Cassie* was just six years old last January when she started to turn pale and feel an unfamiliar ache in her bones. The change was so gradual that months passed before her parents became worried enough to take her to the pediatrician. But before the appointment was scheduled, she was rushed to the emergency room, so weak she could barely stand; by the end of the evening Cassie was diagnosed with ALL: acute lymphocytic leukemia. The white cells that are supposed to defend her body from microbial invasion had instead grown like a parasite in her marrow, strangling out the vital tissues that produce red blood cells and platelets. (*not her real name)
Childhood leukemia is now a treatable disease. Thirty years ago, she probably would have died after a few months of cutting-edge yet still clumsy treatment. A hundred years ago, before people learned to type and transfuse blood, she would have died within weeks, so anemic that she was. Today, about 85% of childhood ALL cases in kids achieve permanent remission with chemotherapy - a minor miracle of modern pharmaco-chemistry that highlights how the laboratory bench is just as important in medicine as compassion and caring.
But Cassie’s rosy outlook shattered when her cancer was genotyped a week later to discover exactly what had caused the wildfire growth of malignant cells. She turned out to have a rare subtype of ALL – one that placed her squarely in the 15% that don’t beat cancer in the first round. In fact, most kids with her genetic twist don’t beat cancer at all. Cassie had the Philadelphia chromosome.
In 1960 researchers in Pennsylvania began to describe a cancerous white cell in which a piece of the ninth chromosome had switched places with a piece of the twenty-second chromosome. No one understands why this happens, but the protein that is read off one of these abnormal strands is named – in the peculiar parlance of molecular biology – bcr-abl. Bcr-abl belongs to a family of enzymes called tyrosine kinases, which are involved in signalling cells to reproduce. Normally, tyrosine kinases are turned off and on by other enzymes, but the mutant bcr-abl protein locks the cell’s reproductive cycle into the on position, spiralling that cell into self-perpetuating expansion which takes over the marrow with ever-multiplying clones. This so-called 9:22 translocation – the “Philadelphia chromosome”– is the basis for most cases of chronic myelogenous leukemia (CML), which mainly affects older adults, and also for a small percentage of ALL cases like Cassie’s.
This arcane bit of biochemical mechanistics sat on the shelf for several decades without much clinical importance, but it held out a tantalizing implication: if a cancer is caused by a well-described signalling error, could a drug be invented that inhibits the mutant enzyme alone, gumming up the machinery that causes the malignant transformation without poisoning the body’s normal cells?
This was the burning question Dr. Brian Druker asked in the early 1990s when he began a cooperative project with the Swiss pharmaceutical giant now known as Novartis to test compounds that showed promise in blocking the bcr-abl protein. Modern cancer chemotherapy broadly targets rapidly dividing cells – including both cancerous and normal cells – which is in part why chemo patients lose their hair and battle intractable gastrointestinal problems. Some clinicians quietly mutter that this treatment will one day be regarded the way we now look at bloodletting: as a barbaric and primitive strategy which too often causes more harm to the long-suffering patient for too little gain.
Druker and other visionaries sought to change all that. Using the specific molecular biology of an individual type of cancer cell, narrow-spectrum drugs could be invented that circumvent the scorched-earth tactics of standard chemotherapy. These hypothetical drugs would not be a “magic bullet” for cancer at large; they would be a magic bullet for a particular type or even subtype of cancer. By 2001, a particularly promising tyrosine kinase inhibitor known as imatinib – branded by Novartis under the name Gleevec – set the record for the fastest drug approval ever by the FDA, effectively transforming CML from a fatal disease into a chronic disorder, and giving new hope for patients with Philadelphia-positive ALL.
But this radical advance came at an immense cost, a gamble that pharmaceutical companies make with every compound they consider: the price of developing a drug like Gleevec from start to finish is estimated at up to $800 million. With only about 4500 CML cases (and a handful of Philadelphia-positive ALL cases) annually in America, those R&D costs must be recovered from a small pool of patients, whose insurance – if they have insurance – is billed over $25,000 a year for a patented drug that many patients will take for the rest of their lives. Invoking cash numbers of this scale inevitably raises debate about access and equity in the distribution of vital medicines, and Novartis has hardly escaped this fray. In fact, Novartis has inadvertently positioned itself at the vortex of an economic and ethical storm.
