The drugs do work, but they can't cure unhappiness

Antidepressants are sometimes prescribed when they aren't needed, but never to use them is to miss an opportunity

• Tim Cantopher
• theguardian.com, Wednesday 20 November 2013 16.20 GMT

Antidepressants buy you time to sort out the issues that caused the depression in the first place. Photograph: Cultura/Rex Features

I can't stand zealots. Unfortunately, the literature on antidepressants is full of them. I'm not impressed by the protagonists in the polarised argument over the efficacy or otherwise of these drugs, whose positions are firmly held and loudly proclaimed. Many researchers appear to have written the conclusion of their study before the protocol.

At the one pole are the pharmaceutical industry and academic psychopharmacologists. I'll call them the pros. They urge us to practise only evidence-based medicine, by which they mean following rigid protocols based on treatments that have achieved positive results either in double-blind placebo-controlled drug trials, or meta-analyses (a method for grouping together results from several trials). Most of these studies focus on antidepressants because their effects are easy to measure.

The pros despise any practice not based on this narrow definition of evidence. One of them once told me: "Employing clinical experience to decide how to treat patients means continuing to make the same mistakes and never learning from them." So much for the lessons I've learned from treating about 3,000 people with this illness.

At the other pole are a group of naysayers who assert that antidepressants don't work any better than placebo. I'll call them the cons. They use the available statistics in the way best suited to their argument and are equally dismissive of any contrary view.

It's part of our culture to take up polarised positions. Our political and legal systems are based on this premise and our media rely on it. The middle ground isn't interesting and is rarely aired. It is this environment in which the pros and cons dominate the literature on antidepressants. Meanwhile, sufferers from the depressive illness don't know which way to turn.

The root of the problem is that good research is difficult and limited. Research is good at showing big effects in large groups of people. It's not so good at showing more subtle, or difficult to define, effects in subgroups of people. The results of your study will depend on whom you study, what you measure, what you define as an effect and what you do with your data.

The cons say that the pros have suppressed some findings that didn't suit them. If you compare two identical groups 20 times, you will find an apparently significant difference between them once. Test your ineffective antidepressant 20 times and you'll be able to publish a positive result, so long as you suppress the other 19. We clinicians knew this was happening years ago. One particular antidepressant was known by everyone to lack efficacy, yet the studies appeared to show that it worked as well as all the rest. Something was wrong with the published research and it seems we may now know what it was. Recent research seems to under-report some side-effects and withdrawal effects of antidepressants.

The cons are equally selective. They point to meta-analyses showing that antidepressants don't out-perform placebo sufficiently to reach this arbitrary level of significance. They conclude that antidepressants don't work. This is the oldest misuse of statistics in the book. An insignificant difference doesn't mean that you've proven no difference; it just means that you haven't proved that there is one.

Another issue is failing to exclude the outlier. As I've already pointed out, one expects occasional misleading results from research. A meta-analysis should deal with this problem by excluding from the analysis any study with results wildly different from all the others. The pros say that this hasn't always happened in the cons' analyses, potentially producing misleadingly negative results.

So research is failing us in this field. Unfashionable though this is in the environment currently existing in medicine, it means we clinicians need to use our experience, powers of observation and common sense, bearing in mind the experience of other clinicians.

We need to take note of the available research, while also taking a critical view of it. Here is the upshot, accepted by most of us on the ground: antidepressants usually work, but only for real clinical depression, the type involving a chemical disturbance in the brain, with a full range of characteristic physical symptoms. They don't work for unhappiness, grief or chemically induced depression and if you take them irregularly or for too short a period, the depression comes back.

Prescription numbers are rising mainly because doctors are getting better at identifying depression, though antidepressants are sometimes prescribed when they aren't needed and won't work. Except for people suffering from recurrent depression they are only first aid, buying you time to sort out the issues that caused the depression in the first place, but never to use them is to miss an opportunity to provide relief from this horrible illness.

Dr Tim Cantopher, consultant psychiatrist, Priory Hospitals Group, author of Depressive Illness – the Curse of the Strong (Sheldon)

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.

