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.

The National Institutes of Health recently administered cancer vaccine PANVAC to 26 women with breast or ovarian cancer. PANVAC, a recombinant poxviral vaccine, produces two proteins associated with tumor cells to stimulate the body’s immune system to attack the cancer. During the trial, the median time it took for the breast-cancer patients’ condition to progress was 2.5 months, and the patients’ median survival time was 13.7 months. One breast cancer patient was still alive 37 months later. Median survival for the 14 ovarian-cancer patients was 15 months, and one woman went 38 months before her disease progressed. Although the trial was small and did not include a control group, these results seem encouraging.

Researchers from Oxford University also have attempted to fight cancer with the immune system. A team led by Paul Fairchild, codirector of the Oxford Stem Cell Institute, used stem-cell technology to create new dendritic cells from a patient’s skin. The dendritic cells, which organize part of the body’s immune response, carried the marker Melan A so that they would trigger an attack on melanomas. In the study, the team’s dendritic cells activated immune cells that produce antibodies and those that kill other cells. Previous studies using other dendritic cells had stimulated only part of the immune system.

Both of these techniques are still in their early phases. It will be some time before the studies lead to therapies from which patients can benefit, but they add to our knowledge of cancer and underscore the importance of oncology research. I take encouragement from these early steps, which I hope will inspire other drugmakers to take up the challenge of battling cancer.

One technique was accelerated approval for drugs to treat serious diseases. This authority allows the agency to approve a drug based on clinical data showing that it is reasonably likely to have a clinical benefit, even if data do not demonstrate that the drug has this benefit. Almost half of the newly approved drugs received Priority Review because they had the potential to offer major advances in treatment, or because no adequate therapy existed. FDA sets a six-month target date to review such drugs.

Although these changes in procedure are well-intentioned, we may legitimately ask how they will affect patients’ safety. After all, GSK’s diabetes drug Avandia received fast-track approval, but an article published in The New England Journal of Medicine later linked the drug to an increased risk of heart attacks. The Wall Street Journal notes that a Senate Finance Committee report last year accused the company of hiding data showing Avandia’s cardiovascular risks, and GSK has just agreed to pay the US government $3 billion to settle this and other claims.

Creating a short timeline for drug approval could hurt the agency’s reviews of clinical data. FDA approved Pfizer’s smoking-cessation drug Chantix after an accelerated priority-review process. The agency concluded that the drug did not increase the risk of psychiatric problems such as depression. But researchers from Wake Forest Baptist Medical Center found that Chantix was eight times more likely to result in suicidal behavior or depression than nicotine-replacement products. One reason for the discrepancy could be that, unlike FDA, the researchers performed disproportionality analysis on the data—a technique that is increasingly being used to find links in side-effect data that normally escape detection in clinical trials.

FDA’s staff includes well-vetted and experienced scientists, but they need sufficient time to work thoughtfully and thoroughly. Even though the agency’s initiative has increased the number of new-drug approvals, it may also be increasing the risk that a company can hide negative data from regulators, or that the agency’s own analyses will not be as complete as they could be. In light of the problems with Avandia and the conflicting studies about Chantix, I think FDA should review its efforts to promote innovation to be sure that the agency maintains high standards for drug safety.

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.

EMA published guidelines for follow-on biologics in 2005, and FDA has been studying its peer’s approach. So far it appears that FDA will follow EMA’s strategy of taking a product-specific approach to approving follow-on biologics. “Given the complex nature of biologics, it’s unlikely that a ‘one size fits all’ systematic assessment of biosimilarity can be developed,” wrote Janet Woodcock, director of the Center for Drug Evaluation and Research, and her colleagues in The New England Journal of Medicine. The agency will likely examine not only the manufacturing process for the therapies, but also the populations for whom the drugs are intended.

Companies that hope to enter this potentially lucrative market have argued that analytical characterization methods have improved to the point where they can establish similarity between a branded and a follow-on product. Some firms have argued that these methods could reduce the need for clinical trials. But FDA does not seem convinced that characterization methods have advanced far enough. Rather, “additional animal and clinical studies will generally be needed for protein biosimilars for the foreseeable future,” they wrote in the article, but “the scope and extent of such studies may be reduced further if more extensive fingerprint-like characterization is used.”