The controversy started when Novartis made the grandiose promise that no patient on the planet who could benefit from Gleevec would go without. Besides several unresolved logistical complications (including the fact that Gleevec was not yet approved in many nations), this promise came with some hefty strings attached. Novartis warned India – one of the world’s largest emerging markets for pharmaceuticals – that the charity would end if the nation allowed any generic knock-offs of Gleevec. In Korea, the government set the prices for Gleevec far below the open market value, and supplies of the drug dwindled while the Novartis and the Korean government bickered over the issue. All over the developing world, Novartis has been accused of using its charitable donations as a strategy to enter a market and then leverage patients into lobbying for governments and private insurers to reimburse for this medication, whose cost far outweighs the average per capita health care spending in many developing nations – sometimes by a factor of ten or even one hundred-fold.
It is tempting to unilaterally condemn Novartis for their exploitation of a vulnerable population, holding leukemia patients hostage to a life-saving drug and demanding a monetary tribute neither they nor their cash-strapped nations can reasonably afford. But without the pharm company’s investment, Gleevec never would have come off the shelf and into patients’ mouths – in fact, it is said that Druker had to gently strong-arm Novartis into investing in the compound at all, because the revenue on such a drug was not projected to bring in sufficient profit. Now Novartis has only a few short years until the patent runs out to recover the initial investment – a chunk of money they put down without a guarantee of any return at all (indeed, most compounds examined by biotech companies never make it out of the test tube, and biotech firms routinely swallow those unrecoverable funds as a cost of doing business). Critics counter that Gleevec would never have existed without the initial research that identified the Philadelphia chromosome - research that Novartis certainly did not fund or compensate anyone for – and that Druker’s work was carried out in a lab supported largely by Oregon Health & Science University, a public medical school in Portland. The fact that Novartis regularly nets over a billion dollars annually on its aggregate drug sales does not lend the company much sympathy from activists either.
In any case, Novartis’ heavy-handed tactics may have already backfired. In January of 2006, the agency that controls patent rights in India ruled that Gleevec is not protected, and half a dozen Indian pharmaceutical makers are now racing into the market to undercut Novartis’ price by up to 90% and effectively end the monopolistic practices allowed by patent rights. This is good news for Indian patients who have sold house and home – even bankrupting themselves – to purchase Gleevec when the promised charitable donations did not come through smoothly. But it may be bad news for sufferers of other diseases that have potential drugs in the pipeline; with patent rights threatened under this precedent, research and development may be hindered by this sharp downward adjustment in projected revenues in the large Indian market.
There is yet a far more fundamental question in the provision of expensive drugs to developing nations: do poor countries really need a fancy new cancer drug? This question addresses what economists call the “opportunity cost” – the list of things you cannot do because you put your money into another activity. One might question what other health assets or advances could be purchased with the $25,000 per patient per year that nations outside India might still have to pay for access to Gleevec. Blowing such a large chunk of public cash on one cancer patient may seem crassly unjust in nations where such money could treat hundreds of tuberculosis, AIDS, or malaria patients – yet that policy is exactly what Novartis is pedalling by exerting pressure on patients to lobby their governments for full reimbursement for Gleevec. On a grander scale, one might ask why a company is spending $800 million on drugs for diseases that affect about 5000 Americans per year when the world is struggling to treat millions of TB patients with drugs that are increasingly inadequate against resistant strains. These questions become even more pressing in light of the fact that novel drugs are now in the pipeline to combat resistance to Gleevec that emerges in many patients on chronic therapy – in effect throwing even more resources into a rare disease that has already merited one miracle drug.
The conflict engendered by pricey drugs is by no means limited to developing nations. In the US, a similar controversy is likely to brew in the coming months over Avastin, which inhibits certain tumors from building the blood vessels needed to feed their growth – at a cost of $100,000 per patient per year, a number which causes patients and insurers alike to balk. Herceptin (a synthethic antibody that marks certain types of breast cancer cells for destruction by the immune system) made headlines in Britain last year when the National Health Service refused to pay the equivalent of $35,000 a year for women in the early stage of the disease to receive the drug. The NHS grounded their decision in the evidence, which had yet to prove any positive effect for women with early cancer, since the drug was largely developed for difficult-to-treat metastatic disease. Moreover, the NHS must control expenditures so that all British citizens can get basic and advanced care without bankrupting the system. The women who challenged the decision argued that with their lives are at stake, any chance of benefit would be worth the cost – and the NHS eventually backed down and agreed to pay for the treatment. The decision was hailed as a landmark advance for patient rights, but by further straining and already-stressed national health system, this victory may help a vocal minority of patients at the expense of other beneficiaries who are less empowered to demand their rights.
