Vaccines are the most important breakthrough in modern medicine: the jewel in the crown of the pharma industry. What can the success of vaccines teach us about healthcare and the industry’s commercial model?

Out of the virus immunity comes.

Killing Joke’s lyric uses vaccines as a metaphor for the human ability to find a positive meaning in the darkest threat. The history of medicine has shown, time and again, that every disease holds the seeds of its own treatment – but to find the answer, you have to look deep inside the problem.

It has been said that no other health initiative, with the exception of clean drinking water, has done as much as vaccines to improve public health. Medical sales professionals love selling vaccines, for two reasons. Firstly, their potential to protect the young and the old against highly dangerous diseases is beyond reasonable doubt. Secondly, the sales model for vaccines is as dramatic as its medical impact: the supplier becomes responsible for securing the immunity of a population.

Yet, on the face of it, the public might wonder what the fuss is about. Vaccines are one-off medical treatments that protect against specific infections. Many are prophylactic: they don’t work if you have the disease. They are not 100% reliable, since pandemic infections have many competing strains. And they can have harmful side effects. So why should healthy people bother?

The answer lies in the list of deadly and disabling diseases that once cast a shadow over human life, but now are preventable: smallpox, polio, tuberculosis, measles, mumps, chickenpox, typhoid, cholera, bubonic plague, rabies, tetanus, diphtheria and pneumonia. For some viral infections, vaccines are the only effective treatment.

Vaccination programmes demand collaboration across disciplines and borders to protect populations and share medical innovations.  This collaboration model meets with scepticism on two sides: those who mistrust public health provision and those who mistrust the pharma industry. It’s not surprising, therefore, that vaccines meet with antagonistic campaigns and conspiracy theories from a coalition of unreason.

The body’s weapons

Vaccines are different from conventional medicines because they do not directly attack the disease: they provoke the body’s natural immune response against the disease, like a mock-invasion used as a military training exercise. A vaccine dose consists of dead or inactivated disease organisms, or biochemical agents derived from them. In designing a vaccine, scientists trade off risks and benefits.

The first vaccination was conducted by the rural English physician Edward Jenner in 1796. Hearing that local milkmaids who contracted a minor infection called cowpox never seemed to contract the deadly smallpox, he deliberately infected a farm lad with cowpox and then, when he had recovered, with smallpox. (Medical research ethics have improved somewhat since then.) The use of a live disease culture for immunisation is now called inoculation.

The first use of an artificial vaccine was conducted by Louis Pasteur in 1885, using a vaccine developed by his colleague Emile Roux by dessicating the spinal tissue of rabies-infected rabbits. Pasteur gave the vaccine to a boy who had been mauled by a rabid dog. He came to no harm.

Vaccines are still news, with global mobility and shifting demographics making the challenge of immunity more complex and urgent than before. In 2012, new vaccines were developed to treat meningitis, shingles, rotavirus (a cause of infant diarrhoea) and whooping cough. Vaccination against HPV, the cause of cervical cancer, is a new priority for health systems. The GAVI Alliance, dedicated to providing vaccination programmes for children in the developing world, has funding from the Bill & Melinda Gates Foundation and the support of many pharma companies.

A vaccine coalition

A leading company in the European vaccines field (and the only specialist firm) is Sanofi Pasteur MSD, a collaboration between two major pharma companies with a long history of investment in immunity. Sanofi Pasteur is founded on the work of the Pasteur Institute, while Merck’s Dr Maurice Hilleman developed vaccines for measles, mumps, hepatitis A and B, chickenpox, meningitis and pneumonia. The joint company protects half a billion European people against 20 major diseases.

Paul Hardiman, Communications Manager for Sanofi Pasteur MSD, told Pf about the company’s unique role in the European immunity landscape. There are three reasons for the collaboration, he explains: “It avoids a duplication of effort in the drive to develop new and innovative vaccines. It also allows a focus on the strengths and suitability of vaccines for different markets from both companies’ portfolios. This in turn gives flexibility and supports public health priorities.”

The two parent companies are both deeply involved in the global project of the GAVI Alliance. Both Sanofi Pasteur and MSD “use a policy of tiered pricing (linked to a country’s ability to pay) to enable access to vaccines in GAVI-eligible countries. This has included significantly reduced prices on vaccines against HPV and rotavirus and a pentavalent childhood vaccine against diphtheria, tetanus, pertussis, polio and Haemophilus influenzae type B.”

