified by HCR is not always unrestrained greed or maliciousness. Sometimes, as in this case, the enemy is a cacophony of small circumstances and extraneous factors that could, if left unattended, invisibly erode something we all hold dear.

Without ongoing attention and support from the entire medical and science communities, we risk the progressive erosion of our essential, venerable research database, until it finally becomes too contaminated for even our most talented editors to heal.

Dr Marjorie Lazoff

ADDENDUM (30 December, 2014) - This post was reposted on the Naked Capitalism blog on 24 December, 2014.

ADDENDUM (7 January, 2015) - See also comments on DSHR's Blog.  

ADDENDUM (19 January, 2015) - This post was reposted by TruthOut on 10 January, 2015.

Wednesday, September 05, 2012

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).

Friday, July 23, 2010

More About What We Don't Know About the Contaminated Heparin from China

We last blogged about the case of Baxter International's adulterated heparin here.  (For a more detailed summary of the case, look here.)

In 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.

Now, an article in the Wall Street Journal by Alicia Mundy tells us more about what we don't know,
The Chinese government didn't pursue an investigation into contaminated heparin sent to the U.S. in 2007 and 2008, despite repeated requests from the U.S. for help, according to a congressional probe.

Two House Republicans said Food and Drug Administration officials recently told them that the agency has been "severely hampered" by the lack of cooperation from China in finding those responsible.

Furthermore,
'It is shocking to find out two years after Chinese-made heparin was killing Americans, the Chinese government still has done no investigating to find out why,' said Mr. Barton, the top Republican on the House Energy and Commerce Committee. He called on ... [FDA Commissioner Margaret] Hamburg to air the issue with Chinese officials.

Chinese officials denied there is a problem,
Yan Jiangying, spokeswoman for China's State Food and Drug Administration, said the congressmen's accusations are 'not true.'

Ms. Yan said her agency 'did a very thorough investigation, including very detailed inspection and testing, and surveys of enterprises as well. We signed an agreement with the FDA on drug safety in the end of 2007, and strengthened the monitoring of heparin.'

Note that their investigation, such as it was, did not appear to identify any misconduct or wrong-doing by anyone.

So now we know more about what we do not know about the deadly adulterated heparin from China.

But remember this is a case about heparin sold in the USA by Baxter International, an American company as an American product, resulting in the death of Americans.  Also, remember that the American company obtained the heparin from another American 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. 

Since Baxter International sold the heparin under its own label, should not its leaders be responsible for the safety and purity of the product?  Since Scientific Protein Laboratories LLC furnished the active pharmaceutical agreement to Baxter, and obtained it from a factory it partially owned in China, should not its leaders also be responsible for the safety and purity of the product?

It would be important to find out ultimately where in China the adulterated heparin entered the supply chain, but the current uncertainty about the initial origin of the contamination does not absolve those in the US who sold the active pharmaceutical ingredient, and then sold that ingredient in bottles with a US company label of responsibility for the safety and purity of the drug.

Why have we heard nothing more from Baxter International's and Scientific Protein Laboratories' leaders about the deadly heparin which they had sold?  Why have we heard nothing more about any investigation of these US based participants in this case? 

Both US companies doubtless saved money by buying the heparin from the cheapest Chinese sources they could find, by not directly inspecting and supervising its production, and by at best ignoring the lack of regulation of producers of active pharmaceutical ingredients in China.  They and their leaders benefited from this out-sourced, off-shore production.  (Note that Baxter CEO Robert L Parkinson Jr received total compensation of $14,361,305 according to the company's proxy statement, and six named officers all received more than $2,200,000.) Why aren't they being held accountable for its bad results?

As we have said until being blue in the face, 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).

Hat tip to Ed Silverman on the PharmaLot blog.