Thrills, pills and paranoia... Pf looks behind the blood-streaked face of this year’s ‘must see’ pharma thriller and finds a ‘me-too’ product that hits easy targets while choking on its own off-patent formula.

Side Effects (2013)

You have to see this film. Not because it’s much good, but because it poses as a smart critique of the pharma industry and its place in modern culture. It’s saturated with references to prescribed drugs and the ways they are promoted. But in the end, it’s not about pharma. That’s just a MacGuffin: a plot device designed to distract the audience from what’s really going on. And what’s really going on in this self-important film is pure, FDA-approved bullshit.

Warning: this review will reveal what happens. If you want to be ‘surprised’ by the ending, don’t read any further. But if you want to know why this film merely pretends to be about pharma – why, in fact, it’s Frank Miller wearing a Ben Goldacre mask – and why its real message is misogynistic nonsense, then read on.

The film starts with bloodstains on an apartment door, then jumps back three months to the release from prison of a businessman, Martin, convicted of insider trading. His wife Emily (the enigmatic Rooney Mara) is suffering from periodic bouts of depression, one of which leads her to drive her car into a wall. While in hospital, she becomes a patient of psychiatrist Dr Banks (the not so enigmatic Jude Law).

Despite being prescribed SSRIs, Emily continues to suffer severe depressive spells. Unsure what else to prescribe, Dr Banks consults with Dr Siebert (Catherine Zeta- Jones, wearing an ‘I’ve got a dark secret’ T-shirt), who recommends a new drug called Ablixa. Emily thrives on Ablixa – but starts sleepwalking, which Dr Siebert says is a side effect. And then, one night, Emily picks up a knife in her sleep and stabs Martin to death.

Dr Banks convinces the court that Emily is innocent and the drug was to blame, but in the process his own career falls apart. Then he begins to suspect that Emily has been lying – and that she is in league with Dr Siebert. He persuades Emily to answer questions after taking the ‘truth drug’ sodium amytal. She says nothing new, but becomes woozy and passes out. This makes Dr Banks suspicious, because he had given her a placebo.

The plot thickens like cement. Dr Siebert sends fake photos to Dr Banks’ wife to make her think he has slept with Emily. She also tries to force Emily to undergo ECT, which gets Emily so scared she tells Dr Banks the truth: that she and Dr Siebert were lovers who gambled money on her husband’s death causing his company’s shares to lose value. She had been depressed after her husband was jailed, but everything later – including the sleepwalking – was faked.

Dr Banks gets Emily freed so she can set up Dr Siebert for arrest. Then he turns the tables on Emily, declaring her too dangerous to be free and condemning her to spend the rest of her life in a secure mental hospital, numbed by thorazine, while he returns to his family.

There’s an awful lot here about pharma marketing. After Martin’s death, his mother says: “I don’t understand. You see the ads on TV, people are getting better.” Dr Banks himself (and isn’t the name a giveaway?) is a store of pharma clichés: SSRIs “stop your brain telling you you’re sad”, Ablixa “helps you to be yourself”, sodium amytal “is a window into the psyche”. Ablixa carries the slogan “Take back tomorrow” – though Emily hilariously admits, “It didn’t do much for me.” Dr Banks is also being paid $50,000 to participate in a clinical trial of the drug.

However, it’s thorazine that gives the film its final and strongest moment: Emily in the mental institution, a shuffling zombie, with the camera panning back to show us the vast prison-like building. It’s a steal from Requiem for a Dream – and the ‘social relevance’ of Side Effects is borrowed from other films, while its only inherent message appears to be that lesbians are scheming psychos. For a film that’s supposed to be cutting-edge, that’s a dismayingly tawdry theme. 

The global market in statins, once the pharmaceutical industry’s lead blockbuster products, is predicted to decline by 40% in the next five years.

The forecast by GBI Research of a negative CAGR of 7.2% up to 2013 for the cholesterol-lowering drugs is based on prospects of generic erosion, weak pipelines and failing prescriber confidence.

The decline in the statins market shows that the shift of healthcare towards prevention and management of long-term conditions is not without pitfalls for the pharma industry.

Statins, which lower cholesterol levels by targeting an enzyme in the liver, have been hailed as ‘wonder drugs’ that could radically reduce the global incidence of cardiovascular events.

Routinely prescribed for ‘high-risk’ patients such as people with high blood pressure or diabetes, statins have also been linked to reduced risk of bowel cancer and reduced death rate from influenza.

