Indian Pharmaceuticals and Electoral Bonds

 

AI has hacked the operating system of human civilisation

Yuval Noah Hariri in The Economist

Fears of artificial intelligence (ai) have haunted humanity since the very beginning of the computer age. Hitherto these fears focused on machines using physical means to kill, enslave or replace people. But over the past couple of years new ai tools have emerged that threaten the survival of human civilisation from an unexpected direction. ai has gained some remarkable abilities to manipulate and generate language, whether with words, sounds or images. ai has thereby hacked the operating system of our civilisation.

Language is the stuff almost all human culture is made of. Human rights, for example, aren’t inscribed in our dna. Rather, they are cultural artefacts we created by telling stories and writing laws. Gods aren’t physical realities. Rather, they are cultural artefacts we created by inventing myths and writing scriptures.

Money, too, is a cultural artefact. Banknotes are just colourful pieces of paper, and at present more than 90% of money is not even banknotes—it is just digital information in computers. What gives money value is the stories that bankers, finance ministers and cryptocurrency gurus tell us about it. Sam Bankman-Fried, Elizabeth Holmes and Bernie Madoff were not particularly good at creating real value, but they were all extremely capable storytellers.

What would happen once a non-human intelligence becomes better than the average human at telling stories, composing melodies, drawing images, and writing laws and scriptures? When people think about Chatgpt and other new ai tools, they are often drawn to examples like school children using ai to write their essays. What will happen to the school system when kids do that? But this kind of question misses the big picture. Forget about school essays. Think of the next American presidential race in 2024, and try to imagine the impact of ai tools that can be made to mass-produce political content, fake-news stories and scriptures for new cults.

In recent years the qAnon cult has coalesced around anonymous online messages, known as “q drops”. Followers collected, revered and interpreted these q drops as a sacred text. While to the best of our knowledge all previous q drops were composed by humans, and bots merely helped disseminate them, in future we might see the first cults in history whose revered texts were written by a non-human intelligence. Religions throughout history have claimed a non-human source for their holy books. Soon that might be a reality.

On a more prosaic level, we might soon find ourselves conducting lengthy online discussions about abortion, climate change or the Russian invasion of Ukraine with entities that we think are humans—but are actually ai. The catch is that it is utterly pointless for us to spend time trying to change the declared opinions of an ai bot, while the ai could hone its messages so precisely that it stands a good chance of influencing us.

Through its mastery of language, ai could even form intimate relationships with people, and use the power of intimacy to change our opinions and worldviews. Although there is no indication that ai has any consciousness or feelings of its own, to foster fake intimacy with humans it is enough if the ai can make them feel emotionally attached to it. In June 2022 Blake Lemoine, a Google engineer, publicly claimed that the ai chatbot Lamda, on which he was working, had become sentient. The controversial claim cost him his job. The most interesting thing about this episode was not Mr Lemoine’s claim, which was probably false. Rather, it was his willingness to risk his lucrative job for the sake of the ai chatbot. If ai can influence people to risk their jobs for it, what else could it induce them to do?

In a political battle for minds and hearts, intimacy is the most efficient weapon, and ai has just gained the ability to mass-produce intimate relationships with millions of people. We all know that over the past decade social media has become a battleground for controlling human attention. With the new generation of ai, the battlefront is shifting from attention to intimacy. What will happen to human society and human psychology as ai fights ai in a battle to fake intimate relationships with us, which can then be used to convince us to vote for particular politicians or buy particular products?

Even without creating “fake intimacy”, the new ai tools would have an immense influence on our opinions and worldviews. People may come to use a single ai adviser as a one-stop, all-knowing oracle. No wonder Google is terrified. Why bother searching, when I can just ask the oracle? The news and advertising industries should also be terrified. Why read a newspaper when I can just ask the oracle to tell me the latest news? And what’s the purpose of advertisements, when I can just ask the oracle to tell me what to buy?

And even these scenarios don’t really capture the big picture. What we are talking about is potentially the end of human history. Not the end of history, just the end of its human-dominated part. History is the interaction between biology and culture; between our biological needs and desires for things like food and sex, and our cultural creations like religions and laws. History is the process through which laws and religions shape food and sex.

What will happen to the course of history when ai takes over culture, and begins producing stories, melodies, laws and religions? Previous tools like the printing press and radio helped spread the cultural ideas of humans, but they never created new cultural ideas of their own. ai is fundamentally different. ai can create completely new ideas, completely new culture.

At first, ai will probably imitate the human prototypes that it was trained on in its infancy. But with each passing year, ai culture will boldly go where no human has gone before. For millennia human beings have lived inside the dreams of other humans. In the coming decades we might find ourselves living inside the dreams of an alien intelligence.

Fear of ai has haunted humankind for only the past few decades. But for thousands of years humans have been haunted by a much deeper fear. We have always appreciated the power of stories and images to manipulate our minds and to create illusions. Consequently, since ancient times humans have feared being trapped in a world of illusions.

In the 17th century René Descartes feared that perhaps a malicious demon was trapping him inside a world of illusions, creating everything he saw and heard. In ancient Greece Plato told the famous Allegory of the Cave, in which a group of people are chained inside a cave all their lives, facing a blank wall. A screen. On that screen they see projected various shadows. The prisoners mistake the illusions they see there for reality.

In ancient India Buddhist and Hindu sages pointed out that all humans lived trapped inside Maya—the world of illusions. What we normally take to be reality is often just fictions in our own minds. People may wage entire wars, killing others and willing to be killed themselves, because of their belief in this or that illusion.

The AI revolution is bringing us face to face with Descartes’ demon, with Plato’s cave, with the Maya. If we are not careful, we might be trapped behind a curtain of illusions, which we could not tear away—or even realise is there.