In the UK, Sanofi Pasteur MSD plays a major role in public health immunisation programmes for children, young adults and elderly people. These “are secured through competitive national tenders, requiring the consistent and timely supply of large volumes of high-quality vaccines”. The company has dedicated vaccine representatives selling directly to pharmacies and GP practices.

“Every year, the Joint Committee on Vaccination and Immunisation (JCVI) carries out a horizon scanning exercise to identify all potential new vaccines expected from manufacturers that may have an impact on public health over the following five years.”

As public health in the UK shifts to local authority provision, vaccine suppliers need to be fully aware of the economics and logistics of immunity. Sanofi Pasteur MSD’s UK sales force are “vaccine experts, engaging with practice nurses and GPs to support them in the areas of vaccine supply, campaign organisation and communication, and the education of vaccinating HCPs.”

The company is now supplying Gardasil for a schools-based vaccination programme to protect teenage girls against HPV and hence against cervical cancer. It is also preparing to supply Zostavax for a national programme, starting later this year, to immunise senior citizens against shingles. In the future, the company hopes to target, cancers, allergies, addictions and diseases of the central nervous system.

Immunisation programmes deliver savings both in the short term (by reducing the need for acute treatment) and in the long term (by reducing disability and chronic illness). As the focus of healthcare shifts further into the community, vaccines are increasingly crucial weapons in the HCP’s armoury. Their value, the company maintains, can be expressed in both health and economic terms.

Diplomatic immunity

In February 2013, nine female health workers responsible for delivering polio vaccination programmes in the Kano province of Kenya were murdered by gunmen after a local preacher condemned the vaccine as a plot to cause infertility. Similar killings have happened in Pakistan. In the US, ideologues opposed to public health programmes have accused the Obama government of spreading disease in order to experiment on the public with dangerous biological agents. The internet has given these conspiracy theorists a large audience.

In the UK, a spurious panic was created around the MMR vaccine by Andrew Wakefield’s article in The Lancet in 1998, which claimed the vaccine was a cause of autism. As the BMJ has recently reported, the article was scientifically discredited within a year, and has since been exposed as an “elaborate fraud” based on research that never took place. However, Wakefield’s claims are still declared to be accurate by the Daily Mail and its bizarre columnist Melanie Phillips.

Why do vaccines inspire so much mistrust? The reasons are complex. Some people believe that harnessing the body’s immune response is ‘interfering’ with nature. Others maintain that public health programmes violate the responsibility of the individual to determine their own healthcare. Still others claim that immunisation programmes are a form of covert surveillance, or even of biological warfare.

Paul Hardiman argues that vaccination may be a victim of its own success: “Anti-vaccine sentiment is thought to arise when people no longer fear the disease for which they are being encouraged to accept vaccination. As vaccine coverage increases, serious disease starts to disappear along with people’s fear of the disease. As people lose sight of the threat, so anti-vaccine sentiment may replace the good reasons for vaccinating – raising concerns in people’s minds.”

Doctor and writer Ben Goldacre, whose book Bad Science is strongly critical of anti-vaccine conspiracy theories, argues that the industry is not blameless: “I think it’s fair to say that anti-vaccine conspiracy theories are a kind of poetic response to the obvious regulatory failure in medicine and in the pharmaceutical industry. People know that there is something a little bit wrong here.”

For example, he notes, the recent murders in Nigeria took place in the same province where Pfizer had run the Trovan antibiotic trial in 1996 – a trial whose controversial nature led to Pfizer paying the Nigerian government £75 million to settle out of court, and inspired John le Carré’s novel The Constant Gardener.

Goldacre comments: “There’s something interesting happening when a very destructive anti-vaccine conspiracy theory built around fear and anxiety that drug companies are behaving badly arises in the same very small province in northern Nigeria where Pfizer have been running a trial which many regard as unethical.”

The ‘open data’ campaign led by the Cochrane Collaboration and the BMJ has called for a boycott of clinical trials whose publication is not guaranteed.

The campaigners have launched a public petition to discourage researchers, academic institutions, funding bodies and patients from supporting drug trials whose results may be ‘confidential’.

