I always seem to be writing about GSK in my blogs but this is a much more sombre subject compared with the recent news of GSK CEO Andrew Witty’s knighthood. This week’s attention on GSK is focused on the COMPAS (Clinical Otitis Media and PneumoniA Study) study, which involved almost 24 000 children and was completed in Argentina in June 2011. The fine issued by the Argentinean National Administration of Medicines, Food and Medical Technology (ANMAT) related to administrative procedures in place for the study in 2007 and 2008. According to media reports (Sky News, CNN), some consent forms were signed by illiterate parents or people who did not have custody of the children. Claims have also been made that some children feeling unwell after vaccination were not seen by doctors.

Fourteen children are reported to have died during the study. Because the trial involved children, it is an extremely sensitive and emotional topic that has evoked strong reactions from some media sources that accuse GSK of “killing” babies and “experimenting with humans”.

But there are two sides to every story. Personally, I don’t believe that any reputable pharmaceutical company would experiment on humans.

GSK emphasised in a press statement that the fine relates to administrative procedures and “does not question the safety of the study vaccine”. Indeed, according to the statement, any deaths in the study were thoroughly investigated and both an independent data monitoring committee and ANMAT both concluded that none of the deaths were related to the vaccine.

The administration irregularities with obtaining informed consent were identified by GSK in 2007 and 2008 as part of routine monitoring, which takes place at 6-week intervals.

“The company proactively reported these findings to ANMAT and immediately put in place a corrective action plan which involved reconfirming informed consent of patients in the study and retraining doctors… where necessary,” explained GSK’s press statement. “The safety of patients participating in the study was not put at risk and ANMAT agreed that the study could continue as planned.”

Some media sources have also accused GSK — and other Western pharma companies — of taking advantage of developing countries to experiment with new treatments. In the case of GSK’s Synflorix, however, developing countries are a logical choice for a clinical trial. Estimates from the World Health Organisation claim that more than 500,000 young children die each year from pneumococcal infection, with the vast majority of these deaths occurring in developing countries. The GAVI Alliance also explains that although a vaccine against pneumococcal disease has been widely used in Europe and the US since 2000, it was not optimal for developing countries because it lacked different strains of pneumococcal bacteria that are common in developing countries.

Although Argentina is not really considered a developing country, it still has a large number of people living in poverty and pneumococcal disease is a significant health burden.

GSK says that it “respectfully disagrees” with the court ruling in favour of ANMAT and will appeal to the Supreme Court of Argentina. However, if unethical practices did take place during the trial then GSK has said it will pursue the matter.

“We are also concerned by allegations that treatment was delayed for some children in the trial if they were unwell and, if true, these events are shocking… we will be looking into this further,” said the GSK statement.

For Andrew Witty, the CEO of British pharma giant GlaxoSmithKline, the year is definitely off to a good start after he was knighted for services to the UK economy and pharmaceutical industry. Sir Andrew as he will now be known received the royal recognition in the UK’s 2012 New Year’s Honours List. Almost 1000 people received awards of varying kinds. 

This year, science and healthcare were well represented with other recipients of knighthoods including, among others, two physics professors, Professor Andre Konstantin Geim and Professor Konstantin Novoselov from the University of Manchester, Professor Stephen Robert Bloom from Imperial College London for services to medical science, and Dr Venkatraman Ramakrishnan from the Medical Research Council’s Laboratory of Molecular Biology for services to molecular biology. Julie Moore, the chief executive of the University hospitals Birmingham NHS foundation was also made a dame. Varying awards were also given out to other researchers and other pahrmaceutical industry particiants, including Richard Barker, the former director general of the Association of the British Pharmaceutical Industry (ABPI). There’s a full list available in The Telegraph. 

If you’re not familiar with the UK’s honours list, it’s a way of recognising merit, gallantry and service to the country. The lists are published twice a year at New Year and on the Queen’s official birthday in mid-June. The lists always comprises a number of film and sports celebrities, but it also reflects a range of skills and talents from across the UK.

The awards are also generally subject to a large amount of cynicism. For instance, The In Vivo Blog says, “Cynics may be suspicious of the timing of this flurry of biopharma-focused decorations. They came only a couple of weeks after the UK government outlined its new Life Sciences Strategy, in which much hope was placed on the sector helping to pull the UK economy out of the doldrums.”

I’ve also read some very cynical pieces that talk about the involvement of the British government in the honours process and the fact that Witty serves on an economic committee for the UK’s Prime Minister David Cameron.

