In the Spotlight
Why the 10/90 Gap is 100% Fiction
Pharmaceutical companies aren’t to blame for the disease burden in poor nations.
Philip Stevens, 12-2-04
One of the central themes of November’s Global Forum on Health Research meeting in Mexico City was that while pharmaceutical companies are pouring billions of dollars into finding cures for baldness and erectile dysfunction, millions of people in low-income countries are dying of tropical diseases for which there is no cure. This is called the “10/90 gap”, i.e. only 10% of the world’s pharmaceutical research goes towards diseases that account for 90% of the global disease burden.
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Bristol-Myers Diabetes Drug Produces Positive Test Results
Wall Street Journal, 11-18-04
Bristol-Meyers announced plans to seek FDA approval for its new diabetes drug, muraglitazar, next month after finding positive results with final stage human trials. The trials involved 4,500 hundred patients and the experimental drug showed that it significantly lowered blood sugar as well as triglycerides (fats in the blood). “It also increased HDL, or ‘good,’ cholesterol levels in patients with Type 2 diabetes.” The drug performed as well or better than other diabetes drugs on market, and showed that it helped patients control glucose for as long as 2 years. The drug also had a better side-effect profile than other diabetes drugs, which tend to cause weight gain.
Reuters Summit-AstraZeneca CEO urges US to spur drug innovation.
Reuters News, 11-17-04
AstraZeneca CEO Tom McKillop warned the U.S. that its dominance of the $400 billion global pharmaceutical industry wasn’t assured, and that price controls or expansion of the U.S.’s unpredictable liability system could send investment fleeing the country to nascent competitors like India and China. “In a 20-year time period [we] went from eight of the top 10 pharmaceutical products being discovered in Europe to eight of the top 10 pharmaceutical products being discovered in America…That's absolutely amazing, and the U.S. is an enormous economic winner from that. If we go down the route in the U.S. that Europe went down, India and China are waiting with vastly bigger populations. They're producing more talented scientists and engineers every year than the United States, and they're going to be the next generation of winners if the U.S. moves away from innovation."
Mouse Study Hints at Effects of Cox-2 Inhibitors on Heart
Wall Street Journal, 11-19-04
Dr. Garrett Fitzgerald and other researchers at the University of Pennsylvania have said that Cox-2 inhibitors “could undermine the protection against heart disease that premenopausal women get from natural levels of the hormone estrogen.” Nonetheless, Dr. Fitzgerald and his colleagues cautioned that too much could be made of their findings, since the study only focused on a mechanism of action in mice and didn’t constitute firm evidence of a clinical risk in humans. Also, “the results don’t reflect actual tests of the drugs since mice weren’t given the medicines as part of the study. Instead mice lacked a receptor for a fatty acid called prostacyclin that may yield heart-related benefits when activated by Cox-2.”
However, what Dr. Fitzgerald’s study does point to is the need for better animal models of human disease (for instance, heart disease), and for more attention to the systems biology behind drug treatment, as opposed to focusing only on “hitting” a single drug target, like the Cox-2 enzyme. Knockout mice studies like this one (so-called because a particular gene is “knocked out” of the animal being studied) can be a valuable tool in developing better drugs and understanding what adverse effects researchers and physicians should be on the lookout for.
F.D.A. Approves a Pill for Lung Cancer to Be Sold by Genentech and OSI
The New York Times, 11-19-04
In one of the fastest drug approvals ever, the FDA has approved the drug Tarceva to treat advanced non-small cell lung cancer, “the most common form of the disease”, in patients who have failed to respond to at least one prior round of chemotherapy. Tarceva is a “targeted” cancer drug that blocks a protein found in tumors, epidermal growth factor receptor, and has been shown to confer a survival benefit of nearly 7 months versus 4.7 months for placebo.
Targeted cancer drugs like Tarceva typically have fewer side effects than conventional treatments. Tarceva has also shown promise in providing a survival benefit for pancreatic cancer patients, a cancer that is notoriously difficult to treat. Genentech and OSI plan to apply for an additional indication for pancreatic cancer next year.