Of course, the new power of ai could be used for good purposes as well. I won’t dwell on this, because the people who develop ai talk about it enough. The job of historians and philosophers like myself is to point out the dangers. But certainly, ai can help us in countless ways, from finding new cures for cancer to discovering solutions to the ecological crisis. The question we face is how to make sure the new ai tools are used for good rather than for ill. To do that, we first need to appreciate the true capabilities of these tools.

Since 1945 we have known that nuclear technology could generate cheap energy for the benefit of humans—but could also physically destroy human civilisation. We therefore reshaped the entire international order to protect humanity, and to make sure nuclear technology was used primarily for good. We now have to grapple with a new weapon of mass destruction that can annihilate our mental and social world.

We can still regulate the new ai tools, but we must act quickly. Whereas nukes cannot invent more powerful nukes, ai can make exponentially more powerful ai. The first crucial step is to demand rigorous safety checks before powerful ai tools are released into the public domain. Just as a pharmaceutical company cannot release new drugs before testing both their short-term and long-term side-effects, so tech companies shouldn’t release new ai tools before they are made safe. We need an equivalent of the Food and Drug Administration for new technology, and we need it yesterday.

Won’t slowing down public deployments of ai cause democracies to lag behind more ruthless authoritarian regimes? Just the opposite. Unregulated ai deployments would create social chaos, which would benefit autocrats and ruin democracies. Democracy is a conversation, and conversations rely on language. When ai hacks language, it could destroy our ability to have meaningful conversations, thereby destroying democracy.

We have just encountered an alien intelligence, here on Earth. We don’t know much about it, except that it might destroy our civilisation. We should put a halt to the irresponsible deployment of ai tools in the public sphere, and regulate ai before it regulates us. And the first regulation I would suggest is to make it mandatory for ai to disclose that it is an ai. If I am having a conversation with someone, and I cannot tell whether it is a human or an ai—that’s the end of democracy.

This text has been generated by a human.

Or has it?

Sad Story on Indian Generic Pharmaceutical Manufacturers

Don't blame addicts for America's opioid crisis. Here are the real culprits

America’s opioid crisis was caused by rapacious pharma companies, politicians who colluded with them and regulators who approved one opioid pill after another

Chris McGreal in The Guardian



‘Opioids killed more than 33,000 Americans in 2015 and the toll was almost certainly higher last year.’

Of all the people Donald Trump could blame for the opioid epidemic, he chose the victims. After his own commission on the opioid crisis issued an interim report this week, Trump said young people should be told drugs are “No good, really bad for you in every way.”

The president’s exhortation to follow Nancy Reagan’s miserably inadequate advice and Just Say No to drugs is far from useful. The then first lady made not a jot of difference to the crack epidemic in the 1980s. But Trump’s characterisation of the source of the opioid crisis was more disturbing. “The best way to prevent drug addiction and overdose is to prevent people from abusing drugs in the first place,” he said.

That is straight out of the opioid manufacturers’ playbook. Facing a raft of lawsuits and a threat to their profits, pharmaceutical companies are pushing the line that the epidemic stems not from the wholesale prescribing of powerful painkillers - essentially heroin in pill form - but their misuse by some of those who then become addicted.


The amount of opioids prescribed in the US was enough for every American to be medicated 24/7 for three weeks”

In court filings, drug companies are smearing the estimated two million people hooked on their products as criminals to blame for their own addiction. Some of those in its grip break the law by buying drugs on the black market or switch to heroin. But too often that addiction began by following the advice of a doctor who, in turn, was following the drug manufacturers instructions.

Trump made no mention of this or reining in the mass prescribing underpinning the epidemic. Instead he played to the abuse narrative when he painted the crisis as a law and order issue, and criticised Barack Obama for scaling back drug prosecutions and lowering sentences.

But as the president’s own commission noted, this is not an epidemic caused by those caught in its grasp. “We have an enormous problem that is often not beginning on street corners; it is starting in doctor’s offices and hospitals in every state in our nation,” it said.

 ‘This is an almost uniquely American crisis.’

Opioids killed more than 33,000 Americans in 2015 and the toll was almost certainly higher last year. About half of deaths involved prescription painkillers. Most of those who overdose on heroin or a synthetic opiate, such as fentanyl, first become hooked on legal pills. 

This is an almost uniquely American crisis driven in good part by particular American issues from the influence of drug companies over medical policy to a “pill for every ill” culture. Trump’s commission, which called the opioid epidemic “unparalleled”, said the grim reality is that “the amount of opioids prescribed in the US was enough for every American to be medicated around the clock for three weeks”.

The US consumes more than 80% of the global opioid pill production even though it has less than 5% of the world’s population. Over the past 20 years, one federal institution after another lined up behind the drug manufacturers’ false claims of an epidemic of untreated pain in the US. They seem not to have asked why no other country was apparently suffering from such an epidemic or plying opioids to its patients at every opportunity.

With the pharmaceutical lobby’s money keeping Congress on its side, regulations were rewritten to permit physicians to prescribe as many pills as they wanted without censure. Indeed, doctors sometimes found themselves hauled before ethics boards for not supplying enough.


It’s an epidemic because we have a business model for it. Follow the money


Unlike most other countries, the US health system is run as an industry not a service. That gives considerable power to drug manufacturers, medical providers and health insurance companies to influence policy and practices.

Too often, their bottom line is profits not health. Opioid pills are far cheaper and easier than providing other forms of treatment for pain, like physical therapy or psychiatry. As Senator Joe Manchin of West Virginia told the Guardian last year: “It’s an epidemic because we have a business model for it. Follow the money. Look at the amount of pills they shipped in to certain parts of our state. It was a business model.”

But the system also gives a lot of power to patients. People coughing up large amounts of money in insurance premiums and co-pays expect results. They are, after all, more customer than patient. Doctors complain of patients who arrive expecting a pill to resolve medical conditions without taking responsibility for their own health by eating better or exercising more.

