No Magic Bullet in Fighting Malaria

The latest Journal of the American Medical Association reviews "The Making of a Tropical Disease—A Short History of Malaria" by Randall Packard, a medical historian at Johns Hopkins University. Says reviewer Markley Boyer of Tufts:

Now that The Gates Foundation, Ted Turner, and the Bush administration have all decided to eliminate malaria from the world, many health workers (especially those at the recent Gates-sponsored "Eradicate Malaria" convocation in Seattle, Washington) should read and reflect on the lessons presented in this excellent monograph . . . Most practitioners are first-rate at understanding the pathology of the illness and how to therapeutically interrupt its course, but they are unusually poor at comprehending that diseases like malaria are ultimately controlled by larger social, economic, and political factors. AIDS, obesity, heart disease, and tuberculosis are among those maladies that are hopelessly dependent on extramedical forces. Until researchers accept that there is more to health than the creation of some medicinal 'magic bullet,' they are doomed, in F. Scott Fitzgerald's well-known words, to 'beat on, ceaselessly, boats against the current . . . ,' with little impact on the disease itself. Packard's book reminds readers—through the lessons of history—of the factors that must be addressed before malaria can be controlled, let alone eradicated.

I interviewed author Packard a few years ago while writing about malaria for The Scientist magazine. I was very impressed by his level-headed analysis of the current situation, and his deep understanding of the past. If someone sends me a copy, I will definitely review it for this or any space.

Nothing But Nets

No, this isn't a column about the imminent elimination of my hometown Wizards from the NBA playoffs.

I was remiss last week by not commenting on World Malaria Day. More than a million people around the world die each year from the mosquito-borne scourge, most of them children. International health agencies and foundations are mobilizing resources to combat the disease. As regular readers know, I have written about anti-malarials, especially the artemisinin-based drugs derived from traditional Chinese medicine. But they are just one leg of the three-pronged strategy that can be used to eradicate the disease in an area. The other two are indoor residual spraying (where the quality of housing allows it) and widespread use of bednets.

There are controversies involved in the deployment of bednets in Africa, where malaria prevalence is most pronounced. Should the nets be distributed free, or sold through "social marketing" so that people will value them and help stimulate the local economy? The New York Times this morning didn't address the distribution question, but did note that there is a global shortage of bednets that could be addressed through greater charitable efforts.

Want to help out? I donated $25 last Friday to the Nothing But Nets campaign, jointly sponsored by the NBA and the UN Foundation. Why don't you join me. You can make your own donation by CLICKING HERE.

DDT and Malaria -- Again

The conservative campaign to make DDT a centerpiece of malaria control efforts in Africa continues unabated, and today the Alternet news service ran an insightful if long-winded article that provides a decent overview of the issues. Journalist Kim Larsen early on points out that DDT even when used only for indoor residual spraying is no magic bullet, largely because mosquitoes develop resistance. Allow me to quote her at length:

Today's most ardent proponents of DDT suggest that the sole obstacle to routing malaria half a century ago was the onset of the environmental movement. Mosquito resistance to DDT and the crippling logistics of effective spraying campaigns are overlooked in favor of the much juicier target of Rachel Carson and her green descendants. Carson's 1962 book, Silent Spring, was indeed a watershed. Invoking DDT as Exhibit A and sounding her alarms in graceful, elegiac prose, Carson awakened readers to the idea that pesticides might have a downside.

The use of DDT was banned in the United States in 1972. But while the chemical is no longer manufactured here, other organochlorine compounds are, and many are or are likely to be subject to scrutiny by regulators. This may be what really concerns DDT's more aggressive advocates in the private sector. In a chapter of a book on "message crafting," economist Roger Bate, a fellow at the Competitive Enterprise Institute, warns, "DDT may be today's target, but it's not going to be long before chemicals that the industry cares about are added to the POPs Convention and other chemicals regulations."

DDT proponents are generally reluctant to acknowledge the complicating and protean factor of mosquito resistance. Entomologist May Berenbaum finds this galling. An expert on insecticide metabolism, Berenbaum is director of the entomology department at the University of Illinois at Urbana-Champaign. "Read the entomological literature of the 1950s," she said in a telephone interview. "Way before Silent Spring, scientists were already trying to understand resistance. That's what insecticide toxicology was all about back then. Resistance to DDT was first detected in Italy, in houseflies, in 1947!"

Environmentalists' objections to DDT, Berenbaum said, were just one piece of an intricate puzzle. In a 2005 Washington Post article that discussed mosquito resistance to DDT, she warned: "Overselling a chemical's capacity to solve a problem can do irretrievable harm not only by raising false hopes but by delaying the use of more effective long-term methods."

After Berenbaum published the article, she said, she was barraged by e-mails demanding that she support her claims. "To get them off my back, I finally culled a list of peer-reviewed articles documenting resistance to DDT and other pesticides in pockets all over Africa. This is not my life's work. I spent 10 minutes--10 minutes--and I found 15 articles. What would I have found if I'd spent an hour?"

She concludes:

DDT will continue to play some role as a front-line weapon in the malaria wars. But it is also a distraction. DDT won't pave a watercourse or feed a child or provide a job, and at the end of the day, malaria is a development issue.

Top Clinton Staffer to Run Malaria No More

Thanks to The Washington Note for letting us know that Sen. Hillary Clinton's top legislative aide, Laurie Rubiner, is heading off to run Malaria No More, a well-funded advocacy group pushing rich countries to do more to combat malaria in the developing world.

Rubiner was instrumental in coming up with Clinton's health care plan. A recent New York Times profile quoted her saying:

“Senator Clinton is 150 percent committed to universal health care coverage, and so am I,” she said. “There’s nothing wrong with our health care in this country; the problem is with the health care system. Insurance companies shouldn’t be competing against each other based on their ability to screen out those who need coverage the most. Right now the deck is stacked against the average consumer.”

