Part 2 of a two-part feature series. Read the first article here.
Back in 2007, when Lawrence Lesko was director of the FDA's Office of Clinical Pharmacology & Biopharmaceutics, he said, “We find more reasons not to proceed with personalized medicine than to proceed with it," summing up the sentiment toward the field at the time. Lesko, who led efforts at the FDA to update the labels of many drugs with pharmacogenetic information, was speaking at the Drug Information Association’s annual meeting, after a particularly discouraging discussion on the reimbursement prospects for genomic technologies.
Seven years later, there are certainly more personalized drugs on the market. In terms of the goal to make precision care mainstream, the field's most boast-worthy accomplishment has been in oncology where molecularly guided strategies – using those multi-gene panels that just a few years ago were thought too complex and expensive – have made their way into most large cancer research centers and are becoming a routine part of care. But there is a long way to go before these tools and strategies are commonplace in community hospital settings and at local physicians' practices where more than 80 percent of cancer patients in the US receive their treatment.
The scientific complexities that seem to deter pharmaceutical firms from investing more readily in the field only increase when one starts looking at diseases outside of cancer. Then, factoring in the difficult regulatory and reimbursement environments, the reasons for not pursuing personalized drug development seem only to have grown since 2007.
The 'forgotten stakeholder'
As far as complexity goes, things can get pretty dicey in the personalized medicine space amid evolving regulations.
The FDA has made clear that tests intended to help doctors decide whether or not to prescribe a particular drug to a patient need to be reviewed by the agency. However, after years of debate with drugmakers, laboratories, and diagnostics firms – each group holding a different view on whether lab-developed tests created and performed at a single lab should require the agency's oversight just as diagnostic kits performed at many labs are – the agency has yet to release a formal plan in this regard. As long as the agency's guidelines on LDTs reportedly remain on hold at the executive branch, FDA-greenlighted predictive tests will continue to exist alongside LDTs that gauge the same drug response markers but don't have the agency's blessing. Against this backdrop, drug developers have been reluctant to openly back the use of LDTs that can not only determine which patients will respond to their drugs, but also so-called complementary tests that can diagnose or gauge the aggressiveness of diseases, as well.
In order for the personalized medicine field to advance, the one-drug-one-biomarker-one-test model that has largely been deployed will have to give way to increasingly complex technologies (ie. multi-gene panels and next-generation sequencing) that are often performed as LDTs. No doubt, in particularly challenging areas of drug development, for example, in clinical trials investigating PARP inhibitors or DNA-damaging agents, firms such as Clovis Oncology, BioMarin, and PharmaMar are starting to use NGS technologies beyond the biomarker discovery phase, as companion diagnostic panels that will identify best responders to their drugs. Meanwhile, as payors become increasingly focused on reducing healthcare costs, it's conceivable that complementary tests that, for example, assess when a patient requires more or less treatment, will become a critical part of a patient's treatment paradigm. And this in turn, has implications for the drugs they might receive.
The unanswered questions around FDA's oversight of LDTs gives many drugmakers pause about using, or even publicly talk about using these types of tests more broadly in drug development programs. "I think in any business with regulators, whether its pharma or banking, or anything else, when the rulebook is not incredibly clear, that increases your risk. And businesses don't like risk," J&J's Mark Curran told PGx Reporter of the regulatory uncertainties in the personalized medicine space. J&J last year launched a project to sequence the genomes of 450 rheumatoid arthritis patients who were involved in a clinical trial of its drug Simponi (golimumab), aiming to discover genes that correlate with disease predisposition, as well as new drug targets. For this project the company is outsourcing the sequencing to BGI, but J&J does internally use various sequencing platforms to validate external findings.
"We have investments to make and we have to make choices,” said Curran, VP of systems pharmacology and biomarkers in the immunology therapeutics area at J&J's Janssen Pharmaceuticals. “We want to make sure that we first do what's right for patients and then that we get a return on the investment, [and] that we're actually able to launch and tell people about these wonderful new products when they come to be."
After having followed FDA's advice, when it comes time to launch a personalized therapy alongside its FDA approved companion test kit, drugmakers run into the problem of having to convince labs that may already be running their own LDTs to adopt the kit. Some labs have been performing their own internally developed genetic tests for years, and integrating a new kit impacts workflow and costs.
Pharma companies have done a poor job educating and incentivizing labs that run these companion kits, believes Peter Keeling, CEO of personalized medicine-focused consulting firm Diaceutics. "The laboratory is the forgotten stakeholder," he said. "We were doing some work around BCR-ABL testing in Europe, and the general mood of the laboratories is that they are angry. They are angry that they're being asked to run these tests without a lot of help on where they will be used and with sorting out reimbursement. They're having to do that themselves."