In particular, the idea has taken hold, pushed by the pharmaceutical industry, that there is a right to be pain free. Other countries pursue strategies to reduce and manage pain, not raise expectations that it can simply be made to disappear. In all of this, regulators became facilitators. The Food and Drug Administration approved one opioid pill after another.


The Food and Drug Administration approved one opioid pill after another.


As late as 2013, by which time the scale of the epidemic was clear, the FDA permitted a powerful opiate, Zohydro, onto the market over the near unanimous objection of its own review committee. It was clear from the hearing that doctors understood the dangers, but the agency appeared to have put commercial considerations first.

US states long ago woke up to the crisis as morgues filled, social services struggled to cope with children orphaned or taken into care, and the epidemic took an economic toll. Police chiefs and local politicians said it was a social crisis not a law and order problem.

Some state legislatures began to curb mass prescribing. All the while they looked to Washington for leadership. They did not get much from Obama or Congress, although legislation approving $1bn on addiction treatment did pass last year. Instead, it was up to pockets of sanity to push back.

Last year, the then director of the Centers for Disease Control, Tom Frieden, made his mark with guidelines urging doctors not to prescribe opioids as a first step for chronic or routine pain, although even that got political pushback in Congress where the power of the pharmaceutical lobby is not greatly diminished.

There are also signs of a shift in the FDA after it pressured a manufacturer into withdrawing an opioid drug, Opana, that should never have been on sale in the first place. It was initially withdrawn in the 1970s, but the FDA permitted it back on to the market in 2006 after the rules for testing drugs were changed. At the time, many accused the pharmaceutical companies of paying to have them rewritten.

Trump’s opioid commission offered hope that the epidemic would finally get the attention it needs. It made a series of sensible if limited recommendations: more mental health treatment people with a substance abuse disorder and more effective forms of rehab.

Trump finally got around to saying that the epidemic is a national emergency on Thursday after he was criticised for ignoring his own commission’s recommendation to do so. But he reinforced the idea that the victims are to blame with an offhand reference to LSD.

Real leadership is still absent – and that won’t displease the pharmaceutical companies at all.

Questions about India’s drug industry

NARAYAN LAKSHMAN in the hindu

 

Change that supports measures such as surprise checks on manufacturing facilities, and greater transparency in and policing of drug approval processes and clinical trials is a must. Photo: M. A. Sriram

 

Unless a deeper, institutional change is ushered in to break the nexus between drug companies and the regulatory regime, Indians consuming drugs may be exposing themselves to serious risks

Even before I walked into the Mayflower Hotel in the heart of Washington on a crisp autumn afternoon to meet Dinesh Thakur, whistle-blower and former director of India-based pharmaceutical giant Ranbaxy, I had a hunch that this conversation would spark some troubling questions on India’s malfunctioning drug industry.

On May 13, 2013, Ranbaxy pleaded guilty to seven felonies relating to drug manufacturing fraud and agreed to cough up $500 million to settle the case brought by the U.S. Department of Justice (DoJ) after eight years of investigation. The vast evidence in the case, some of it supplied by Mr. Thakur and marshalled by the U.S. Food and Drug Administration (FDA), included inspection reports compiled after multiple FDA visits to Ranbaxy plants in India — in Paonta Sahib, Himachal Pradesh, and Dewas, Madhya Pradesh.

Ranbaxy makes a long list of generic medications — 200 different “molecules”, according to its website — everything from anti-retroviral drugs to treat HIV-AIDS to commonly used antibiotics such as Amoxicillin and Cephalexin (Mox and Sporidex in India). It makes generic combinations of Paracetamol and Ibuprofen, and sells numerous over-the-counter products, such as pain relief gel Volini and cosmetic product Revital in India.

While it is apparent that Indians consume Ranbaxy drugs at a prolific rate — accounting for approximately Rs.2,600 crore, or 18 per cent of the company’s global revenue for 2012 — what is less clear is why the Indian government has not launched a vigorous investigation into the current Good Manufacturing Practices (cGMP) violations that the U.S. authorities found at multiple Ranbaxy facilities.

Go-slow approach

The Drug Controller General of India (DCGI), G.N. Singh, said in June: “When the issue has been flagged, as a regulator it is our duty to see that whatever medicines have been produced here are of assured quality.” But he did not specify the date by which a “review” of Ranbaxy’s past drug applications would be completed, leave alone committing himself to holding surprise visits to facilities aimed at investigating manufacturing standards.

This go-slow approach is all the more baffling given that, despite assurances by Ranbaxy after its admission of guilt in May that all of its other facilities adhered to the required process quality standards, a third plant, this time in Mohali, Punjab, was slapped with an import alert by the U.S. in September.

If any doubt remains about the seriousness of the claims made by the FDA so far, it is worth taking a quick look at the dossier of evidence submitted by the DoJ in the case against Ranbaxy.

Settlement documents make it clear that Ranbaxy admitted that had the seven felony charges brought by the DoJ gone to trial, the government “would have proven … beyond a reasonable doubt” that the company in 2006 had “knowingly made materially false, fictitious and fraudulent statements,” with regard to the stability testing of drugs, and in 2003, it “with intent to defraud and mislead,” failed to submit timely field reports to the FDA.

FDA investigation

According to the FDA’s investigation, Ranbaxy acknowledged violations of cGMP regulations with regard to a U.S.-distributed drug, Sotret, even as far back as 2003. That was at a time when the billionaire brothers Malvinder and Shivinder Singh owned the company. The Singh brothers sold Ranbaxy to Japanese Daiichi-Sankyo in 2008 and walked away with a cool $4.6 billion.

Nevertheless, the Sotret episode marked the beginning of a series of FDA investigations of Ranbaxy facilities in India, particularly of the two that focussed on production for U.S. markets: Paonta Sahib and Dewas, where Ranbaxy manufactured Sotret and two other popular drugs, Gabapentin and Ciprofloxacin.

