MS Research News

We aim to bring you all the latest research news on issues relating to MS. You can read about what's going on in recent research and all the latest stories.

For the most up-to-date news, please subscribe our Latest MS Research News RSS Feed by clicking here:

Disease progression, or gradual worsening, experienced by people who have multiple sclerosis usually occurs over many years, and it is difficult to track with the standard clinical measurement scales used by doctors to assess disease activity.

An international meeting was convened to determine how to improve clinical measures so that MS progression can be better tracked, especially during clinical trials of experimental therapies aimed at stopping progression. Better ways of measuring changes in disability will help to speed the development of new therapies for MS, in particular for progressive forms of the disease.

The meeting was organized by the International Advisory Committee on Clinical Trials in MS, an international group of MS experts jointly sponsored by the National MS Society and the European Committee for Treatment and Research in MS (ECTRIMS).* A summary of this meeting has now been published in Lancet Neurology (2012 May;11(5):467-476). The Society is responding to the group’s recommendations, and sponsoring a collaborative effort to revise one clinical measure for primary use as a means of measuring disability in MS studies.

The Meeting: The “International Conference on Disability Outcomes in MS” was held in Washington, D.C. in 2011. Over 70 experts in MS and clinical trial design from around the world – including academic physicians and scientists, representatives of companies pursuing new therapies in MS and regulators from the U.S., Europe and Canada – gathered to discuss the measures currently used to measure MS disability, including the Expanded Disability Status Scale (EDSS), and the MS Functional Composite (MSFC). They agreed that these measures do not adequately measure the changes in MS progression that occur over time, or the patients’ own perceptions of their health and quality of life.

The group reviewed disability rating methods that show promise but require more study, such as “composite” endpoints that combine several measures, and innovative tools such as smart phones and other instruments that may offer better ways of tracking a person’s mobility.

Imaging, such as sophisticated MRI techniques used to examine changes in MS in the brain and spinal cord, and techniques to assess changes in the visual system over time (such as optical coherence tomography, OCT), were also discussed in terms of their abilities to objectively track signs of disease progression.

Meeting participants also reviewed a variety of “patient reported outcomes” being explored in MS clinical trials. These are surveys of clinical trial participants’ perspectives of their own health status and response to therapies, and are increasingly incorporated into clinical trials in MS and many other disorders. These subjective measures can add a dimension of clinical relevance to the objective measurements used by physicians to assess disability and the effectiveness of therapies.

The attendees made recommendations for improving upon current measures. In the case of the EDSS, they recommended developing a standard interview script so that all clinicians would administer this scale similarly, and simplifying the complex scoring rules. In the case of the MSFC, the group recommended that the MSFC could be improved by the addition of a test that measures change in visual function over time, by replacing the currently used method of assessing cognitive function, and by developing alternative scoring methods.

Following the meeting, these recommendations were discussed by the National MS Society’s senior research advisors, who concluded that the Society should sponsor an effort to revise the MSFC. The advisors appointed an interdisciplinary group of people with expertise in the clinical trials arena, from academia, industry, regulatory agencies and patient advocacy groups. This team is shepherding the process of revising the MSFC scale for use as a primary disability outcome in MS clinical trials.

The goal is to speed clinical trials of promising therapies aimed at stopping progression or restoring function. “We can’t afford to wait years to determine whether a therapy is working against MS progression,” noted Timothy Coetzee, PhD, Chief Research Officer of the Society.

*Additional support for the meeting was provided by the Americas Committee for Treatment and Research in MS, MS International Federation, MS Society of Canada, Bayer Healthcare Pharmaceuticals, Inc., Biogen Idec, Inc., F Hoffmann-LaRoche Ltd., Genzyme Corporation, Novartis Corporation, Sanofi-Aventis SA, and Teva Pharmaceutical Industries Ltd.

Source: The US National MS Society (11/05/12)

Randomised controlled trials of multiple sclerosis drugs have consistently improved since the first positive result in 1993, but more transparent methodology is required as trials enter a “new era”, experts argue.

After analysing the methodology of 53 eligible RCTs that took place in the eighteen years up to 2010, the Italian trio note a steady rise in quality – mainly down to “many journals having statistical refereeing and clearer guidelines to authors.”

But with the clinical scenario in MS changing “rapidly” as trials become increasingly benign, certain questionable practices need closer scrutiny, the authors say.

“The advent of new therapies has made the use of placebo unethical, at least in trials lasting more than six months,” they write in Multiple Sclerosis Journal.

Despite general improvements there also remain problems with the use of significance tests for detecting baseline differences.

Occurring in about half of the trials analysed, the authors argue its use is null since randomisation guarantees that any baseline differences are due to chance.

A more significant practice would be to provide information on whether baseline factors are associated with outcome. This, however, is rare.

As well, there are enduring problems with subgroup analysis.

Interaction tests, used to assess the heterogeneity of treatment effect across different subgroups, are the “correct approach” but remain underused.

Smaller trials are often underpowered to use such tests effectively, say the authors, who argue for companies to work together and pool collective analyses – something they habitually avoid out of a reluctance to share information.

It is up to journals, so instrumental in boosting methodological quality to date, to encourage pooled analysis, they conclude.

Multiple Sclerosis Journal, 2012; doi:10.1177/1352458512444327

Source: Neurology Update (01/05/12)

Innovative online community for researchers aims to advance scientific collaboration and research for MS.

The Accelerated Cure Project for Multiple Sclerosis (ACP) and the MassGeneral Institute for Neurodegenerative Disease (MIND) today announced the launch of the Multiple Sclerosis Discovery Forum (MSDF) ( http://www.msdiscovery.org/ ), a new, interactive virtual community and information portal that connects and educates investigators who study MS and other demyelinating disorders of the central nervous system, including transverse myelitis, neuromyelitis optica, and acute disseminated encephalomyelitis.

"Many important advances have been made in recent years toward bringing new therapies to people with MS, but we still have a long way to go before we can celebrate a cure for the disease," said Robert McBurney, president and chief executive officer of ACP. "The Multiple Sclerosis Discovery Forum will shorten that path by creating an open research environment that fosters the generation and exchange of novel ideas about the causes, mechanisms, and potential cures for MS. We anticipate that the site will catalyze connections across disciplines that help accelerate us toward a cure."