Ultimately, we won’t be able to predict the shape of the follow-on biologics industry in the US until FDA publishes its final guidance. Large-molecule therapies are more complex than small-molecule products, and it remains to be seen how burdensome the agency’s approval requirements will appear to the industry. Firms will have to weigh regulatory costs against the potential future profits before taking the plunge into this new market.

Scientists have written an open letter, published in The Lancet, to UK Prime Minister David Cameron and Health Secretary Andrew Lansley to express concerns about drug failures and adverse drug reactions. The root of the problem? Our reliance on animal tests.

“Our reliance on animals to establish safety results in the exposure of clinical volunteers and patients to many treatments that are at best ineffective and at worst dangerous,” say the authors of the letter. “The stark differences, not only in the diseases of different animal species, but also the ways that they respond to drugs, are now well known.”

Citing figures from the European Commission, the authors claim that adverse drug reactions are responsible for the deaths of approximately 197000 people in the EU, with an estimated total cost of €79 billion. Additionally, the authors blame the rising cost of drugs, and the subsequent burdens on national health services, on drug failures during clinical trials.

“The major reason for the rising cost of new drugs is the fact that more than 90% of them fail in clinical trials. Companies need to recoup the cost of development not only for the drug that succeeds, but for the nine others that fall by the wayside,” explain the authors.

Speaking to Sky News, Tony Dexter, who runs a research lab in Cheshire (UK) and is one of the signatories of the letter, said: “A fundamental problem is that a rat is not a human.”

I’m sure that many of us, although uncomfortable with the subject, will tentatively agree that animal tests are a necessary evil given that such tests are mandated by medicine regulators. Indeed, many important medical advances have been made thanks to our furry friends.

However, I’ve read many health-related research stories about tests in rats and wondered how on earth the results can translate to humans. Here are a couple of news stories I’ve just dug up — all of which are based on rat studies:

Binge-Drinking Teens May Be Risking Future Depression

Maternal Fructose Intake Impacts Female and Male Fetuses Differently

Too Many Sisters Affect Male Sexuality

I’m sure that these studies may potentially translate to human findings, but I can’t really get over my ‘but rats are different to humans!’ mindset. There are a number of similarities between rat genes and human genes, which is why they are frequently used in tests, but does a binge-drinking rat behave the same way as a binge-drinking human?

I also believe that researchers can sometimes get too carried away with the results of animal studies. How many times have we read about an amazing new cancer cure that works in mice? Yes, it’s a fantastic development, but it also raises the hopes of cancer sufferers, even though the research may never translate to humans. In 2007, for instance, there was a really interesting news piece about mice that had been bred to be resistant to cancer.

It’s not just rats and mice where results can fail to translate, there have also been issues in humans following tests in monkeys.

“Take for example the notorious Northwick Park clinical trial drug, TGN1412, that left six young men in intensive care in 2006,” say the authors of the Lancet letter. The drug was demonstrated safe in monkeys at doses 500 times higher than those that nearly proved fatal to the volunteers.

Following this trial, an assay using human cells was developed to predict immune system over-reactions, but the authors point out that the trial would never have taken place in the first place if the assay had been in use beforehand.

Now, the authors of the letter are calling on the UK Government to compare tests based on human biology with currently used testing methods to see which are more effective. A number of such tests have been proposed in the UK’s Safety of Medicines Bill 2010–11. The Bill does not propose any replacement of animal tests, merely their assessment of fit for purpose,” say the authors of the letter. “One hundred and forty eight Members of Parliament have already signed a motion in support of this proposal.”

“Some of us recently made representations to the UK Department of Health, and were told that the Government believes that human-biology-based systems have not been established as being more predictive than are animal studies for developing safer medicines,” say the authors. “We agree, but that is because no rigorous examination of such systems has been undertaken. The very purpose of the proposed comparison is to initiate such an examination, which is urgently necessary for the sake of the NHS, the pharmaceutical industry, and, most importantly, patients.”