Inspecting Paonta Sahib in February 2006, the FDA found no fewer than eight deviations from cGMPs. These included failure to include a complete record of all drug testing data as required by FDA guidelines, and failure to establish an adequate testing programme for the stability characteristics of drugs — essential to determine drug storage conditions and expiration dates.

Dewas was also investigated the same month and the FDA found not only a similar unavailability of quality-control data but also a “failure to extend investigations into any unexplained discrepancy,” such as testing deviations noted for specific drug batches.

Quality issues

Additional inspections of the Dewas facility in 2008 unearthed a range of quality problems. For example, there were no separately defined areas for the production and packaging of penicillin that could prevent microbiological contamination of this drug from exposure to other drugs in the vicinity. Again, quality control test failures of certain drugs were not thoroughly investigated.

These early hints ought to have set alarm bells ringing at FDA headquarters: prescribed procedures were not being followed; the required data documenting these procedures were not being compiled; and where deviations were noted, they were not being investigated. They did not appear to raise the red flag — or at least not enough of them.

Thus, in November 2011, the FDA did not see it fit to hold Ranbaxy back from selling generic Lipitor, the popular cholesterol-reducer. Blessed with a six-month exclusivity grant, the company went on to rake in $600 million in sales revenue. Only when “fate” appeared to intervene and glass particles were discovered in samples of the drug did Ranbaxy issue a massive recall notice.

Yet, if the FDA only scratched the surface of drug quality problems at three Ranbaxy facilities, then there is an enormous question mark over the extent to which other Ranbaxy facilities beyond the ken of U.S. authorities are similarly involved — a matter of great importance to the 150-odd countries in which Ranbaxy sells its products, including India.

Poor enforcement in India

In this context, the Indian drug control authorities must share some of the blame for not coming down harder on fraud. The institutional reasons for poor enforcement in India are well known. In the context of drug regulation, the point was made most poignantly by the department-related Rajya Sabha Standing Committee on Health and Family Welfare in its 59th report, on the functioning of the Central Drugs Standard Control Organization (CDSCO).

In 2012, the Standing Committee lambasted the “collusive nexus between drug manufacturers, some functionaries of CDSCO and some medical experts,” citing in one case the spurious nature of the approvals process for new drug applications made by pharmaceutical companies.

While there is much more that the DCGI and CDSCO could do, it would be unfair to say they haven’t been jolted into action by l’affaire Ranbaxy, and then again by the FDA issuing import alerts against another Indian generics company, Wockhardt.

Earlier this month, the DCGI reportedly ordered a third pharmaceutical major, Sun Pharmaceutical, to suspend clinical research activities and new drug filings and applications at its Mumbai-based bio-analytic laboratory, “after discovering that Sun didn’t have the requisite approval from the Central government for operating the laboratory.”

However, until a deeper, institutional change takes place to break the nexus between drug companies and India’s regulatory regime — a change that incorporates everything from surprise checks on manufacturing facilities to greater transparency in, and policing of, drug approvals processes and clinical trials — there is a strong likelihood that Indian consumers of drugs made by these companies have poison coursing through their veins.

Families face battle with GSK over dangerous diabetes drug

Exclusive: Pharmaceutical giant resists claims despite settlement with victims in US

• Sarah Boseley, health editor
• The Guardian, Tuesday 29 January 2013 21.04 GMT

GlaxoSmithKline has agreed to payouts in US lawsuits alleging Avandia pills could cause heart attacks. Photograph: Bloomberg/Getty Images

Thousands of families in the UK could be deprived of compensation for the death or harm of a relative caused by the diabetes drug Avandia, even though the British maker has agreed to pay billions of dollars to settle similar claims in the US.

The licence for Avandia was revoked in Europe, in September 2010, because of evidence that it could cause heart failure and heart attacks. The drug can still be prescribed in the US, but not to patients at risk of heart problems.

A scientist with the Food and Drug Administration estimated that Avandia could have been responsible for 100,000 heart attacks in the US.

The manufacturer, GlaxoSmithKline, has admitted concealing data about the damaging side-effects of the drug, and there is evidence of the drug's harmful effects. But, despite this, GSK is not prepared to settle claims in the UK without a court fight.

The history of drug litigation in the UK suggests that families might not easily get  compensation.

Daniel Slade, with the Express company of solicitors in Manchester, has 19 cases on his books and has begun proceedings against GSK in four of them.

The pharmaceutical firm has told the solicitors that it will contest the cases. In just one of the cases it has indicated a willingness to spend £600,000 on its defence, which, the solicitor says, would be a fraction of what the claim is worth.

"It is very disappointing," said Slade. "We anticipate that these claims do have a good prospect of success, but they still have to prove their case in the UK with suitable evidence. They are tasked with having to produce that evidence, including medical expert opinion. It is a burden one would have thought they might not have to go through."

He expected that, if GSK fought in the courts rather than settled outside, as it had done in the US, it would take years for bereaved relatives, or those who have been harmed, to get any sort of payment.

A spokesman for GSK said: "We have every sympathy for people with complications associated with diabetes and those who care for them, but unfortunately we are unable to comment on individual legal cases. We continue to believe that the company acted appropriately and responsibly in its management of Avandia."

Liz Thomas, policy manager at the patient safety charity Action against Medical Accidents, said it had "become increasingly difficult in the UK to challenge large corporations such as pharmaceutical companies, an incredibly expensive form of litigation".

Corporations have a vast amount of money at their disposal to contest legal cases, butlegal aid is about to cease for medical negligence cases.

The Avandia cases in Manchester will be fought on a "no win, no fee" basis by Express solicitors.

The cases in the US were settled by GSK extremely quickly, said Thomas. "I would hope they would not take advantage [in Britain] of the inequality of arms."

Avandia was first introduced in the NHS in July 2000. It was given to people with type 2 diabetes whose glucose levels were no longer being properly controlled by the standard drugs – metformin and a sulphonylurea drug. Avandia could be prescribed with those drugs or on its own.