It may seem as if these opposing groups – the NHS versus breast cancer patients, pharmaceutical companies versus impoverished leukemia patients – are speaking different languages: one of hard numerical reality and the other of the unquantifiable value of their own lives, with an added subtext of controversy regarding patient autonomy over treatment decisions that are historically left only to doctors (and more recently placed in the hands of private and public insurers – a fact of modern life that neither patients nor doctors are particularly happy about). In fact, both of these are languages we all speak. Every lay person knows that gut-wrenching feeling of being faced with a sudden, unexpected expense that throws even the best budgeting projections into a tailspin. Contrarily, no insurance executive, health economist, or NHS official is immune to cataclysmic illness in the family.
And it is within that common ground that a more effective dialogue needs to be opened between the stakeholders: patients, physicians, pharmaceutical companies, insurers, and the general public whose funds are allocated for these treatments. In a world of limited resources, tough decisions have to be made between pursuing expensive novel treatments for rare diseases and providing routine care for the world’s top killers. The open market has not been particularly apt at doling out these resources to the satisfaction of the masses – as evidenced by the breast cancer patients in Britain and the leukemia patients in India. Creative new solutions are in demand – perhaps giving pharm companies tax breaks for keeping drug prices in the reasonable range, or increasing federal funding for basic research while capping prices on drugs that are produced with such public funds. Whatever the proposed solution, it is imperative that patient advocates take their place at the negotiating table, but equally vital that decisions are made with the limits of real-life economics in mind – economics of production, economics of purchasing, and economics of the relative value of health in rich and poor nations.
In the end, Gleevec is good medicine – even great medicine – though its existence implies some problematic economics. Dr. Druker has become a folk hero among patients whose lives have been given new promise by Gleevec; websites have sprung up dedicated to posting letters of thanks to the man who reinvented hope for a terminal disease. Meanwhile, with the help of Gleevec, Cassie’s stubborn leukemia was forced into remission this spring, but because long-term data on remission in Philadelphia-positive ALL is still lacking, in May she underwent a bone marrow transplant to eradicate any possible remaining pockets of hidden cancer. In June she was declared cancer-free for the first time, but after enduring all the pre-transplant radiation and chemotherapy, she suffered a profound lung injury and has been on life support for endless weeks now, struggling to stay alive while her lungs slowly heal over. The grave consequences of such invasive procedures like bone marrow transplant point to the importance of developing effective and well-tolerated drugs – drugs like Gleevec, Avastin, and Herceptin – that treat the disease while circumventing the heroic but costly interventions that modern medicine employs so commonly. Despite the ongoing struggle for Cassie’s life, for her mommy and daddy and the mesh of family and friends who love their young daughter, any price was worth the cost of Gleevec.
Posted by skylanda.
Childhood leukemia is now a treatable disease. Thirty years ago, she probably would have died after a few months of cutting-edge yet still clumsy treatment. A hundred years ago, before people learned to type and transfuse blood, she would have died within weeks, so anemic that she was. Today, about 85% of childhood ALL cases in kids achieve permanent remission with chemotherapy - a minor miracle of modern pharmaco-chemistry that highlights how the laboratory bench is just as important in medicine as compassion and caring.
But Cassie’s rosy outlook shattered when her cancer was genotyped a week later to discover exactly what had caused the wildfire growth of malignant cells. She turned out to have a rare subtype of ALL – one that placed her squarely in the 15% that don’t beat cancer in the first round. In fact, most kids with her genetic twist don’t beat cancer at all. Cassie had the Philadelphia chromosome.
In 1960 researchers in Pennsylvania began to describe a cancerous white cell in which a piece of the ninth chromosome had switched places with a piece of the twenty-second chromosome. No one understands why this happens, but the protein that is read off one of these abnormal strands is named – in the peculiar parlance of molecular biology – bcr-abl. Bcr-abl belongs to a family of enzymes called tyrosine kinases, which are involved in signalling cells to reproduce. Normally, tyrosine kinases are turned off and on by other enzymes, but the mutant bcr-abl protein locks the cell’s reproductive cycle into the on position, spiralling that cell into self-perpetuating expansion which takes over the marrow with ever-multiplying clones. This so-called 9:22 translocation – the “Philadelphia chromosome”– is the basis for most cases of chronic myelogenous leukemia (CML), which mainly affects older adults, and also for a small percentage of ALL cases like Cassie’s.
This arcane bit of biochemical mechanistics sat on the shelf for several decades without much clinical importance, but it held out a tantalizing implication: if a cancer is caused by a well-described signalling error, could a drug be invented that inhibits the mutant enzyme alone, gumming up the machinery that causes the malignant transformation without poisoning the body’s normal cells?