The Multiple Sclerosis Discovery Forum provides a neutral venue where members of the MS research community can:

-- Learn about cutting-edge findings and their significance through original articles by top-flight science writers;

-- Participate in peer-hosted discussion forums and webinars;

-- Access professional and research resources such as a custom drug-pipeline database and the MSGene database of MS genetic association studies;

-- Share and receive feedback from other researchers on study findings and key learnings; and

-- Collaborate with researchers from other organizations on opportunities for translational research.

"MS researchers face a daunting task as they strive to keep up with discoveries in their own area of expertise, never mind other disciplines," said MSDF scientific adviser Richard M. Ransohoff, director of the Neuroinflammation Research Center and staff neurologist at the Mellen Center for MS Treatment and Research, both at the Cleveland Clinic. "The sheer scope of MS research, from immunology to neuroscience to genetics to epidemiology to imaging, entails more raw literature than anyone can absorb. Furthermore, many research communities are siloed and don't effectively communicate to others. Through the Multiple Sclerosis Discovery Forum, this data sharing becomes easier. Information about new findings and resources, accessible on a single site, will spur innovative ideas and speed progress. Knowledge sharing at scientific conferences can now continue online and will engage the broader community, allowing MS researchers to untangle the causes of this often-devastating illness and develop therapeutic compounds and strategies."

"Scientific social media are emerging as a new way to help enhance the efficiency of research and generate new approaches to medical challenges," said Tim Clark, director of Informatics at the Mass General Institute for Neurodegenerative Disease (MIND). "Our joint effort with ACP to create the Multiple Sclerosis Discovery Forum has provided a platform that will build knowledge and inspire new and fruitful scientific collaborations."

About the Multiple Sclerosis Discovery Forum

The Multiple Sclerosis Discovery Forum is a joint project of the Accelerated Cure Project for MS (ACP), which creates the site's content; the MassGeneral Institute for Neurodegenerative Disease (MIND), which has developed and supports the site's platform; and the Max Planck Institute for Molecular Genetics, which curates MSGene. The Multiple Sclerosis Discovery Forum is a free resource supported by a generous grant from its founding donor, EMD Serono. The Forum operates completely independently of its funders, who have no influence over the site's content or operations. The site, which provides a neutral forum for discussion and information exchange, is guided by a distinguished scientific advisory board from various institutions within the MS research community.

For more information about the site and to register as a member of the MSDF .

About Accelerated Cure Project for MS (ACP)

Accelerated Cure Project for MS (ACP) is a nonprofit organization whose mission is to accelerate efforts toward a cure for multiple sclerosis (MS) by rapidly advancing research that determines its causes and mechanisms. We provide biomedical researchers with resources that catalyze open scientific collaboration and enable them to explore their novel research ideas rapidly and cost-efficiently. ACP's strategic initiatives include the Multiple Sclerosis Discovery Forum and the ACP Repository, a large-scale collection of highly-characterized biosamples available to scientists at any organization conducting research that contributes to our mission. All results generated through analysis of Repository samples and data are contributed back to the ACP Repository Database, resulting in an increasingly valuable and comprehensive information resource that can be analyzed to reveal new insights about MS. To date, ACP has enrolled almost 3,000 participants into the Repository through a network of 10 MS clinical centers across the United States. The samples provided by people with MS and related disorders have supported more than 60 research studies worldwide and generated more than 150 million returned data points.

Source: Market Watch Copyright © 2012 MarketWatch, Inc (18/04/12)

In an analysis piece, the Bureau argued that there should be more research into Multiple Sclerosis treatments. At present, there are a number of generic drugs that have shown promise in initial MS trials.

However, none listed below have completed Phase III level of trialing. This phase of trial aims to be the definitive assessment of the drug’s effectiveness and so would be expected if the drug was to become an accepted standard treatment.

It is acknowledged that there are some inherent difficulties in reading too much into early stage trials, notably with animal models or small test groups. However, the lack of funding to take these trials to include a larger number of MS sufferers means that this is the only proof often available.

As such the data below still reflects as yet unproven treatments.

VITAMIN D

There is considerable evidence linking people lacking vitamin D and those at higher risk of developing MS. Despite this, there has been no major trial looking at MS disease progression and vitamin D supplementation. In preventative terms, some work has been done. One study showed women taking supplemental vitamin D had a 40% lower risk of developing MS than women not taking vitamin D.

But in terms of treating patients with a diagnosis, little has been done on a large scale, despite there being a compelling case for such a study to be undertaken. There have been some studies that, looking at a six month supplementation with vitamin D3, produced an increased vitamin D status and serum TGF-β1 in the blood tests of MS patients. A tiny study showed that only 16% of 25 people with MS given an average of 14,000 international units (IU) of vitamin D a day for a year suffered relapses.

In contrast, close to 40% of 24 MS patients who took an average of 1,000 IU a day — the amount recommended by many MS specialists — relapsed. Also, people taking high-dose vitamin D suffered 41% fewer relapses than the year before the study began, compared with 17% of those taking typical doses. Another study into paediatric MS has demonstrated an additional 2,000 international units of vitamin D supplementation a day, could theoretically cut a patient’s relapse rate in half.

In one two-year study of a course of treatment with vitamin D and calcium, 10 patients with MS had a 60% reduction in the predicted number of relapses, but there was no control group. In another uncontrolled study, 15 patients who received Vitamin D supplements for 48 weeks experienced a 50% reduction in relapses. Lastly, a Canadian team recently demonstrated that the use of high doses of vitamin D3 during a long period (6 months–1 year) showed a 41% reduction in the number of relapses and a significant improvement in disability scores was observed in the treated patients. The authors concluded that this provided ‘ample justification for much more extensive therapeutic trials’.

There have been some concerns that taking Vitamin D might result in hypercalcemia. However, some initial research has shown that vitamin D intake beyond the current upper limit is safe by a large margin, although this was not for a prolonged period of time.

MINOCYCLINE

Minocyline, a relatively cheap, readily available and well-tolerated tetracycline antibiotic has shown potential for the treatment of MS. In small trials it has been shown to have reduced MS lesions by as much as 84%, reduced annualized relapse rates from an average of 1.2 a year to 0.25 a year, and found only one in 40 people with MS on the drug having active lesions (and that person was on half-dose).

FUMARIC ACID ESTERS

Fumaric acid esters (FAE) have also been shown to have some effect on people with Relapse Remitting Multiple Sclerosis. It seems that by detoxifying radicals released during the inflammation process, FAE protects nerve and glial cells. In one trial, FAE produced significant reductions in the number and volume of lesions and improved disability scores. In this, treatment with FAE reduced by 69% the mean total number of new lesions compared with placebo.