WikiLeaks publishes secret draft chapter of Trans-Pacific Partnership

Treaty negotiated in secret between 12 nations 'would trample over individual rights and free expression', says Julian Assange

• Alex Hern and Dominic Rushe
• theguardian.com, Wednesday 13 November 2013 18.12 GMT

Demonstrators protest against the Trans-Pacific Partnership (TPP) after the May Day rally in Tokyo, Japan. Photograph: EPA/Kimimasa Mayama

WikiLeaks has released the draft text of a chapter of the Trans-Pacific Partnership (TPP) agreement, a multilateral free-trade treaty currently being negotiated in secret by 12 Pacific Rim nations.

The full agreement covers a number of areas, but the chapter published by WikiLeaks focuses on intellectual property rights, an area of law which has effects in areas as diverse as pharmaceuticals and civil liberties.

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Also Read

Transatlantic Trade and Investment Partnership: Wake up people, we’re being shafted

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Negotiations for the TPP have included representatives from the United States, Canada, Australia, New Zealand, Japan, Mexico, Malaysia, Chile, Singapore, Peru, Vietnam, and Brunei, but have been conducted behind closed doors. Even members of the US Congress were only allowed to view selected portions of the documents under supervision.

"We're really worried about a process which is so difficult for those who take an interest in these agreements to deal with. We rely on leaks like these to know what people are talking about," says Peter Bradwell, policy director of the London-based Open Rights Group.

"Lots of people in civil society have stressed that being more transparent, and talking about the text on the table, is crucial to give treaties like this any legitimacy. We shouldn't have to rely on leaks to start a debate about what's in then."

The 30,000 word intellectual property chapter contains proposals to increase the term of patents, including medical patents, beyond 20 years, and lower global standards for patentability. It also pushes for aggressive measures to prevent hackers breaking copyright protection, although that comes with some exceptions: protection can be broken in the course of "lawfully authorised activities carried out by government employees, agents, or contractors for the purpose of law enforcement, intelligence, essential security, or similar governmental purposes".

WikiLeaks claims that the text shows America attempting to enforce its highly restrictive vision of intellectual property on the world – and on itself. "The US administration is aggressively pushing the TPP through the US legislative process on the sly," says Julian Assange, the founder and editor-in-chief of WikiLeaks, who is living in the Ecuadorean embassy in London following an extradition dispute with Sweden, where he faces allegations of rape.

"If instituted," Assange continues, "the TPP’s intellectual property regime would trample over individual rights and free expression, as well as ride roughshod over the intellectual and creative commons. If you read, write, publish, think, listen, dance, sing or invent; if you farm or consume food; if you’re ill now or might one day be ill, the TPP has you in its crosshairs."

Just Foreign Policy, a group dedicated to reforming US foreign policy, managed to crowdfund a $70,000 (£43,700) bounty for Wikileaks if the organisation managed to leak the TPP text. "Our pledge, as individuals, is to donate this money to WikiLeaks should it leak the document we seek." The conditions the group set have not yet been met, however, because it required the full text, not individual chapters.

Related to the TPP is a second secret trade agreement, the Transatlantic Trade and Investment Partnership (TTIP), which ties together regulatory practices in the US and EU. George Monbiot, writing in this paper, referred to the treaty as a "monstrous assault on democracy". Ken Clarke, the minister without portfolio, replied that it "would see our economy grow by an extra £10bn per annum".

Campaign group Fight for the Future has already collected over 100,000 signatures in an online petition against what it calls the “extreme Internet censorship plan: contained in the TPP.

Evan Greer, campaign manager for Fight for the Future, said: "The documents revealed by WikiLeaks make it clear why the US government has worked so hard to keep the TPP negotiatons secret. While claiming to champion an open Internet, the Obama administration is quietly pushing for extreme, SOPA-like copyright policies that benefit Hollywood and giant pharmaceutical companies at the expense of our most basic rights to freedom of expression online."

DRUG PRICE REGULATION - Another bitter pill for patients

SAKTHIVEL SELVARAJ

  

 

The current market prices are essentially over and above the actual cost of production — a difference that could run from 100 per cent to 5,600 per cent, depending upon various therapeutic categories

In a liberalised market economy, do we need price controls on drugs? Policymakers and the pharmaceutical industry do not think so. They believe that price controls are an inefficient tool that distorts resource allocation, squeezes revenue, reduces profit, and breeds corruption. However, the evidence around the world runs counter to this view. Every country imposes price controls on medicines, including the most liberalised market economies. Although the design and pattern of price controls may vary, they are an important public policy tool to make drugs affordable. Medicine price controls are critical because unlike other commodities, consumers (patients) do not exercise ‘choice’ in the market when buying drugs, but are guided by the doctors or dispensers, whose primary objective may not be guided by the factor of affordability for patients.