However, most of the negative attention on the honour’s list this year has focused on other award recipients, such as Paul Ruddock who received a knighthood for services to the arts for his work as chairman of the Victoria and Albert museum. Ruddock’s hedge fund management company Landsdowne Associates made around £100 million after betting on the collapse of the bank Northern Rock. News reports have also pointed out that Ruddock has donated nearly £500,000 to the Conservative party. Some scathing has also been directed at the knighting of Paul Bazalgette, a TV executive who brought Big Brother to the UK. 

As a blog on our sister site Pharmaceutical executive points out, Sir Andrew could be seen as a bit of a knight in shining armour compared with other names on the list! GSK has pledged loyalty to the UK economy and has also sought to help developing economies by improving access to medicines. He’s also looking at some innovative ways to improve the company’s R&D by partnering with the McLaren Group. The knighthood will certainly be a good thing for GSK’s reputation, which has taken a bit of battering in the last year. In 2011, the company had to pay £1.6 billion to settle litigation cases concerning Avandia, which has been banned in Europe, while in the US the company has agreed to pay $3 billion to settle investigations into the way the company marketed certain products.

Related articles

GlaxoSmithKline Agrees in Principle to $3-Billion Settlement with the US Government

Pfizer, GSK Commit to Supplying Developing World with Vaccines

GSK to Harness Formula 1 Technology

Avandia Costs GSK $3.4 Billion

GSK isn’t the first pharma company to set its eyes on the automobile industry. In 2009, AstraZeneca borrowed some experts in lean manufacturing from Jaguar Land Rover, who were to apply their knowledge of efficient car production techniques to medicines. I’m researching at the moment how the project went so watch this space and hopefully I’ll be able to provide an update on this in the near future.

So what is it that cars and pharmaceuticals have in common? Today, the majority of a car’s value is attributable to suppliers but before this the industry used to be dominated by Western companies, much like the pharma industry. As the industry found the need to implement aggressive streamlining and cost cutting, carmakers now maintain only a few core operations, with everything else taking place across a huge network of contractors.

In the pharma industry, we’re already seeing greater numbers of companies outsourcing certain functions, such as clinical trials, or in-licensing new compounds from smaller companies.

The article (available here) pulls out a lot more similarities between the two industries. If you like pharma and cars then it’s definitely worth a read!

The article doesn’t provide any updates on the GSK partnership, which is a shame because it’s something I’m really looking forward to hearing more about. Where as AstraZeneca was looking to cars for lean expertise, GSK is hoping to extrapolate some of the technology using in Formula 1 racing to improve its R&D, such as seeing whether real-time monitoring technologies can be applied to human studies.

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 Fast Pharma – The Best of British

Last week, the World Intellectual Property Organization (WIPO), an agency of the United Nations, founded WIPO Re:Search, a forum for public and private organizations to share intellectual property (IP) and expertise with global-health researchers. By establishing a public database of IP, WIPO Re:Search aims to help develop new drugs and vaccines to treat neglected tropical diseases, malaria, and tuberculosis. The National Institutes of Health and companies such as AstraZeneca, Eisai, GlaxoSmithKline, Novartis, Pfizer, and Sanofi have agreed to work with the group.

To join WIPO Re:Search, member organizations agree to let the group license their IP to researchers on a royalty-free basis in many cases. But some observers say that these terms will not make information accessible enough. “Instead of allowing all countries where neglected diseases are prevalent to access the products, the initiative restricts royalty-free licenses to least-developed countries only, with access for other developing countries negotiable,” said Doctors without Borders in a press statement. Many patients that suffer from neglected tropical diseases do not live in least-developed countries. “In the Americas, for example, Chagas disease affects 21 countries, but the consortium will only provide royalty-free licenses for Haiti, where Chagas is not endemic,” according to the statement.

I think that WIPO’s initiative has great potential to help ease suffering and save lives. It’s encouraging to see the pharmaceutical industry dedicate resources to treating diseases that do not necessarily represent lucrative markets. And, by pooling a large amount of expertise, collaborations such as this one promise to solve stubborn problems more quickly than might otherwise be the case. But Doctors without Borders seems to be raising legitimate concerns. Considering its overall profitability, does the pharmaceutical industry have an obligation to help countries in need?

I like cars, and I like fast cars even more. So too, it would seem, does GlaxoSmithKline’s CEO Andrew Witty as the company is embarking on a long-term strategic partnership with the McLaren group, which is best known for its Formula 1 racing cars. The phrase “best of British” really does sum up the partnership and both companies seem extremely proud of it. The aim for GSK? Applying McLaren’s engineering and technical expertise to production lines to reduce breakdowns and improve costs, amongst other things.