Frankly, I think there's a lot wrong with U.S. health care, and Clinton's plan admits as much with its heavy emphasis on prevention and her strong support for comparative effectiveness studies and their use, which, as we learned yesterday from the Commonwealth Fund, could save the health care system $368 billion over the next ten years -- a third of what it would take to pay for the uninsured.

It will be interesting to watch this Malaria No More group. Its website noticeably lacks the endorsement of the World Health Organization, its main effort, the Roll Back Malaria initiative, or the World Bank, which has been tasked to come up with a subsidy program for getting low-cost drugs for combating malaria to the developing world.

This year, according to its website, Malaria No More focused a lot of attention on the President's Malaria Initiative (one of the few laudable things done by this administration) and Laura Bush's promotional travels in Africa to boost the government program. The First Husband in Waiting has also made global health a primary focus of his Clinton Global Initiative.

Unintended Consequences?

Major donors have lavished attention on the "big three" health care epidemics plaguing the developing world: HIV/AIDS, tuberculosis and malaria. But is this emphasis detracting from helping poor countries develop their basic health infrastructure? An investigation in the Sunday Los Angeles Times says yes. The story quotes several prominent physician-activists like Paul Farmer of Partners in Health criticizing the tunnel-vision approach of the Global Fund to Fight Aids, Tubeculosis and Malaria and the Bill and Melinda Gates Foundation.

The article has generated a heated debate in the posted on-line comments, with many thoughtful comments on both sides of the argument.

When Big Egos Clash -- Over Rival Malaria Vaccines

The New York Times this morning prominently features the efforts of Sanaria, Inc. of Rockville, MD to develop an malaria vaccine. Sanaria president Stephen Hoffman, a former military researcher, and his team use the attenuated whole-parasite method of triggering an immune reaction, which is the classic method used in the polio vaccine, for instance.

Near the end of the story, Hoffman is roundly attacked by rival researcher Pierre Druilhe of the non-profit Pasteur Institute in France. His rival research team uses a protein fragment from the parasite's genome, expresses it in large quantities using biotech methods, and injects the fragment in human volunteers to provoke the immune response.

Besides quarreling over their rival methods, Druilhe accuses Hoffman of performing the research at a private firm so he can sell the vaccine for a ton of money in the first world to tourists who will be traveling in the Third World. Both will offer their vaccines, if successful, at low-cost to the developing world.

The Bill and Melinda Gates Foundation is only backing Hoffmann with its mega-millions, according to the story. You'd think they would promote a race by ensuring that both sides in the competition are well-funded.

WHO Considers Patent Pooling, Prizes

Knowledge Ecology International, the U.S.-based non-profit, has pushed a proposal for pooling patents and awarding prizes for developing drugs for neglected diseases onto the World Health Organization agenda. A WHO committee is meeting in Geneva this week to consider that proposal along with other approaches to this thorny problem, according to yesterday's Financial Times (registration required).

The WHO mainstream is leaning towards "cheaper distribution of medicines through measures including more support for generic companies, compulsory licences under World Trade Organisation rules, and transparent, consistent and lower prices for drugs," the FT reports.

A few thoughts: It's important in this debate to disentangle the issues of access to existing drugs and development of new drugs. HIV/AIDS medicine, for instance, has a well-developed market in the advanced industrial nations, and results in billions of dollars of sales. This is adequate to incentivize continued drug company investment in newer medicines, to tackle drug resistant strains of the disease, for instance. Therefore, companies can afford to sell the drugs to the poor countries at the marginal cost of production. It will have no impact on their willingness to invest in research and development.

But the search for a new drug for a disease for which there is no cure, or for which there is no first world market is very different. Here, there are two choices: either you incentivize the private sector to throw significant resources at the problem. Or, you can rely on the non-profit model.

The American Society of Tropical Medicine and Hygiene annual meeting now underway in Philadelphia is filled with sessions about non-profits developing new and better drugs and vaccines for malaria, African sleeping sickness, and river blindness. Many private firms are collaborating with the non-profits like Medicines for Malaria Venture, One World Health and the DNDi (Drugs for Neglected Diseases Initiative, a project of Doctors Without Borders). But, in a new wrinkle, many of these for profit firms are small start-ups like Scynesix of Research Triangle Park, NC, which was started by idealistic refugees from large pharmaceutical firms who devote substantial resources to the neglected disease arena while simultaneously serving as a contract house for Big Pharma's R&D department. In taking money to do research from groups like DNDi (which gets most of its own money from the Bill and Melinda Gates Foundation), these firms agree to turn over the intellectual property they develop at no or extremely low cost to generic manufacturers for eventual production, should the research efforts prove successful.

Prizes and patent pooling are great ideas. But, as things stand now, they are of greater relevance to creating a model for developing affordable medicine in the advanced industrial world than they are to incentivizing drug development for neglected diseases. To the extent that drugs for the diseases of the global poor already exist and are patent protected, strong laws protecting country rights to compulsory licensing ought to be sufficient to ensure that those drugs are offered at affordable prices in the developing world.

On the neglected disease R&D side, the deep pockets of Bill Gates and Warren Buffett have changed the equation. A large amount of money is flowing into neglected disease R&D. Could there be more? Of course. But as I listened to the arguments between sessions (I could only attend for one day, alas), I was pleasantly surprised to hear that the strongest disagreements among scientists came over what targets to pursue, not where to deploy scarce resources.

