May 2005 Archives

Good news is always welcome in the dire state of affairs of environmental degradation and species extinction. Headlines earlier this year featured the presumed extinct but rediscovered Ivory Billed Woodpecker. News last year of a new species of macaque in India and a new variety of titi in Bolivia was welcome, as was a recent report of a new species of monkey Highland Mangabey (Lophocebus kipunji).

Most recently the elusive snow leopard was spotted in Nepal. This animal of legend is more famous in books such as Peter Mathiessen's The Snow Leopard or featured by wildlife funds such as this conservancy, or this trust, than in real life. Native to Asia and the mountains of Central Asia, Earthwatch says about the rare feline:

"[S]now leopards are distributed across 12 countries and 2 million square kilometers, making their populations difficult to study. Snow leopards are nowhere considered common, and there are an estimated 4,500 to 7,000 left in the wild. Despite being protected in parts of their range, they are still hunted for their pelts, for body parts used in traditional medicine, and to protect livestock."

The snow leopard has been tracked by Som Ale, a doctoral student at the University of Illinois, Chicago, for the past 15 years. He finally sighted and photographed the leopards in Nepal. On this first fruitful outing, he successfully tracked the leopards by noting the behaviour of the Himalayan tahr, a wild goat that is prey for the leopard.

While scientists know that many unidentified species exist, it's somehow welcome news when they are discovered or uncovered. At the same time, however, you wonder whether uncovering these fragile ecosystems will actually help or further endanger these more inconspicuous species.

Global warming is contributing to drought conditions in Australia, where currently 90% of NSW is affected by the exceedingly dry conditions. A report by the World Wildlife Fund WWF earlier this year found that of the four droughts since 1950, the latest one in 2002 was the most severe. A study of that drought stated:

"While higher temperatures are expected during El Nino triggered droughts, the 2002 drought temperatures are extraordinary when compared to the four major droughts since 1950, with average maximum temperatures more than 1 degree Celcius higher than these other droughts," he said.

At least half of Australia's arable land is currently affected by the drought and the livelihoods of farmers are looking dire. The government has already provided $A670 million dollars in aid to farmers, and more is needed. The drought not only impacts the $30 billion farm export industry it causes tangential problems such as an increase in suicide rates among those affected. and problems with thirsty wildlife such as feral camels wandering into harms way.

Prime Minister John Howard believes that global warming is not a myth according to this story, (news.com.au) "PM warms to climate evidence" (May 22, 2005)

"I don't believe it (global warming) is all a myth - no, I don't," Mr Howard said. "I have seen enough scientific evidence - I think some of the descriptions of it, some of the extreme manifestations of it, are mythical - but I do think there is a very strong case for controlling greenhouse gas emissions."

Nevertheless the PM hasn't signed the Kyoto protocol on climate change. Nor will he assert that the drought is related to global warming, a connection that is still contested by national leaders and skeptics.

In 1992 the Food and Drug Administration (FDA) took silicone implants off the market because of concerns about the health affects of leaking silicone when the implants burst, which they often did. The manufacturers were not deterred though. From the late 1990's on, they persistently lobbied the FDA to get silicone implants allowed back on the market.

The FDA periodically reviewed available clinical safety data, however analysis of the data wasn't straightforward and the results from all sources; studies, patient's and doctor's testimonies, and silicone manufacturers' testimonies were often contradictory. For instance in 1999 the Institute of Medicine published a literature review of clinical data that although health problems with implants were often recounted by patients and documented in numerous clinical and research studies, they concluded there was no link between health problems and implants. Many were suspicious of this conclusion since there were so many immunological, connective tissue, neurological diseases and systemic complaints, as well as conditions in breast feeding children that seemed be contracted from moms with silicon implants. Some people criticized IOM for considering too much data produced by the manufacturers.

There are passionate advocates for and against silicone implants and each side argues that public opinion, the media, junk science or corporations bias the views' of the other. The truth may hard to sort out but recent evidence reported in Sunday May 22, 2005, The New York Times indicates that the manufacturers who are providing the silicone breast implant safety data to the FDA may not be the most reliable source of the information for evaluating the health affects of implants or potential market suitability.