However, their global market declined from $23.7 billion in 2004 to $20.5 billion in 2011 (a negative CAGR of 2.5%), due largely to patent expiry.

The report predicts a much steeper decline in the statins market over the next five years, for four reasons:

• Patent expiry – the generic share of the statins market is predicted to grow from 11% in 2011 to 34% in 2018.

• Austerity health budgets – spending on prevention is likely to be cut back.

• Weak product pipelines – the ‘me-too’ nature of most statins betrays a lack of potential for innovation.

• Increased use of alternative drugs.

Medical writer Ben Goldacre has argued that the marketing of statins in terms of relative risk reduction glossed over the low absolute risk reduction they offer, and left the products open to a backlash over side-effects.

Statins are associated with both symptomatic side-effects (including digestive disorders) and potential ones (including increased risk of type 2 diabetes).

As the overall statins market declines, the report says, individual products will struggle to gain or keep a place within it: “The global statins market has reached the competitive stage of its lifecycle, with many branded and generic drugs competing with each other on price.”

Different statins vary in their potential to cause diabetes as a side-effect in certain patients, new research has shown.

Evidence presented at the World Congress on Prevention of Diabetes and its Complications (WCPD) in Madrid suggests that pitavastatin and pravastatin may pose less risk than other statins.

The Congress also noted that concern over diabetes risk has affected worldwide prescribing of statins in general.

Despite being the most-prescribed type of drug, statins – which have been shown to reduce blood cholesterol levels and this risk of cardiovascular events – have a range of medically significant side-effects.

Most notably, a meta-analysis of 13 trials with 91,000 participants has found that statin use is associated with 9% increase in risk of new-onset diabetes.

More recent studies suggest this effect varies strongly between drugs in the statin class, with atorvastatin increasing long-range blood glucose in intensive doses but with pitavastatin and pravastatin having no such impact.

The new J-PREDICT trial in Japan, due to conclude in 2015, is testing the effect of pitavastatin on risk of diabetes in 1,200 people with ‘pre-diabetes’ (impaired glucose tolerance).

Pitavastatin, the lead product of Japanese company Kowa, will be marketed (as Livazo) by Recordati in Europe, where it received MHRA approval in 2010.

Prof. Kausik Ray, Professor of Cardiovascular Disease Prevention at St George’s, University of London, said: “These insights demonstrate how the medical community is taking the diabetogenic risk of statins seriously and highlight the need for further research and guidance in how to treat patients with high cholesterol who are at risk of developing diabetes.”

As the industry adjusts to life after the patent cliff, Maxine Vaccine suggests it may be time to abandon the ‘blockbuster’ mentality and look to a new model of integrated care.

Sometimes the pharmaceutical industry needs a voice. And – regardless of rhyming slang – we could do worse than the ABPI’s Stephen Whitehead. His speech to the trade association’s annual conference this week fired a resounding shot over the bows of the austerity-fixated NHS.

In a week when we learned that the coalition’s austerity policies have plunged the UK economy back into recession, Whitehead commented that the NHS is altogether too smug about its ability to save £3 billion per year by switching wholesale to generics. That’s all well and good, he said, but what happens to that money? If it simply disappears from the NHS budget instead of being reinvested in innovative new treatments, the NHS will be a snake eating its own tail – with the pharmaceutical industry frozen out of the austerity circle.

Then he delivered the payoff: “Generic medicines do save us money, but it is innovation that saves lives. We have to be careful not to focus on cost saving when we should be focusing on patients. The effective use of innovative new medicines can often reduce costs elsewhere in the healthcare system by reducing the need for expensive primary and secondary care.

“In fact, with diseases like Alzheimer’s placing an increasing burden on NHS resources, the development of new medicines by the pharmaceutical industry will be pivotal in not only fighting disease but ensuring the financial burden they impose doesn’t cripple the healthcare system.”

This statement challenges the NHS and other health systems to match the industry’s commitment to beating the recession through innovative drug development – echoing the recent statements by GSK’s Andrew Witty and Lilly’s John Lechleiter that only robust pipeline development, not austerity measures, can ensure a strong future for their companies.

Whitehead called for more effective partnership between the industry and the NHS to ensure that innovative medicines are seen as part of the solution for a health system struggling with increasing demand and shrinking budgets.