Drug Companies Look to China For Cheap R&D
Wall Street Journal, 11-22-04
The cost of developing drugs in Western nations has risen exponentially in recent years – along with ever-tightening price controls in Europe, and the threat of price controls in the U.S. In order to ward off profit pressures, companies are increasingly looking to expand operations in low-cost countries with highly skilled populations like China. “[Companies] are finding highly educated scientists who work for a fraction of what their Western counterparts are paid, as well as vibrant and growing biotechnology businesses.” This is a critical factor, since as much as 80% of R&D costs can go toward researcher compensation. Patent protection for pharmaceuticals has been a concern in China in recent years, but with China joining the World Trade Organization, even that concern is abating.
American policymakers take note: the U.S. economy will remain a hotbed of pharmaceutical and biotech innovation only as long as we can keep regulation to a minimum and offer investors a high return on their investments. Otherwise, the U.S. will cede its high tech dominance to lower-cost, more flexible competitors.
Protein May Prevent Damage After Heart Attack
Wall Street Journal, 11-26-04
How do you regenerate human tissues and organs once thought irreparably damaged? Media attention on this medical front is focused on embryonic stem cell research, partly because it is a promising technology, and partly because it is ethically ambiguous and controversy sells.
However, researchers are pursuing other therapies outside the media glare, and some are now hopeful that a protein that is critical in pre-natal heart development will also prove effective as a treatment to prevent damage caused by heart attacks. “Through a series of experiments, researchers showed that – when given to mice that were induced to have heart attacks – treatment with the protein, called thymosin beta-4, protected heart muscle cells from dying and was associated with improved heart function.” Weeks after the induced heart attacks, protein treated mice had less muscle damage and stronger hearts than mice treated with saline solution.
Animal tests, no matter how encouraging, are only a first hurdle; moving from mice to man has killed many a promising therapy. Nonetheless, the lead author of an article in Nature describing the experiments has said that the results suggested that the protein could be a powerful frontline treatment, if it could be delivered to patients within a few hours after suffering a heart attack.
Many See Hope in Parkinson's Drug Pulled From Testing
The New York Times, 11-26-04
What constitutes a failed, unsafe drug? Given the backlash against Vioxx, that answer may seem clear cut. However, in reality drug safety is a very slippery concept – drugs once thought the epitome of failure, like thalidomide, can be rehabilitated to become powerful cancer treatments. Safety issues often involve delicate risk-balancing tests, and when patients have few viable options – or have exhausted the options available to them – what looks like a bad gamble can suddenly become a good bet.
Parkinson’s is a crippling neurological disease characterized by severe motor impairment, and patients afflicted by the disease have few good options and are anxious to develop new treatments, no matter how remote the prospect of success. Adding to the challenges facing companies seeking new treatments is that the condition has a very high placebo response rate, meaning that drugs that look effective in small, early tests can fade abruptly when subjected to the rigors of placebo controlled trials.
One example of the dilemmas facing companies and regulators is the Parkinson’s drug glial cell line-derived neurotrophic factor (GDNF) developed by Amgen. GDNF showed enormous promise in early trials, but Amgen withdrew it from patients receiving it as an experimental treatment last August after the drug failed to outperform placebo in a controlled trial and some patients developed antibodies against the drug.
Patients (and some doctors) in earlier trials still swear by the drug and are begging the company to license it to another company or university for development, or at least continue providing it to clinical trial patients on a “compassionate use” basis – which the company says that it cannot do for ethical and legal reasons. Currently, The Michael J. Fox Foundation for Parkinson’s Research is holding talks with Amgen to try and work out a compromise.
Still, this is a critical side of the drug safety debate that is apt to be missed by policymakers and activists eager to find corporate scapegoats. The reality is that we don’t have any perfect tools for measuring safety or efficacy, and every decision by corporations and FDA is open to second guessing by people looking for easy answers.
Flu Crisis Sparks Fresh Look at Vaccine Production
Washington Post, 11-27-04
Which came first, the chicken or the egg? When it comes to flu shots, it’s the egg.
For about fifty years, the U.S has relied on the same technology for its flu vaccinations: “flu shots containing liquid drawn from 11-day-old fertilized chicken eggs.” The eggs are used as tiny incubators for viruses that are then killed and used in vaccines. However, as the nation discovered recently, the process is expensive, time-consuming, and prone to contamination – a problem that prevented the British company Chiron Corporation from delivering on its promise to send 48 million flu shots to the U.S. for the current flu season.