The FDA is currently reviewing two manufacturers safety data, Mentor's and Inamed's. On April 13, 2005 the an FDA advisory committee voted (7-2) to approve Mentor's breast implants for re-entry in the market, with some conditions. But despite similar results, the same panel voted against Inamed's implants. The FDA committee is being criticized for relying on Mentor's own reports disputed self-reporting of low rupture rates.

The Mentor data is controversial because of other documents recently released to the New York Times. These documents show discrepancies between accounts from Mentor's employees and the records produced by the company at the hearing. The NYT reported that, "In its recent filing with the FDA, Mentor said that it received a total of 8,060 rupture complaints from 1985 to September 2003". However according to the NYT, one of the employees in their deposition, "said that Mentor received about 6,000 complaints of ruptured implants in each of her three years there."

A plaintiff testified a case against Mentor before the Senate in 2002 (HTML version at senate.gov) that as a participant in a post-operative clinical study her health complaints to her surgeon, the manufacturer of the implants and the FDA were ignored. A longer version of the complaints is here.

The plaintiff, whose case was dismissed by the court, just turned over depositions from two former Mentor employees to the NYT. The ex-employees reported, that they had falsified records, that often the silicone was contaminated and sometimes "contaminated with fleas", and that workers sometimes "[hid] defective implant parts above ceiling tiles so managers and inspectors would not realize how often the plant failed to make the parts properly". Why didn't the employees speak out sooner? Reportedly:

[T]op executives instructed him to destroy reports detailing the high rupture rates and poor quality of some types of implants because the products "are in the customers".

As if the leaking, defective, and flea-infested implants weren't enough to dissuade the FDA from allowing them to re-enter the market, a study released in April shows that silicone from implants does enter the lymph nodes. The study, published in the American Journal of Surgical Pathology, reports the pathology of 96 women who had breast plants removed. The results of this study were reported to the FDA on April 12, 2005 according to Public Citizen:

"Although there was evidence of implant rupture in only 47 (49%) of these women, lymph nodes from 86 women (90%) contained droplets consistent with consistent with silicone. A control group consisted of 12 women with breast surgery mainly associated with breast cancer but without silicone gel implants. None of the lymph nodes from these 12 women contained silicone droplets. Similarly, microscopic examination of the lymph nodes revealed abnormal cells, "foamy macrophages," occurring much more frequently in women with silicone gel breast implants than in the control group."

The National Organization of Women is among many groups who weighed in on the matter. NOW sent a a letter (PDF) (PDF!) to Congress questioning the bias of the FDA committee, the Mentor's lack of response to specific toxicity data requests, and the company's skewed clinical trial patient selection protocols.

Despite the allegations of document manipulation, the unsavory clinical evidence, and the FDA's questionable review process, the demand for implants continues to rise. The Institute of Medicine estimated that 1.5 million women had breast implants as of 1997 and 70% of those were cosmetic procedures. The San Francisco Chronicle reported in "Limiting Options for Breast Implants" (May 12, 2005) that many women testified to the FDA in favor of allowing implants in 1992 and in 2003, and last month at the latest hearing. The SF Chronicle reported that the women often reiterated the theme of an American Society of Plastic Surgeons marketing slogan, that breast implants were "A Women's Right to Choose". Co-opting the pro-choice women's rights slogan and recruiting women to chant it on behalf of manufacturing companies who produce silicon implants associated with multiple health risks seems particularly untoward.

A Wall Street Journal article by Bernard Wysocki Jr. (May 23, 2005) WSJ front page (log-in required) talks about research journals and the growing trend among researchers to publish via the web. He also discusses universities' increasing resistance to paying the high institutional subscription costs of academic journals. It's an interesting article, though the title; "Scholarly Journals' Premier Status Is Diluted by the Web", is somewhat misleading.