Scientist: Glaxo Credit for Malaria Vaccine Misplaced

One of the scientists behind Glaxo's experimental malaria vaccine wrote a comment to my GoozNews post from last month that lauded the company's efforts. I thought it worth highlighting, since it illustrates the theme of my book (that government research is behind most medical advances), and properly chastises me for not doing my homework:

I am disappointed in your assertion that "There's no quarreling with the assertion that this Glaxo effort to develop a much-needed malaria vaccine -- an effort, by the way, that has bedeviled scientists for decades because of the complexity of the parasite -- ought to receive a multi-billion-dollar reward if it succeeds." You seem to think that Glaxo has pulled this out of the thin air after poor bedeviled scientists had failed miserably. Actually work by us bedeviled scientists has been going on for more than 40 years with the support of taxpayer money from the NIH, USAID and Dept. of Defense. The first immunization study was " Nussenzweig, R., J. P. Vanderberg, H. Most and C. Orton. 1967. Protective immunity produced by the injection of X-irradiated sporozoites of Plasmodium berghei. Nature 216: 160-162". I later discovered the antibody (CSP antibody) that led to the identification of the CS protein, which is the very basis of the Glaxo vaccine (Vanderberg, J. P., R. Nussenzweig and H. Most. 1969. Protective immunity produced by the injection of X-irradiated sporozoites of Plasmodium berghei. V. In vitro effects of immune serum on sporozoites. Mil. Med. (Suppl.) 134: 1183-1190.) And I later led the efforts that used malaria sporozoites for the first successful vaccination of a human against malaria (Clyde, D., H. Most, V. McCarthy and J. P. Vanderberg. 1973. Immunization of man against sporozoite-induced falciparum malaria. Am. J. Med. Sci. 266: 169-177.). I am glad that Glaxo is now coming to the aid of us poor bedeviled scientists. There are things in basic research that scientists are able to do and there are vaccine production things that can be done only by a large corporation such as Glaxo. But please give a break to the poor bedeviled scientists (me and many others) who spent their entire professional lives doing the groundwork for a vaccine and then find that you are crediting Glaxo and insulting us. By the way, I believe that it is immoral for scientists who have had their work supported by taxpayers profit personally from a vaccine that they helped to develop but I believe that I am in a minority on this subject.

Dr. Jerome Vanderberg

New York University

Correction

An addendum to my story on Ruth Nussenzweig: Her husband Victor is alive and well and was sitting with her at Friday's session at Sanaria. I've corrected the story, and my apologies!

The Dr. Ruth of Malaria Research

She’s the Dr. Ruth of malaria research. She’s short, has meticulously coifed gray hair, and speaks with a thick accent. But she’s no parvenu of mosquito mating habits.

Ruth Nussenzweig, trained in Brazil, long at New York University, published her first paper on the microbiology of parasites in 1954. She and her husband Victor outlined the path to an X-ray attenuated antimalaria vaccine in Nature in 1967. In the 1970s, she helped discover the parasite’s cloaking protein, which GlaxoSmithKline is using to make a malaria vaccine now in clinical trials.

And as she stepped away from the podium Friday at the launch of the Sanaria, Inc. manufacturing facility in Rockville, Md., the 20 staffers who will make an X-ray attenuated vaccine that could go into human clinical trials as soon as next year, along with the 200 public health officials, scientists and dignitaries who’d come to cheer them on, gave her a standing ovation, not so much for anything she’s done lately, but for having carried the torch through the long, dark night when there was no money in the field of malaria vaccine research.

That’s no longer the case, thanks to the generosity of the Bill and Melinda Gates Foundation. John McNeil, director of research at the Foundation-supported PATH Malaria Vaccine Initiative, told the crowd that not only are there two vaccines in or heading for clinical trials, but his group is funding researchers who have at least three more promising candidates in their labs.

Financial largesse can be a mixed blessing, of course, and the malariologists of the world can be excused if they are feeling a bit of pressure. At a forum held earlier this month in Seattle, the computer mogul-turned-philanthropist told his grant recipients that malaria’s eradication – a goal not articulated in global health circles since the 1970s – was back on the agenda. “I’m optimistic that we can make this disease history,” he said.

A vaccine isn’t needed to make major inroads against the disease, which strikes an estimated half billion people a year and kills one to two million, mostly children in sub-Saharan Africa. Mass distribution of insecticide-treated bednets, selective use of indoor spraying, and widespread deployment of artemisinin-combination therapy – the most effective new drug to come along in half a century – could go a long way towards eliminating the disease in countries where public health systems are effective at deploying these strategies.

But eradicate the disease where grinding poverty, corrupt governments and endless civil strife are endemic? That’s where the PATH-MVI research program, based on the pioneering work of Ruth Nussenzweig, is seen as crucial. “How do we contain disease in low-infrastructure settings,” asked Kent Campbell, a senior epidemiologist with the group. “Vaccines.”

Leave it to the one African on the podium to warn about the limits of technology in conquering this age-old scourge. “How many infectious diseases have we eradicated,” asked Adel Mahmoud, an Egyptian-born infectious disease researcher who served as president of Merck’s vaccine unit from 1999 to 2005 and is now a professor at Princeton University. The answer to his rhetorical question is one – smallpox – and researchers have repeatedly shown that only its limited scale in the general population made it an ideal target for isolation and elimination. “We have been warned not to use that as a model,” he said.

Given the technical difficulties of producing a successful vaccine of any type, the odds against developing a vaccine that provides immunity against a complex and adaptable organism that is old as mankind itself are huge. And even if the researchers succeed, the roadblocks to getting it massively deployed are enormous.

But the richest man in the world has thrown down the gauntlet, and backed it with his money. Eradication of malaria is back on the global public health agenda after a two-generation absence. Ruth Nussenzweig, her head barely able to reach the microphone, said only that she was “happy to be able to play a small part.”

Malaria Vaccine Advances

There is good news for children in the developing world this morning as The Lancet reports on an early safety trial for a malaria vaccine. An estimated one to two million children die a year from malaria because their relatively weak immune systems cannot fight off the high fevers caused by the mosquito-borne parasite.

The trial was limited -- just 214 kids. It was designed to test safety, and passed. But the study also showed a moderate reduction in malaria infections among the innoculated group.

The company manufacturing the vaccine -- GlaxoSmithKline -- is planning a third stage clinical trial to show efficacy. The New York Times report says the company plans to spend up to $600 million in developing the vaccine, just $100 million of which is coming from the Bill and Melinda Gates Foundation. The company told the Times that should the third stage trial prove successful, it will make the vaccine available at a price that health agencies in the developing world can afford.