PARASITIC INFECTION


There is also evidence that parasite infection is correlated with a reduced number of exacerbations and altered immune reactivity in multiple sclerosis. In one Argentinian analysis, conducted over almost 5 years, doctors looked at MS sufferers who happened to have an infection with parasites compared to MS sufferers who did not. The parasite-infected MS patients showed a significantly lower number of exacerbations, minimal variation in disability scores, as well as fewer magnetic resonance imaging changes when compared with uninfected MS patients. And in a recent Phase 1 study of pigworm eggs, the number of new lesions showing up on MRI scanning fell from an average of 6.6 to 2.0. After the pigworm doses were discontinued, the mean number of lesions rose from 2 to almost 6. There is an ongoing Phase II study at Nottingham University, funded by the British MS Society, into whether infecting MS patients with helminths could provide a simple, cheap, natural and controllable treatment for the debilitating condition.

LIPOIC ACID


Lipoic acid (LA) is an antioxidant that suppresses and treats and disease similar to MS in mice. It’s antioxidant properties amongst other benefits, make it a contender for a therapeutic alternative for multiple sclerosis. One study has shown that a dose of 1200 mg oral lipoic acid can achieve beneficial changes in serum levels in patients with multiple sclerosis, by increasing the ratio of Th2 to Th1 cytokines in circulating cells. But the study showed no evidence in terms of relapse rates or disability progression.

LOW DOSE NALTREXONE (LDN)

One small trial showed that this drug, that is also used in higher quantities as an opiate antagonist to treat recovering drug addicts, showed that Low Dose Naltrexone was associated with significant improvement in mental health quality of life measures. Another small trial in people with primary progressive multiple sclerosis showed that there was a ‘significant reduction of spasticity’ in patients.

by Iain Overton

Source: The Bureau of Investigative Journalism (05/08/11)

With unprecedented debt affecting many of the developed world’s economies, there is much concern about the impact of cost savings on healthcare. In the UK the NHS needs to save £20bn by 2015.

Where savings will come from is a source of deep contention.

But some reports have focused on the fact that the NHS is spending unacceptable amounts on the cost of some of its medicine. Latest annual figures show pharmaceuticals cost the NHS £11.9bn in primary and secondary care – almost 12% of total revenue. Cost-benefit analysis of treatment, though, is a tricky subject.

Multiple sclerosis
Multiple sclerosis (MS) is a good example. It is a very costly disease. The estimated cost to the UK economy of MS is over £1.4bn a year. Of this about 8% was spent on the cost of disease-modifying drugs.

Recently, however, the leading journal Neurology published a report comparing two groups of MS sufferers. One group was on treatment and the other was not. Not seeing a dramatic difference in the two groups, the authors concluded that many disease-modifying therapies (DMTs) in multiple sclerosis are far from cost-effective. Interferon β-1a, interferon β-1b, and glatiramer acetate were seen to deliver ‘modest health gains’ at best.

‘It is very unlikely that under current pricing and prescribing patterns, DMT may be considered cost-effective for patients with relapsing-remitting MS and secondary progressive MS,’ the authors concluded.

Some have challenged the methodology of this report, but it serves to highlight a major issue. That of the challenge of finding drugs that are both effective and in terms of costs, financially justifiable.

Drugs effectiveness
On a drugs effectiveness – if DMTs for MS were more effective then treatment should reduce the longer-term costs of disabled care by reducing disability progression.

A new raft of drugs are being developed to treat MS that might be more up to the job.

The immunomodulatory drug, Fingolimod, for instance, shows promise. A trial comparing its effectiveness with a placebo showed relapse rates reduced by as much as 60% and reduced disability progression by about 30% over six months. When compared to one of the older standard treatments of MS, beta-interferon-1a, it was shown to be better at reducing relapse rates by some 53%.

But in a little publicised note on the NHS Nice website, the committee who would sign off on Fingolimod, pushed back the deadline for its decision by almost a year. It cited ‘resource constraints and efficiency scheduling’. This seems to be code for ‘the drug is very expensive and we have to wait to see if we can afford it’.

Old Treatments, New Tricks
In a cash-strapped era, the far bigger question is this: can healthcare providers, particularly state ones, afford such expensive drugs?

Fingolimod is reported to cost up to $48,000 a year to patients in the US. It is likely to cost less in the UK, but still more than the current first-line DMTs offered by the NHS.

The thornier issue, then, is not the effectiveness of the drug, but rather the cost.

When faced with this reality, we have to acknowledge then that there are a number of generic, older treatments that might be as efficient in treating MS as the new wave of drugs, but at a much lower cost.

These are older remedies that could, in the case of MS, be used for new tricks. These treatments include vitamin D, Minocyline, Fumaric Acid Esters, Parasites, Lipoic Acid, Low Dose Naltrexone and Uric Acid. They have all been shown to have some promise for MS. And being generic treatments they are not under patent from a drug company, so they are comparatively much cheaper.

But the trouble is this – there is no hard, categorical proof that any of these are as good or better than the standard treatment. It is a dilemma summed up in an editorial in Journal of Neuroimmunology writing on the use of parasites to treat Multiple Sclerosis:

What is required is rigorous, objective evaluation … at the levels of animal models, clinical trials, and immunology.

The trouble is that ‘rigorous, objective evaluation’ of treatments that cannot be licensed is costly – a Phase III trial can run into the millions of pounds. And this, of course, is not something that will be done by the drug companies.

Dr D. Craig Hooper of the Thomas Jefferson University in the United States, who has done much work in whether antioxidants have the potential to treat MS, is clear on the conundrum: ‘this is not something that big pharma is going to get into – governments have to do this sort of thing’.

Government needs to step up to do the work drug companies will not do.

Admittedly, something like this does exist. The Health Technology Assessment programme (HTA) produces independent research about the effectiveness of different healthcare treatments and commissions the research it thinks is most important through different funding routes.

But, despite not suffering the cuts that have befallen other public sectors, the HTA still has limited funding and does not always commission bold work. Recently, for instance, a Phase 3 trial of vitamin D for MS was considered by the HTA but was rejected, despite there being seemingly compelling evidence that low levels of Vitamin D is linked in those who develop MS.