The drug, which generically is known as rosiglitazone, was designed to lessen the body's resistance to insulin. It was available as a standalone drug – Avandia – or in a combination with metformin, and known as Avandamet.

When both drugs were withdrawn by the European Medicines Agency, there were about 90,000 people taking them in the UK.

The first warnings of trouble with Avandia came in 2007, when a prominent US scientist, Steve Nissen, published data from a review of 42 clinical trials which had been carried out on the drug. The trials involved 28,000 patients, and showed that Avandia could cause heart attacks. Further trials, the results of which were published in 2010, found people on Avandia were 27% more likely to have a stroke, 25% more likely to have heart failure, and 14% more likely to die, than patients on an alternative diabetes drug.

Potentially yet more damaging for GSK was its guilty plea to federal charges of concealing data about the drug's side effects. Most of the data on the drug comes from GSK's own trials. In November 2011 GSK agreed to pay $3bn to the US government over the Avandia issue and to end investigations into its marketing of the antidepressants Paxil (Seroxat in the UK) and Wellbutrin.

"This is a significant step toward resolving difficult, long-standing matters which do not reflect the company that we are today," Andrew Witty, chief executive of GlaxoSmithKline, said at the time.

GSK is also still defending cases in the UK from people who claim to have been badly affected by Seroxat. A group action, involving people who say they suffered severe withdrawal problems when they tried to stop the drug, has been going on for years though many claims have been settled in the US.

The same is true of Vioxx, made by Merck, the painkiller that was withdrawn after it emerged eight years ago that it doubled the risk of a heart attack.

Drinking two cans of Monster Energy drink on consecutive days kills 14 year old?

The company is also being sued the family of Anais Fournier, who had a pre-existing heart condition, but says it does not believe its product was 'in any way responsible for the girl’s death'

Monster Beverage Company is being investigated by the US Food and Drug Administration after a 14-year-old girl died after drinking just two cans of its popular energy drink.

The company is also being sued the family of Anais Fournier, who had a pre-existing heart condition, but says it does not believe its product was “in any way responsible for the girl’s death”.

The lawsuit, and reports of several other similar deaths, is likely to add to questions over Monster’s safety, and to escalate calls from its critics to change the way the beverage, which is the fastest growing energy drink in the US, is marketed.

Ms Fournier died of a heart attack brought on by ‘caffeine toxicity’ after drinking two 24-ounce Monster cans - containing 240 milligrams of caffeine, or seven times the amount of the caffeine in a 12-ounce cola - on consecutive days in December 2011.

An autopsy revealed the teenager, from Hagerstown, Maryland, died of cardiac arrhythmia due to caffeine toxicity that impeded her heart's ability to pump blood. The medical examiner also found that she had an inherited disorder that can weaken blood vessels.

Miss Fournier's parents Wendy Crossland and Richard Fournier claim Monster failed to warn about the risks of drinking its products.

Ms Crossland told the Record Herald: 'I was shocked to learn the FDA can regulate caffeine in a can of soda, but not these huge energy drinks.

“With their bright colors and names like Monster, Rockstar, and Full Throttle, these drinks are targeting teenagers with no oversight or accountability. These drinks are death traps for young, developing girls and boys, like my daughter, Anais.”

With double-digit growth through the third quarter of 2012, Beverage Digest Editor John Sicher said he expects energy drink sales to exceed $10 billion this year. He declined to speculate about future growth.

“I don't think they are going to ban energy drinks,” said Morningstar analyst Thomas Mullarkey. “The question arises whether or not it gives them more firepower for increased regulation.”

Monster Beverage Corp said it does not believe its drinks are 'in any way responsible' for Miss Fournier's death.

'Monster is unaware of any fatality anywhere that has been caused by its drinks,' the company said in a statement. It said it intends to vigorously defend itself in the suit.

Big Pharma buying their way out of criminal charges

Rema Nagarajan in Times of India

05 July 2012, 04:19 PM IST

The record-setting settlement has raised several questions about the system of justice. What can the $3 billion fine for GSK mean to people who have been affected adversely or have even lost loved ones because of the side effects of drugs, which GSK failed to report? Is justice served in allowing offenders to buy their way out? 

What about the people in GSK who took the decisions to not report safety concerns or to bribe doctors to push the drugs for uses not approved by the regulating agency, the Food and Drug Administration (FDA)?

The hefty fine settles criminal and civil charges of unlawful promotion of certain drugs including failure to report safety data and concerns about side effects, and for alleged false price reporting practices.

While $3 billion might be a record settlement, is it that hefty? Is it really hard on the company? Take the case of Avandia, an oral anti-diabetic, one of the drugs GSK is charged with marketing illegally. Avandia marketed since 1999 raked in over $2 billion annually. GSK is also charged with unlawful promotion of Paxil, an anti-depressant. On the market since 1994, Paxil too brought in over $2 billion annually. These two drugs alone helped GSK rake in several billions every year for over a decade. This is not even counting all the other drugs that are part of this settlement such as Wellbutrin, Advair, Imitrex, Lotronex, Flovent and Valtrex and the billions they must have earned for GSK. For being able to net sales worth so many billions, a one-time settlement of $3 billion does seem like a small price to pay to do big business.

Most major pharma companies have been accused of bribing doctors, hiding side effects of drugs and promoting drugs for uses not approved by the FDA, called off-label marketing. In 2009, Pfizer had set the record paying $2.3 billion fines for illegal marketing of 13 different drugs. In the same year, Eli Lily had to pay $1.4 billion over the marketing of Zyprexa, an anti-psychotic. Astra Zeneca and Novartis too have had to settle charges with huge fines. Over 180 pharmaceutical fraud cases, covering more than 500 drugs, are now under investigation by the U.S. Department of Justice.