In the same week, the BMJ published an article covering new research that suggests the clinical case for widespread antidepressant use has been overstated by suppliers and clinicians alike. Researchers at Canada’s McMaster University argue that while the therapeutic benefits of long-term antidepressant use are slight, the cumulative evidence of systemic damage is conclusive. Long-term side-effects include increased risk of stroke in the elderly, sexual dysfunction and digestive problems such as IBS.

Prozac was the blockbuster drug par excellence: a ‘happy pill’ promoted as a universal panacea for depression, and prescribed to millions. Side-effects were routinely dismissed as a small price to pay for the correction of a ‘chemical imbalance’ that could not be treated in any other way.

Except that wasn’t true. As another BMJ article explained in 2010, SSRIs do not restore biochemical normality: they create a drug-induced state, comparable to being mildly stoned, in which the symptoms of depression are masked. These days, few doctors persist in the delusion that any drug is an adequate monotherapy for a complex and chronic mental health condition. Medication can be useful for crisis management, but improvement of the patient’s systemic health through behavioural changes, lifestyle management and other medical interventions is the only adequate long-term strategy. The evidence that antidepressants can have lasting and serious side-effects strengthens the case for treating the patient, not the symptoms.

Whitehead’s speech and the debunking of the Prozac myth are two sides of the same coin. The era of the blockbuster drug is over. Innovation is not about seeking the ‘magic bullet’ that treats as many patients as possible. It’s about working with healthcare providers to build complex, flexible solutions for the patient – who is viewed not just as a composite of symptoms but as a living system that changes profoundly over the limited but unique interval we call a human lifetime.

Maxine’s views are not necessarily those of Pharmaceutical Field.

An innovative diabetes drug that the FDA declined to approve in January 2011 has been endorsed by the European Medicines Agency (EMA).

Forxiga (dapagliflozin), co-developed by AstraZeneca (AZ) and Bristol Myers-Squibb (BMS), is the first drug to treat type 2 diabetes by promoting excretion of sugar by the kidneys.

Concern over liver toxicity and cancer risks led the FDA to request more data on the drug, but the EMA determined that its benefits outweigh its risks.

Forxiga inhibits a target in the kidney known as SGLT2, blocking the absorption of blood glucose and causing its excretion in urine.

BMS, who discovered dapagliflozin, partnered with AZ in 2007 to develop the drug – which, if approved, would be the first SGLT2 inhibitor to reach the market.

However, in 2011 the FDA declined to give the drug marketing approval, citing evidence of increased rates of breast and bladder cancer and liver toxicity.

The agency requested further clinical data “to allow for a better assessment of the benefit-risk profile,” including results from ongoing studies and perhaps from new clinical trials.

The EMA said the increasing prevalence of type 2 diabetes and the side-effects of some current therapies meant there was a need for new treatment options.

According to the agency, clinical trials have shown that Forxiga improves blood glucose control either alone or in combination with other diabetes drugs, and its effect is sustained up to 102 weeks.

However, it noted, the increased risk of bladder and breast cancer was of concern, “especially in the light of potentially long treatment periods and a possible widespread use”.

The EMA said it will maintain “close observation” of these risks, following a planned study of the drug’s cardiovascular side-effects. It requested that the companies carry out an epidemiological study of Forxiga.

BMS Chief Executive Lamberto Andreotti said: “We are pleased the CHMP has given a positive assessment of the benefit/risk profile of this novel product in a new class for the treatment of type 2 diabetes, an area of high unmet medical need.”

A US consumer group has called on the FDA to withdraw its approval of Novo Nordisk’s injectable diabetes drug Victoza on safety grounds.

Public Citizen cited evidence that Victoza is associated with increased rates of pancreatitis and kidney failure, as well as causing thyroid cancers in rodents.

Novo Nordisk commented that the evidence cited in the petition is adequately covered by Victoza’s label.

The FDA approved Victoza in 2010 against the recommendation of three staff scientists, the consumer group claimed.

One of them, Dr Karen Mahoney, wrote in an FDA memo: “The need for new therapies for Type 2 diabetes is not so urgent that one must tolerate a significant degree of uncertainty regarding serious risk concerns.”

The FDA had noted that Victoza caused thyroid tumours in rats and mice. The product label states that it is “unknown” whether the drug could have a similar effect in humans, and recommends that patients with a family history of thyroid cancer should avoid the drug.

Similarly, Victoza’s label refers to the increased risk of pancreatitis and to certain incidents of kidney failure.