The origin of a comprehensive and well-designed drug price control system in India dates back to 1978, when 350 life-saving and essential drugs were brought under regulation. However, in 1986 and in 1995, the number of medicines under the Drug (Prices Control) Order (DPCO) dwindled to 186 and 76 respectively. As a result, the percentage of medicines in the market under price control declined from over 90 per cent in 1978 to nearly 10 per cent now. Currently, a free market scenario prevails in the pharma sector, and the new drug price policy only legitimizes this trend.

In 2002, a price control order sought to reduce price control by half, but after civil society took up the issue, the High Court in Karnataka struck it down. Since then the Supreme Court has directed the Government of India to bring all essential drugs under price control.

The drug price control mechanism until now is based on cost-plus based (CPB) pricing. Under this arrangement, as per DPCO 1995, a 100 per cent mark-up is allowed over and above the ex-factory price, to allow for post-manufacturing expenses including packaging cost, margins of wholesalers, retailers and so on. In bringing in all 348 life-saving and essential medicines under ‘price control’, the new drug price order of 2013, adopting sleight of hand, takes away the advantage available to the patient because it moves away from CPB to MBP (Market-Based Pricing). Under the MBP, prices of essential medicines would be determined based on average price of various brands of a medicine with one (or more) per cent market share. Thereafter, a 16 per cent margin would be added as retailer’s margin. Thus the ceiling price of drugs will now be based on prevailing market prices of various brands of a drug rather than the actual cost.

The current market prices are essentially a premium price paid over and above the actual cost of production — a difference that could run from 100 per cent to 5,600 per cent depending upon various therapeutic categories. It is strange logic that the government appears to have bought into, one that was sold solidly by the pharma companies. The drug market in India is very complex and unique. We have a scenario where, often the market leader who sets the price is also the brand leader. In several other competitive markets, market leader prices are much lower than the brand leader. Take Glibenclamide, one of the key medicines in diabetes treatment. Sanofi Aventis, which sells the medicines, is not only a market leader in terms of market share but its price is also the highest in the market, despite the presence of a dozen producers. Atorvastatin (10 mg, 10 tablets), a critical drug used in the treatment of high cholesterol, for prevention of heart attacks and strokes, is manufactured and marketed in India by over 50-plus producers. However, Ranbaxy clearly has an edge over the others and its prices are the highest. Therefore, any ceiling price based on a formula derived from market prices will tend to move towards the higher range, instead of bringing it down.

The new pricing formula will be several per cent more than the old cost-plus based pricing methods. For instance, Atorvastatin (10 tablets of 10mg) will be fixed at Rs 65.30 according to the new DPCO 2013 formula, while the same would have been sold for Rs. 5.60 if CPB method were to be used. In fact, the Tamil Nadu Medical Services Corporation currently buys it directly from the manufacturer at a cost of Rs. 2.10, for the same strength and dosages. The premium on cost of production and the ultimate prices paid by the patients are, evidently, several hundred or even thousand per cent higher. This is nothing but profiteering in the name of curing patients.

FIXED DOSE COMBINATIONS LEFT OUT

Moreover, the DPCO 2013 has left out Fixed Dose Combinations (FDCs) of drugs involving one or more essential drugs. By simply combining one essential medicine with another non-essential drug, a manufacturer can wriggle out of the ceiling price. Nearly half of most therapeutic categories of medicines in India now consist of FDCs, and this trend has intensified in recent years, especially in drugs used in chronic conditions. India is also the capital of many ‘me-too’ drugs, where several versions of a similar chemical substance are produced with therapeutically equivalent effect. By not bringing similar therapeutic drugs under price ceiling, a wide open escape route has been provided to the pharma manufacturer. Drug producers often find it easy to convince the medical community to move towards a particular brand and to a specific therapeutic product. In view of restrictive and narrowed definition and interpretation of the Essential Drug List and its dosages and strengths, the new DPCO 2013 is expected to cover only 18 per cent of the overall oral solid market.

The aam admi has been yet again administered a bitter pill, while the pharma companies are pleased. The government would claim to have fulfilled its commitment given to the court, of bringing all essential drugs under ‘price control’.