Medics, also, have proven unwilling to pursue research like this. The HTA recently advertised for a trial of an off-patent drug – azathioprine – in MS. It had no applications.

The need for innovation
The seeming reticence to innovate and experiment in the NHS has been highlighted in other areas. Sir John Bell, who led an inquiry into the future of NHS genetics, has said: ‘There has already been a lot of innovation, almost none of which has been adopted by the NHS…There’s more than enough we could be doing here, but the NHS is completely unprepared’.

And in The Times’ letters pages there was a recent headline that ran: ‘Chronic Fatigue syndrome needs more research’.

There is both a moral and an economic argument for the NHS to prioritise and aggressively push research both in terms of funding and in terms of pushing clinicians into this field.

Moral in the sense that more government-sponsored trials could help find highly effective uses for older drugs for people afflicted by terrible diseases.

And economic in that the overall cost to patient and state for these old drugs performing new tricks would be considerably less than many existing low-functioning disease modifying treatments.

by Iain Overton

Source: The Bureau of Investigative Journalism (04/08/11)

Big Pharma has developed new forms of 'research' to serve its own interests.

The medical research world has been concerned about the problem of ghost writing for more than a decade. Over the past few years, the issue has been repeatedly raised in the mainstream media. Most of the commentary has focused on the ethics of academics signing their name on papers they did not write and on some of the most egregious actions by pharmaceutical companies.

But these efforts miss the ways in which Big Pharma has developed new forms of medical research to serve its own interests.

How Ghost Writing Feeds Big Pharma Profits

According to a study by Marc-André Gagnon and Joel Lexchin in PLoS Medicine, Big Pharma firms spend twice as much on promotion as on research and development. But it is worse than that: More and more medical R&D is organized as promotional campaigns to make physicians aware of products. The bulk of the industry’s external funding for research now goes to contract with research organizations to produce studies that feed large numbers of articles to medical journals.

Internal documents from Pfizer, made public in litigation, showed that 85 scientific articles on its antidepressant Zoloft were produced and co-ordinated by a public relations company. Pfizer itself thus produced a critical mass of the favourable articles placed among the 211 scientific papers on Zoloft in the same period. Internal documents tell similar stories for Merck’s Vioxx, GlaxoSmithKline’s Paxil, Astra-Zeneca’s Seroquel, and Wyeth’s hormone-replacement drugs.

To promote the now-notorious Vioxx, Merck organized a ghost-writing campaign that involved 96 scientific articles. Key ones did not mention the death of some patients during clinical trials. Through a class-action lawsuit against Vioxx in Australia, it was discovered that Elsevier had created a fake medical journal for Merck – the Australasian Journal of Joint and Bone Medicine – and perhaps 10 other fake journals for Merck and other Big Pharma companies.

In another example, GlaxoSmithKline organized a ghost-writing program to promote its antidepressant Paxil. According to internal documents made public in 2009, the program was called “Case Study Publication for Peer-Review,” or CASPPER, a playful reference to the “friendly ghost.” Such strategies are not exceptions; they are now the norm in the industry.

Most new drugs with blockbuster potential are introduced accompanied by 50, 60, or even 100 medical journal articles. Any firm that refused to play this game in the name of ethics would likely lose market share. Profits in the pharmaceutical industry depend on companies’ capacity to influence medical knowledge, and create market share and market niches for their products.

A Call for Evidence-Based Medicine

In 2008, research showed that pharmaceutical companies systematically failed to publish negative studies on their SSRIs – formally called selective serotonin reuptake inhibitors, the Prozac generation of antidepressants. Of 74 clinical trials, 38 produced positive results and 36 did not; 94 per cent of the positive studies were published, compared to only 23 per cent of those that were negative, and two-thirds of those were spun to make them look more positive.

Physicians reading the scientific literature got a biased view of the benefits of SSRIs. This helps to explain the huge number of antidepressant prescriptions, in spite of the fact that, according to a meta-analysis in the Journal of the American Medical Association in January 2010, the drugs did not bring more benefits than a placebo for 70 per cent of people taking SSRIs. Compared to a placebo, however, SSRI antidepressants can result in serious adverse drug reactions.

With this we see one of the problems with the ghost management of medical research and its publication. Pharmaceutical companies want upbeat reports on their drugs. They design, write, and publish studies that are likely to show their drugs in a positive light – and there are myriad ways to do so. Ghosts sometimes bend the truth, and sometimes even commit fraud, with grave results.

Why do academics sign their name on scientific articles they did not write, using research they did not perform? Because they are rewarded, both by their universities and by their colleagues, for how much they publish and for the prominence of the publications. Pharmaceutical companies and their agents are very good at placing articles in prestigious journals, and they then make them even more prominent by having their armies of sales reps circulate them and talk them up.

Researchers who sign their name on studies and analyses (perhaps scientifically correct) that are favourable to the industry can expect to see these articles increase their prestige and influence, and possibly even funding.

What happens, however, when a researcher produces studies and analyses (also scientifically correct) showing that some products are dangerous or inefficient, as some did about Vioxx before the scandal broke? Reading Merck’s internal emails, revealed during the class-action lawsuit, it was exposed that the company drew up a hit list of “rogue” researchers who needed to be “discredited” or “neutralized” – “seek them out and destroy them where they live,” one email read. Eight Stanford University researchers say they received threats from Merck after publishing unfavourable results.

Corporate Science

In the ghost management of research and publication by drug companies, we have a new model of science. This is corporate science, done by many unseen workers, performed for marketing purposes and drawing its authority from traditional academic science. The high commercial stakes mean that all of the parties connected with this new corporate science can find reasons or be induced to participate, support, and steadily normalize it. It also biases the available science by pushing favourable results and downplaying negative ones – and sometimes through outright fraud.

As long as pharmaceutical companies hold the purse strings of medical research, medical knowledge will serve to market drugs, not to promote health. And as long as universities grovel for more partnerships with these companies, the door will remain wide open to proceed with the corruption of scientific research.

Source: THE MARK COPYRIGHT 2010 (12/05/11)

The US Department of Justice is scrutinising payments by leading pharmaceuticals companies for hospitality, consultants, licensing agreements and charitable donations in markets around the world as part of a wide-ranging corruption probe.

GlaxoSmithKline, Pfizer, Bristol-Myers Squibb and Eli Lilly, among others, have disclosed being contacted by the DoJ and Securities and Exchange Commission in connection with the investigation. Merck, the US drugs group, announced last week that it had also been contacted and was co-operating with investigators.