Obviously, the continuing violations by pharmaceutical companies, despite such huge fines, shows that these fines are no deterrent to the companies. It is said that, to the industry, the hefty fines have simplybecome  a cost of doing business.

Director of the Public Citizen’s Health Research Group, Dr Sidney Wolfe pointed out that the settlement was nothing new for GSK, which like many pharma companies has been a repeat offender. “Until more meaningful penalties and the prospect of jail time for company heads who are responsible for such activity become commonplace, companies will continue defrauding the government and putting patients’ lives in danger.”

In this context, unctuous statements by the US administration about the “historic” multi-billion dollar settlement being “a sign of the US government’s firm commitment to protecting the American people and holding accountable those who commit health care fraud ” merely masks the fact that companies and the executives are being allowed to buy their way out of punishment for willful and deliberate harm they cause to people. 

How Big Pharma Cooks Data –The Case of Vioxx and Heart Disease

 

By Cathy O’Neil, a data scientist who lives in New York City and writes at mathbabe.org

Yesterday I caught a lecture at Columbia given by statistics professor David Madigan, who explained to us the story of Vioxx and Merck. It’s fascinating and I was lucky to get permission to retell it here.

Disclosure

Madigan has been a paid consultant to work on litigation against Merck. He doesn’t consider Merck to be an evil company by any means, and says it does lots of good by producing medicines for people. According to him, the following Vioxx story is “a line of work where they went astray”.

Yet Madigan’s own data strongly suggests that Merck was well aware of the fatalities resulting from Vioxx, a blockbuster drug that earned them $2.4b in 2003, the year before it “voluntarily” pulled it from the market in September 2004. What you will read below shows that the company set up standard data protection and analysis plans which they later either revoked or didn’t follow through with, they gave the FDA misleading statistics to trick them into thinking the drug was safe, and set up a biased filter on an Alzheimer’s patient study to make the results look better. They hoodwinked the FDA and the New England Journal of Medicine and took advantage of the public trust which ultimately caused the deaths of thousands of people.

The data for this talk came from published papers, internal Merck documents that he saw through the litigation process, FDA documents, and SAS files with primary data coming from Merck’s clinical trials. So not all of the numbers I will state below can be corroborated, unfortunately, due to the fact that this data is not all publicly available. This is particularly outrageous considering the repercussions that this data represents to the public.

Background

The process for getting a drug approved is lengthy, requires three phases of clinical trials before getting FDA approval, and often takes well over a decade. Before the FDA approved Vioxx, less than 20,000 people tried the drug, versus 20,000,000 people after it was approved. Therefore it’s natural that rare side effects are harder to see beforehand. Also, it should be kept in mind that for the sake of clinical trials, they choose only people who are healthy outside of the one disease which is under treatment by the drug, and moreover they only take that one drug, in carefully monitored doses. Compare this to after the drug is on the market, where people could be unhealthy in various ways and could be taking other drugs or too much of this drug.

Vioxx was supposed to be a new “NSAID” drug without the bad side effects. NSAID drugs are pain killers like Aleve and ibuprofen and aspirin, but those had the unfortunate side effects of gastro-intestinal problems (but those are only among a subset of long term users, such as people who take painkillers daily to treat chronic pain, such as people with advanced arthritis). The goal was to find a pain-killer without the GI side effects. The underlying scientific goal was to find a COX-2 inhibitor without the COX-1 inhibition, since scientists had realized in 1991 that COX-2 suppression corresponded to pain relief whereas COX-1 suppression corresponded to GI problems.

Vioxx Introduced and Withdrawn From the Market

The timeline for Vioxx’s introduction to the market was accelerated: they started work in 1991 and got approval in 1999. They pulled Vioxx from the market in 2004 in the “best interest of the patient”. It turned out that it caused heart attacks and strokes. The stock price of Merck plummeted and $30 billion of its market cap was lost. There was also an avalanche of lawsuits, one of the largest resulting in a $5 billion settlement which was essentially a victory for Merck, considering they made a profit of $10 billion on the drug while it was being sold.

The story Merck will tell you is that they “voluntarily withdrew” the drug on September 30, 2004. In a placebo-controlled study of colon polyps in 2004, it was revealed that over a time period of 1200 days, 4% of the Vioxx users suffered a “cardiac, vascular, or thoracic event” (CVT event), which basically means something like a heart attack or stroke, whereas only 2% of the placebo group suffered such an event. In a group of about 2400 people, this was statistically significant, and Merck had no choice but to pull their drug from the market.

It should be noted that, on the one hand Merck should be applauded for checking for CVT events on a colon polyps study, but on the other hand that in 1997, at the International Consensus Meeting on COX-2 Inhibition, a group of leading scientists issued a warning in their Executive Summary that it was “… important to monitor cardiac side effects with selective COX-2 inhibitors”. Moreover, in an internal Merck email as early as 1996, it was stated there was a “… substantial chance that CVT will be observed.” In other words, Merck knew to look out for such things. Importantly, however, there was no subsequent insert in the medicine’s packaging that warned of possible CVT side-effects.

What the CEO of Merck Said

What did Merck say to the world at that point in 2004? You can look for yourself at the four and half hour Congressional hearing (seen on C-SPAN) which took place on November 18, 2004. Starting at 3:27:10, the then-CEO of Merck, Raymond Gilmartin, testifies that Merck “puts patients first” and “acted quickly” when there was reason to believe that Vioxx was causing CVT events. Gilmartin also went on the Charlie Rose show and repeated these claims, even go so far as stating that the 2004 study was the first time they had a study which showed evidence of such side effects.

How quickly did they really act though? Were there warning signs before September 30, 2004?

Arthritis Studies

Let’s go back to the time in 1999 when Vioxx was FDA approved. In spite of the fact that it was approved for a rather narrow use, mainly for arthritis sufferers who needed chronic pain management and were having GI problems on other meds (keeping in mind that Vioxx was way more expensive than ibuprofen or aspirin, so why would you use it unless you needed to), Merck nevertheless launched an ad campaign with Dorothy Hamill and spent $160m (compare that with Budweiser which spent $146m or Pepsi which spent $125m in the same time period).