The Wall Street Journal reports that the median expenditure of periodicals per academic institution has risen from a little over one million dollars per institution in 1986, to over five million dollars per institution in 2003, in a global academic publishing market that is currently about five billion dollars per year. The article focuses on various researcher and institutional efforts to change the face of academic publishing, especially at the University of California (specifically the Berkeley campus). The 10 campus UC system spends about 30 million dollars a year on periodicals. According to the article, the University has recently balked at subscription rates and negotiated lower rates for some journals in what is apparently a precedent setting coup.

At the same time, competing publishing models are emerging. Michael Eisen, whose lab focuses on gene expression in development, has co-founded the Public Library of Science (PLos), with Harold Varmus of Memorial Sloan Kettering in New York. The non-profit on-line publisher will compete with the mainstream research journals and give access to publications for free. There are three online PLoS Journals so far, PLoS Computational Biology, PLoS Genetics, and PLoS Pathogens.

On-line research publishing is certainly not new, but is increasingly becoming a preferable publishing model. Cornell produces a physics publishing database called ArXiv that has published over 100,000 articles (primarily physics research) since 1991. UC Davis has augmented the Cornell site with a front end for math articles. The Cornell site has a more utilitarian sensibility then PLoS, which has more of a corporate feel. With the look of PLoS and the staff involvement it's hard to avoid wondering about the exact business model. Will it be subscriber funded plus grants...will it be grant funded? Will there be paid advertising? ArXiv has a mix of funding.

The costs for articles in print publications can run three to ten thousand dollars per article, according to the WSJ, and therefore "to experienced publishers, much of the open access talk seems naive." However ArXiv has found that electronic communication of research is efficient and effective compared to traditional publishing. In a talk to Unesco in 1996, Paul Ginsparg, physicist at Cornell, laid out Cornell's experience with electronic publishing and left no doubt as to the future of print publishing:

"A major lesson we learn is that the current model of funding publishing companies through research libraries (in turn funded by overhead on research grants) is unlikely to survive in the electronic realm. It is premised on a paper medium that was difficult to produce, difficult to distribute, difficult to archive, and difficult to duplicate -- a medium that hence required numerous local redistribution points in the form of research libraries. The electronic medium shares none of these features and thus naturally facilitates large scale disintermediation, with the resulting communication of research information both more efficient and more cost-effective....The essential question at this point is not *whether* the scientific research literature will migrate to fully electronic dissemination, but rather *how quickly* this transition will take place now that all of the requisite tools are on-line."

As much as print publishers raise their eyebrows and cast doubt around there is great interest on the part of potential on-line publishers. UC Berkeley has started it's own database and encouraged researchers to deposit research there. The NIH (National Institutes of Health) proposed last year that all NIH grant money recipients (who comprise a large percent of bioscience and medical researchers) archive their articles in its database, however after protests from various publishers the NIH made the program voluntarily. Acronym Required reported here that the Dutch government also started a publicly accessible database of research for its nations researchers. Everyone has interests in free research accessibility, the researchers and public, governments who fund research, less developed countries, universities who benefit from the notoriety, as well as non-profits who propose to vie with the publishers. Although publishers claim that giving away content isn't a viable business model it is certainly gathering momentum and it will be interesting to watch the realm of free academic content develop. Physics- where electronic communication is dominant- is charting a path for other fields. For now, peer reviewed print research journals continue to reign.

Slashdot brings our attention to this article in The Register: "Dutch Academics Declare Research Free-for-All".

The Dutch website Darenet, available in English as well (though not working when I checked), serves as a repository for all research and will be accessible to the public via the Internet. Dutch academics will publish to the repository but be free to publish as well in journals or wherever else.

The Register article suggests that this would challenge the proprietary edge that science journals have on publishing research. It will also avail studies to a potentially wider audience, since academic journal publishing is competitive so not everyone gets published. As well, many journals dictate the terms of publication, in effect controlling how and when a researcher's work reaches what audience. Practices imposed by journals include charging per page to publish, coordinating press releases with journal publication dates, and dictating that research be kept confidential until it is published. These practices curtail the researchers ability to propagate their work and impose biases on what gets published. Since so much of research is publically funded, these restrictions bring to mind questions about how publically funded research can be restricted by the private interests of publishers. The Dutch government spends generously on research therefore wider exposer should be beneficial.