This was the burning question Dr. Brian Druker asked in the early 1990s when he began a cooperative project with the Swiss pharmaceutical giant now known as Novartis to test compounds that showed promise in blocking the bcr-abl protein. Modern cancer chemotherapy broadly targets rapidly dividing cells – including both cancerous and normal cells – which is in part why chemo patients lose their hair and battle intractable gastrointestinal problems. Some clinicians quietly mutter that this treatment will one day be regarded the way we now look at bloodletting: as a barbaric and primitive strategy which too often causes more harm to the long-suffering patient for too little gain.
Druker and other visionaries sought to change all that. Using the specific molecular biology of an individual type of cancer cell, narrow-spectrum drugs could be invented that circumvent the scorched-earth tactics of standard chemotherapy. These hypothetical drugs would not be a “magic bullet” for cancer at large; they would be a magic bullet for a particular type or even subtype of cancer. By 2001, a particularly promising tyrosine kinase inhibitor known as imatinib – branded by Novartis under the name Gleevec – set the record for the fastest drug approval ever by the FDA, effectively transforming CML from a fatal disease into a chronic disorder, and giving new hope for patients with Philadelphia-positive ALL.
But this radical advance came at an immense cost, a gamble that pharmaceutical companies make with every compound they consider: the price of developing a drug like Gleevec from start to finish is estimated at up to $800 million. With only about 4500 CML cases (and a handful of Philadelphia-positive ALL cases) annually in America, those R&D costs must be recovered from a small pool of patients, whose insurance – if they have insurance – is billed over $25,000 a year for a patented drug that many patients will take for the rest of their lives. Invoking cash numbers of this scale inevitably raises debate about access and equity in the distribution of vital medicines, and Novartis has hardly escaped this fray. In fact, Novartis has inadvertently positioned itself at the vortex of an economic and ethical storm.
The controversy started when Novartis made the grandiose promise that no patient on the planet who could benefit from Gleevec would go without. Besides several unresolved logistical complications (including the fact that Gleevec was not yet approved in many nations), this promise came with some hefty strings attached. Novartis warned India – one of the world’s largest emerging markets for pharmaceuticals – that the charity would end if the nation allowed any generic knock-offs of Gleevec. In Korea, the government set the prices for Gleevec far below the open market value, and supplies of the drug dwindled while the Novartis and the Korean government bickered over the issue. All over the developing world, Novartis has been accused of using its charitable donations as a strategy to enter a market and then leverage patients into lobbying for governments and private insurers to reimburse for this medication, whose cost far outweighs the average per capita health care spending in many developing nations – sometimes by a factor of ten or even one hundred-fold.
It is tempting to unilaterally condemn Novartis for their exploitation of a vulnerable population, holding leukemia patients hostage to a life-saving drug and demanding a monetary tribute neither they nor their cash-strapped nations can reasonably afford. But without the pharm company’s investment, Gleevec never would have come off the shelf and into patients’ mouths – in fact, it is said that Druker had to gently strong-arm Novartis into investing in the compound at all, because the revenue on such a drug was not projected to bring in sufficient profit. Now Novartis has only a few short years until the patent runs out to recover the initial investment – a chunk of money they put down without a guarantee of any return at all (indeed, most compounds examined by biotech companies never make it out of the test tube, and biotech firms routinely swallow those unrecoverable funds as a cost of doing business). Critics counter that Gleevec would never have existed without the initial research that identified the Philadelphia chromosome - research that Novartis certainly did not fund or compensate anyone for – and that Druker’s work was carried out in a lab supported largely by Oregon Health & Science University, a public medical school in Portland. The fact that Novartis regularly nets over a billion dollars annually on its aggregate drug sales does not lend the company much sympathy from activists either.
In any case, Novartis’ heavy-handed tactics may have already backfired. In January of 2006, the agency that controls patent rights in India ruled that Gleevec is not protected, and half a dozen Indian pharmaceutical makers are now racing into the market to undercut Novartis’ price by up to 90% and effectively end the monopolistic practices allowed by patent rights. This is good news for Indian patients who have sold house and home – even bankrupting themselves – to purchase Gleevec when the promised charitable donations did not come through smoothly. But it may be bad news for sufferers of other diseases that have potential drugs in the pipeline; with patent rights threatened under this precedent, research and development may be hindered by this sharp downward adjustment in projected revenues in the large Indian market.