So how will the company earn back its investment? Glaxo isn't a charitable organization after all. One little-noticed provision in the recently passed Food and Drug Administration reform bill offers one form of reimbursement. Inserted by Sen. Sam Brownback (R-KA), it states that companies that develop a breakthrough drug or vaccine for a disease that affects mostly poor countries will get a voucher for one expedited review at the FDA of any other drug of its choosing. These are known as "priority" reviews.

So if a company has a me-too drug for, say, cholesterol reduction that has the potential of garnering $3 billion a year in sales, the review at the FDA will have to be completed within six months instead of the regular 12 or 18 months that it takes the agency to complete a "standard" review. That will give the company anywhere from six to 12 months of additional marketing exclusivity for this drug while it is still on patent. That translates into an additional $1.5 to $3 billion in sales.

No one objected to this provision as it sailed through Congress along with the rest of the FDA legislation. It's like the controversy surrounding spraying huts with DDT. Who wants to be sticking their finger in the air and whispering, "hey, isn't there a better way to do this" when you know all you'll get for your efforts is the right wing noise machine (yes, that machine is active on global health issues, too) accusing you of standing in the way of poor kids getting vaccinated or protected from malaria.

So, in the spirit of strapping a bullseye on my back this morning, allow me to stick my finger in the air and whisper, "there is a better way to do this." It's called the prize system.

The economic logic of the Brownback incentive scheme is to get patients in the developed world to pay for breakthroughs for diseases of the developing world. It does this by creating a perverse, new incentive for drug companies to continue developing me-too drugs. Doesn't it make more sense to create an incentive that only encourages the good and not the not-so-worthy? Moreover, doesn't it make sense to have everyone pay for this breakthrough on malaria, not just people who suffer from whatever condition the me-too drug is aimed at?

A prize system would eliminate the perverse incentive while preserving the good one. How would it work? All pharmaceutical industry sales all across the globe could be taxed one percent (this would raise about $5 billion a year on the roughly $500 billion in sales) to go into an innovation prize fund that would be awarded to companies that develop significant new drugs and vaccines, whether they are for the developed world or the developing world. Then the technology could be turned over to generic manufacturers, who could provide it at cost to the world's health care systems, whether publicly or privately operated.

I'm told Sen. Bernie Sanders (I-VT) is preparing legislation creating such a prize system. I've written about this concept before in the context of stem cell research.

There's no quarreling with the assertion that this Glaxo effort to develop a much-needed malaria vaccine -- an effort, by the way, that has bedeviled scientists for decades because of the complexity of the parasite -- ought to receive a multi-billion-dollar reward if it succeeds. However, the best way for paying that reward ought to be an open question.

Fighting Malaria -- Free Distribution of Bednets Best

A few months ago, a study appeared in PLOS Medicine showing that free distribution of bednets to prevent malaria in poor countries worked better than charging a small fee. The idea behind the latter program, sometimes called social marketing, is that poor people will place a greater value on and make greater use of the bednets if they have to pay something for them.

Responding to the study, the World Health Organization in mid-August officially endorsed free distribution of bednets to all poor people in malaria-endemic countries, a change from the prior policy which only gave them out free to children under five. The policy put the WHO at odds with the Bush administration, whose malaria initiative had focused on social marketing of nets.

Today's New York Times covered the growing success of the movement toward free bednet distribution, based on reporting by a Kenya-based stringer. The story included a quote from Sen. Tom Coburn, the Oklahoma Republican with close ties to the parts of the evangelical Christian movement that has made combating malaria part of its missionary work. He called free distribution "a great move" by the WHO. "We knew social marketing doesn't work."

The story, curiously, did not report if policy is shifting at the President's malaria intiative in response to the study and WHO directive. Here's a situation where the administration's free-market ideology is at odds with the position of its Christian fundamentalist base. It will be interesting to see if Christ and science win out over mammon.

Meanwhile, the Washington Post plays catchup with the Los Angeles Times in reporting on the DDT-breast cancer link, which also has implications for malaria control now that the pesticide is making a comeback. You can find a link to the original story here.

What Works Best in Fighting Neglected Tropical Diseases

I don't know if Mark Hanna ate in the New York City restaurant where Mary Mallon (Typhoid Mary) cooked, but he is among the prominent American political figures (they include Abigail Adams and Stephen A. Douglas) who succumbed to typhoid fever. The disease is caused by the bacteria Salmonella enterica serovar typhi, which is spread through water or food contaminated with the fecal matter of infected persons. S. typhi causes a three-to-four week fever, which, if left untreated, is fatal ln up to a third of patients. School-age children are especially vulnerable.

The disease has largely been banished from the advanced industrial world through improved sanitation and prompt treatment with antibiotics. But occasional outbreaks still occur, often among people who have traveled in the developing world or live in precincts of the U.S. that approximate third world conditions. Last year, the Centers for Disease Control rushed to the Marshall Islands to help contain an outbreak of at least 22 confirmed cases.

Today, the disease remains common in the developing world's rural areas and urban slums, where typhoid strikes an estimated 16 million to 33 million people a year, and kills anywhere from 216,000 to 600,000. And, unlike the middle part of the last century when typhoid was licked in the U.S., most current strains of S. typhi have developed resistance to antibiotics, including powerful new ones like ciprofloxacin.

But, like most other drug-resistant diseases, this is one that can still be licked through effective public health measures. According to a timely wake-up call published in today's New England Journal of Medicine, there are vaccines that can provide immunity to typhoid fever. The vaccines could have an almost immediate impact because the most vulnerable population -- school-age kids -- are easily reached through public schools. And best of all, the vaccines are cheap -- about 50 cents a dose from the Indian generic companies that manufacture them.

But as with so many technology-driven solutions, the global public health community hasn't figured out a way to get children inoculated in the countries where it would matter most. In last week's NEJM, Peter Hotez and a host of colleagues associated with the Global Network for Neglected Tropical Diseases called for a comprehensive public health approach to treating and preventing the most common diseases that are ravaging the developing world.

