Ineffective drugs are prescribed by 97% of GPs as ‘impure placebos’, according to a study by researchers at two UK universities.

A survey of UK doctors found that nearly all admitted prescribing treatments they knew would have no direct pharmacological effect, including antibiotics for viral infections.

The survey findings present strong practice-level evidence that placebos have a real health impact – which has implications for the debate around whether homeopathic medicines should be used in the NHS.

The study authors emphasised that the ‘placebo effect’ is not medically negligible: a placebo treatment can help to stimulate neurological and endocrine reactions to the disease, reducing the symptoms.

‘Impure placebos’ are real treatments whose efficacy for that particular patient is doubtful. It differs from off-label use, where the drug is not approved for that indication but there is trust in its efficacy.

In addition, 12% of GPs admitted prescribing ‘pure placebos’ (with no active ingredient) to reassure patients whose anxiety was itself a health risk factor.

Researchers at the Universities of Oxford and Southampton analysed the responses of 783 GPs to an online survey. The respondent population was analysed and judged representative of registered GPs in general.

The survey found that doctors used impure placebos to induce psychological treatment effects, to counter patient anxiety or to comply with patient choice.

While 84% of doctors judged the use of impure placebos to be acceptable in some situations (and 66% supported the use of pure placebos), more than 80% said their use should not involve deception.

Professor George Lewith, co-lead author of the University of Southampton study, said the two studies showed that “doctors are generally using placebos in good faith to help patients”.

Previous studies “have clearly shown placebos can help many people and can be effective for a long time after administration,” he added. “The placebo effect works by releasing our body’s own natural painkillers into our nervous system.

“In my opinion the stigma attached to placebo use is irrational, and further investigation is needed to develop ethical, cost-effective placebos.”

The use of placebos is discouraged by the General Medical Council. However, Dr Jeremy Howick, co-lead author of the University of Oxford study, argued: “Current ethical rulings on placebos ought to be revisited in light of the strong evidence suggesting that doctors broadly support their use.”

Sanofi has responded to protests against the withdrawal of its drug Campath by restoring access for a limited number of patients with multiple sclerosis (MS).

Campath (alemtuzumab) is approved for treatment of leukaemia but is prescribed off-label for treatment of MS.

To offset the effects of its withdrawal from the market, prior to a rebranding, Sanofi has agreed to make 201 vials available for MS patients in the UK.

In September 2012, Sanofi’s subsidiary Genzyme withdrew Campath to allow a new version, Lemtrada, to be licensed for treatment of MS in the UK.

This meant both that the drug’s price would increase by a factor of 15–20 and that a gap would be created in its availability.

There was widespread protest from doctors, including a letter to the Health Secretary from three specialists warning that patients could miss the window of ‘therapeutic opportunity’, with serious medical consequences.

One of the letter’s authors, Professor John Zajicek, commented that Sanofi’s approach was “morally corrupt”.

Genzyme has agreed to supply a further 201 vials of the drug for the patients of six specialists who were using it as a treatment for MS – however, it will not be available for new patients.

Professor Zajicek said the company’s response was “disappointing”, with Genzyme setting conditions that “don’t make sense”.

The decision to rebrand Campath was based on clinical trials that showed it to be more effective against MS than the current treatment, interferon beta-1a.

Researchers at the University of Cambridge said the drug had a “transformative” effect, and could be given to two-thirds of patients newly diagnosed with MS.

Genzyme stated that gaining regulatory approval for alemtuzumab as a treatment for MS was the best way to ensure patient access.

However, critics have predicted that its price as a licensed drug in this indication will be 15–20 times as high as its current price (which follows patent expiry).

Leading UK neurologists claim Sanofi’s decision to replace an off-label multiple sclerosis (MS) drug with a costlier licensed version “shows little regard for patients”.

The French pharma giant is withdrawing Campath (alemtuzumab) from unlicensed use as an MS treatment ahead of the regulatory approval of new version Lemtrada, which is expected to cost up to 20 times as much.