Public Citizen noted that in the first 17 months of Victoza’s use, the FDA received 200 reports of patients diagnosed with pancreatitis. The group estimated that only 10% of actual cases were reported.

Novo Nordisk said the FDA’s approval was based on extensive studies involving more than 4,000 patients, and that since then the company “has continued to work closely with the FDA and the medical community to monitor the benefits and appropriate use” of the drug.

Novo Nordisk’s Chief Science Officer, Mads Krogsgaard Thomsen, commented that the rodent studies were of no relevance to human patients. “We do not expect any consequences for Victoza from Public Citizen’s petition,” he said.

Johnson & Johnson has been fined $1.2bn by an Arkansas circuit court for fraudulent marketing of its antipsychotic drug Risperdal (risperidone).

The judge said the company and its US subsidiary Janssen Pharmaceuticals had lied about the drug’s benefits and risks in order to obtain Medicare reimbursement.

The fine is among the largest ever imposed in a US state fraud case involving a drug company.

J&J, which denies any improper conduct or actual harm, is calling for a retrial.

The judge, Tim Fox, fined the companies $1.19bn for nearly 240,000 violations of the state’s Medicaid fraud law and $11m for violations of its law on deceptive practices.

To date, 11 states have prosecuted J&J over its marketing of Risperdal, which is approved as a treatment for schizophrenia and bipolar disorder in adults and behaviour problems in young people.

Prosecutors have claimed that J&J inaccurately stated Risperdal to be more effective than generic alternatives, while concealing the increased risks of diabetes, stroke and weight gain associated with the drug.

Since reimbursement for Risperdal was available through the state-funded Medicaid system, J&J is accused of defrauding state authorities.

Arkansas attorney general Dustin McDaniel commented that the court’s verdict “sends a clear signal that big drug companies like Johnson & Johnson and Janssen Pharmaceuticals cannot lie to the FDA, patients and doctors in order to defraud Arkansas taxpayers”.

The fine was based on minimum penalties for each individual violation of state law through a prescription or marketing message – coming in this case to over 250,000 violations.

Janssen spokeswoman Teresa Mueller said the company would call for a retrial and, if that was denied, would appeal against the state verdict.

The court “did not show any Arkansas patient was ever harmed by using Risperdal” or “that any Arkansas physician or Arkansas Medicaid was ever misled by the drug’s label or package insert,” she asserted.

In the last year, J&J has reached a $158m settlement with Texas over the marketing of Risperdal and been fined $327m by South Carolina.

At the federal level, the company is in talks with the Justice Department to settle a misdemeanour criminal charge. However, the JoD has rejected a $1bn offer from J&J to settle all outstanding civil charges.

The FDA has requested label changes for Lipitor and other statins to warn of an increased risk of diabetes and cognitive effects.

Pfizer’s Lipitor (atorvastatin), AstraZeneca’s Crestor (rosuvastatin) and Merck’s Zocor (simvastatin) are among the ‘blockbuster’ drugs to carry new warnings.

Statins, which lower blood cholesterol levels, are widely prescribed to help prevent cardiovascular events, but concern over their possible side-effects has been rising for years.

The new label changes were prompted by studies showing that patients treated with statins may be at a slightly higher risk of developing type 2 diabetes and/or cognitive symptoms including mild confusion and memory loss.

According to the FDA, the reported cognitive effects in some patients have been successfully reversed by discontinuing statin use.

The new statin labels have also removed the warning that liver enzyme levels in patients taking the drugs should be routinely monitored, as later evidence has shown this to be a rare and unpredictable side-effect.

The indications now recommend liver enzyme tests before starting statin therapy, with follow-up tests only if there is evidence of liver damage.

“The value of statins in preventing heart disease has been clearly established,” said Dr Amy Egan, Deputy Director for Safety in the FDA’s Division of Metabolism and Endocrinology Products. “Their benefit is indisputable, but they need to be taken with care and knowledge of their side effects.”

Another rainy January, another cold weekend – but if you’ve got some DVDs then you don’t need a friend. Maxine Vaccine offers her personal viewing list of classic films about prescription drugs and the pharmaceutical industry.