“I am delighted to announce this partnership with McLaren which brings together two British companies whose continued success hinges on the ability to innovate and rapidly respond to change and competitor activity.” said Witty in a GSK press release. Witty considers the unusual pairing to be “looking outside its sector for inspiration and fresh perspectives” – and where better to look than a sport with 720 bph engines and grid girls? What the McLaren Group stands to gain, I can only guess…

Reading the joint press releases, it really does seem to make some sense; in particular, the state-of-the-art facility planned for 2013 to be called The McLaren GSK Centre for Applied Performance sounds like a novel way of breathing a little fresh air into pharma’s slightly sagging sails. Scientists, engineers and technologists from both camps will be able to share ideas and collaborate on innovative, dynamic and exciting joint working projects. And let’s face it, sometimes a fresh outlook is exactly what is required to make real progress. In some ways, it puts me in mind of the Novartis-MIT Center for Continuous Manufacturing – though admittedly, this collaboration is more readily justifiable and the aim a lot less vague…

Having said that, there are some defined goals. Alongside the aforementioned application of McLaren’s modelling system to the GSK production line, the R&D organisation will examine whether real-time monitoring technologies can be applied to human studies and the GSK Consumer Healthcare business will work with McLaren’s “Mission Control” unit to enable faster responses to competitor activity and customer needs.

Some might say that it smacks of a marketing stunt, and certainly it will do GSK no harm to be associated with such a fast-paced, exciting, technologically advanced, continually improving world—aren’t these all qualities that we would like to see demonstrated by pharma companies? I guess the level of investment that GSK pumps into the project may answer any critics and I look forward to seeing what comes into fruition.

The news has left me wondering what else the future may hold… Sanofi and Red Bull Racing? Merck and Merc? The race to the chequered flag is on!

No matter the real reasons behind the partnership, I will certainly be settling down on the sofa this weekend to see the top F1 drivers battle it out in Singapore—the perfect accompaniment to a traditional home-cooked Sunday lunch – another best of British.

Just last week, Representative Michele Bachmann (R-MN) told Fox News that the vaccine for human papillomavirus “can have very dangerous side effects.” Bachmann, who hopes to be the Republican candidate for president next year, mentioned a mother who claimed that her daughter had suffered mental retardation because of the vaccine.

Bachmann has taken a lot of heat for her remarks. The American Academy of Pediatrics and public-health efforts have denounced them. Arthur Caplan, a bioethicist at the University of Pennsylvania, offered to donate $10,000 to the charity of Bachmann’s choice if she “can produce a case in one week . . . verified by three medical experts that she and I pick of a woman who became ‘retarded’ (her words) due to the vaccine.”

Unfortunately, Bachmann is not the first to question vaccines’ safety. For years, a small but vocal group has been claiming that the vaccine for measles, mumps, and rubella causes autism. Early this year, the research paper that lent credence to this claim was revealed to rely on sloppy science and questionable methods. More recently, a panel assembled by the Institute of Medicine found no evidence that the vaccine causes autism.

Rumors that vaccines are harmful continue to circulate even in the absence of sound evidence. Comments such as Bachmann’s help foster this misperception. The group warning about vaccines’ putative dangers may be small, but it has gained media attention and could potentially influence patients’ decisions about healthcare. The pharmaceutical industry, and public officials such as FDA, would do well to publicly reaffirm that vaccines are safe. Drugmakers could describe the safety information garnered during clinical trials of their now-approved vaccines. And perhaps FDA could include a Q&A about vaccines on its website to dispel doubts. Communicating accurate information about vaccines will help the industry and patients alike.

Cases of narcolepsy with a potential connection to the vaccine first began hitting headlines in August 2010, prompting the European Medicines Agency (EMA) to launch a safety review. Six months on, however, it’s not entirely clear what’s going on. Is there a connection? Possibly, but only in certain countries and a certain age group! Although cases of narcolepsy have been reported in at least 12 countries, the majority of these come from Sweden, Finland and Iceland in children and adolescents aged 4–19 years.

“Even at this stage, it does not appear that narcolepsy following vaccination against pandemic influenza is a general worldwide phenomenon and this complicates interpretation of the findings in Finland,” explained a statement from the WHO.

The issue is also further confounded by the fact that an increased risk of narcolepsy has never been observed in association with the use of any vaccine — whether against influenza or other diseases — before.