An industry attorney familiar with the probe said that the DoJ was looking at whether pharma companies had ignored a “systematic risk” inherent in the global drugs business and ignored obligations under local and US anti-bribery law.

The highly regulated nature of the business, combined with the fact that healthcare officials in many non-US markets were government funded, made the industry a natural target for such a probe, the person added.
The investigation is at a relatively early stage but is considered a priority for the DoJ.

While hospitality – including meals and all expenses-paid travel for conferences – has long been considered a potential risk for pharma groups, the DoJ’s probe is looking at all aspects of companies’ dealings in non-US markets, people familiar with the matter say. That includes the recruitment of physicians for clinical trials. In some markets, the same physicians may serve on regulatory boards that approve or deny drugs.

The DoJ declined to comment. But last November, Lanny Breuer, head of the DoJ’s criminal division, announced that investigators would be focusing on international corruption in the pharmaceuticals industry for “years”.
Mr Breuer warned a conference of pharmaceutical industry lawyers that prosecutors were gearing up for an investigation of international corruption in the sector. The drugs companies took notice.

That threat has now become a reality. Merck, AstraZeneca, Eli Lilly, Baxter, SciClone, and Bristol-Myers Squibb have in recent months received inquiries from the DoJ and the Securities and Exchange Commission in connection with an industry-wide bribery ­investigation.

GlaxoSmithKline, the UK drugmaker, told the Financial Times on Thursday that it too had received “inquiries” from US authorities, but that it disclosed the issue “reactively” only to selected reporters in April.

Pfizer, the world’s largest pharmaceutical group, said in February that it had voluntarily provided the DoJ and SEC with information concerning potentially improper payments outside the US and was exploring resolution of the matter.

There is perhaps no industry that is as vulnerable to violations of US anti-bribery laws as the pharmaceutical industry. In markets round the world, the companies deal, sometimes thousands of times in a single day, with doctors, clinicians, hospital operators and regulators who are considered under US law to be government officials, because they are employed by state-owned facilities.

Under the Foreign Corrupt Practices Act, the US anti-bribery law, companies may not offer items of value to foreign government officials for profit. One industry lawyer involved in the matter said global pharmaceutical companies operating in countries with state-run medical institutions deal with government officials at every turn of their business: whether it is seeking the go-ahead for a manufacturing site; obtaining drug licences; conducting clinical trials; importing drugs; selling and marketing drugs to physicians; or getting a product on to a hospital’s approved list.

“What most companies will find is that all of these areas are risky and, if they don’t train and educate their people, they are going to find themselves with issues. For example, if you have hired customs brokers, how do you know they aren’t bribing officials?” the attorney said.

According to the law firm Arnold & Porter, the DoJ is particularly interested in corrupt payments that may have influenced the reliability or integrity of data in clinical trials performed outside the US. A recent report by the Department of Health and Human Services found 80 per cent of marketing applications for drugs approved by the Food and Drug Administration in the US had relied on at least one foreign trial.

“Companies may find themselves facing critical legal issues if approval of products rested on the results of studies the DoJ deems corrupt,” Arnold & Porter said in an advisory letter to clients last month.

A person familiar with the investigation confirmed that clinical trials were one of several areas the DoJ was examining.

Alexandra Wrage, the president of Trace, a non-profit organisation that helps companies establish anti-corruption practices, said that alleged wrong­doing at pharmaceutical companies could often centre on inappropriately lavish hospitality, such as wining and dining doctors from state-run hospitals at conferences in Bali or Monaco.

“What we hear is not that doctors are expecting cash. But that doctors are only going to give companies time [for meetings] in front of a meal or a training session,” said Ms Wrage. Such sessions often involve all-expenses-paid travel.

In the US, drugs companies are also coming under more intense scrutiny for their interactions with doctors. Pfizer in April disclosed that it paid $35m over six months to 4,500 doctors in private practice for education and the development and marketing of new drugs – payments that are legal in the US.

But legal experts familiar with the inquiries say they expect that the DoJ is examining egregious behaviour that smells of bribery.

Source: The Financial Times Copyright The Financial Times Limited 2010 (15/08/10)

Marcia Angell ex-editor New England Journal of Medicine

In May of 2000, shortly before I stepped down as editor-in-chief of the New England Journal of Medicine, I wrote an editorial entitled, “Is Academic Medicine for Sale?” It was prompted by a clinical trial of an antidepressant called Serzone that was published in the same issue of the Journal.

The authors of that paper had so many financial ties to drug companies, including the maker of Serzone, that a full-disclosure statement would have been about as long as the article itself, so it could appear only on our Web site. The lead author, who was chairman of the department of psychiatry at Brown University (presumably a full-time job), was paid more than half a million dollars in drug-company consulting fees in just one year. Although that particular paper was the immediate reason for the editorial, I wouldn’t have bothered to write it if it weren’t for the fact that the situation, while extreme, was hardly unique.

Among the many letters I received in response, two were especially pointed. One asked rhetorically, “Is academic medicine for sale? These days, everything is for sale.” The second went further: “Is academic medicine for sale? No. The current owner is very happy with it.” The author didn’t feel he had to say who the current owner was.

The boundaries between academic medicine—medical schools, teaching hospitals, and their faculty—and the pharmaceutical industry have been dissolving since the 1980s, and the important differences between their missions are becoming blurred. Medical research, education, and clinical practice have suffered as a result.

Academic medical centers are charged with educating the next generation of doctors, conducting scientifically important research, and taking care of the sickest and neediest patients. That’s what justifies their tax-exempt status. In contrast, drug companies—like other investor-owned businesses—are charged with increasing the value of their shareholders’ stock. That is their fiduciary responsibility, and they would be remiss if they didn’t uphold it. All their other activities are means to that end. The companies are supposed to develop profitable drugs, not necessarily important or innovative ones, and paradoxically enough, the most profitable drugs are the least innovative. Nor do drug companies aim to educate doctors, except as a means to the primary end of selling drugs. Drug companies don’t have education budgets; they have marketing budgets from which their ostensibly educational activities are funded.

This profound difference in missions is often deliberately obscured—by drug companies because it’s good public relations to portray themselves as research and educational institutions, and by academics because it means they don’t have to face up to what’s really going on.