Other supporters of the petition include the charity Sense About Science; the James Lind Alliance, an alliance of patients and clinicians focused on medical research; the Centre for Evidence-Based Medicine in Australia; and journalist Ben Goldacre (pictured), author of Bad Pharma.

The ‘Tamiflugate’ controversy over the ongoing non-publication of clinical trial results relating to Roche’s influenza drug has fuelled the campaign. The BMJ has campaigned for the medical profession to put pressure on Roche to reveal the missing data since November 2012.

Ben Goldacre’s book claimed that pharmaceutical companies systematically distort the landscape of clinical evidence by withholding the results of less favourable drug trials.

MPs including Conservative MP Sarah Wollaston have called for a public enquiry into the £500m spent by the Government in stockpiling Tamiflu during the ‘swine flu’ crisis.

Tracey Brown, Director of Sense About Science, commented: “There have been years of foot dragging and non-compliance with requirements. We expect regulatory bodies to evaluate the best available evidence, not half of it.”

Launching the petition, the BMJ argued that patients should not participate in ‘confidential’ trials: “Participants in clinical trials assume that they are contributing to the advancement of medical knowledge; non-publication of study results negates this reasonable assumption and betrays those who have volunteered.”

The National Institute for Health and Clinical Excellence (NICE) has been drawn into the ongoing row over Roche’s failure to disclose clinical trial data.

The British Medical Journal’s Editor in Chief, Fiona Godlee, has asked NICE to withdraw its recommendation for antiviral drug Tamiflu (oseltamivir) until the missing data are available.

NICE’s Chairman, Sir Michael Rawlins, has said that Roche could be reported to the General Medical Council (GMC) if the company is found to have withheld data relevant to the NICE appraisal.

The BMJ is campaigning for the release of data from at least 123 clinical trials which, according to the Cochrane Collaboration, were promised by Roche in 2009, when Tamiflu received marketing authorisation in Europe.

The Cochrane researchers recently rejected a proposal from Roche to form a joint panel that would discuss what clinical trial data were needed, in order to balance commercial confidentiality with public interest.

Godlee’s letter to NICE proposed that the regulator withdraw its guidance on Tamiflu until it “has received and reviewed the full clinical trial data”.

She also accused NICE of “colluding with the status quo” by failing to insist on seeing the missing clinical trial data at the time of its approval – and pointed out that the FDA has not given the same approval to the drug because it has “performed a more thorough assessment of the trial data”.

Rawlins replied that if the missing data supported the use of Tamiflu then “patients would be damaged by precipitate withdrawal of our guidance” – thus implying a Catch-22 situation.

However, he noted, if Roche’s medical director had “knowingly” withheld relevant data then NICE would report the matter to the GMC.

Merz Pharma, Eli Lilly and Daiichi-Sankyo have all been found guilty of breaching the ABPI Code of Practice by its regulator the Prescription Medicines Code of Practice Authority (PMCPA).

The PMCPA found Merz Pharma guilty of breaking the Code on two separate occasions and decided that Eli Lilly and Daiichi-Sankyo breached five different clauses when promoting Efient.

In breaching the Code, the PMCPA said, the companies had “brought discredit upon, and reduced confidence in, the pharmaceutical industry.”

All three companies breached Clause 2 of the Code and have been made to issue corrective statements in the BMJ, The Pharmaceutical Journal and The Nursing Standard.

Clauses 2, 7.2, 7.3, 7.4, 9.1 and 25 of the Code were breached when Merz was found to have made misleading and unsubstantiated claims and for failing to comply with an undertaking by implying that that Bocouture/Xeomin was clinically equivalent to Vistabel/Botox.

Merz was also found to have breached Clause 2, 9.1 and 25 when it failed to comply with an undertaking by implying that Bocouture was clinically equivalent to Botox.

Eli Lilly and Daiichi-Sankyo were reprimanded for promoting Efient in a manner that was misleading and inconsistent with its summary of product characteristics. In doing so the PMCPA decided the pair had breached Clause 2, 3.2, 7.2, 7.9 and 9.1.

The Daily Mail has voiced its approval of Andrew Wakefield’s ‘research’ linking the MMR vaccine to autism, despite his ‘research’ having been exposed as fraudulent.

