Personalized medicine -- the ability to tailor therapies to patients' individual genetic characteristics -- has long been the holy grail of the life sciences industry. The effort has produced a string of recent successes, including a host of drugs targeted to people with specific genetic profiles, the European approval of the world's first gene therapy treatment, and a much-heralded leukemia treatment pioneered at Children's Hospital of Philadelphia (CHOP) that uses tweaked versions of patients' own cells to eliminate their cancer.
While these advances are certainly exciting for patients, they raise a host of ethical, legal and financial challenges that people
'We need to be skeptical' about the economics and viability of personalized medicine, says Ezekiel Emanuel, MD, PhD, MSc, former White House health advisor and Chair of the University of Pennsylvania's Department of Medical Ethics and Health Policy.
Genetic signature testing now generates $26 billion in annual revenues, says Locust Walk Partners' Managing Director Jay Mohr.
An 'annuity-like' payment plan may be used to sell his company's new $1 million-per-patient gene therapy drug, says uniQure CEO Jörn Aldag.
Decisions about gene therapy treatments 'should be taken on as a policy issue rather than an issue of private enterprise,' says University of Pennsylvania Professor of Medicine Jason Karlawish, MD.
Genetic testing is a double-edged sword in the way it can reveal unexpected information, says Reed Pyeritz, MD, PhD and Chief of the Division of Medical Genetics as the University of Pennsylvania's Perelman School of Medicine.
'When you test for things of familial origin, what you find affects the entire family, so you have to be very careful,' says co-founder of the Rare Genomics Institute Jimmy Lin, MD, PhD.
working in the field will need to address before personalized medicine is likely to succeed on a large scale.
Renaissance or hyperbole? The challenges are so great, contends Ezekiel Emanuel, that claims of a renaissance in medicine brought on by individualized approaches often seem hyperbolic. "Before we buy into this, we need to remember that almost every evaluation of what drives health care costs up points to new technologies," said Emanuel, who is Professor and Chair of Medical Ethics and Health Policy at the University of Pennsylvania's Perelman School of Medicine and a Senior Fellow at Penn's Leonard Davis Institute of Health Economics (LDI). "We need to be skeptical. We need to see the data before people buy into the idea that personalized medicine is going to produce cost savings and be so much better for the system."
Despite skepticism, recent advances have given proponents of personalized medicine reason to cheer. On December 7, CHOP announced that oncologists on its staff brought about a complete remission in a child with acute lymphoblastic leukemia by taking T cells from her immune system and genetically programming them to hunt down and kill cancerous cells. The therapy, called CART-19, was developed in conjunction with Penn scientists and licensed last August to drug giant Novartis, which is developing it for more widespread use.
$1 million per patient On November 2, Amsterdam-based uniQure B.V. received European approval for Glybera, a gene therapy treatment for a rare disease called lipoprotein lipase deficiency. Patients with the disease have errors in a gene that produces a protein for processing fat from food, so fat builds up dangerously in their bodies. Glybera, which is a one-time treatment, uses a virus to deliver into the body a functional gene, which produces the critical fat-processing protein. The per-patient cost for the treatment will reportedly be more than $1 million per patient.
In the U.S., 23 FDA-approved drugs -- mostly for treating cancer -- are being marketed with tests designed to identify "biomarkers," or genetic signatures indicating which patients are most likely to respond. "Those products now account for more than $26 billion in revenues on an annualized basis," notes Jay Mohr, who has worked in the personalized medicine field and is currently managing director of Locust Walk Partners, a life sciences consulting firm in Cambridge, Mass. "The opportunity is huge, and it's really where medicine is going."
Not really 'personalized'? According to Emanuel, a former White House health care advisor who was one of the architects of the Affordable Care Act, capitalizing on that opportunity won't be so simple. "Using genetics is just one more way of subdividing patients. It's not 'personalized' in that way. You still have a group of people who are going to be treated in the same way. And for some people, the treatment will work. For [others], it will not work."
He adds that the financial hurdles of personalized approaches may be insurmountable, disputing the argument from many health care industry experts that subdividing patients based on who is most likely to respond to a treatment is more cost effective than throwing random therapies at them until they find what works.