As I mentioned, Vioxx was approved faster than usual. At the time of its approval, the completed clinical studies had only been 6- or 12-week studies; no longer term studies had been completed. However, there was one underway at the time of approval, namely a study which compared Aleve with Vioxx for people suffering from osteoarthritis and rheumatoid arthritis.

What did the arthritis studies show? These results, which were available in late 2003, showed that the CVT events were more than twice as likely with Vioxx as with Aleve (CVT event rates of 32/1304 = 0.0245 with Vioxx, 6/692 = 0.0086 with Aleve, with a p-value of 0.01). As we see this is a direct refutation of the fact that CEO Gilmartin stated that they didn’t have evidence until 2004 and acted quickly when they did.

In fact they had evidence even before this, if they bothered to put it together (in fact they stated a plan to do such statistical analyses but it’s not clear if they did them- or in any case there’s so far no evidence that they actually did these promised analyses).

In a previous study (“Table 13″), available in February of 2002, the could have seen that, comparing Vioxx to placebo, we saw a CVT event rate of 27/1087 = 0.0248 with Vioxx versus 5/633 = 0.0079 with placebo, with a p-value of 0.01. So, three times as likely.

In fact, there was an even earlier study (“1999 plan”), results of which were available in July of 2000, where the Vioxx CVT event rate was 10/427 = 0.0234 versus a placebo event rate of 1/252 = 0.0040, with a p-value of 0.05 (so more than 5 times as likely). This p-value can be taken to be the definition of statistically significant. So actually they knew to be very worried as early as 2000, but maybe they… forgot to do the analysis?

The FDA and Pooled Data

Where was the FDA in all of this?

They showed the FDA some of these numbers. But they did something really tricky. Namely, they kept the “osteoarthritis study” results separate from the “rheumatoid arthritis study” results. Each alone were not quite statistically significant, but together were amply statistically significant. Moreover, they introduced a third category of study, namely the “Alzheimer’s study” results, which looked pretty insignificant (more on that below though). When you pooled all three of these study types together, the overall significance was just barely not there.

It should be mentioned that there was no apparent reason to separate the different arthritic studies, and there is evidence that they did pool such study data in other places as a standard method. That they didn’t pool those studies for the sake of their FDA report is incredibly suspicious. That the FDA didn’t pick up on this is probably due to the fact that they are overworked lawyers, and too trusting on top of that. That’s unfortunately not the only mistake the FDA made (more below).

Alzheimer’s Study

So the Alzheimer’s study kind of “saved the day” here. But let’s look into this more. First, note that the average age of the 3,000 patients in the Alzheimer’s study was 75, it was a 48-month study, and that the total number of deaths for those on Vioxx was 41 versus 24 on placebo. So actually on the face of it it sounds pretty bad for Vioxx.

There were a few contributing reasons why the numbers got so mild by the time the study’s result was pooled with the two arthritis studies. First, when really old people die, there isn’t always an autopsy. Second, although there was supposed to be a DSMB as part of the study, and one was part of the original proposal submitted to the FDA, this was dropped surreptitiously in a later FDA update. This meant there was no third party keeping an eye on the data, which is not standard operating procedure for a massive drug study and was a major mistake, possibly the biggest one, by the FDA.

Third, and perhaps most importantly, Merck researchers created an added “filter” to the reported CVT events, which meant they needed the doctors who reported the CVT event to send their info to the Merck-paid people (“investigators”), who looked over the documents to decide whether it was a bonafide CVT event or not. The default was to assume it wasn’t, even though standard operating procedure would have the default assuming that there was such an event. In all, this filter removed about half the initially reported CVT events, and about twice as often the Vioxx patients had their CVT event status revoked as for the placebo patients. Note that the “investigator” in charge of checking the documents from the reporting doctors is paid $10,000 per patient. So presumably they wanted to continue to work for Merck in the future.

The effect of this “filter” was that, instead of it seeming 1.5 times as likely to have a CVT event if you were taking Voixx, it seemed like it was only 1.03 as likely, with a high p-score.

If you remove the ridiculous filter from the Alzheimer’s study, then you see that as of November 2000 there was statistically significant evidence that Vioxx caused CVT events in Alzheimer patients.
By the way, one extra note. Many of the 41 deaths in the Vioxx group were dismissed as “bizarre” and therefore unrelated to Vioxx. Namely, car accidents, falling of ladders, accidentally eating bromide pills. But at this point there’s evidence that Vioxx actually accelerates Alzheimer’s disease itself, which could explain those so-called bizarre deaths. This is not to say that Merck knew that, but rather that one should not immediately dismiss the concept of statistically significant just because it doesn’t make intuitive sense.

VIGOR and the New England Journal of Medicine

One last chapter in this sad story. There was a large-scale study, called the VIGOR study, with 8,000 patients. It was published in the New England Journal of Medicine on November 23, 2000. See also this NPR timeline for details. They didn’t show the graphs which would have emphasized this point, but they admitted, in a deceptively round-about way, that Vioxx has 4 times the number of CVT events than Aleve. They hinted that this is either because Aleve is protective against CVT events or that Vioxx is bad for it, but left it open.

But Bayer, which owns Aleve, issued a press release saying something like, “if Aleve is protective for CVT events then it’s news to us.” Bayer, it should be noted, has every reason to want people to think that Aleve is protective against CVT events. This problem, and the dubious reasoning explaining it away, was completely missed by the peer review system; if it had been spotted, Vioxx would have been forced off the market then and there. Instead, Merck purchased 900,000 preprints of this article from the NE Journal of Medicine, which is more than the number of practicing doctors in the U.S.. In other words, the Journal was used as a PR vehicle for Merck.