Industry and academia

No area of overlap between industry and academia is more important than clinical trials. Unlike basic medical research, which is funded mainly by the National Institutes of Health (NIH), most clinical trials are funded by the pharmaceutical industry. In fact, that is where most pharmaceutical research dollars go. That’s because the Food and Drug Administration (FDA) will not approve a drug for sale until it has been tested on human subjects. Pharmaceutical companies must show the FDA that a new drug is reasonably safe and effective, usually as compared with a placebo. That requires clinical trials, in which treatments are compared under rigorous conditions in a sample of the relevant population. The results of drug trials (there may be many) are submitted to the FDA, and if one or two are positive—that is, they show effectiveness without serious risk—the drug is usually approved, even if all the other trials are negative.

Since drug companies don’t have direct access to human subjects, they’ve traditionally contracted with academic researchers to conduct the trials on patients in teaching hospitals and clinics. That practice continues, but over the past couple of decades the terms and conditions have changed dramatically.

Until the mid-1980s, drug companies simply gave grants to medical centers for researchers to test their products, and then waited for the results and hoped their products looked good. Usually the research was investigator-initiated, that is, the question was something the academic researcher thought scientifically important. Sponsors had no part in designing or analyzing the studies, they did not claim to own the data, and they certainly did not write the papers or control publication. Grants were at arm’s length.

Thanks to the academy’s increasing dependence on industry, that distance is a thing of the past. The major drug companies are now hugely profitable, with net incomes consistently several times the median for Fortune 500 companies. In fact, they make more in profits than they spend on research and development (R&D), despite their rhetoric about high prices being necessary to cover their research costs. (They also spend twice as much on marketing and administration as they do on R&D.) The reasons for the astonishing profitability of these companies aren’t relevant here, but suffice it to say that as a result the industry has acquired enormous power and influence. In contrast, medical centers have fallen on difficult times (or so they believe), mainly because of shrinking reimbursements for their educational and clinical missions. To a remarkable extent, then, medical centers have become supplicants to the drug companies, deferring to them in ways that would have been unthinkable even twenty years ago.

Often, academic researchers are little more than hired hands who supply human subjects and collect data according to instructions from corporate paymasters. The sponsors keep the data, analyze it, write the papers, and decide whether and when and where to submit them for publication. In multi-center trials, researchers may not even be allowed to see all of the data, an obvious impediment to science and a perversion of standard practice.

While some new companies—called contract research organizations (CROs)—do clinical research for the drug manufacturers by organizing doctors in private practice to enroll their patients in clinical trials, the manufacturers typically prefer to work with academic medical centers. Doing so increases the chances of getting research published, and, more importantly, provides drug companies access to highly influential faculty physicians—referred to by the industry as “thought leaders” or “key opinion leaders.” These are the people who write textbooks and medical-journal papers, issue practice guidelines (treatment recommendations), sit on FDA and other governmental advisory panels, head professional societies, and speak at the innumerable meetings and dinners that take place every day to teach clinicians about prescription drugs.

Medical centers increasingly act as though meeting industry’s needs is a legitimate purpose of an academic institution.

In addition to grant support, academic researchers may now have a variety of other financial ties to the companies that sponsor their work. They serve as consultants to the same companies whose products they evaluate, join corporate advisory boards and speakers bureaus, enter into patent and royalty arrangements, agree to be the listed authors of articles ghostwritten by interested companies, promote drugs and devices at company-sponsored symposia, and allow themselves to be plied with expensive gifts and trips to luxurious settings. Many also have equity interest in sponsoring companies.

Much of the time, the institutional conflict-of-interest rules ostensibly designed to control these relationships are highly variable, permissive, and loosely enforced. At Harvard Medical School, for example, few conflicts of interest are flatly prohibited; they are only limited in various ways. Like Hollywood, academic medical centers run on a star system, and schools don’t want to lose their stars, who are now accustomed to supplementing their incomes through deals with industry.

Schools, too, have deals with industry. Academic leaders, chairs, and even deans sit on boards of directors of drug companies. Many academic medical centers have set up special offices to offer companies quick soup-to-nuts service. Harvard’s Clinical Research Institute (HCRI), for example, originally advertised itself as led by people whose “experience gives HCRI an intimate understanding of industry’s needs, and knowledge of how best to meet them” - as though meeting industry’s needs is a legitimate purpose of an academic institution.

Much of the rationalization for the pervasive research connections between industry and academia rests on the Bayh-Dole Act of 1980, which has acquired the status of holy writ in academia. Bayh-Dole permits—but does not require, as many researchers claim—universities to patent discoveries that stem from government-funded research and then license them exclusively to companies in return for royalties. (Similar legislation applies to work done at the NIH itself.) In this way, academia and industry are partners, both benefiting from public support.

Until Bayh-Dole, all government-funded discoveries were in the public domain. The original purpose of Bayh-Dole was to speed technology transfer from the discovery stage to practical use. It was followed by changes in patent law that loosened the criteria for granting patents. As a consequence, publicly funded discoveries of no immediate practical use can now be patented and handed off to start-up companies for early development. The start-up companies are often founded by the researchers and their institutions, and they usually either license their promising products to larger companies or are bought by large companies outright.

The result of Bayh-Dole was a sudden, huge increase in the number of patents—if not in their quality. And the most prestigious academic centers now have technology-transfer offices and are ringed by start-up companies. Most technology-transfer offices at academic medical centers don’t make much money, but every now and then one strikes it rich. Columbia University, for example, received nearly $300 million in royalties from more than 30 biotech companies during the seventeen-year life of its patent on a method for synthesizing biological products. Patenting and licensing the fruits of academic research has the character of a lottery, and everyone wants to play.

A less-appreciated outcome of Bayh-Dole is that drug companies no longer have to do their own creative, early-stage research. They can, and increasingly do, rely on universities and start-up companies for that. In fact, the big drug companies now concentrate mainly on the late-stage development of drugs they’ve licensed from other sources, as well as on producing variations of top-selling drugs already on the market—called “me-too” drugs. There is very little innovative research in the modern pharmaceutical industry, despite its claims to the contrary.

Over the past two or three decades, then, academia and industry have become deeply intertwined. Moreover, these links, though quite recent, are now largely accepted as inherent in medical research. So what’s wrong with that? Isn’t this just the sort of collaboration that leads to the development of important new medical treatments?