There’s no feelgood movie like a thoroughly bitter take on the industry you work for. After a week of board meetings (note to self: improve spelling), blue sky thinking, brainstorming, thinking outside the box and fighting to the death over the last Jaffa cake, nothing turns that frown upside down more effectively (or more cost-effectively) than punching the air as big pharma takes a left hook from the film industry. So on the way home, stop off at Blockbuster, the Chinese takeaway and the off-licence, then settle down for a long Friday night.

Here’s my recommended list of the top 10 films dealing with the drug industry, its products and its customers. I’ve listed them in chronological order so you can make up your own mind which is the best. Enjoy – and remember: love may be the most potent drug, but all the others have a better risk-benefit profile.

Dr Ehrlich’s Magic Bullet (1940) – controversial biopic starring Edward G. Robinson as Paul Ehrlich, the doctor who found a cure for syphilis. It’s thanks to the drug industry that we don’t still have the horrible diseases and fears of the Victorian age. And what thanks do we get?

Drugstore Cowboy (1989) – a bunch of addicts cut out the middle man and raid small-town pharmacies across the USA, coming up with more good ideas for off-label drug use than [that’s enough – HSP legal team].

The Fugitive (1993) – after his wife is killed, a man discovers he was the target for a drug company hit due to his exposure of its illegal marketing. Incredibly far-fetched and offensive to all right-thinking [that’s enough, no need to overdo it – HSP legal team].

Requiem for a Dream (2000) – dual narrative draws parallels between heroin traffic and the prescription of amphetamines to lonely housewives by crooked doctors drumming up business for the city hospital. Grim.

Prozac Nation (2001) – intelligent young woman finds her career derailed by depression. SSRIs may not be the answer, but they help her to start asking the right questions.

Equilibrium (2002) – in an oppressive future, emotion-numbing drugs are compulsory for all citizens. The title is a clue to this film’s target.

The Constant Gardener (2005) – a medical researcher and an aid worker try to blow the whistle on illegal drug trials in Africa, and are murdered horribly (believe me) at the order of a drug corporation. No comment.

Charlie Bartlett (2007) – cool kid sets himself up as high school therapist and sells prescription drugs to his classmates. Andrew Lansley’s favourite film (allegedly).

Love and Other Drugs (2010) – the yummy Jake Gyllenhaal displays his trademark big and lasting smile as a mid-90s pharma rep who breaks every code of conduct (including some you didn’t know existed) while selling Viagra.

Contagion (2011) – heroic doctors struggle to develop a vaccine that can save humanity from being wiped out by a deadly virus. American anti-vaccination conspiracy theorists didn’t like this film, though how they saw it through their tinfoil hats is a mystery.

Maxine has a very busy social life and lots of blogging to do, but could probably find a window on February 14^th if you’re at a loose end.

Lundbeck has launched the first sublingual treatment for bipolar 1 disorder, also known as manic depression, in the UK.

Sycrest (asenapine) is a new type of antipsychotic that stabilises manic episodes and has been shown to cause less weight gain than standard antipsychotic drugs such as olanzapine.

The launch accompanies the publication of a study showing that over three-quarters of patients taking antipsychotics suffer unwanted weight gain, and nearly half consider their medication unsatisfactory.

Bipolar disorder affects an estimated 623,000 patients in the UK, including many high-performing professionals.

In two active-controlled monotherapy trails, Sycrest was shown to be significantly more effective than olanzapine in reducing both manic and depressive symptoms over three weeks.

In a third trial, the use of Sycrest as an adjunctive therapy to lithium was shown to be more effective over 12 weeks than lithium alone in patients who did not respond well to lithium monotherapy.

In addition, patients given Sycrest experienced a mean weight gain of 1.9kg over 12 weeks, compared to 4.1kg in patients given olanzapine.

A recent Patient Insight Research study, conducted by Lundbeck in partnership with four UK mental health charities, showed that weight gain is a major issue with existing antipsychotics: of 988 patients taking antipsychotics, 78.5% said they had suffered unwanted weight gain and 44% that they considered their medication unsatisfactory.

Professor Allan Young of Imperial College and West London Mental Health Trust said: “Many bipolar patients are concerned about the side-effects of taking antipsychotics. The availability of a new treatment option is likely to be valuable in my daily practice.”

“We are pleased that people with bipolar disorder experiencing manic episodes will have the option of this new treatment, which offers hope for effective management of distressing symptoms,” commented Marjorie Wallace, Chief Executive of UK mental health charity SANE.

Based in Denmark, Lundbeck is a pharmaceutical company specialising in the treatment of central nervous system disorders.