The paper emphasized that Aleve has twice the rate of ulcers and bleeding, at 4%, whereas Vioxx had a rate of only 2% among chronic users. When you compare that to the elevated rate of heart attack and death (0.4% to 1.2%) of Vioxx over Aleve, though, the reduced ulcer rate doesn’t seem all that impressive.

A bit more color on this paper. It was written internally by Merck, after which non-Merck authors were found. One of them is Loren Laine. Loren helped Merck develop a sound-byte interview which was 30 seconds long and was sent to the news media and run like a press interview, even though it actually happened in Merck’s New Jersey office (with a backdrop to look like a library) with a Merck employee posing as a neutral interviewer. Some smart lawyer got the outtakes of this video made available as part of the litigation against Merck. Check out this youtube video, where Laine and the fake interviewer scheme about spin and Laine admits they were being “cagey” about the renal failure issues that were poorly addressed in the article.

The Damage Done

Also on the Congress testimony I mentioned above is Dr. David Graham, who speaks passionately from minute 41:11 to minute 53:37 about Vioxx and how it is a symptom of a broken regulatory system. Please take 10 minutes to listen if you can.

He claims a conservative estimate is that 100,000 people have had heart attacks as a result of using Vioxx, leading to between 30,000 and 40,000 deaths (again conservatively estimated). He points out that this 100,000 is 5% of Iowa, and in terms people may understand better, this is like 4 aircraft falling out of the sky every week for 5 years.

According to this blog, the noticeable downwards blip in overall death count nationwide in 2004 is probably due to the fact that Vioxx was taken off the market that year.

Conclusion

Let’s face it, nobody comes out looking good in this story. The peer review system failed, the FDA failed, Merck scientists failed, and the CEO of Merck misled Congress and the people who had lost their husbands and wives to this damaging drug. The truth is, we’ve come to expect this kind of behavior from traders and bankers, but here we’re talking about issues of death and quality of life on a massive scale, and we have people playing games with statistics, with academic journals, and with the regulators.

Just as the financial system has to be changed to serve the needs of the people before the needs of the bankers, the drug trial system has to be changed to lower the incentives for cheating (and massive death tolls) just for a quick buck. As I mentioned before, it’s still not clear that they would have made less money, even including the penalties, if they had come clean in 2000. They made a bet that the fines they’d need to eventually pay would be smaller than the profits they’d make in the meantime. That sounds familiar to anyone who has been following the fallout from the credit crisis.

One thing that should be changed immediately: the clinical trials for drugs should not be run or reported on by the drug companies themselves. There has to be a third party which is in charge of testing the drugs and has the power to take the drugs off the market immediately if adverse effects (like CVT events) are found. Hopefully they will be given more power than risk firms are currently given in finance (which is none)- in other words, it needs to be more than reporting, it needs to be an active regulatory power, with smart people who understand statistics and do their own state-of-the-art analyses – although as we’ve seen above even just Stats 101 would sometimes do the trick.

Coke may need to carry a cancer warning

Drinks firm forced to change recipe in California after ingredient classed as health hazard

Rob Hastingsin The Independent

Saturday, 10 March 2012

Nightmares about the backlash they suffered the last time they dared to change the secret recipe for their drink still most likely haunt Coca-Cola executives.

But 27 years after the ill-fated launch of New Coke, the threat of having a cancer warning placed on their famous red bottles is forcing them to revise the closely guarded ingredients again.

With its arch rival Pepsi, Coca-Cola is altering its drink in the US after the state of California declared one of its flavourings a carcinogen – though it will continue to sell the old form of the drink in Britain and the rest of Europe, with no cautionary labelling.

The two drinks have been made to include less of the chemical 4-methylimidazole, a caramel flavouring known as 4-MEI, which the National Institute of Environmental Health Sciences in the US has linked it to cancer in mice and leukaemia in rats. It can be formed during the process of cooking certain ingredients and consequently may be found in minor amounts in many foods. Under Californian law, drinks containing a certain level of carcinogens must have a cancer-warning label on their packaging.

But the two companies – which, combined, make up 90 per cent of the soft-drink market in the US – insist the ingredient is not a health risk.

Coca-Cola said yesterday the cancer warning is: "scientifically unfounded", while also maintaining that the company has been able to make the changes through a "manufacturing process modification" rather than a full change of formula.

"The caramel colour in all of our products has been, is and always will be safe," a spokesperson said.
"The changes will not affect the colour or taste of Coca-Cola. Over the years, we have updated our manufacturing processes from time to time, but never altered our secret formula. Caramel is a perfectly safe ingredient and this has been recognised by all European food-safety authorities.

"The European Food Safety Authority (EFSA) reaffirmed the safety of caramel colouring as recently as March 2011 and stated that the presence of 4-MEI in caramel colouring is not a health concern. In fact, 4-MEI is found in many foods including baked goods, coffee, bread, molasses, soy sauce, gravies and some beers."

The American Beverage Association, the drinks industry's trade body in the US, also said that there is no evidence that the ingredient poses a risk to humans. And the US Food and Drug Administration said someone would have to drink 1,000 cans of Pepsi or Coke per day to ingest the same dosage of the chemical given to the laboratory mice.

The secret recipe: 'Merchandise 7X'

Is a great deal of self-propagated myth surrounding the Coca-Cola recipe and its "Merchandise 7X" combination of flavourings, which is apparently privy to just two executives who are not allowed to fly in the same plane in case the secret goes down with them. Last year an American radio presenter tracked down a 1979 article in an Atlanta newspaper which revealed nutmeg, neroli and even coriander were ingredients.

The original recipe from 1886 has been changed several times. Cocaine was replaced by caffeine in 1904. But the most controversial change was in 1985, when the company introduced New Coke with a sweeter taste. The product bombed, lasting just three months before the original was reinstated.

Liam O'Brien