Coming soon: invasion of the marauding nymphomaniacs

Thanks to 'female Viagra' and government regulation, we women can enjoy sex again – just hopefully not too much

• 
• • Naomi McAuliffe
  • guardian.co.uk, Monday 27 May 2013 17.18 BST

'People like sex. Sex is sexy.' Photograph: Jennifer Szymaszek/AP

We are standing on the brink of the breakdown of society. A world in which the economy grinds to a halt. Schools stand empty; there are no teachers left and the dinner ladies have found something better to do. Hospitals career towards crisis point as nurses become the uniformed sex-crazed bunnies that porn has long suspected them to be. This is the land of the marauding nymphomaniacs – hypersexed women who are hardly able to walk straight, never mind function as citizens.

This is the risk potentially posed by Lybrido, the female arousal drug (or "female Viagra"), according to some "experts" who are worried that this drug won't get past the regulators unless there are assurances that it won't lead to women becoming raptorial sex beasts. Women should like more sex, but not too much.

Of course this is another pharmaceutical attempt to cure social ills with a pill. A lower libido in both men and women may well have more to do with that screaming baby in the next room or the pending redundancy at work than anything physiological. But dealing with individuals' psychology or social circumstances is boring and hard and complex while pharmaceutical marketing is fun and easy and quick.

And this involves SEX. People like sex. Sex is sexy. Diarrhoea isn't sexy, lung disease isn't sexy and things that aren't sexy get less of our attention and investment. Female sexuality is even more dark and mysterious and feeds those odd social constructs that say women don't like sex as much as men do and therefore have to be "fixed", unless they do like sex as much as men do and so must be broken and are either mad, bad or wanton. Maybe women need a recommended daily fornication allowance.

Interestingly, the inspiration for the lady-horn enhancer was not a desire to create a louche legion of loose women, but came from one tragic man's way of getting over a broken heart. Dr Adrian Tuiten, head of the Dutch firm Emotional Brain, which developed the drug, was trying to understand why his long-term girlfriend dumped him in his 20s. Apparently "the breakup inspired a lifelong quest to comprehend female emotion through biochemistry and led to his career as a psychopharmacologist." (I'd suggest the desire to comprehend female emotion through biochemistry might actually be part of the reason for the break-up). The developers of this drug actually want it to promote monogamy, not instigate indiscriminate sex mania.

The trials completed so far on this drug have been exclusively with women in long-term, monogamous relationships where simply the spark has gone. However, increasingly evidence shows that for many women the cause of their sexual malaise appears to be monogamy itself. Evolutionary psychologists (or as I like to call them, Just So Story tellers) claim that it is innate biology that gives men a naturally higher sex drive. But ameta-analysis of studies by psychologists in 2010 shows little sex differences in the sexuality of men and women and where there were differences – such as rates of masturbation or pornography use – they were heavily influenced by culture and the gender equity of the social group studied.

It is almost impossible to separate female sexuality from culture. Depending on a variety of factors from the number of sexual partners you have had, how much flesh you show, whether you use contraception, how much you masturbate (because women do masturbate!), whether or not you "use" pornography (read it, watch it, look at it) and what kind of pornography it is ("it's a book, therefore erotica!") all variously determine whether you are a slut, whore, slag, prude, lesbian, harlot, prig or the veritable Mrs Grundy.

Society is as concerned by women who like sex as those who don't. Nymphomania was a form of mental illness or disease in the Victorian era with seemingly endless symptoms; masturbation, homosexuality, sexual dreams, or in one case the "lascivious leer of her eye and lips, the contortions of her mouth and tongue, the insanity of lust which disfigured [her]". This disease was variously "cured" with abstinence, vegetarianism, cold douches or more viciously with confinement to an asylum or even a form of female genital mutilation where the clitoris was removed.

The modern version is seemingly to attain that perfect balance between women enjoying sex more in their long-term, increasingly loveless, monogamous relationship through some kind of love potion and also resisting the ever-present lure of the strumpet within us. Only a heady combination of drugs, government regulation (through marriage, adultery laws, access to contraception) and overwhelming social pressures seem to be able to regulate female sexuality around the world. Who knows what would happen if we could discover and develop our own sexuality and properly understand how that changes and fluctuates over time and circumstance? Who knows what might have been achieved had people spent their energy on things other than regulating female sexuality? Perhaps everyone might be happier and hornier.

Novartis loses landmark patent case in India

India’s Supreme Court dealt a significant blow to Western drugs firms on Monday when it rejected an application by the Swiss pharmaceutical company Novartis to patent an anti-cancer drug.