Medical research

Increasingly, industry is setting the research agenda in academic centers, and that agenda has more to do with industry’s mission than with the mission of the academy. Researchers and their institutions are focusing too much on targeted, applied research, mainly drug development, and not enough on non-targeted, basic research into the causes, mechanisms, and prevention of disease.

Moreover, drug companies often contract with academic researchers to carry out studies for almost entirely commercial purposes. For example, they sponsor trials of drugs to supplant virtually identical ones that are going off patent. And academic institutions are increasingly focused on the Bayh-Dole lottery. A few years ago, the Dana Farber Cancer Institute sent Harvard faculty an invitation to a workshop called “Forming Science-Based Companies.” It began:

So you want to start a company? Join the Provost, Harvard’s Office for Technology and Trademark Licensing (OTTL), leading venture capitalists, lawyers and entrepreneurs for a conference on the basics of forming a start-up based on university technology.

There’s a high scientific opportunity cost in serving the aims of the pharmaceutical industry. For example, new antibiotics for treating infections by resistant organisms are an urgent medical need, but are not economically attractive to industry because they are not likely to generate much return on investment.

In addition to distorting the research agenda, there is overwhelming evidence that drug-company influence biases the research itself. Industry-supported research is far more likely to be favorable to the sponsors’ products than is NIH-supported research. There are many ways to bias studies—both consciously and unconsciously—and they are by no means always obvious. I saw a good number of them during my two decades as an editor of the New England Journal of Medicine. Often, when we rejected studies because of their biases, they turned up in other journals essentially unchanged. And looking back, I now realize that despite our best efforts, we sometimes published biased studies without knowing it. One problem is that we thought that if studies were subjected to rigorous peer review, it was sufficient to disclose authors’ commercial ties—essentially to tell readers caveat emptor, as in the Serzone study I mentioned earlier. I no longer believe that’s enough.

The pharmaceutical industry devotes much, if not most, of its vast marketing budget to what it calls the ‘education’ of doctors.

An important cause of bias is the suppression of negative results. But clinical trials are also biased through research protocols designed to yield favorable results for sponsors. There are many ways to do that. The sponsor’s drug may be compared with another drug administered at a dose so low that the sponsor’s drug looks more powerful. Or a drug that’s likely to be used by older people will be tested in young people, so that side effects are less likely to emerge. The standard practice of comparing a new drug with a placebo, when the relevant question is how it compares with an existing drug, is also misleading. Supporters of the status quo claim that attempts to regulate conflicts of interest will slow medical advances, but the truth is that conflicts of interest distort medical research, and advances occur in spite of them, not because of them.

To be clear, I’m not objecting to all research collaboration between academia and industry—only to terms and conditions that threaten the independence and impartiality essential to medical research. Research collaboration between academia and industry can be fruitful, but it doesn’t need to involve payments to researchers beyond grant support. And that support, as I have argued, should be at arm’s length.

Expert advice

Conflicts of interest affect more than research. They also directly shape the way medicine is practiced, through their influence on practice guidelines issued by professional and governmental bodies and through their effects on FDA decisions.

Consider three examples I’ve written about before: first, in a survey of 200 expert panels that issued practice guidelines, one third of the panel members acknowledged that they had some financial interest in the drugs they assessed. Second, in 2004, after the NIH National Cholesterol Education Program called for sharply lowering the acceptable levels of “bad” cholesterol, it was revealed that eight of nine members of the panel writing the recommendations had financial ties to the makers of cholesterol-lowering drugs. Third, of the 170 contributors to the most recent edition of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), 95 had financial ties to drug companies, including all of the contributors to the sections on mood disorders and schizophrenia.

Perhaps most important, many members of the eighteen standing committees of experts that advise the FDA on drug approvals also have financial ties to the industry. After the painkiller Vioxx was removed from the market in 2005 (it increased the risk of heart attacks), the FDA convened a panel consisting of two of these committees to consider whether painkillers of the same class as Vioxx should also be removed from the market. Following three days of public hearings, the combined panel decided that, although these drugs—called COX-2 inhibitors—did increase the risk of heart attacks, the benefits outweighed the risks. It therefore recommended that all three of the drugs, including Vioxx, be permitted to remain on the market, perhaps with strong warnings on the labels.

A week after the panel’s decision, however, The New York Times revealed that of the 32 panel members, ten had financial ties to the manufacturers, and that if their votes had been excluded, only one of the drugs would have been permitted to stay on the market. As a result of this embarrassing revelation, the FDA reversed the panel and left only one of the drugs, Celebrex, on the market, with a warning on the label.

Medical education

Conflicts of interest are equally troubling in medical education, where industry influence is perhaps greatest and least justified. The pharmaceutical industry devotes much, if not most, of its vast marketing budget to what it calls the “education” of doctors. The reason is obvious: doctors write the prescriptions, so they need to be won over.

Drug companies support educational programs even within our best medical schools and teaching hospitals, and are given virtually unfettered access to young doctors to ply them with gifts and meals and promote their wares. In most states doctors are required to take accredited education courses, called continuing medical education (CME), and drug companies contribute roughly half the support for this education, often indirectly through private investor-owned medical-education companies whose only clients are drug companies. CME is supposed to be free of drug-company influence, but incredibly these private educators have been accredited to provide CME by the American Medical Association’s Accreditation Committee for Continuing Medical Education—a case of the fox not only guarding the chicken coop, but living inside it.

One of the most flagrant examples of the merging of education and marketing is Pri-Med, which is owned by M/C Communications, one of the largest of the medical-education companies. In partnership with Harvard Medical School, Pri-Med provides CME conferences throughout the country at virtually no cost to those who attend, courtesy of the huge income it receives from industry sponsors. The programs feature industry-prepared symposia during free meals, as well as academic talks by faculty during the rest of the day. The two types of talks are listed separately, but take place at the same meeting, where there is also a gigantic exhibit hall for industry sponsors. The Harvard name and logo figure prominently in Pri-Med’s advertising and at the conferences, in return for which Harvard Medical School receives direct income, as well as payments to participating faculty.

If drug companies and medical educators were really providing education, doctors and academic institutions would pay them for their services. When you take piano lessons, you pay the teacher, not the other way around. But in this case, industry pays the academic institutions and faculty, and even the doctors who take the courses. The companies are simply buying access to medical school faculty and to doctors in training and practice.