Whether this will be a more prevalent trend remains to be seen. Although published medical research is available via Pubmed, a lot is still difficult to access without a subscription. And while some academics disseminate their research freely, there is a certain cache- if you are a scientist- to getting published in Nature, Science or Cell and other top journals. The stature of these journals will no doubt continue to drive demand to be published in them.

Airborne particles and ozone are measured by health officials when determining levels of pollution in cities. The American Lung Association (AMA) recently released their "State of the Air" 2004 report that lists ozone and particle pollution across the U.S. by state. Officials generally monitor "course" particles in the 2.5um (micron) and 10um diameter range.

Andre Nel, a professor of Clinical Immunlogy and Allergy in the Department of Medicine at UCLA provides an overview of some of the research on airborne particles in a recent issue of Science Front Page (May 6, 2005). Nel classifies particles into three categories; coarse, fine and ultrafine. He reports that it is the fine (.1-2.5um) and ultrafine (less than .1um) particles that are unmeasured that are potentially the most dangerous. Fine and ultrafine particles are especially prevalent in cities as a result of vehicle emissions. Coarse particles are more like salts in ocean spray. The finer particles are not only difficult to measure, they are most likely to persist in the environment and to penetrate the lungs at the alveoli level.

Airborne particles in polluted air are thought to cause hundreds of thousands of premature deaths according to the World Health Organization (WHO) (here's a PDF report). As well as mortality increases, morbidity is affected by ozone. Cardiac and respiratory problems are associated with ozone pollution. Additionally health problems resulting from tissue inflammation, decreased cell clearance, oxidation stress and the release of cytokines are also suspected. More research is needed and we should be paying more attention to pollution producers.

In December 2004, the Journal of the American Medical Association(JAMA) published a meta-study examining the frequency reported outcomes of clinical trials that differed from study protocols and data (Chan et. al Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles. JAMA. 2004;291(20):2457-2465. doi:10.1001/jama.291.20.2457.) The authors reported: "[Of] One hundred two trials with 122 published journal articles and 3736 outcomes were identified. Overall, 50% of efficacy and 65% of harm outcomes per trial were incompletely reported."

"...In comparing published articles with protocols, 62% of trials had at least 1 primary outcome that was changed, introduced, or omitted. [86%] percent of survey responders (42/49) denied the existence of unreported outcomes despite clear evidence to the contrary."

Today, a Wall Street Journal front page story, "Worrisome Ailment in Medicine Misleading Journal Articles" (May 10, 2005) focuses on the same problem. The article presents the responses of various journal editors to questions about the problem of journalistic integrity, before concluding that journals are all addressing the problem and striving to present more balanced studies. Do the Wall Street Journal's assurances settle the issue?

Briefly, publishing has multiple points of responsibility. Scientists in the lab from techs to post-docs and residents report up to the principal investigator, who oversees and sets the direction of the lab research and assumes responsibility as an author on the paper. Publishing authors should be forthright about their results, and journal editors and publishers must select articles that compel readers and sponsors to support the magazine, while at the same time maintaining journalistic integrity. The multiple goals of all the players aren't always easy to balance.

The issue at stake is that the medical journals are increasingly dependent on advertising from pharmaceutical companies, and are therefore increasingly beholden to their influence. Journal editors would trust sponsored drug efficacy studies but for the reality that a pharmaceutical company has every incentive to report positive (and therefore sometimes biased) results. Journals in effect receive advertising support from the very same authors they are publishing.

What is most clear from the WSJ article is that at every juncture all parties both recognize the problem and at the same time shrug off their own responsibility in the solution. There are two problem areas, according to the WSJ account:

• 1) The editorial challenge of verifying submitted research.
• 2) The tension between the pharmas and journals about which results and conclusions are valid.