Until recently patent and intellectual property disputes have been limited to HIV drugs as campaigners have accused Western firms of profiteering while poor patients in developing countries die. The Novartis ruling however marks a widening of the conflict to other proprietory drugs. Photo: Alamy

By Dean Nelson, in New Delhi

1:51PM BST 01 Apr 2013

22 Comments

The company said the decision raised serious, wider implications for the industry and reflected India’s ‘growing non-recognition’ of intellectual property.

Its ruling, however, was hailed by campaigners and Indian pharmaceutical firms as a victory for the country’s poor who cannot afford expensive Western medicines. Indian drug firms sell generic versions of Western drugs for up to one tenth of the price.

India’s trade minister Anand Sharma yesterday hailed the decision as an “historic judgment” which reinforced Indian laws preventing companies from extending patent protection unfairly by minor tweaks to their products, a process known in India as ‘ever-greening. Y.K Hamied, chairman of Cipla, one of India’s largest generic drugs companies, said the ruling will “pave the way for affordable medicines in India.”

Novartis however yesterday warned the ruling will discourage expensive investment in new drug treatments. The decision “provides clarification on Indian patent law and discourages innovative drug discovery essential to advancing medical science for patient," it said in a statement.

“The primary concern of this case was with India's growing non-recognition of intellectual property rights that sustain research and development for innovative medicines. As a leader in both innovative and generic medicines, Novartis strongly supports the contribution of generics to improving public health once drug patents expire,” it added.

The company had applied for a patent for a new tablet version of its anti-cancer drug Glivec, which had taken years to develop, it said. The Supreme Court however ruled that the tablet did not amount to an advance sufficient to merit a patent. Around 16,000 Indian cancer patients use Novartis' Glivec - 95 per cent free of charge, the company said, while an estimated 300,000 use cheaper Indfan versions.

Until recently patent and intellectual property disputes have been limited to HIV drugs as campaigners have accused Western firms of profiteering while poor patients in developing countries die.

The Novartis ruling however marks a widening of the conflict to other proprietory drugs. Merck, the US-based drugs company is facing a dispute with the Indian pharmaceutical firm Glenmark which has launched a generic version of its diabetes drug Januvia which is almost a third cheaper.

“It's all about interpretation of section 3(d) of the Indian Patent Act,” said Ran Chakrabarti, a commercial lawyer based in New Delhi.

“Essentially, it says that you can't tweak something that already exists and then patent it, if it doesn't enhance the known efficacy of that thing, or result in a new product. No doubt lawyers will have spent a lot of time pouring over the meaning of 'enhance', 'efficacy' and 'new product', but it looks as if the Supreme Court has ruled that this is old wine in a new bottle.

"Drug companies are going to have to come up with something pretty unique to get patent protection, and while that's good news for consumers, it pushes the threshold for innovation northwards,” he added.

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A Just Order

Editorial in The Hindu

The Supreme Court order rejecting a plea to grant patent protection for Glivec, a cancer-fighting drug from Novartis, is a landmark. It will greatly strengthen the quest for access to affordable medicines in India. The decision affirms the idea that a patent regime loses its social relevance when a drug is priced beyond the reach of the vast majority of a country’s people. That pharmaceutical companies employ high pricing to limit the number of beneficiaries of “blockbuster” patented molecules and even older “evergreened” medicines is an irony, because making additional copies of a drug is not expensive. On the other hand, cost control and dispensing of essential medications in government-run health facilities is affected, because many States have no centralised procurement system. It is unsurprising, therefore, that less than 10 per cent of medicines sold in India are under patent, while the vast majority are branded generics. The court order should prompt producers of patented drugs to move towards liberal licensing and low cost manufacture in India, the pharmacy of the South that produces Rs.100,000 crore worth of medicines annually and sells nearly two thirds within the country. It is a matter of concern that at least a dozen pharmaceutical innovations used in the treatment of cancer, HIV/AIDS, and Hepatitis B and C are not affordable to even the upper middle classes, and impossible to access for the poor.