Finland’s National Institute for Health and Welfare has been heavily involved in investigating the issue and established a National Narcolepsy Task Force last year. According to a report from the task force, 60 children and adolescents aged 4–19 years fell ill with narcolepsy in 2009–2010. Of these cases, almost 90% had received Pandemrix.

“Based on the preliminary analysis, the risk of falling ill with narcolepsy among those vaccinated in the 4–19 years age group was 9-fold in comparison to those unvaccinated in the same age group,” said a press statement from the National Institute for Health and Welfare.

Who’s to blame?

But given that no other vaccine has ever caused narcolepsy before, is Pandemrix really to blame?

A number of countries used similar pandemic vaccines in 2009, but the sharp increase in narcolepsy cases only seems to have occurred in Sweden, Finland and Iceland. Iceland has also reported greater than expected numbers of narcolepsy cases in unvaccinated children and teenagers in the country. GSK believes it’s too early to draw conclusions until the European investigation has been completed, but the company says it is working closely with the EMA to understand the situation.

Narcolepsy has also been shown to have a strong genetic linkage to a specific genotype, which all of the people diagnosed with narcolepsy during 2009–2010 in Finland possessed. The WHO explained that the National Institute “considers it most likely that the Pandemrix vaccine increased the risk of narcolepsy in a joint effect in those genetically exposed with some other, still unknown, genetic and/or environmental factor”.

For now, there’s no clear picture of exactly what is happening. According to GSK, more than 31 million doses of the vaccine have been administered worldwide in 47 countries, with only 162 cases of narcolepsy reported to GSK as of 31 January 2011.

The European Centre for Disease Prevention and Control, in collaboration with a number of EU member states, including Finland, is currently conducting epidemiological studies of narcolepsy and pandemic influenza vaccines. These studies will evaluate the contribution of pandemic vaccines and other risk factors to narcolepsy, and confirm whether an increase in narcolepsy has been seen in other countries. The outcomes of the study will be announced this summer.

Gladys Mensing sued PLIVA (Zagreb, Croatia), alleging that metoclopramide, which she took to treat diabetic gastroparesis, gave her tardive dyskinesia, a neurological movement disorder. As required by federal rules, the labels for generic metoclopramide matched those of the innovators, which did not warn about tardive dyskinesia while Mensing was taking the medicine. The US Food and Drug Administration ordered such warnings to be added in February 2009.

A federal judge threw out Mensing’s lawsuit, saying that it was preempted by federal regulations requiring the labels to match. The Eighth US Circuit Court of Appeals overturned this decision, however. “The generic defendants were not compelled to market metoclopramide,” the appeals court said, according to the Associated Press. “If they realized their label was insufficient but did not believe they could even propose a label change, they could have simply stopped selling the product. Instead, they are alleged to have placed a drug with inadequate labeling on the market and profited from its sale.”

It would seem unfair to punish PLIVA after it had marketed its product according to federal regulations. But the Eighth Circuit Judge raises a crucial point: ethical considerations should have stopped PLIVA from selling its drug if it knew that the label was insufficient. But how much did PLIVA know about metoclopramide’s potential side effects?

The fact that FDA originally approved the drug without a warning, only to add it later, reminds me of the controversy surrounding GlaxoSmithKline’s (GSK, London) Avandia. During a 10-year period after the drug was approved, more than 47,000 people taking it needlessly suffered a heart attack, stroke, heart failure, or death, according to one study. It would be wrong to blame the unfortunate adverse events entirely on FDA for approving the drug; the agency may not have gotten all of the relevant data. Senate investigators concluded that GSK did not share with regulatory authorities clear indications that Avandia increased heart risks.

The Avandia story illustrates that, despite its best efforts, FDA cannot yet completely protect us against drugs’ harmful side effects. The belated modification of the metoclopramide label indicates to me that the drug entails a significant risk of causing tardive dyskinesia. Given that FDA sometimes fails to mandate that drugs carry adequate warnings, I think that patients who can demonstrate that approved drugs have harmed them should have legal redress. I look forward to seeing how the Supreme Court decides this case.

The cable is organized by region, and many of the drug and biologic facilities that it mentions are located in Europe. Among them are Baxter’s (Deerfield, IL) immune globulin intravenous facility in Vienna, GlaxoSmithKline’s (London) pertussis-vaccine facilities in Belgium, Novo Nordisk’s (Bagsvaerd, Denmark) insulin facility in Denmark, and Genzyme’s (Cambridge, MA) fill–finish plant in Waterford, Ireland. Contract manufacturers also are represented by Vetter’s Ravensburg, Germany, facility.