Through a division called Labceutics, Keeling and his colleagues are trying to increase adoption of personalized medicine by facilitating the broad availability of companion tests across the 14,000 labs in the EU that operate in a decentralized fashion. An example of the kind of work Labceutics does is the project it launched last year with Asuragen to track how variable BCR-ABL testing is across European labs. One of the key takeaways of that survey was that despite the availability of BCR-ABL test kits, the surveyed labs usually default to an LDT.
BCR-ABL testing is more a complementary, rather than a companion, diagnostic. By periodically testing BCR-ABL transcript levels doctors can track if a chronic myeloid leukemia patient is relapsing or maintaining remission, key determinations that influence treatment strategy. Asuragen and Gleevec sponsor Novartis inked an exclusive agreement in 2010 to develop calibrators and laboratory software reporting tools, which they hoped would help labs standardize BCR-ABL testing.
Even if drugmakers are reluctant to invest in an LDT from a companion diagnostic standpoint, Keeling recommends to his pharma clients that they partner with labs to standardize methods for sample collection and complementary testing. He is planning to launch a Labceutics network in the US as well, where drug developers have similarly struggled to convince hospital labs to adopt an FDA-approved kit over their own LDTs. An example of this was when Roche launched its personalized melanoma drug Zelboraf (vemurafenib) with a companion kit that picked out best responders with BRAF-mutated tumors.
Industry players are hoping that long-awaited LDT regulations from the FDA will help smooth many of these tensions in the field. When the agency released a final guidance on marketing research-use/investigational-use only IVD products however, it didn't necessarily align the views of disparate players in the personalized medicine space – the entities that were always against greater FDA regulation maintained their opposition – but at least there is now less doubt about the agency's expectations and regulatory intentions, which is some progress.
Additionally, the FDA recently cleared the first next-generation sequencing platform, Illumina's MiSeqDx, and many in the industry believe this provides a framework for other NGS-based tests to go through regulatory approval or clearance. With this clearance, the agency said it hoped that labs previously using Illumina's MiSeq research-use platform to develop internal lab tests, would now run their LDTs on the FDA-cleared platform. At least one drug developer so far, Amgen, has announced it would develop a companion test using MiSeqDx for its pharmacogenetically targeted colorectal cancer drug Vectibix.
"There is a misunderstanding that it has to be either a lab-developed test, or an FDA-approved kit. It's not a this or that," Lakshman Ramamurthy, director of FDA Regulatory & Policy at healthcare strategic advisory firm Avalere Health told PGx Reporter. "Drug companies are hamstrung by the fact that in order to seek a companion testing claim they have to come to the altar holding somebody's hand," said Ramamurthy, formerly a senior reviewer and policy advisor at FDA's diagnostics division. "Is a clinical laboratory willing to do that? Some labs may be willing to but don't forget, many labs cannot pursue that path from a financial standpoint."
Earlier this year, the cost of sequencing a whole-genome purportedly went down to under $1,000, crossing that magic threshold that was supposed to make it possible for more well-off people, if not the everyman, to get tested. Illumina claims that its HiSeq X Ten, a set of 10 sequencers, can produce 18,000 human genomes per year. It cost $3 billion to sequence the first human genome, and the below $1,000 price point to sequence a genome using the HiSeq X Ten is widely believed to be the tipping point for advancing personalized medicine.
Proponents of precision medicine say so often that the incorporation of biomarkers and genomic technologies will lower the cost of drug development that it has become conventional wisdom. Just as often, one hears that the price tag for bringing a new drug to market is $1 billion. Despite the plummeting cost of whole-genome sequencing, that number hasn't come down. A new Forbes report estimated the cost of developing a drug at $5 billion for large companies that have launched multiple therapies, but in the process, have also had a number of molecules fail in clinical trials.
Whether broad incorporation of molecularly guided strategies ultimately lowers the number late-stage therapeutic failures and lowers development costs, remains to be seen. For the time being, as pharma companies figure out how best to commercialize their drugs alongside companion tests, they are encountering costs they hadn't accounted for. Keeling has encountered many a pharma executive with "sticker shock" when they realize that it will cost $50 million to market the companion test alongside the drug across 10 of the most lucrative markets.
"In order to drive a diagnostic to peak sales, you need to spend money to get the diagnostic installed into laboratories. That's a couple of million dollars. Then, you need to spend money trying to get reimbursement. That's about $10 million right there," Keeling said. "You maybe need to put in an independent sales and marketing team behind the diagnostic to make sure there is sufficient communication about it with healthcare providers … And very quickly you add up to a bill, in our estimation, that's about $50 million." Then, if a drugmaker is daring enough to throw in next-generation sequencing or even whole-genome sequencing into that mix, that increases the risks as well as the cost. For example, customers interested in accessing the $1,000 genome through Illumina will pay $10 million for the HiSeq X Ten sequencers and this doesn't include overhead or data analysis costs.