But infants need medicines so a solution has to be found. In Europe, the development of paediatric medicines has just been bolstered with a research grant of 1.2 million euro, which will go towards a programme called PAMPER (Pharmaceutical Accelerator Mass Spectrometry Microdose Pediatric Evaluation Research Study), which will investigate new ways of developing drugs for infants. A number of research organisation across Europe are involved in this project, including the Netherlands-based research organisation TNO, the University of Liverpool (UK), Alder Hey Children’s Hospital (UK), Tartu University Hospital (Estonia), the Pharmaceutical Research Institute (Poland), Good Clinical Practice Alliance (Belgium) and Garner Consulting (UK). The funding was awarded through the PRIOMEDCHILD ERA-NET programme.

As the programme title suggests, the focus of the study will be on microdosing. To find out more, I spoke with Wouter Vaes, who is responsible for early clinical development at the TNO.

“Children are not just small adults,” said Vaes. “Drug kinetics, metabolism and dynamics can vary substantially between adults and infants. Therefore, it is complex to derive effective but safe starting doses of drug candidates in pediatric clinical trials.”

Which is why microdosing is such an exciting development in this area. Microdosing involves administering a very small dose of a drug (defined by the European Medicines Agency as less than 1/100^th of the pharmacologically active dose), which is unlikely to lead to clinically significant toxicity. Microdisng is not supposed to explore therapeutic effect; rather, it provides data about a drug’s pharmacokinetics and pharmacodynamics in humans at a very early stage of development.

“Microdosing is one of the best tools that industry can choose to obtain human data at early stage in development,” said Vaes. “We expect an increase in the use of microdosing, especially as a tool for candidate selection.”

The aim of the PAMPER study is to validate the microdoisng technology to obtain pharmacokinetic data that can, in the future, be used to study new drugs in infants.

“Eventually, we expect that microdosing will be used to derive kinetic and metabolic information for all age groups at the same time,” explained Vaes. “This information can be used to derive appropriate dosing regimes for further pediatric investigations. One of the important issues that the consortium will address is to develop methodology to determine the extremely low concentrations in tiny blood samples using the accelerator mass spectroscopy at the TNO.”

Although it’s still early days, the consortium hopes that the research will lead to safer tools that enable better, faster paediatric clinical investigations, as well as better labelling and less off-label use. The fact that the research could have such a huge impact on drug discovery and the resulting approved medicines is a testament to the value that research consortiums can bring.

“Precompetitive research is essential for the validation and subsequent application of new technologies and ideas,” said Vaes. “To increase the acceptance of new technological advancements that might lead to better drugs should be a joined effort between industry, governments, regulators and research institutes.”

The problem of slowing growth has been compounded by the difficulty in developing new branded products, according to a Datamonitor analyst. As more drugs lose patent protection, companies’ profits are eaten away by competing generic medicines, and meager pipelines have not been able to compensate for the loss in revenue so far.

In apparent despair of finding worthwhile candidates, several companies have reduced spending on research and development. Other companies have laid off research scientists. The Wall Street Journal reports that Elan cut roughly 65 research jobs at its San Francisco site. The fact that research has borne so little fruit likely is contributing to drugmakers’ decisions to cut staff and spending, although I’m not sure that the approach is a good one.

Enter the US government, a bugbear that industry often decries for imposing burdensome regulations and impeding innovation. To help find promising drug candidates and to demonstrate their potential to the industry, the National Institutes of Health (NIH) plans to found a National Center for Advancing Translational Sciences (NCATS). This new center will gather research from various institutes under one roof, use robotic screeners to identify promising chemicals, and conduct animal and human testing to confirm that the drugs are safe and efficacious.

“I am a little frustrated to see how many of the discoveries that do look as though they have therapeutic implications are waiting for the pharmaceutical industry to follow through with them,” Francis S. Collins, director of NIH, told The New York Times. NCATS will not compete with the private sector, but rather do some of its legwork for it.

I am glad that NIH is putting time, effort, and money into helping discover and develop the new drugs that patients need. Now that the low-hanging fruit has been picked, every extra effort could help bring essential therapies to the market. Pharmaceutical companies should be grateful for the assistance that NIH is trying to provide. It bears mentioning that this is not the first government effort to aid pharmaceutical research, and that companies routinely get other help, such as tax breaks, from the government. A combination of public and private efforts could well help keep the industry strong, and keep patients healthy.