It would be a gross distortion to paint the Glivec order, which follows the compulsory licensing of Bayer’s drug Nexavar, as an innovation killer. There is evidence to show that major pharma companies recover more than the cost of innovation of a drug in a single year from the United States market alone. Moreover, the costing done by industry has come in for criticism from scientists and policymakers on the grounds that the bloated, irrelevant investments of recent decades are used as the baseline to make calculations. It should not, as the industry claims, cost a billion dollars (and take a dozen years) to produce a new drug; the informed estimate is a third of that figure. The contested field of drug discovery now calls for greater scrutiny of costs and therapeutic value, and control of prices through various legal avenues available under the Indian Patents Act and the Trade-Related Aspects of Intellectual Property Rights as confirmed by the Doha Declaration. It would naturally strengthen the case for grant of patents and consensus pricing, if the industry opens its books for verification. Until the golden mean is reached, governments with vast populations that are denied access to medicines due to economic reasons can justifiably use unilateral price control mechanisms.

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Calling big pharma’s bluff

 e

DWIJEN RANGNEKAR in the hindu

   

 

The lesson from the Supreme Court ruling on Gleevec is that pharmaceutical multinational corporations need to focus research on genuine innovations rather than on ways to evergreen their patents

The much awaited Supreme Court judgment on Gleevec has been delivered. Novartis has failed in reversing the rejection of its patent. And, predictably — like a scratched record — there have been suggestions that pharma investments in India will dry up and take flight to China. At each twist of this case, Novartis has produced such bluster. We need to pay attention to the judgment as it is a nuanced handling of difficult questions concerning a hastily drafted section — Section 3(d) of the Indian Patents Act, which allows new forms of existing drug formulations to be patented only if they result in increased efficacy. The judgment adopts a gentle caution in parsing out Section 3(d); yet, it is firm in reading 3(d) as a “second tier of qualifying standards” for patentability. Further, the judgment also stands out by reprimanding the “artful drafting” of patent applications adopted by big pharma.

CHRONOLOGY

To begin, it is useful to draw out some of the chronology concerning Gleevec that the judgment reveals. The story of the patent begins with Jurg Zimmerman’s invention of derivatives of N-phenyl-2- pyrimidine-amine, one of which in freebase form was called “Imatinib,” and together constituted a U.S. patent application (no. 5,521,184) granted on May 28, 1996 (which, the judgment terms “the Zimmermann Patent”). Subsequently, a European patent was also acquired. Later, a patent application was filed for the beta crystalline form of Imatinib Mesylate (the subject in dispute) in January 2000. Initially rejected, the patent was awarded in May 2005 following Novartis’s appeal to a U.S. appellate court. What is interesting is that the filings for new drug approval, submitted in April 1998, was for Gleevec, and a filing for original drug approval in February 2001 was for Imatinib Mesylate. Confusing as this may seem, the judgment highlights this to establish that Imatinib Mesylate was covered by the Zimmerman patent and that Gleevec was its market name. Any remaining doubt, the judgment notes, is extinguished by the application for patent term extension: “This application leaves no room for doubt that Imatinib Mesylate, marketed under the name Gleevec, was submitted for drug approval as covered by the Zimmermann patent.”

CONTEXT

One of the useful aspects of the judgment is in distilling the significance of “context” in giving meaning to statute. Early on, it notes that to understand the import of the various amendments introduced in the third amendment to the Patent Act, 1970 — to come into full compliance with TRIPS — it is “necessary to find out the concerns of Parliament … What was the mischief Parliament wanted to check and what were the objects it intended to achieve through these amendments?” In this respect, the judgment recalls not only the heated Parliamentary debate, but also the concerns of public health practitioners the world over, and of public statements and petitions from U.N. agencies and civil society organisations. With India being the leading global supplier of bulk drugs, formulations and generic Antiretrovirals (ARV), the global concerns layered domestic worries about affordability of drugs.

Evidence in a widely cited study by the National Institute of Health Care Management, Changing Patterns of Pharmaceutical Innovation, is telling. Between 1989 and 2000, the U.S. Food and Drug Authority approved 1,035 new drug applications — of these, 65 per cent contained active ingredients that were already on the market (i.e. incrementally modified drugs), 11 per cent were identical and only 15 per cent were considered a “highly innovative drug.” Mischief like this results in a patent thicket around a single molecule to delay generic entry which Section 3(d) seeks to avoid. Consequently, the Supreme Court heralds Section 3(d) as a “second tier of qualifying standards for chemical substances/pharmaceutical products in order to leave the door open for true and genuine inventions but, at the same time, to check any attempt at repetitive patenting or extension of the patent term on spurious grounds.”