Three UK professors of neurology have written to Health Secretary Jeremy Hunt, saying the decision “has serious implications for vulnerable UK patients”.

Lemtrada is manufactured by US biotech company Genzyme, which Sanofi acquired in 2011.

Sanofi claims that off-label use of Campath, which has taken place since 1998, could put the approval of Lemtrada (expected in 2013) at risk.

It has allowed the continued use of Campath for treatment of leukaemia (its licensed indication) via patient access schemes.

However, French business journal Challenges argued that the withdrawal of Campath as an MS treatment was “dictated only by the logic of profit”.

The letter to the Health Secretary from professors Neil Scolding, Neil Robertson and John Zajicek says the withdrawal leaves patients who have started treatment stranded, while new patients may miss the “window of therapeutic opportunity”.

As the licensed version is expected to cost “15 to 20 times” as much, they comment, the decision “shows little regard for patients whose opportunity to alter the course of their disease is time-limited, and may represent an over-enthusiastic attempt by the parent company to profit from the current situation.”

Speaking to the Independent, Professor Zajicek called Sanofi’s approach “morally corrupt”.

However, a Genzyme spokesman argued: “Off-label use of alemtuzumab in MS has always been at the discretion of individual clinicians without reference to the company.”

The Rarer Cancers Foundation (RCF) has called for action to ensure that when the Cancer Drugs Fund ends, access to drugs for rare cancers continues.

Over 16,000 NHS patients per year may lose access to life-extending drugs when the fund ceases in March, the charity warns.

It suggests that a “transitional” continuation of the Cancer Drugs Fund (CDF) may be needed while steps are taken to ensure that new pricing and prescribing arrangements maintain these treatments.

The CDF provides £200m per year for trusts to purchase cancer drugs that do not have NICE approval.

According to the RCF’s new report on the fund’s impact, it has enabled over 3,600 patients with rarer cancers to access treatments in the last year.

The report points out that the fund has enabled NICE to increase its cancer drug rejection rate from 40% to 60% by making cost a higher priority.

It recommends that NHS authorities examine variations in access to cancer drugs according to location and age, leading to “an urgent review” by the NHS CB of “population cohort policies for funding cancer treatments”.

The RCF also calls for “national protocols” for off-label cancer treatments to be established, allowing their efficacy and safety to be assessed.

Looking forward, it says the DH “should clarify as a matter of urgency how it intends to ensure access to treatments currently reimbursed through the Cancer Drugs Fund in 2014 and beyond.”

The review proposes two measures:

• a mechanism to include these treatments in the new value-based pricing framework, with the CDF being extended as a “transitional” system if necessary

• a national system for off-label prescribing of rare cancer drugs that cannot be covered by VBP.

Children’s healthcare in England needs to be more integrated, timely and focused on individual needs, the Children and Young People’s Health Outcomes Forum has said.

The Forum’s recommendations, proposed as the basis of a national strategy, include a strong emphasis on pharmacovigilance and avoiding the use of off-label medications.

Other key recommendations relate to the goal of “joined up” care, seeking to address gaps in the consistency and continuity of children’s healthcare.

The report describes the view that children in England are well cared for as “sentimental and complacent”, and states: “the UK is worse than other countries in Europe for many outcomes that could be improved through better healthcare and preventative interventions”.

To address this situation, the report argues, it is vital for children and young people to be more involved in decisions about their care; for GPs and other clinical staff to have better training in paediatric care; and for healthcare to meet the changing needs of the young individual over time.

Four new outcome indicators are proposed:

• time from first NHS presentation to diagnosis or start of treatment

• integrated care – developing a new composite measure

• effective transition from children’s to adult services

• age-appropriate services, with particular reference to teenagers.

More generally, the report recommends that all NHS organisations “should take a life-course approach, coherently addressing the different stages in life and the key transitions instead of tackling individual risk factors in isolation”.