"You have to test it empirically to see whether there are savings," Emanuel said. "You have to look at the cost of a screening test over a large group of people. Then you need doctors to actually adhere to the test results. Then, when you identify a smaller group of patients to treat, the pivotal question is, how expensive is the new treatment? You need to add up what you're saving and what you're spending."
'Going to be very expensive' Furthermore, he notes, the financial challenge is complicated by the motivations of profit-making enterprises. "You're going to use the drug on ever fewer people, but then [companies] have to recoup the development costs and [see] corporate profits. The idea that this is going to be cheap is a myth. It's going to be very expensive."
Even the companies that are pioneering personalized treatments are grappling with the challenge of making sustainable businesses out of them. Jörn Aldag, CEO of uniQure, admits that it is hard to envision how a one-time gene therapy treatment for lipoprotein lipase deficiency -- which only affects about 3,000 patients worldwide -- could produce an ongoing revenue stream for his company. For that reason, uniQure's executives are working with a consulting group to consider a range of options, which include establishing an annuity-like payment plan that would provide the company with ongoing payments for each treatment, rather than one lump-sum payment. "It's complicated," Aldag said, "because you're asking someone to pay for something that's supposed to have a long-lasting effect, but how do you know up front that it will have that effect?"
Who owns genetic data? According to Mohr, who is also President of The Wharton School Health Care Management Alumni Association, there are some signs that players in personalized medicine are starting to work out viable business models. Mohr was one of the pioneers in the personalized medicine space, having served a decade ago as acting CEO of Cambridge-based Variagenics, which developed technology to sequence DNA from individual patients' tumors and use it to predict their response to certain therapies. Variagenics was acquired in 2003, and the company that resulted from a series of subsequent deals, called ARCA Biopharma, is no longer pursuing the cancer-sequencing technology, he said.
One of the challenges Variagenics faced -- and an ongoing issue in personalized medicine -- was figuring out the best way to compensate all the players involved in matching the right patients to the right therapies. In the early days of Variagenics, Mohr negotiated a deal with Novartis to explore the use of its genetically targeted cancer drug, Gleevec, in prostate cancer. "One of the challenges we had in the negotiation around that deal was determining whether our company should receive a portion of the revenues coming from sales of Gleevec in prostate cancer," he recalls. "In effect, our diagnostics and our biomarkers -- [which were] our intellectual property -- were going to be instrumental in predicting patients who would respond best to Gleevec. We thought we should be compensated for that." The ultimate terms of the deal were not disclosed. "If a company is doing the research to understand variations that predict whether a person responds to a particular drug or not, it should get compensated," Mohr argues. "That should be the proprietary domain of industry."
National policy rather than private enterprise Not everyone agrees. "How we invest as a society in the discovery of biomarkers that describe who's at greater or lesser risk [in terms of] responding to therapy should be taken on as a policy issue, rather than an issue of private enterprise," said Jason Karlawish, Professor of Medicine and a Senior Fellow at both the University of Pennsylvania's LDI and the Center for Bioethics.
Karlawish was one of the leading voices in the debate over a lawsuit brought against the Mayo Clinic earlier this year by Prometheus Laboratories, which patented a method of determining the correct dosage of a drug used to treat gastrointestinal disorders by measuring metabolites in patients' blood. When the Mayo Clinic developed a similar process, Prometheus sued for patent infringement. "Essentially, what Prometheus was doing was patenting a way of thinking -- not so much an invention," Karlawish said. "That, fundamentally, is not what patents are for."
The case made it all the way to the Supreme Court, which concurred with Karlawish. Justice Stephen Breyer ruled in March that allowing companies to patent tests based on naturally occurring phenomena in the body would be akin to allowing Newton to patent the law of gravity. The ruling generated ire from the Biotechnology Industry Association lobbying group and other industry players, who worried that limiting patentability would discourage companies from innovating in the field of personalized medicine.
But Karlawish worries the opposite might occur if patentability is granted too broadly in medicine. "If Prometheus had succeeded with the suit, Mayo's discovery and its application would never have made it out into medical practice," he said. "It may be good for business to have the ability to patent these discoveries, but it's not so clear to me it's good for science and public health."