What that would entail is equipping health care workers in developing countries with the tools needed to fight the health problems faced by the world's poorest citizens. This should include the proven generic drugs for fighting common infectious like hookworm or elephantiasis (the GNNTD identifies 13 diseases that need immediate attention in addition to the "big three," HIV/AIDS, tuberculosis and malaria). Though they don't mention it in their article, this piggy-back approach could also include proven vaccines like the one that is available for typhoid fever.

This is a very different approach from the current efforts of the Global Fund, the President's Malaria Initiative or bilateral aid organizations the the U.S's Agency for International Development. Their programs are aimed at specific diseases like HIV/AIDS, malaria or onchocerciasis (river blindness). Very often, this leads to different emissaries from various aid organizations concerned about different diseases knocking on the door of the same rural health clinic or government ministry. No doubt the one offering the most money and resources gets the most attention.

But is this what is best for achieving the greatest gains in public health in that area? The silo mentality fostered by the specialist approach to medicine is widely recognized as a major flaw in the U.S. health care delivery system. That failed model shouldn't be exported to the developing world.

India Disallows 'Obvious' Patents

India's Supreme Court voided Novartis' application for a patent on a variation of Gleevec, the company's miracle cure for one form of leukemia. The ruling is being hailed by groups like Doctors Without Borders as a major victory for charitable organizations that are trying to get inexpensive medicines to the developing world.

I was struck by the similarities between this case and recent fallout from the KSR v. Teleflex Supreme Court case in the U.S., which involved gas pedals but may have broad implications for many pharmaceutical industry patents. At issue is whether a small change in an existing product qualifies as a new invention, or whether it fails one essential quality of anything considered innovative: it must not be obvious.

What's obvious? When a drug company makes a minor changes in a small molecule drug so it can extend its patent life, that's obvious.

The news coverage this morning of the Novartis case in India left me wondering, though. Is Gleevec off patent? I don't think so. So has Novartis patented this variation as a replacement for later in the drug's life cycle? Is it possible that the Indian company came up with the obvious change in the Gleevec molecule as a way of getting around the original patent, and that variation was already patented by Novartis? And if the Indian company did that, did it also conduct new clinical trials to ensure the new drug works?

This is one case where a barebones story from ten thousand miles away didn't give us the whole picture. Perhaps some of my readers know the answers to these questions.

Brazil Gets a Better Deal

When I was visiting Brazil in early May, that country was enmeshed in touchy negotiations with Abbott Labs over the price of one of its more important AIDS drugs -- Kaletra. Brazil was threatening to issue a compulsory license that would enable it to begin generic manufacturing unless Abbott lowered the price. The Wall Street Journal went into high dudgeon mode, railing against countries that rip off the intellectual property of U.S.-based multinational drug companies. Given the uproar, I went out of my way to visit with a local economist/politician, who said the threatened compulsory license was nothing more than a negotiating tactic on the part of the Lula da Silva administration.

Today's news confirms his view: Reuters is reporting that Abbott Labs has agreed to lower the price of Kaletra by nearly 30 percent for Brazil. If it works for Brazil, why not Medicare, which was specifically forbidden by the 2003 Medicare Modernization Act from negotiating lower drug prices on behalf of U.S. seniors -- and the taxpayers.

Carson Bashing and the Ill-Informed DDT Campaign

As I've written several times in this space, the New York Times has become the chief outlet for an ill-informed and unscientific campaign to boost DDT use to combat malaria. Today's entry comes from John Tierney, a conservative columnist who even includes a link to corporate defender Steve Milloy's "junkscience.com" website alongside his diatribe.

His hook is the 100th anniversary of Rachel Carson's birth, which has set off a mostly negative set of responses in the national press. Whether or not Carson overestimated the damage done by DDT, the cudgel with which writers like Tierney beat her and her latter-day disciplies are the dying children of Africa. As he put it:

The human costs have been horrific in the poor countries where malaria returned after DDT spraying was abandoned. Malariologists have made a little headway recently in restoring this weapon against the disease, but they’ve had to fight against Ms. Carson’s disciples who still divide the world into good and bad chemicals, with DDT in their fearsome “dirty dozen.” Ms. Carson didn’t urge an outright ban on DDT, but she tried to downplay its effectiveness against malaria and refused to acknowledge what it had accomplished.

His chief witness? One I.L. Baldwin, who wrote a review of Carson's book, "Silent Spring," in Science Magazine. Unless you paid very close attention to the attribution, you might have missed the fact that Baldwin at the time was an agriculturalist from Wisconsin. How would he know what was happening on the ground in Africa, Asia and Latin America, where the World Health Organization's campaign to eradicate malaria was taking place? That campaign was largely based on the faulty proposition that widespread mosquito control, such as had taken place in agricultural areas of the U.S., could eliminate malaria in the rest of the world as it had in the southern U.S.

Tierney's article is laced with references to Carson's unscientific methods. It's a funny charge for one journalist to level against another. She was, after all, a New Yorker writer. Her mission was to excite interest and concern. And the fact that we know her name today suggests she did a pretty good job.

But defending Carson is not my mission. The real question is why the New York Times continues to open its pages to diatribes by people who obviously have axes to grind, and who make statements that can be refuted by spending just fifteen minutes in online databases that contain scientific abstracts. The facts are that the pro-DDT campaign spearheaded by writers like Tina Rosenberg, John Tierney, and corporate flack Steven Milloy has only limited application in the real world, and even a brief tour of the scientific literature would corroborate that point.

For instance, here's what I culled from recent papers on the specific points he raise -- that the malaria eradication campaign in the 1960s failed because of growing first world environmentalist concern about DDT:

“Perhaps the most important (reason for the eradication campaign's failure) was the rapid development of immunity to DDT and later to other insecticides. . . . But politicians and other decision-makers were dazzled by the power of DDT.”

-- Arthur Brown, WHO representative in Southeast Asia from 1955-1962, writing in 2002 in the Journal of the Royal Society of Medicine.

Are there better methods that ought to be getting the emphasis?