A feature by Michael Hanlon on the newspaper’s website states that Wakefield’s claims are supported by ‘statistics on autism’ but are not accepted by ‘the scientific establishment’.

The Daily Mail article was published in reaction to the news that uptake of the MMR vaccine in infants has passed 90% in England for the first time since Wakefield’s 1998 paper questioning its safety.

However, uptake is still below the WHO target of 95%, which experts consider sufficient to prevent outbreaks of measles – and the Daily Mail is clearly trying to discourage further use of the vaccine.

Hanlon also claims that Wakefield was recently forced to resign his research post at the Royal Free and University College in North London because his work did not ‘fit in’ with the college’s strategy.

The feature does not mention the fact that Wakefield’s resignation followed his exposure in the British Medical Journal as a fraud.

His ‘research’ was criticised for flawed methodology within the medical research community, but it was taken up by newspapers and became a celebrated ‘scare story’, with drastic effects on the vaccine’s uptake in the UK.

In January 2012, the BMJ published a series of articles based on General Medical Council hearings, documenting how “Wakefield altered numerous facts about the patients’ medical histories in order to support his claim to have identified a new syndrome”.

The Daily Mail feature echoes the anti-vaccine conspiracy theories that are common online, reflecting a widespread fear that vaccines – a crucial area of modern-day medical science and pharmaceuticals – are ‘interfering with nature’.

The public row over Tamiflu has intensified with the rejection by the Cochrane group of Roche’s offer of an “advisory board” to discuss the issue.

Roche suggested that the “debate” over its non-disclosure of trial data on the antiviral be resolved through joint discussion of what kind of analysis public health studies require.

The Cochrane Collaboration, Europe’s leading drug appraisal authority, rejected the implied criticism of its methods and insisted that Roche honour its 2009 promise to publish the data.

Tamiflu (oseltamivir) neared £3 billion sales worldwide in 2009, allegedly due to Roche telling governments that it was about to publish trial data proving its effectiveness in combating ‘swine flu’.

Roche has still not released most of the data, citing lack of confidentiality as the reason. The available data are described by the Cochrane group as not supporting the drug’s widespread use.

Weeks ago, the BMJ published an ‘open letter’ to Roche insisting that it should publish the trial data or be disgraced in the medical world.

Editor-in-chief Fiona Godlee said that “billions of pounds of public money” had been spent on Tamiflu, but the evidence of its value “remains hidden from appropriate and necessary independent scrutiny”.

Peter Gøtzsche, head of the Nordic Cochrane Centre in Copenhagen, argued that doctors should boycott Roche’s products until it published the missing data.

Don MacLean, Roche’s lifecycle leader for Tamiflu, wrote to the Cochrane group, offering to construct an expert advisory board with their input “to agree on a statistical analysis plan outlining the types of analyses that would be useful in a public health discussion on Tamiflu.”

MacLean argued that this proposal “is a sensible, fair and transparent way of addressing this public debate” and ensuring the need for transparency is balanced with the need to respect commercial sensitivity.

The Cochrane Collaboration responded: “We have requested these data numerous times and have yet to receive a single full study report from Roche.

“There is no debate nor can there be any debate about the data whilst you do not honour your promise.”

It rejected the implicit criticism of its study methods: “Given the same methods and analyses have now been applied to over 5000 reviews in the Cochrane Library, what are your disagreements?”

With the European Medicines Agency moving towards an ‘open data’ policy, the pharma industry is under increasing pressure to be more transparent.

A leading researcher for the Cochrane Collaboration has called for doctors to boycott Roche over its failure to release clinical trial data on Tamiflu.

Peter Gøtzsche, head of the Nordic Cochrane Centre in Copenhagen, also argued that European governments should sue Roche for the funds spent on the drug.

His comment was made in response to an open letter from BMJ editor Fiona Godlee, accusing Roche of stepping “outside the circle of responsible pharmaceutical companies”.

The Cochrane Collaboration is the leading global authority for medical drug evaluation, known for its emphasis on randomised controlled trials.

Roche claims that it was unable to supply the Cochrane group with certain clinical data because its members refused to sign a confidentiality agreement.

However, the Collaboration insists that no such confidentiality agreement was offered to them at the time.