It also calls for better systems to allow sharing of information between care providers in different sectors, with “sentinel conditions and pathways” being selected to help identify “gaps in services, including prevention”.

The report notes high levels of medication error and use of off-label or unlicensed medications with children, and calls on the MHRA to prioritise these issues “in line with the new EU legislation effective in July 2012”.

To improve the evidence base for healthcare, it recommends breaking down health data for the first two decades of life into five-year age bands.

To improve clinical leadership, it says, the NHS Commissioning Board should appoint a National Clinical Director and CCGs should appoint a senior clinical lead in this area.

Finally, it recommends that the QOF and PbR systems for child healthcare should be developed and improved.

A PCT cluster on the south coast of England has abandoned its policy of allowing the use of unlicensed medication Avastin to treat wet AMD.

The Southampton, Hampshire, Isle of Wight and Portsmouth (SHIP) PCTs will now use only the licensed medication, Lucentis, for the eye condition.

The decision was prompted by a drop in the price of Lucentis and a legal challenge by its manufacturer, Novartis, to the use of Avastin.

While only Lucentis is licensed for the treatment of wet age-related macular degeneration, a widespread cause of blindness, the much cheaper Avastin is prescribed by some GPs.

The SHIP cluster’s decision in September 2011 to approve the use of Avastin in this indication is subject to a judicial review requested by Novartis.

The legal challenge made the policy impossible to implement, according to the cluster’s Board – especially given the impending handover of commissioning authority to CCGs.

Other factors driving the policy change were:

• The Royal College of Ophthalmologists supports the use of Lucentis, and this has driven nearly all prescribing decisions.

• New discounts for Lucentis have been agreed between SHIP and Novartis as part of a national patient access scheme.

Professor Jonathan Montgomery, Chairman of the PCT Cluster Board, said the Board remained convinced its policy was “lawful, sensible and safe”. However, it did not wish to leave an “undesirable legal legacy” to the region’s CCGs and the local area team of the NHS Commissioning Board.

More positively, he noted, “taking advantage of the significant discounts now being made available” would be “in the best interests of local patients”.

ABPI Chief Executive Stephen Whitehead commented: “It continues to be our view that off-label and unlicensed prescribing should be strictly limited to those circumstances where there is no licensed alternative.”

The European Alliance for Access to Safe Medicines (EAASM) has called for the regulation of off-label drug use in Europe to be improved.

The patient safety group’s comments were triggered by the current debate over the unlicensed use of Avastin to treat wet AMD.

There should be a system of written patient consent for off-label medication, the EAASM said, as well as mandatory reporting of adverse events.

Following the publication of two studies into the use of Avastin as a cheaper alternative to the licensed medication (Lucentis), the AMD Society said: “The overall question of the safety of Avastin is, unfortunately, not answered to everyone’s satisfaction. The use of Avastin will remain a matter of judgement for clinicians.”

EAASM Chair Jim Thomson commented: “This is not an issue solely for the discretion of physicians. We are talking about an elderly population and these patients should be fully informed and give written consent.”

The CATT and IVAN studies have suggested an increased risk of adverse events from the use of Avastin rather than Lucentis.

This risk is exacerbated by the cost-saving strategy of dividing a single Avastin dose between many patients – a direct result of its formulation not being geared to the off-label use.

“Patients remain not only at risk but uninformed about those risks,” argued Jim Thomson, warning that the wet AMD debate was “just the tip of a barely visible patient safety iceberg” arising from pressure to reduce medical costs.

Abbott Laboratories has agreed to pay a total of $1.6bn to settle federal and state charges of off-label marketing regarding its anti-seizure drug Depakote.

The company admitted actively promoting the unlicensed use of Depakote in nursing homes to sedate dementia patients from 1998 to 2006.

The US Government alleges that Abbott exploited a loophole in the legislation protecting elderly patients from inappropriate medication.