Policymakers also fear that current technology will be unable to respond quickly in the event of a pandemic outbreak of a new virus like the avian flu, which some experts think might kill hundreds of millions worldwide if it makes the jump to human beings. Consequently, federal officials are encouraging biotech companies to develop a new technology whereby viruses are incubated in cells drawn from insects, monkeys, dogs, or even human tissues. The technology is somewhat faster and certainly less prone to the problems affecting the egg based vaccine. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, has said that he will ask Congress for $100 million to design a better national vaccine procurement process, with pilot projects focusing on cell based vaccine development methods.
Still, the technology is several years away from large scale deployment, and it may not coax new companies into the vaccine market absent one critical ingredient: higher profits. Until industry has better incentives to spend money on vaccine development, technology alone won’t solve the problem. Said one analyst, “If the profit margins are horrible, why would any company want to take that chance otherwise?”
Novel Vaccine Activates HIV Immunity, Slows AIDS Virus
To date, AIDS vaccine development has been a tale of great hopes followed by crushing failures.
However, one experimental vaccine has shown preliminary effectiveness in human beings after being studied in mice and monkeys. The so called “designer” vaccine is created by extracting cells from an AIDS patient’s own immune system and HIV isolated from the patient’s blood. The immune cells are then “loaded” with pre-killed HIV viruses and reinjected into the patient, helping to activate a powerful immune response against the virus.
Patients in one small study who received the designer vaccine saw their viral loads drop by 80%. “After a year, eight of the 18 patients still had a 90% drop in HIV levels”, and T cell counts in all the patients had stabilized. Researchers involved in the project warn that their study is only a “proof of principle”, and that randomized clinical trials will be required to prove efficacy. Still, a ray of hope is better than none at all.
New Therapies Target Once-Untreatable Cancers : New Techniques Shift Thinking on Options for Sickest Patients; 'Convinced I Was Going to Die'
Wall Street Journal, 11-30-04
When it comes to cancer, many physicians are reconsidering the entire concept of what constitutes an “untreatable disease”. New targeted radiation and chemotherapy treatments have made cancer therapy more bearable, even as clinical evidence suggests that many patients can bear more radiation exposure than had been previously thought possible.
“The shift is largely being driven by new thinking among doctors about how much radiation a person can stand, and by technology that makes it possible to deliver treatment straight to a tumor and spare surrounding organs. Previously inoperable tumors in the lungs, liver, head and neck can now be isolated, shrunk, and then removed using minimally invasive surgical techniques.”
Of course, there is always the question of whether the pursuit of treatment in a terminally ill patient will merely prolong suffering, but a wide range of new medicines and technologies are giving patients with advanced cancer a fighting chance that they never had before.
UPDATE: 2-Cipla anti-AIDS drugs back on WHO approved list.
Reuters News, 11-30-04
The WHO has reinstated two generic AIDS medicines formerly withdrawn by the Indian company Cipla, six months after they were first removed when concerns surfaced regarding the quality of data Cipla had submitted to prove that its drugs were equivalent to patented medicines. “The life-extending drugs are back on the list of WHO-approved products after fresh inspection proved they were equivalent to their patented counterparts, the United Nations agency said, pledging continued ‘rigorous assessment and monitoring’ of anti-AIDS drugs known as retrovirals.”
A total of 28 Indian generic AIDS drugs were on the WHO list as of early last summer. Since then, 18 have been removed, 2 were reinstated, and 16 remain delisted. Dr. Roger Bate, a Fellow at the American Enterprise Institute, thinks that the WHO is focused more on meeting treatment quotas than ensuring that generic anti-retroviral drugs (ARVs) perform as advertised.
Dr. Bate says that “in its attempt to see others treat three million HIV patients by the end of next year, The World Health Organization has cut corners on the quality of medicines it approves. The latest re-instatement of two Cipla ARVs, previously withdrawn over the summer, and after 16 other Indian copy drugs have been withdrawn in the past 6 months, points to an honor system that is so flawed that one wonders at the quality of the drugs that remain on the pre-qualification list. The WHO should scrap its pre-qualification process and take the FDA up on its offer to test all ARVs for bioequivalence. Only then will we know which drugs actually work. Let us be clear, this is an issue of safety - if the drugs do not work properly then patients will die.”