This is marketing masquerading as education. It is self-evidently absurd to look to companies for critical, unbiased education about products they sell. It’s like asking a brewery to teach you about alcoholism, or a Honda dealer for a recommendation about what car to buy. Doctors recognize this in other parts of their lives, but they’ve convinced themselves that drug companies are different. That industry-sponsored education is a masquerade is underscored by the fact that some of the biggest Madison Avenue ad agencies, hired by drug companies to promote their products, also own their own medical-education companies. It’s one-stop shopping for the industry.

But doctors do learn something from all the ostensible education they’re paid to receive. Doctors and their patients come to believe that for every ailment and discontent there is a drug, even when changes in lifestyle would be more effective. And they believe that the newest, most expensive brand-name drugs are superior to older drugs or generics, even though there is seldom any evidence to that effect because sponsors don’t usually compare their drugs with older drugs at equivalent doses. In addition, doctors are encouraged to prescribe drugs for uses not approved by the FDA (known as “off-label” prescriptions).

While I favor research collaboration between industry and academia under certain terms and conditions, I believe the pharmaceutical industry has no legitimate role in graduate or post-graduate medical education. That should be the responsibility of the profession. In fact, responsibility for its own education is an essential part of the definition of a learned profession.

No excuses

It’s easy to fault drug companies for much of what I’ve described, and they certainly deserve a great deal of blame. Most of the big drug companies have paid huge fines to settle charges of illegal activities. Last year Pfizer pleaded guilty and agreed to pay $2.3 billion to settle criminal and civil charges of marketing drugs for off-label uses—the largest criminal fine in history. The fines, while enormous, are still dwarfed by the profits generated by these activities, and are therefore not much of a deterrent. Still, apologists might argue that, despite its legal transgressions, the pharmaceutical industry is merely trying to do its primary job—furthering the interests of its investors—and sometimes it simply goes a little too far.

Doctors, medical schools, and professional organizations have no such excuse; the medical profession’s only fiduciary responsibility is to patients and the public.

Drugs licensed from academic institutions are supposed to be made ‘available on reasonable terms’ to the public, but that legal requirement has been ignored.

What should be done about all of this? So many reforms would be necessary to restore integrity to medical research, education, and practice that they can’t all be summarized here. Many would involve congressional legislation and changes in the FDA, including its drug-approval process. But the medical profession also needs to wean itself from industry money almost entirely.

For some time now, I’ve been recommending these three essential reforms:

First, members of medical school faculties who conduct clinical trials should not accept any payments from drug companies except research support, and that support should have no strings attached. In particular, drug companies should have no control over the design, interpretation, and publication of research results. Medical schools and teaching hospitals should rigorously enforce this rule and should not themselves enter into deals with companies whose products are being studied by members of their faculty.

Second, doctors should not accept gifts from drug companies, even small ones, and they should pay for their own meetings and continuing education. Other professions pay their own way, and there is no reason for the medical profession to be different in this regard.

Finally, academic medical centers that patent discoveries should put them in the public domain or license them inexpensively and non-exclusively, as Stanford does with its patent on recombinant DNA technology based on the work of Stanley Cohen and Herbert Boyer. Bayh-Dole is now more a matter of seeking windfalls than of transferring technology. Some have argued that it actually impedes technology transfer by enabling the licensing of early discoveries, which encumbers downstream research. Though the legislation stipulates that drugs licensed from academic institutions be made “available on reasonable terms” to the public, that provision has been ignored by both industry and academia. I believe medical research was every bit as productive before Bayh-Dole as it is now, despite the lack of patents. I’m reminded of Jonas Salk’s response when asked whether he had patented the polio vaccine. He seemed amazed at the very notion. The vaccine, he explained, belonged to everybody. “Could you patent the sun?” he asked.

I’m aware that my proposals might seem radical. That is because we are now so drenched in market ideology that any resistance is considered quixotic. But academic medical centers are not supposed to be businesses. They now enjoy great public support, and they jeopardize that support by continuing along the current path.

And to those academic researchers who think the current path is just fine, I have this to say: no, it is not necessary to accept personal payments from drug companies to collaborate on research. There was plenty of innovative research before 1980—at least as much as there is now—when academic researchers began to expect rewards from industry. And no, you are not entitled to anything you want just because you’re very smart. Conflicts of interest in academic medicine have serious consequences, and it is time to stop making excuses for them.

This article is adapted from a talk delivered by Marcia Angell at Harvard University’s Edmond J. Safra Foundation Center for Ethics on December 10, 2009.

Source: Boston Review  © 1993-2010 Boston Review and its authors (20/07/10)

“Experimental allergic encephalomyelitis (EAE) is a true autoimmune disorder. It has been accepted as an animal model of multiple sclerosis … However, a false orthodoxy claiming that multiple sclerosis is an autoimmune disorder has developed and formed the present basis of treatment, drug trials and research. The outcome of this misplaced creed has been truly catastrophic.”

The enigma of this curious disease can be demonstrated by the occurrence of MS being greater in first-, second- and third-degree relatives, while its definite polygenic etiology still defies elucidation. The disease bears some clinical resemblance to acute disseminated encephalomyelitis (ADEM), a disorder that may occur spontaneously, or after a viral infection or different immu¬nizations, including rabies. Their ten¬tative similarity suggests that MS could be an immunological disorder, an idea that gained support from those accepting experimental allergic encephalomyelitis (EAE) as the putative animal model for MS. EAE is an experimental disease in which animals are sensitized to brain products, and as a result develop varying degrees of paralysis.

Experimental allergic encephalomyelitis has now been conclusively proven to be a true model for ADEM, but not yet for MS. Detailed analyses reveal distinct dif¬ferences between MS histology and that of ADEM and EAE. While ADEM and EAE are comparable disorders, MS is shown to be a different disease. This is further attested to by the failure of large epidemiological studies to show an associa¬tion between MS and other autoimmune disorders.

These significant data seem to have been ignored by some researchers, who are willing to defend the theory that MS is an autoimmune disease mediated by immunopathological mechanisms despite the overwhelming evidence to the contrary. Over the past 60 years, a huge literature has accumulated claim¬ing immunological abnormalities in MS, despite the failure of repeated attempts to confirm such data.................. [Full Article]

“Over the past 60 years, a huge literature has accumulated claiming immunological abnormalities in multiple sclerosis, despite the failure of repeated attempts to confirm such data.”

Source: Expert Rev. Neurother. 10(7), 1023–1025 (2010) (02/07/10)

© Multiple Sclerosis Resource Centre (MSRC)