“The historically most effective campaign against African vectors . . . relied overwhelmingly upon larval control. . . These affordable approaches were neglected after the advent of dichlorodiphenyl trichloroethane (DDT) and global malaria-control policy shifted toward domestic adulticide methods.”

-- Gerry Killeen of the Swiss Tropical Institute writing in Lancet Infectious Diseases in 2002.

While it may be effective in some settings, are there any downsides to spraying homes with DDT?

“In high transmission settings, indoor residual spraying (IRS) must be implemented indefinitely and at high quality to achieve control. As current infrastructure limitations and unpredictable funding make this unlikely, each country must carefully consider the role of IRS. There remains a need to support ongoing insecticide-treated net scale-up. Insecticide choice is hampered by the lack of economic costing data.”

-- A group of Uganda specialists writing in a soon-to-be-published article in Transactions of the Royal Society of Tropical Medicine and Hygiene.

Their argument, based on experience on the ground: Give individuals their own bednets, rather than ask governments to go door-to-door spraying every home twice a year.

When will the New York Times send a reporter to Africa to report some facts about mosquito resistance to DDT and other insecticides? When will the paper explore cultural barriers to widespread use of indoor residual spraying (which in large parts of Africa, means someone from the government showing up on your doorstep with a spray gun, not a tommy gun, and saying, "Hi, I'm from the government and I'm here to help.")

And when will they report what might be more effective malaria control policies in the face of those realities? Continuing to rely on people holed up in right wing think tanks grinding axes is shamefully bad journalism.

Brazil and Innovation

The Wall Street Journal (subscription required) is in high dudgeon this morning on drug issues. An editorial attacks Brazil for its efforts to negotiate lower prices on AIDS drugs. The diatribe is based on a faulty premise, that reduced revenue for the research-based pharmaceutical industry from overseas sales will harm innovation. Here's what the editorial had to say:

Drug innovation is a risky business, and companies won't be willing to sink hundreds of millions of dollars into research and development, especially on diseases that affect the poor and sick in developing countries, if they fear their intellectual property will be stolen.

I'm sorry. I hadn't noticed the industry investing hundreds of millions of dollars in neglected diseases. The only organization that fits that description is the Bill and Melinda Gates Foundation. The drug industry doesn't invest in diseases that affect the poor unless the disease also affects the advanced industrial world, where people and/or health plans can afford to pay for drugs. That's why we have lots of drugs for AIDS.

On Saturday, I spoke with a leading Brazilian politician about the current flap. Sen. Eduardo Matarazzo Suplicy, who earned a Ph.D. in economics from Michigan State University in the 1960s and whose musical tastes run to Bob Dylan (he included the phrase "Blowing in the Wind" in the title of his latest book), said this is par for the course on negotiations over patented medicines. Brazil negotiated lower prices with Abbott in 2003 for AIDS drugs, and is now trying to do the same with Merck.

"The government is trying to negotiate a reasonable price that is consistent with the price in some countries that buy this medicine in Africa and Asia," he said. "This is no different than when we negotiate with Bolivia over the price of natural gas. I believe we will reach an agreement."

Brazil To Break Merck Patent

SAO PAOLO, Brazil -- It is fascinating to be sitting here reading today´s news that Brazil has moved one step closer to breaking a patent on an important HIV/AIDS drug produced by Merck. Brazil doesn´t have much of a generic manufacturing industry, but its state-owned drug producers are quite adept at buying drugs from India and China and repackaging them for the state-run health service, which services most of the population.

There are two Brazils. Beyond the post-modern facade of this sprawling metropolis (second largest city in the world after Mexico City) lies a country where the extremes between rich and poor defy easy description. I spent most of this week in the wilds of Minas Gerais province, where two-thirds of the 19 million people are at risk of parasitic diseases like hookworm, schistosomiasis and Chagas disease.

The least well off among them still eke out a living as subsistence farmers. They live so remotely that a Ford 4x4 took two hours to traverse the 20 miles that separated the village I was visiting from the closest paved road. These poorest of the poor live in mud huts without running water or electricity. Sanitation -- toilets or outhouses -- is non-existent. Many are illiterate.

Even the relatively well-off in the 1000-person village and the better-off farms that have electricity (and thus lights, small refrigerators, and satellite dish-fed televisions) live without proper sanitation facilities. As a result, upwards to 60 percent of the population in the district I was visiting suffers from a half dozen parasitic diseases like hookworm, Chagas disease, and schistosomiasis.

AIDS is not much of a problem in rural Brazil. But in a country that is struggling to provide health care for all of its people, every real (pronounced hey-al) that the health ministry spends for Merck´s drug is a real that can´t be spent on the health care teams that travel between villages deworming the peasants. If left untreated, they suffer from the iron deficiency anemia, lost work days and intellectual impairment caused by the parasitic worms that have infected their bodies.

I´ll have lots more to say about Brazil´s health care system and the state of its economy and politics when I return from this week-long working vacation. But from this vantage point, the argument that Brazil or other developing countries have to contribute to the drug industry´s profits on AIDS drugs in order to sustain research and development rings hollower than ever. These companies invest almost nothing researching cures for the diseases that are causing the most harm in countries like Brazil.

Where's Wolfowitz on World Malaria Day?

While the Al Kamen of the Washington Post is reporting the latest emails emanating from Paul Wolfowitz's bunker at the World Bank, the Financial Times has uncovered evidence that the architect of the Iraq War has also been busy censoring reports on global warming.

For those not following this saga, the erstwhile Bush administration Middle East policymaker is enmeshed in a conflict-of-interest scandal that involves giving his companion a big raise and a prestigious job at that institution. If I'm reading between the lines properly, she didn't deserve the job, or at least didn't deserve it as much as some other long-time employees at the Bank.

Now that Wolfowitz is in the press's crosshairs, an enterprising reporter could tackle another major flaw in Wolfowitz's leadership at the Bank. It's especially relevant to raise this issue today, which has been designated as World Malaria Day.