REVIEW & OUTLOOK (Editorial): The Trials of Merck
Wall Street Journal, 11-18-04
The Journal notes that there are two distinct accusations against Merck, “the first broad and fallacious and the second narrow and possibly true.” The broad charge is that Vioxx and other Cox-2 drugs are virtually identical to older, cheaper drugs like aspirin and ibuprofen, and that “bringing them to market after even a hint that they increase cardiovascular risks is irresponsible.” This is manifestly untrue, since the older drugs, which are taken long term by many arthritis sufferers, cause “16,000 deaths every year from gastrointestinal bleeding.” So much for generic safety. Cox-2s do prevent those gastrointestinal effects, and for a “sizable minority” of patients with disabling pain, Vioxx and other Cox-2 drugs were a valuable addition to the nation's medicine chest.
However, if Merck knew about the heart risks “much earlier than it let on, yet inappropriately marketed the drug too widely as if it was just easy on the stomach aspirin”, then Vioxx crossed the line and should pay the penalty – for “marketing fraud, not for producing an inherently unsafe drug”. Only time will tell if the second, narrower accusation is true or not. All-in-all, the Journal opines that the best course of action would’ve been to leave Vioxx on market with a very stringent label recommending use only in patients without heart disease and with a history of gastrointestinal problems.
No matter what happens to Merck, the most troubling facet of the case is that it will “lead to longer drug approvals and new liability standards that will wreck havoc throughout the whole industry.”
Commentary: Why new drugs cost so much
Deroy Murdock, Washington Times, 11-22-04
After visiting Merck’s research center in New Jersey, Mr. Murdock has answer: drug development is very hard and very expensive. As one researcher notes, “Of the 1,200 molecules tested here last year…eight went on to the next step. And not all of those will go on to become drugs.”
Take for instance, Merck’s thus far successful effort to create a vaccine to prevent the spread of the Human Papilloma Virus (HPV). HPV infects 50 to 75 percent of sexually active adults, causing cervical cancer, genital warts and other very unwholesome outcomes. Merck has spent hundreds of millions of dollars developing the vaccine and producing equipment to manufacture it. “If approved, the drug’s price will reflect, in part, this huge up-front investment.” But if the drug fails to get FDA approval Merck might as well have flushed its money down a toilet.
Activists and industry critics like to complain that drug development is fast, cheap, and easy – and that high drug prices are only the result of greedy corporations trying to line their pockets. Perhaps they should take the same tour Mr. Murdock did before they make such glib accusations.
Commentary: The Curse of Too Much Caution
Henry Miller, M.S., M.D., Wall Street Journal, 11-26-04
Miller says that the FDA is a favorite target of Congress and the media because, as one former FDA commissioner puts it, the FDA is a “slow-moving target that bleeds profusely when hit.”
The current round of FDA bashing may be a prequel to yet more regulation of the pharmaceutical industry in pursuit of the holy grail of perfect drug safety. Miller takes issue with reflexive calls for greater regulation, wisely pointing out that “greater safety is not synonymous with greater regulation.” In fact, more regulation may lower the “net benefit” to patients and society because regulation is only designed to catch one type of error: the drug that is approved that should have been withheld or withdrawn.
When regulators approve a new drug that later proves unsafe, they will inevitably be excoriated by Congress, consumer groups, and the media. On the other hand, if they fail to approve an otherwise beneficial product, or drag out the approval process interminably, the guardians of public health will utter nary a peep. Says Miller, “the first kind of error is highly visible”, and thus correctible. The second is invisible and largely incorrectable.
In fact, not once in all its history has the FDA been investigated because it failed to approve a new drug. Miller concludes that a drug safety agency that only focused on killing unsafe drugs would make the FDA too risk averse, and keep valuable new drugs from ever reaching market.
Instead, he suggests an independent FDA ombudsman who would have the power to sanction the agency for both types of errors, thus ensuring that FDA has the right incentives to pursue safety and innovation simultaneously.
Editorial: Looking for Adverse Drug Effects
The New York Times, 11-27-04
This editorial posits that drug approval is essentially a zero sum game when it comes to pharmaceutical innovation and patient safety. Push the pendulum too far towards innovation, and patient health inevitably suffers. The Vioxx debacle shows that the FDA is too quick to approve new medicines, and thus must be reined in with onerous new regulations.
While the Vioxx withdrawal does indicate some gaps in the FDA’s drug safety process (particularly postmarketing), we should remember that all drugs have adverse effects in addition to benefits. The goal should not be to completely withdraw valuable drugs with rare side-effects, but to keep them away from high risk patients. Building a better drug safety system will require the FDA to employ more and better datamining technology, and embrace new tools (like pharmacogenomics) that will help both FDA and industry to segment treatment more effectively.