The significance of this rendering of Section 3(d) is borne out in the Supreme Court’s mix of caution in parsing out the section and firm pronouncements on patent drafting. Section 3(d) states, the mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance or the mere discovery of any new property or new use for a known substance or of the mere use of a known process, machine or apparatus unless such process results in a new product or employs at least one new reactant.

And, has the following explanation appended: For the purposes of this clause, salts, esters, ethers, polymorphs, metabolites, pure form, particle size, isomers, mixtures of isomers, complexes, combinations and other derivatives of known substance shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy.

MADRAS HC READING

Recall that the Madras High Court’s reading that efficacy is a pharmacological idea associated with the ability of a drug to produce a desired therapeutic effect independent of potency, i.e. “healing of disease.” And, the Intellectual Property Appellate Board (IPAB) had noted with respect to enhanced efficacy that “it is not possible to quantify this term by any general formula” and that an assessment would “vary from case to case.” In revisiting these readings, the Supreme Court also had the views of Shamnad Basheer (as an intervenor-cum-amicus) and Anand Grover (Counsel for Cancer Patients Aid Association). The latter had argued for a strict reading of 3(d) which would see efficacy entirely in pharmacological terms. While Basheer agreed that all advantageous properties may not qualify under 3(d), he held that increased safety and reduced toxicity should be seen favourably. Even as the Supreme Court recalls the concerns that author 3(d) — thus, urging a “strict and narrow reading” for medicines — it prefers to delay definitive pronouncement and allow for jurisprudence to develop on this matter. Yet, it is firm in noting that enhancements in the “physical properties” of a product would render a patent application foul of 3(d).

It is here that the evidence — either in the patent applications or submitted later through affidavits to Controller were found wanting in establishing enhanced efficacy. Take for instance the “Massimini” affidavit, filed before the Controller and directed at 3(d), where two points emanate. First, that the beta crystalline form of Imatinib Mesylate is highly soluble, and second that it demonstrates a number of improved physical properties (e.g. flow properties, thermodynamic stability). Yet, in probing, it becomes clear that the comparison is to Imatinib — and not Imatinib Mesylate, where the latter is the “known substance” in terms of 3(d). Which leaves the issue of increased bioavailability — and here the court finds “there is absolutely nothing on this score apart from the adroit submissions of the counsel” and dismisses the argument.

ON DRAFTING

A final aspect of the judgment that needs highlighting is the pronouncement concerning drafting. The careful interrogation of the sequence of events leading to the patent application for the beta crystalline form of Imatinib Mesylate opened up gaping holes in the claims made by Novartis. These included that Gleevec was “‘disclosed” in the Zimmerman patent and this point is also implied by Novartis’s legal notice to NATCO in the U.K. to stop production of its generic version, VEENAT. In response, Novartis argued that even while Gleevec could be claimed by the Zimmerman patent, it was not fully disclosed in an enabling manner. Thus, seeking to differentiate between claims and disclosure. This wonderful legalese was eloquently rejected by the Supreme Court; both, in terms of U.S. legal history that was cited and in terms of the argument’s merits. And it’s useful to quote at length: “We certainly do not wish the law of patent in this country to develop on lines where there may be a vast gap between the coverage and the disclosure under the patent; where the scope of the patent is determined not on the intrinsic worth of the invention but by the artful drafting of its claims by skilful lawyers, and where patents are traded as a commodity not for production and marketing of the patented products but to search for someone who may be sued for infringement of the patent.”

LAPSES

Looking back over the last several years, it is useful to recall the several lapses committed by Novartis. It failed to heed petitions by health groups and civil society to drop the case. For that matter it failed to also heed the wisdom of its own shareholders who urged it to withdraw the challenge. And at the Supreme Court along with losing the case, we also find that the Gleevec patent application “appears to be a loosely assembled, cut-and-paste job, drawing heavily upon the Zimmermann patent.”

The judgment should be well noted and celebrated. It recalls the context of 3(d) and reminds us of the matters of concern that punctuated its crafting. While the section may have been hastily drafted and insufficiently specified, it has the elements to withstand ever-greening. Pharma companies will always be rewarded for their inventive work and effort — and by drawing in a secondary qualifier, they will have to focus their efforts on genuine inventions rather than overlapping patents.

(Dwijen Rangnekar is Associate Professor of Law at the University of Warwick, U.K. E-mail: d.rangnekar@warwick.ac.uk)

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.