Abbott will pay $800m to settle civil allegations, a $700m federal criminal fine and $100m in state level consumer protection fines.

Depakote is licensed by the FDA as a treatment for epilepsy, migraine and manic episodes.

Abbott has pleaded guilty to ‘misbranding’ the drug as a treatment to control agitation and aggression in elderly dementia patients.

From 1998, the company trained a special sales force to promote the off-label use of Depakote to nursing homes.

This promotion continued despite a 1999 clinical trial that showed the drug caused drowsiness, dehydration and anorexia in elderly patients.

Abbott’s marketing highlighted the fact that Depakote was not included in a list of medications banned in nursing homes under by a 1987 law.

Representing one of four ‘whistleblower’ Abbott sales representatives, attorney Reuben Guttman said: “Abbott directed its sales force to get Depakote widely used in nursing homes, principally to neutralise older patients as a substitute for proper staffing.”

Deputy US Attorney General James Cole commented: “We are resolute in stopping this type of activity and today’s settlement sends a strong message to other companies.”

Novartis is taking a PCT cluster to court over its off-label prescribing of a cheaper alternative to its wet AMD drug Lucentis.

The Southampton, Hampshire, Isle of Wight and Portsmouth (SHIP) cluster’s recommendation of Avastin in an unlicensed indication could save prescribers over £800 a dose.

The Swiss company claims the cluster’s policy is unsafe, and is seeking a judicial review.

Lucentis, which costs £890 per dose, is the only NICE-approved treatment for the eye disease wet AMD.

Avastin, which costs £50–100 per dose, is widely used in that indication in Europe and the US, but is not licensed for it in the UK.

The SHIP cluster estimates it can save up to £5m per year by using the off-label drug.

Both Lucentis and Avastin are manufactured by Roche, but only the former is marketed in the UK by Novartis.

“It is unacceptable to put the safety of patients at risk through the widespread use of an unlicensed treatment when a licensed medicine is available,” said a spokesman for Novartis. “It undermines the regulatory process that was introduced to safeguard patients.”

However, a spokesman for the SHIP cluster argued: “The PCTs have reached the view that the published evidence suggests that Avastin is as clinically effective as Lucentis and is far more cost effective.

“The PCTs consider that, in a time of substantial financial pressure on the NHS, this is a responsible as well as lawful approach.”

If the court determines the SHIP cluster’s action is legal, other clusters may follow suit. The East and Central Cheshire PCT cluster has adopted a similar policy. If rolled out across England, the policy could save the NHS as much as £134m.

Johnson & Johnson has agreed to pay $158 million to settle a US lawsuit brought by the state of Texas, alleging that it promoted off-label use of its antipsychotic drug Risperdal (risperidone) and misled doctors about its risks.

Witnesses stated that J&J officials concealed data indicating the drug posed a high risk of weight gain and type 2 diabetes, and that it instructed its sales force to promote the drug’s off-label prescription for minors.

The settlement is the latest chapter in the ongoing dispute over J&J’s marketing of Risperdal in the USA (for more details, click here).

The state of Texas had originally sought $579 million in damages, but the company’s payment is reported to settle the dispute – though several other states, including most recently Massachusetts, intend similar lawsuits.

In the Texas court hearing, Harvard Medical School psychiatrist Joseph Glenmullen said that a clinical trial, Study 113, found that about half of people given Risperdal developed diabetes after a year of therapy. In 2000, when the FDA investigated potential links between antipsychotics and diabetes risk, J&J did not provide the results of Study 113 and two related studies.

Earlier in the trial, the court saw an internal memo instructing J&J’s sales representatives to “flood clinics with Risperdal stuff” as part of a 2004 campaign to increase off-label prescriptions for the drug in children and adolescents.

In his final ruling, Judge Roger Couch said of the Study 113 data: “It is apparent to this court that this information was not disclosed because it did not fit the marketing department’s vision for the promotion and marketing of this drug.”