Double-edged sword Despite concerns about patent litigation stifling innovation, the desire to match patients with therapies based on their genomic profiles has spurred a raft of entrepreneurship. For example, Switzerland-based MolecularHealth, backed by the founder of software giant SAP, is developing a technology platform that oncologists can use to pinpoint therapies for patients based on their genetic variants. And in September, a company called MyoKardia started up in San Francisco with the intention of developing drugs for patients with a type of cardiomyopathy that is caused by certain genetic mutations.
Reed Pyeritz, Professor of Medicine, Chief of the Division of Medical Genetics at the Perelman School and LDI Senior Fellow, believes that personalized medicine could be particularly useful for treating cardiac diseases, many of which have a genetic basis that's well defined. "To the extent that you can both prescribe the appropriate dose, as well as prescribe the appropriate drug, then you're going to be far ahead of the game," he said.
In fact, he notes, economic studies have shown the potential value of genetic screening in heart disease. Roughly one-third of patients with aortic disease, for example, have a particular genetic mutation, Pyeritz said. "That helps us manage that person, because it tells us whether they should have surgery sooner rather than later, or if they should be on a certain medication." Screening those patients' relatives can also be valuable. "If they don't have the mutation, they don't have to worry about it, whereas if they do, we know how to follow them. If you can eliminate half the relatives from needing to be screened with expensive imaging and so forth, that more than pays for the cost of the genetic testing in the family."
Family-wide genetic tests Pyeritz was a co-author of a June 2012 paper published in the journal Genetics in Medicine that he believes proves the value of genetic testing. The researchers took a group of 100 patients with a genetic vascular disease called hereditary hemorrhagic telangiectasia and compared the cost of routinely screening their relatives for signs and symptoms to the cost of running genetic tests on all at-risk relatives. They found that genetic testing saved more than $22,000 for a family with four relatives at risk. The total savings across the entire patient group, over the diagnostic lifetime, was more than $9 million.
Still, Pyeritz said, genetic testing presents a double-edged sword. Recent genomic advances have made it possible to scrutinize a person's genetic makeup in increasingly greater detail -- an exercise that may have unintended consequences. Pyeritz has looked in particular at microarray testing, a new technology that enables deep examination of chromosomes. "The microarray allows you to look for small gaps or duplications in a person's chromosomes," he said. "This has been a great tool for defining new syndromes. However, when you do these kinds of microarray analyses, you find all sorts of variations, and you don't know what they mean."
Then there's the problem of what some in the field of personalized medicine refer to as "incidentalnomas" -- genetic tests that uncover details about a person's disease risk that they might not have known otherwise. "Let's say you have a child with developmental delay, and you do this microarray analysis, and you find they have a deletion in a gene that causes Parkinson's disease in middle age," Pyeritz said. "Then you may test the parents and find that the 30-year-old mother has the same deletion. Yet this isn't why you did the test. Then you're stuck with this quandary of whether or not to report this [to the individuals you tested]."
Awkard issue of 'Incidental findings' Figuring out the best way to deal with incidental findings in genetic testing has become a priority in personalized medicine, said Jimmy Lin, Research Instructor of Genomics and Pathology Services at Washington University School of Medicine in St. Louis. Lin is the co-founder of the non-profit Rare Genomics Institute, which provides genomic sequencing and analysis services to families affected by rare and little-understood genetic diseases. "When you test for things of familial origin, what you find affects the entire family, so you have to be very careful," Lin said.
The Rare Genomics Institute puts all parents who apply for its services through a long and extensive consent process. "We ask them, 'If we find something that shows a pre-disposition to cancer, do you want to know? If we find a gene for a disease that's late onset and there is no treatment for it, do you want to know? If there's a disease that's late onset, and there may be something you can do now, do you want to know?'" Lin said. "Ultimately, it's an individual decision."
The bottom line, said Karlawish, is that many questions still need to be answered before the promise of personalized medicine can be reality. "As a society, we're going to need to start to think about the ethical, legal and social implications of this," he said. "Frankly, this is numbers-driven medicine, and there are a lot of for-profit and proprietary interests at hand in owning the numbers. It's a new model that presents novel challenges."
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Arlene Weintraub is a New York-based journalist specializing in life sciences and techology. A former senior health writer at BusinessWeek, she has also written for Knowledge@Wharton, USA Today, US News & World Report and other major media outlets.