Both of these reforms, however, are a win-win for industry and patients: they encourage better, safer, and more powerful drug treatment without compromising public health. Creating a false dichotomy between innovation and safety will only slow the pace of medical progress and cause more harm in the long run as patients are deprived of valuable new medicines.
Biting the Hand that Feeds You
Roger Bate, American Enterprise Institute, 11-29-04
Bate takes the international community to task for its hypocrisy in criticizing the U.S. for not doing enough to fight AIDS when the U.S. is the single largest global AIDS donor, and other nations are reneging on their commitments. “The G8 group of nations declared last year that the fund should get $3 billion a year, with French President Jacques Chirac proposing $1 billion from Europe, $1 billion from the United States, and $1 billion from other countries. But since European nations have not donated their share, the U.S. has so far paid more than its share--its support has been as high as 37 percent and is currently at 35 percent, exceeding the originally proposed 33 percent.”
It is hard to overstate the animus directed at the U.S. in international donor circles, even as the U.S. is a global leader in the fight against AIDS. The genius of this effort is that as long as people are pointing fingers at the U.S., none of the other stakeholders have to own up to their own shortcomings.
Commentary: A Culture Of Subsidies Inflates Costs
Steven Pearlstein, Washington Post, 12-1-04
What do college education, health care, and housing have in common? Mr. Pearlstein’s answer: rapidly rising costs that constantly outstrip the rate of inflation, and massive government subsidies.
The problem is that subsidies, in the form of federal student loans, tax deductions for employer provided health care, or mortgage deductions, all shield consumers from the full cost of the services or commodities they use. For instance, generous college loans allow colleges to raise tuition at a rapid clip year after year because the government will just bump up student subsidies to keep tuition “affordable”.
Pearlstein says that “these well-intentioned subsidies have the perverse effect of shielding colleges from the kind of market discipline that would have forced them to hold down prices by constantly improving their productivity and efficiency, as happens in just about every other industry.”
Government subsidies fuel a vicious cycle of rising demand and rising prices until costs threaten to bankrupt consumers and government alike. Until we bring real market discipline to these sectors, we can expect more of the same.
EDITORIAL: Healing the FDA from within
The Star-Ledger, 11-30-04
A stronger postmarketing drug safety regime may be long overdue, but a new, separate agency is not the answer. “What’s needed is for the FDA to become a strong watchdog for both new drug applications and postmarket use. That means giving the agency new powers to order necessary tests and yank products off the market.”
There is yet another reason we should add to the mix: creating an adversarial agency that would police the FDA would work about as successfully as having the FBI watch the CIA. Experience has shown that competing federal agencies inevitably become demoralized and self-defeating, giving rise to destructive rivalries that can only hurt the public interest.
The FDA is the agency with the most expertise and experience in this sector, and thus is best positioned to compare real risks and benefits. Strengthening agency funding and empowering it to undertake more targeted, science based regulation is the best response to the current challenges facing the FDA and its stakeholders.
Diseases of poverty and the 10/90 Gap
Philip Stevens, International Policy Network, 12-1-04
The "10/90 Gap" is shorthand for the premise that only 10% of global pharmaceutical research funding is devoted to conditions accounting for 90% of the global disease burden. The rest goes to research on “lifestyle” diseases afflicting wealthy nations. This would be a damning accusation if it was true, but a new report from the Campaign for Fighting Diseases shows that the 10/90 Gap is a myth, and that it is often government policies in poor nations that deny their own citizens access to essential medicines.
Gene Map of the Extended Human MHC
Roger Horton, Laurens Wilming, et.al, Nature Reviews Genetics, 12-2-04
MHC – the major histocompatibility complex – is the “most important region in the vertebrate genome in relation to infection, autoimmunity, and transplantation.” The MHC is also associated with “hundreds of diseases, including most, if not all, autoimmune diseases.” Several large studies of the MHC have recently been completed that “offer the opportunity to assimilate the latest data into an integrated map of the MHC”, a map that is presented in this article.
The extended MHC provides researchers with a valuable tool for charting the workings of the human immune system and translating that knowledge into new treatments for infectious diseases and autoimmune disorders.
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