Three years ago, an Institute of Medicine committee chaired by Nobel Prize-winning economist Kenneth Arrow issued a report called "Saving Lives, Buying Time." It outlined a strategy for bringing life-saving anti-malarials to the developing world. Nearly two million people, most of them children, die from the disease every year. In many parts of the world, the mosquito-born parasite has grown resistant to chloroquine, an extremely cheap drug that can be bought for pennies in most developing world pharmacies or local dispensaries. The parents who buy the drug for their children discover too late that it doesn't work.

There is a proven therapy for treating resistant malarial strains. It is a combination of drugs that includes artemisinin, a derivative of the sweet wormwood bush. For a history of its development and more background on this issue, you can click here to read my story that ran in last December's The Scientist magazine.

Despite the efforts of Doctors Without Borders to develop less expensive versions of this drug, the cheapest version now on the market still costs $1 a day, ten times the price of chloroquine. The IOM report came up with a plan for overcoming this problem: the global health agencies should get together, establish a centralized purchasing fund, and buy enough artemisinin-based combination treatments to treat everyone in the world who needs it. This would cost less than $500 million a year.

Then, the centralized authority could simply sell its supply into normal distribution channels as the same price as chloroquine (about 10 cents a dose) and let the market do its magic. The good drug would rapidly supplant the bad one.

The World Bank was given the job of bringing this plan to fruition. Last month, I spoke to the coordinator of public health programs at the World Bank "on background." (They always make you do that over there, especially if you're a lowly blogger.) He brought me up to date on the plan.

Netherlands and Tanzania are co-chairing a group that is creating the "mechanism" for implementing the plan. They still haven't raised the money. They've decided they can't create another bureaucracy but need to find a "partner" who can execute the plan. They're debating whether it should be direct purchase or a voucher system. They hope to launch by the end of the year.

Sound like typical bureaucratese to you? It sure did to me. Where was the sense of urgency, I kept asking. "The discussions are ongoing," he said. "They're intense."

Novartis, which makes the expensive formulation of the combination drug (theirs is called Coartem), announced a major charity program in Tanzania this morning. They'll deliver 4.7 million free doses of the drug to a country where malaria is the leading killer. My morning paper has large ads from ExxonMobil assuring me how much they are worried about the global malaria epidemic. Is there any problem on earth that their p.r. department can't address with a full page ad?

What I would like to see on World Malaria Day is Paul Wolfowitz come out of his bunker and announce the formation of a fully-financed global purchasing authority for artemisinin-combination therapy -- the best hope in the world for rapidly curbing the devastating impact of this disease.

Study Slams DDT Use in Malaria Control

The conservative campaign to bring back DDT to combat malaria got some bad news today. South African researchers report that the widespread use of DDT for indoor spraying to control mosquitoes has dramatically lowered sperm counts and disrupted reproductive systems among men exposed to the pesticide. The study involved 300 men in Limpopo province.

The study was conducted by Tiaan de Jager of the University of Pretoria. According to the Mercury newspaper:

The researchers said there was mounting evidence from around the world that DDT acted as an endocrine-disrupting substance, which altered the normal human hormone balance, lowered testosterone levels and possibly interfered with sexual accessory organs such as the seminal vesicle and prostate gland.

And, despite recent assurances by the World Health Organisation that DDT can be used safely in controlled anti-malaria campaigns, the new Journal of Andrology study has shown a direct link between high DDT exposure levels in people whose houses had been sprayed with the pesticide.

Concentration levels of DDT in some of the Limpopo men were among the highest recorded in the medical literature.

The researchers say the World Health Organization may have made a mistake in calling for the return of DDT to control malaria. They recommend switching to safer pesticides for indoor residual spraying to hold down mosquitoes.

Those Uppity Thais

It hasn't gotten much attention in the mainstream press, but Thailand's decision to issue compulsory licenses for several critical HIV/AIDS drugs has drawn a heated reaction from the global pharmaceutical industry. Abbott Labs announced earlier this week that it would no longer market its drugs in Thailand.

Abbott makes several protease inhibitors that are very important components of many AIDS regimens because they have the desireable side effect of delaying the body's metabolism of other drugs in the triple-cocktail. That allows for less frequent dosing schedules, which increases compliance.

But two years ago, Abbott established prices for their latest version of the drug that was well beyond affordability for most developing countries, including Thailand. That country responded by issuing a compulsory license, which voids intellectual property rules enforced by the World Trade Organization. However, WTO rules also allow for compulsory licenses when a nation thinks it is in its interest to do so.

Abbott's decision to strike back drew a heated response from Medecins Sans Frontieres (Doctors Without Borders) yesterday.

"Thailand's move to issue compulsory licenses is an important way to help bring prices down and increase availability of medicines," said Ellen 't Hoen, Policy Director at MSF's Campaign for Access to Essential Medicines. "In light of this, Abbott's move is appalling."

According to MSF, Abbott offered its latest drugs for $500 per patient per year for the least developed countries and $2,200 per patient per year in middle income countries like Thailand. That's a huge markup over the $140 per patient per year costs of older, less effective regimens.

Abbott was one of the first companies to get involved in AIDS research. Its HIV/AIDS research program began in the late 1980s after receiving a five-year U.S. government grant.

Where's the World Bank Plan on Fake Drugs?

Last June, the free online journal Public Library of Science - Medicine ran an important article warning about the proliferation of fake drugs in the developing world. It focused largely on artemisinin, the wonder drug derived from traditional Chinese medicine that is now the world's best hope for combating malaria, which has become largely resistant to older drugs. Last summer, while reporting a story on the development of artemisinin for The Scientist magazine, I learned about World Bank efforts to develop a plan that would largely eliminate the problem.

The plan would implement the Institute of Medicine proposal -- the committee was headed by Nobel Prize-winning economist Kenneth Arrow -- that the Global Fund centrally purchase sufficient quantities of pre-packaged artemisinin-based combination therapy, and then provide it at very low cost (about 10 cents a dose) to normal distribution channels throughout the developing world. This would push out both chloroquine, which is largely ineffective because the parasite that causes malaria has grown resistant to that drug, and fake drugs, which, of course, don't work.