Pharmaceutical companies feel they are being unfairly scrutinized. All parties disagree about who has greater responsibility. WSJ quotes JAMA's editor in chief, who says: "The single thing we change the most often is the conclusion....It comes in as: 'This product is the greatest thing' and we say, 'Under these circumstances, in this population, this medications seems to control a,b and c.'"

JAMA's deputy editor adds: "Science depends on trust...[b]ut if you have trust, you're going to be fooled. You can't have a policeman in every lab." He suggests that the problems stem from dishonest research, which is out of the hands of editors.

The editor of Arthritis and Rheumatism quoted by WSJ is willing to let others to sort out the fray:

"People have to be realistic about what a journal can do." He said that the job of verifying the drug data was the job of the FDA.

An associate vice president of PHARMA (The Pharmaceutical Research and Manufacturers of America) complained: "Why are our submitted articles different from all other submitted articles?"

But when the FDA criticized article authored by Merck-Johnson & Johnson on the pros of selling a drug over the counter, a Merck official was very critical: "[The FDA] went very, very strictly by the label."

Depending on who you talk to, it's either the actual researchers doing the experiments that are at fault, the interpretation of the data by the authors, the journal editors who aren't scrutinizing papers closely enough, or the FDA.

The Wall Street Journal article is interesting, but focuses undue attention on the "tension" between the pharmas, pharma researchers and the journals and therefore fails to uncover an important part of the story. Undeniably, university researchers AND journal publishers in the past 50 years are more reliant on pharma funding and partnerships. Consequently the integrity of study results (and not just those from pharmaceutical companies) should be brought into question, shouldundergo greater scrutiny.

Journal editors may indeed be increasingly challenged to adequately check the veracity of the research studies that are submitted. Without trivializing these issues however, there is another side to the story, which is not the tension between the researchers or journals and pharmaceuticals, but the symbiotic and increasingly intertwined relationship between the journals and the pharmaceutical companies. The story beyond the on-cue responses quoted would focus on the story that the WSJ chose to omit. It is not a new story.

In a 2003 journal article by Alexander Tsai in the International Journal of Health Services titled "Conflicts Between Commercial and Scientific Interests in Pharmaceutical Advertising for Medical Journals", "A Doctor's World; Inside Medical Journals, A Rising Quest for Profits"): "drug companies stopped advertising, costing the journal $1 million to $1.5 million, Dr. [Susanne] Fletcher [editor of the Annals at the time] said".

The ensuing turmoil at the journal highlighted the increasingly co-dependent relationship between medical journals and pharmas and underscored the diverging goals of editors and publishers. The NYT article elaborated on the rising conflicts of interest between successful - meaning profitable - medical publishing, where the pharmaceuticals were the source of most advertising dollars, and content integrity. The change was noticeable:

"These societies were kind of frumpy and esoteric, and they are no longer that way," Dr. Fletcher said. "They are big businesses, and editors who traditionally worked with small staffs and had time to read a lot now go to meetings about new ventures."

While the mission of medical journals to disseminate current, useful information to doctors may not have changed in essence, the advertising revenues grew astronomically. According to the New York Times report:

"...the journals have increasingly become cash cows for the medical societies and companies that own them, with annual profits in the tens of millions of dollars, largely from drug company advertisements....The New England Journal of Medicine [reported it's earnings in] 1979, when its earnings were less than $400,000 a year. Now [it's] earnings are estimated to be at least $20 million a year..."

The Times went on to quote Dr. Suzanne W. Fletcher, who until 1994 was the co-editor of The Annals of Internal Medicine, owned by the American College of Physicians (she is currently a Harvard professor):

"The journals' success has created an enormous new market force that is beginning to dominate the way medical societies are run," Dr. Fletcher said. In some not-for-profit societies, the business staff is gaining influence over editors, creating frictions between the two traditionally separate sides..."

So the question is, if medical journals are dependent on pharmaceutical companies for advertising dollars, can they afford not to be biased? For a journal, it seems that it becomes not merely a question of publishing the latest research, but a question of what the journal publishers and editors need to do to balance obligations to readers, doctors, and advertising sponsors -- to publish the latest findings responsibly while meeting the revenue expectations.