The antiviral Tamiflu (oseltamivir) was heavily stockpiled by European governments during the ‘swine flu’ crisis, on the basis of assurances from Roche that clinical data proving its efficacy existed and would be supplied.

Gøtzsche commented: “Roche has withheld data that purports to show that Tamiflu has dramatic effects. We all wonder why it is so difficult to get these data from Roche and why Roche has not published them if it is really true that they show these effects.”

He recommended: “European governments should sue Roche, which might have the effect that the hidden trial results come out in the open. Furthermore, I suggest we boycott Roche’s products until they publish missing Tamiflu data.”

Roche has been urged by the British Medical Journal to keep its promise and release the trial data on Tamiflu (oseltamivir).

The antiviral was widely prescribed across Europe during the ‘swine flu’ crisis, but its efficacy and safety have been questioned.

Roche, who promised three years ago to publish the trial data, are accused of stepping “outside the circle of responsible pharmaceutical companies”.

Dr Fiona Godlee, BMJ Editor-in-Chief, wrote in an open letter to Professor Sir John Bell, Roche’s Company Director: “Billions of pounds of public money have been spent on [Tamiflu] and yet the evidence on its effectiveness and safety remains hidden from appropriate and necessary independent scrutiny.”

The European Medicines Agency has started infringement proceedings against Roche, alleging that it failed to make available 80,000 reports on adverse reactions to Tamiflu.

Dr Godlee and 27 other doctors have also written an open letter to The Times urging UK pharmaceutical companies to release all clinical trial data on drugs that are currently in use.

Health Minister Norman Lamb has agreed to meet experts and discuss the issue of clinical trial transparency.

According to an investigation headed by members of the Cochrane Commission, there is no compelling evidence that Tamiflu prevents pneumonia or other complications of influenza.

According to the Cochrane team, 60% of the patient data from Roche’s 123 Phase III trials of Tamiflu have still not been released. They accuse Roche of “the likely overstating of effectiveness and the apparent under-reporting of potentially serious adverse effects.”

In her letter to Professor Bell, Dr Godlee said: “In refusing to release these data of enormous public interest, you put Roche outside the circle of responsible pharmaceutical companies.”

A new health strategy from the World Health Organization (WHO) challenges European governments to improve public health capacities and services.

European governments have been invited to adopt the Health 2020 framework, which focuses on reducing health inequalities and improving governance for health.

With its emphasis on the direct role of government in improving healthcare provision, Health 2020 conflicts with the current direction of NHS reform.

Launching the strategy, WHO noted that while life expectancy has increased in Europe over the past 20 years, health inequalities have also increased.

The strategy identifies four public health priorities:

• Investing in health through a life course approach and empowering people.

• Tackling the major health challenges of non-communicable and communicable diseases.

• Strengthening people-centred health systems, public health capacity, and emergency preparedness, surveillance and response.

• Creating resilient communities and supportive environments.

While noting the limitations imposed by the current economic climate, WHO argued that “good health is essential for economic and social development”.

Health 2020 proposes a number of headline targets for European member states by 2020: reducing premature death and health inequalities, increasing life expectancy and ensuring universal healthcare coverage.

Writing in the BMJ, health policy expert David J. Hunter noted that “political will in many [EU] member states is currently against state investment and intervention to improve health and to tackle its social determinants”.

European leaders will shortly be invited to endorse the WHO action plan for strengthening public health capacities and services.

Patients taking both metformin and insulin to help control their type 2 diabetes instead of insulin alone may not benefit from dual therapy, a new study claims.

Researchers from the Copenhagen Trial Unit, Steno Hospital, and the Copenhagen University Hospital agree the combination has a number of positive aspects but questioned the long term benefits for patients.

Authors of the study, published on bmj.com, say that more trials are necessary to provide firm evidence about the effectiveness of the combination, its long term risks and, in particular the risk of premature death.

The study included 2,217 patients over the age of 18 who had type 2 diabetes. It found various examples where levels of HbA1c were reduced with the combination of an oral glucose lowering drug and insulin.

Also, BMI levels and weight gain were also significantly reduced by metformin plus insulin by an average of 1.6kg.

However, a sparse number of important patient outcomes, including mortality from cardiovascular disease and other causes, have led the study’s authors to call for further research on long term risks.

Metformin is currently recommended by guidelines for patients with type 2 diabetes starting on insulin.