This controversial comment comes from a press statement issued by the American Sociological Association about a study — Pharmaceuticals: A Two-Tier Market for Producing ‘Lemons’ and Serious Harm —that was presented at the associations annual meeting, which was held earlier this week. The study, authored by Donald Light, a professor of comparative health policy at the University of Medicine and Dentistry in New Jersey (USA), claims that about 85% of new drugs offer “few if any” new benefits and claims that drug companies sometimes hide or downplay information about side effects and overstate the drug’s efficacy.

It’s a harsh statement against pharma, as is Light’s claim that pharma companies spend “two to three times more on marketing than on research”. After a quick look at some third-party takes on the story though it seems that not everyone is shocked by the claims being made.

“I’d like to tell you this comes as a shock. But like every other doctor, I remember sitting in pharmacology lectures at medical school, being taught how drug companies would try to trick us into prescribing their latest wonder drug, and poring over the statistics to try to work out how they had manipulated the research to produce a positive result,” wrote Max Pemberton, a doctor who writes for the UK’s The Telegraph.

According to Light, there are three reasons why the pharma industry is producing “lemons”:

• having companies in charge of testing new drugs
• providing barriers of legal protection to hide information about the harm or effectiveness of drugs
• the low bar set for drug efficacy in order for a new drug to be approved.

He also claims that some pharma companies “swamp the regulator” with large numbers of “incomplete, partial substandard clinical trials”. In the press statement he said: “In one study of 111 final applications for approval, 42% lacked adequately randomized trials, 40% had flawed testing of dosages, 39% lacked evidence of clinical efficacy and 49% raised concerns about serious adverse side effects.”

According to the UK’s The Independent, the study has initiated a response from the Association of the British Pharmaceutical Industry (ABPI). The ABPI is claimed to have released a statement saying:

“Professor Light is long on accusation and woefully short on hard evidence. There is now much greater transparency in clinical trial results. The UK pharmaceutical industry also adheres to a strict code of practice on the sales and marketing of its products.

“The patient information leaflet provided in every pack with a medicine details the side effects which have been reported in clinical trials and reviewed by the regulator.”

The trial will study a combination of two vaccine candidates, Ad26.ENVA.01 (manufactured by Crucell) and Ad35-ENV (developed by IAVI), in healthy adults who do not have HIV. The trial will focus on the vaccines’ safety and effectiveness as a prime-boost regimen. The goal of a prime-boost combination is that one vaccine is administered to prime the immune system and elicit a certain immune response before a second, or booster, dose is given to enhance the overall immune response.

A previous clinical trial based on a prime-boost combination took place in Thailand and represents the first time an AIDS vaccine showed promise in reducing the risk of infection. Results released in September 2009 showed that the combination of vaccines lowered the risk of acquiring HIV by roughly 30%. Additional data were presented at the AIDS Vaccine 2009 Conference and published in the New England Journal of Medicine. The research team wrote that, “Although the results show only a modest benefit, they offer insight for future research.”

Also announced this week was that the International AIDS Vaccine Initiative (IAVI) appointed Michael Caulfield executive director of the IAVI AIDS Vaccine Design and Development Laboratory (DDL). Caulfield previously held research positions at Merck (Whitehouse Station, NJ) and the Cleveland Clinic. As leader of the DDL, he will be responsible for IAVI’s translational research and vaccine discovery, as well as for expanding its R&D team.

“Mike’s joining at a critical time for the field,” said Wayne Koff, IAVI’s chief scientific officer, in a press release. “We’re in the middle of a renaissance in AIDS vaccine design and development.”

In related news, scientists at the National Institutes of Health (NIH) announced the discovery of two human antibodies that can stop more than 90% of HIV strains from infecting human cells in the laboratory. The team, part of the Vaccine Research Center, a division of the National Institute of Allergy and Infectious Diseases at NIH, also demonstrated how one of the antibodies does this. The scientists said the antibodies could be used to design improved HIV vaccines, or could be further developed to prevent or treat HIV infection, according to the group’s press release. The work was published in Science in two articles, found here and here.

The NIH team’s discovery plus the results of the Thailand vaccine trial are examples of exciting progress in the field of AIDS vaccine research. Many are hopeful that the Crucell clinical trial will add to the upswing of encouraging results.

See previous posts on this topic:

The AIDS Vaccine Challenge

Roche Ends HIV Research Program

Vaccine Makers Prepare for Challenges Old and New