Chemical suppliers also make an appearance. BASF’s Ludwigshafen, Germany, plant is called the “world’s largest integrated chemical complex.” And the cable asserts that Siemens’s Erlangen, Germany, location provides “essentially irreplaceable production of key chemicals.”

The leaked cable contains no revelations. The mentions of the Siemens and BASF facilities are no surprise, nor is it a shock to know that Hoffman–LaRoche’s (Basel) headquarters is an important supplier of Tamiflu. Any interested journalist or college student could have found this information—which is public, after all—through a bit of research. I’d argue that the leaked cable does no significant harm, nor does it aid any would-be terrorist.

The cables that revealed diplomats’ candid assessments of international leaders could complicate relations between the US and other countries. But the leaked CFDI list actually could benefit the pharmaceutical and biopharmaceutical industries—and the world at large—if it prompts the cited companies to take steps to secure their facilities.

Controversy has surrounded Avandia ever since it was first approved but in recent months there has been increasing pressure — including published articles and a UK television documentary highlighting the risks associated with Avandia — on the FDA and the European Medicines Agency (EMA) to take action.

“The availability of recent studies has added to the knowledge about rosiglitazone and overall, the accumulated data support an increased cardiovascular risk of rosiglitazone,” said a statement from the EMA. “In view of the restrictions already in place on the use of rosiglitazone, the Committee could not identify additional measures that would reduce the cardiovascular risk.”

As such, the EMA concluded that the benefits of the medicine no longer outweigh the risks in any groups of patients and recommended marketing authorization suspension, which has been forwarded to the EC for the adoption of a legally binding decision.

The move was strongly backed by the UK’s Medicines and Healthcare products Regulatory Agency, which conducted its own assessment of the safety of rosiglitazone and concluded that the product no longer had a place on the UK market. In the UK, the Diabetes UK charity has also supported the news, but added in a statement: “We would urge the EMA to make swifter decisions in the future to ensure patient safety.”

The marketing authorization suspension will remain in place unless GSK can provide “convincing” data to identify a group of patients in whom the benefits of the medicines outweigh their risks.

US restrictions

On the other side of the Atlantic, the FDA has chosen not to withdraw the product completely but has implemented stringent restrictions until “more substantial evidence of its safety becomes available”, according to a statement from Janet Woodcock, MD of the FDA’s Center for Drug Evaluation and Research. She also added that the “cardiovascular safety profile of rosiglitazone is still an open question because there are conflicting data on the existence and magnitude of the risk”.

The FDA has also ordered GSK to undertake a restricted access program to assure safe use and commission an independent re-adjudication of the RECORD study — a clinical trial initiated in 2001 that examined Avandia’s cardiovascular safety, but which has sparked a great deal of controversy regarding the validity of the data. The FDA has also placed GSK’s TIDE study, designed to compare the cardiovascular safety of Avandia and Actos, on hold and rescinded all regulatory deadlines.

GSK has said it will be working hard to clear the name of its product. “The company continues to believe that Avandia is an important treatment for patients with type 2 diabetes and is now working closely with the FDA and EMA to implement the required actions,” said a statement.

The loss of sales from the once blockbuster-touted product will be a heavy loss to GSK. According to analyst firm Datamonitor, a number of patients will probably switch to Takeda’s competitor product Actos; however, this product is also currently being subjected to a safety review following a possible link with bladder cancer. “The chances for Takeda to capitalize on Avandia’s further misfortune are limited, as Actos loses patent protection in January 2011,” explained Christine Henry, Healthcare Analyst at Datamonitor, in a statement.

More bad luck for GSK

Bad luck often comes in threes and this also seems to be true for GSK — two of the company’s other medicines, Rotarix and Pandemrix, have also been in the headlines this week for the wrong reasons.

Rotarix, a vaccine for infants to prevent rotavirus disease, has faced a labeling change because of research suggesting that it may increase the risk of intussusception — a potentially fatal bowel problem. Considering a similar vaccine from Wyeth was pulled off the market in 1999 for the same reason, it’s not a good omen for GSK.

The third bit of bad luck stems from Pandemrix. Earlier this month, the safety of the pandemic influenza vaccine was being investigated by the EMA following a possible link between vaccination and narcolepsy. On the plus side, the latest update from the EMA does not confirm a link between Pandemrix and narcolepsy, but the investigation is still ongoing, and it will be 3–6 months before GSK finds out whether or not the vaccine is in the clear.