As many know, Germany's healthcare reform has been in the works for years and for as many years Germany's pharmaceutical industry (that includes many global companies) has been fighting the changes as unfair. The Wall Street Journal reported this week ("German Curbs on Drug Costs Rile Big Brands" -Monday May 2, 2005), on the affect of German health care reforms on the pharmaceutical industry, specifically the reference pricing on drugs recently instituted to cull costs. The drug formulary and reimbursement plan will favor drugs that are available as generics or in cheaper dispensing forms.

"The ministry decided last year it would no longer cover the higher prices of branded drugs that it deemed to have the same medical efficacy as available generics. So the commision drew up a list of drugs that it won't pay full price to cover."

The reform was undertaken for good reason. Germany was spending almost as much per capital on healthcare as the United States, yet with higher unemployment rates and inefficiency. The goal of the reforms is to reduce by 23 billion the annual 142 billion Euros spent on statutory health funds. The healthcare system, largely funded by the state, is bloated and corrupt. Health fraud and corruption among doctors, insurance funds and drug companies was costing the country up to 1 billion euros per year. The Financial Times reported about the widespread fraud in a July 13, 2003 article in Comments and Analysis ("Fraud is a very serious problem - and one that is getting worse all the time': German Health Care Reform"). Hundreds of doctors, as well as insurers and equipment companies were involved in multi-million Euro schemes. The pharamaceutical companies, the article notes, were not above the fray:

"...four large drug retailers and 250 specialist doctors, mostly radiologists and urologists, are under investigation over kickback payments"

..And another investigation revealed:

"Some 1,600 doctors and 270 sales representatives of a German branch of the former SmithKline Beecham are under investigation in a bribes scandal...The company is accused of paying doctors across Germany up to Euros 25,000 each, often as gifts or holidays - including trips to the 1998 football World Cup in France - in exchange for using its drugs"

Although the pharmaceuticals interests are clearly to maintain market share of their name brand drugs, the pharma industry has couched their fears differently at different times. Bernd Wegener, chairman of the BPI association of pharmaceutical companies, as quoted by Hugh Williamson of the Financial Times May 15, 2003 ("Drug Industry Attacks German Health Care Reforms"), said that the reforms were "a severe blow for patients" because they would push up the cost of many drugs.

The response has been sometimes been dramatic, sometimes over the top, sometimes babbling. One title in MMW -Fortschritte der Medizin (Germany, Nov. 2001) noted in a crypically translated title: "Drug manufacturer on the savings package of Ulla Schmidt [Health Minister]: Grip in the moth box of planned economics"

The pharmaceutical companies have naturally been actively lobbying against the reform measures with direct appeals to the Chancellor, lawsuits that challenge the changes, and direct campaign efforts by the pharmaceutical industry to politicians, patients and physicians. Philip Burchard, the head of AstraZeneca PLC's business in Germany, quoted by WSJ spoke ominously of the affects on the pharmaceuticals:

"It's actually a pretty disastrous thing for us...In a way, it's like losing your patents because your forced to reduce your price."

Or being exposed to open market competition.

The costs savings at stake for the German government are significant. Lipitor (Pfizer) is one of the drugs that is targeted, as the generic Simvastatin, introduced in 2003 is being favored by the German government as a cheaper cholesterol reducing drug. The patients are responding by increasingly choosing generics over brand name pharmaceuticals for cost reasons.

"German patients who used to get Lipitor free of charge at their local pharmacy now must pay almost $65 out of pocket for a three-month supply. Simvastatin, the generic that the commission says is comparable to Lipitor, is almost free to patients"

Despite all the howls from the pharmaceutical companies, they continue the post record sales profits year after year. Lipitor is one of many drugs with generic equivalents that the German government wants to save money on. Despite the threats from generics though, year after year Lipitor has led pharmaceutical sales both overall and in it's class. Last year (2004) Lipitor topped previous years with record revenues of 10.9 billion.