There is yet a far more fundamental question in the provision of expensive drugs to developing nations: do poor countries really need a fancy new cancer drug? This question addresses what economists call the “opportunity cost” – the list of things you cannot do because you put your money into another activity. One might question what other health assets or advances could be purchased with the $25,000 per patient per year that nations outside India might still have to pay for access to Gleevec. Blowing such a large chunk of public cash on one cancer patient may seem crassly unjust in nations where such money could treat hundreds of tuberculosis, AIDS, or malaria patients – yet that policy is exactly what Novartis is pedalling by exerting pressure on patients to lobby their governments for full reimbursement for Gleevec. On a grander scale, one might ask why a company is spending $800 million on drugs for diseases that affect about 5000 Americans per year when the world is struggling to treat millions of TB patients with drugs that are increasingly inadequate against resistant strains. These questions become even more pressing in light of the fact that novel drugs are now in the pipeline to combat resistance to Gleevec that emerges in many patients on chronic therapy – in effect throwing even more resources into a rare disease that has already merited one miracle drug.
The conflict engendered by pricey drugs is by no means limited to developing nations. In the US, a similar controversy is likely to brew in the coming months over Avastin, which inhibits certain tumors from building the blood vessels needed to feed their growth – at a cost of $100,000 per patient per year, a number which causes patients and insurers alike to balk. Herceptin (a synthethic antibody that marks certain types of breast cancer cells for destruction by the immune system) made headlines in Britain last year when the National Health Service refused to pay the equivalent of $35,000 a year for women in the early stage of the disease to receive the drug. The NHS grounded their decision in the evidence, which had yet to prove any positive effect for women with early cancer, since the drug was largely developed for difficult-to-treat metastatic disease. Moreover, the NHS must control expenditures so that all British citizens can get basic and advanced care without bankrupting the system. The women who challenged the decision argued that with their lives are at stake, any chance of benefit would be worth the cost – and the NHS eventually backed down and agreed to pay for the treatment. The decision was hailed as a landmark advance for patient rights, but by further straining and already-stressed national health system, this victory may help a vocal minority of patients at the expense of other beneficiaries who are less empowered to demand their rights.
It may seem as if these opposing groups – the NHS versus breast cancer patients, pharmaceutical companies versus impoverished leukemia patients – are speaking different languages: one of hard numerical reality and the other of the unquantifiable value of their own lives, with an added subtext of controversy regarding patient autonomy over treatment decisions that are historically left only to doctors (and more recently placed in the hands of private and public insurers – a fact of modern life that neither patients nor doctors are particularly happy about). In fact, both of these are languages we all speak. Every lay person knows that gut-wrenching feeling of being faced with a sudden, unexpected expense that throws even the best budgeting projections into a tailspin. Contrarily, no insurance executive, health economist, or NHS official is immune to cataclysmic illness in the family.
And it is within that common ground that a more effective dialogue needs to be opened between the stakeholders: patients, physicians, pharmaceutical companies, insurers, and the general public whose funds are allocated for these treatments. In a world of limited resources, tough decisions have to be made between pursuing expensive novel treatments for rare diseases and providing routine care for the world’s top killers. The open market has not been particularly apt at doling out these resources to the satisfaction of the masses – as evidenced by the breast cancer patients in Britain and the leukemia patients in India. Creative new solutions are in demand – perhaps giving pharm companies tax breaks for keeping drug prices in the reasonable range, or increasing federal funding for basic research while capping prices on drugs that are produced with such public funds. Whatever the proposed solution, it is imperative that patient advocates take their place at the negotiating table, but equally vital that decisions are made with the limits of real-life economics in mind – economics of production, economics of purchasing, and economics of the relative value of health in rich and poor nations.
In the end, Gleevec is good medicine – even great medicine – though its existence implies some problematic economics. Dr. Druker has become a folk hero among patients whose lives have been given new promise by Gleevec; websites have sprung up dedicated to posting letters of thanks to the man who reinvented hope for a terminal disease. Meanwhile, with the help of Gleevec, Cassie’s stubborn leukemia was forced into remission this spring, but because long-term data on remission in Philadelphia-positive ALL is still lacking, in May she underwent a bone marrow transplant to eradicate any possible remaining pockets of hidden cancer. In June she was declared cancer-free for the first time, but after enduring all the pre-transplant radiation and chemotherapy, she suffered a profound lung injury and has been on life support for endless weeks now, struggling to stay alive while her lungs slowly heal over. The grave consequences of such invasive procedures like bone marrow transplant point to the importance of developing effective and well-tolerated drugs – drugs like Gleevec, Avastin, and Herceptin – that treat the disease while circumventing the heroic but costly interventions that modern medicine employs so commonly. Despite the ongoing struggle for Cassie’s life, for her mommy and daddy and the mesh of family and friends who love their young daughter, any price was worth the cost of Gleevec.
Posted by skylanda.