Today's New York Times story on the problem of fake drugs reports that Global Fund is "considering" centralized purchasing. It's been three years since the IOM report. It's been two years since the World Bank began exploring ways to raise the money needed to implement the centralized purchasing/subsidization strategy. Isn't it time to move past considering and begin acting?

ACT in Pregnancy

Malaria Journal has just published a meta-analysis of all the clinical trials that have examined the unwanted effects of using artemisinin combination therapy in pregnant women with malaria. The conclusion? Not enough studies have been done to know for sure if there are negative consequences for the developing fetus.

While traveling in southeast Asia last summer, I interviewed Francois Nosten of the Shoklo Malaria Research Unit, who has conducted most of the handful of trials that have looked at ACT use during pregnancy. He complained that there was simply no financial support from donors for such research. "These are precisely the kind of studies that the World Health Organization ought to be financing," he complained. This latest study echoes that sentiment.

Beating Malaria

Last summer, I traveled to the Thai-Burmese border to report on the pioneering physicians who have been on the front lines of developing artemisinin, the World Health Organization's drug of choice for combating malaria. That trip is now the cover story in The Scientist magazine, which can be viewed here (subscription required).

Here's an excerpt:

If a research team led by Francois Nosten and his mentor, Nicholas White of Mahidol University in Bangkok (whom many consider the world's leading malariologist), lead the way to better protocols for treating pregnant women and others with artemisinin-combination therapy (ACT), it won't be the first time that the duo has used the tools of clinical science to teach the world new methods for combating this age-old scourge. In 2001, the World Health Organization (WHO) declared ACT the preferred method for treating malaria, especially the most deadly form of the parasite, Plasmodium falciparum, which in most parts of the world has evolved resistance to older drugs such as chloroquine. WHO's 2001 decision was based largely on clinical trials that SMRU had conducted during the early 1990s.

This breakthrough came despite the fact that artemisinin's mechanism is poorly understood. When the parasite invades a red blood cell to reproduce, it destroys the hemoglobin and frees up iron. In the presence of artemisinin, this free iron forms highly reactive oxygen radicals that some scientists believe inhibit the parasite's ability to digest more hemoglobin, thus breaking the chain in its lifecycle. By contrast some older drugs such as chloroquine disrupt membrane function, thus disabling the invaded blood cell's ability to disgorge the newly formed parasites.

Not knowing the chemistry hasn't stopped the drug's deployment in the field, though. Early in this decade, Nosten and colleagues at the Shoklo Malaria Research Unit spearheaded a joint public health program with the Thai government that trained rural health workers, most of them recruited from local villages, to use test kits to diagnose malaria and then administer ACT. The campaign also attacked the Anopheles mosquito that spreads the disease by conducting indoor home spraying with deltamethrin, a pyrethroid ester insecticide considered one of the safest in the world. (DDT, recently resuscitated by WHO, was banned in Thailand in 1997.) Distribution of insecticide-treated bed nets was also part of the campaign.

The result? Malaria in mountainous Tak province was reduced by 34% and mortality was cut in half. Though the program was cut short when the Thai government's funds were depleted, it proved that even in remote areas, where people live exposed to the elements and have no formal healthcare system, it is possible to roll back malaria.

That's the goal of the campaign that world health officials launched in 1998 to cut the incidence of malaria in half by 2010. The campaign has so far fallen woefully short of expectations. This year will see an estimated 500 million cases of malaria, two-thirds more than the 300 million cases estimated in 1999. Somewhere between one and two million people will die of the disease, most of them children under the age of five in sub-Saharan Africa.

To Nosten, who has devoted his life to fighting the resurgence of drug-resistant malaria, it's inexplicable that global health officials and policymakers haven't moved faster to deploy the knowledge and tools that he helped to create - especially the three-day regimen of ACT. (Two combinations tested by Nosten and colleagues included artemether-lumefantrine and mefloquine-artesunate, both of which proved more than 96% effective against P. falciparum.) "The death toll is enormous. It's like five jumbo jets filled with children crashing every day," he says. "By 2010, there could be twice as much malaria. That, to me, is a failure."

The Adaptability of Parasites

The virulent strain of the malaria parasite has grown resistant to chloroquine, the most common drug used to combat the disease. So several million mostly African children die every year even though many of their desperate parents buy them medicine that they think is going to work.

The economics of the situation are perverse. Chloroquine costs 10 cents a day, something poor people can afford. Drugs that work like artemisinin (the fast-acting, fast-clearing drug is used in combination with older drugs to avoid its falling victim to resistance) costs $2.50 a day. If you made $2 a day or less like most people in Africa, which would you choose?

Today's New England Journal of Medicine contains a report from Malawi showing that if chloroquine is discontinued for a decade or so, the malaria parasite evolves to the point where it once again become susceptible to the drug's action. It turns out that the genetic mutation that confers resistance makes the parasite somewhat weaker overall. Without the selective pressure of the drug, the susceptible strain resumes its dominance in the overall population.

So should chloroquine be reintroduced in those countries that are following the World Health Organization's advice and switching to artemisinin-based combination therapy for treating malaria? Absolutely not, says Nicholas White of Mahidol University in Bangkok, who is probably the world's leading malariologist. In an accompanying perspective article, White points out that "if chloroquine were reintroduced alone, resistant parasites would probably return rapidly, imported in people from neighboring areas." He holds out hope that chloroquine can once again become a useful drug, but not until it is stopped everywhere for a long period of time. "It needs to leave before it can come back."

Meanwhile, the World Bank and other multi-lateral aid organizations are dragging their feet in implementing the 2004 Institute of Medicine report that called for setting up a global fund to purchase 500 million doses of ACT a year for use in the developing world (it would cost about $1.5 billion a year). This central authority could then distribute it through the same channels that currently distribute chloroquine -- and at the same price.

That way, the desperate mothers of the two million children who die each year could not only afford to buy their children medicine, but they would be assured that the medicine they give them works.