The drugmaker's financial agreement with the diagnostic firm for developing the test can vary widely, between $1 million to $30 million in fees, depending on whether the terms cover development of one test or a long-term partnership for a range of projects. A large genetic testing program like the one Merck and MDxHealth undertook for the glioblastoma drug cilengitide – where approximately 5,000 patients were screened and 3,500 patients were tested for methylated MGMT – can cost between $1 million and $5 million, according to MDxHealth Chief Scientific Officer Wim Van Criekinge. Merck paying for developing the companion test shielded MDxHealth from having to take a financial hit when Merck's cilengitide trial failed in newly diagnosed glioblastoma patients. MDxHealth's 2013 revenues were $7.6 million, compared to Merck's $44 billion.
Given the low margins of the diagnostics business, labs and test makers can't share in the financial risks of drug development, and so, they also don't get a share of the drug profits, which is where the big money is. "I will be dead and in my grave before that happens," Keeling said. "The concept that a diagnostic company will take a royalty out of a drug is never going to happen." However, it is more plausible, he offered, that as large shops like Abbott, Qiagen, and Illumina enter the clinical diagnostics realm, they may absorb some of the risks of launching a drug/test combination product, and in doing so, they can at least expect larger milestone payments from pharma.
What drugmakers have to pay to develop and commercialize a companion test seems a paltry figure when compared to what pharma is spending on the drug. Nonetheless, if drugmakers are already reluctant to cut into the market for a therapy using a molecular test, then an unanticipated bill for $50 million is enough of a deterrent for investing in the strategy. "To say to a therapy team that's already uncertain about the complexities of the diagnostic, 'Oh by the way, not only is the test complex, but we're going to suck $50 million out of your drug budget over the next three years, and we're going to devote it to the diagnostic,' this requires a mindset leap for the pharma team," Keeling said.
The outlook gets even more grim once reimbursement comes into play. In the US, labs complain about low payments for their tests from Medicare and private payors. For example, Medicare reimbursement can be as low as $200 for KRAS testing to gauge best responders for drugs like Erbitux (cetuximab), costing around $10,000 per month. Outside of the US, however, getting any payment for companion testing can be a struggle.
In some geographies, pharma companies are footing the bill for testing during the first year or more after a drug launch to ensure access to the treatment. Pfizer had to pay for CCR5 tropism testing in certain European countries for its HIV drug Selzentry (maraviroc), which works by blocking the CCR5 receptors on immune cells to keep the virus from entering. Before getting the drug, patients need to have a test to confirm whether the virus is binding to the CCR5 receptor to enter cells.
In Canada's publicly funded healthcare system, EGFR mutation testing was only available through research labs before 2010. AstraZeneca had to reimburse labs for EGFR testing for a year in order to ensure that NSCLC patients with these mutations who are likely to respond to its drug Iressa (gefitinib), would have access to it. According to one study led by Peter Ellis of McMaster University and published last year in the Journal of Thoracic Oncology, while AZ was reimbursing labs for EGFR testing, between 200 and 250 tests were performed monthly. For six months after AZ's reimbursements to labs stopped, the number of monthly tests ordered dropped to between 50 and 120.
The problem, according to Keeling, is that most insurers in the US and elsewhere aren't used to paying for newly launched diagnostics, because to show that a test has clinical value – that testing improves patient outcomes – takes many years of follow up. After a drug is launched, however, pharmaceutical firms are on hyperdrive to make a return on investment during their period of exclusivity. "What pharma needs is to make money in the first four or five years a drug is on the market," he said. "They can't wait for the diagnostic access, and so they have to step in in the short term." Keeling advises clients that while they might have to pay for testing in the short term, they should "have an exit strategy" by doing the necessary health economic studies to prove the value of the companion diagnostic.
But even the most rigorously conducted economic studies present difficult choices for payors. In the British Journal of Cancer two years ago, University of Colorado researchers Adam Atherly and Ross Camidge modeled the health economics of administering Pfizer's NSCLC drug Xalkori (crizotinib) to patients whose tumors are ALK mutation positive. Based on an estimated price of $1,400 for ALK testing – considered way too high by some critics of the study – the researchers calculated that testing all advanced NSCLC patients in order to identify the 5 percent of ALK-positive individuals who should be treated with Xalkori did not meet a cost-effectiveness bar of less than $100,000 per quality-adjusted life year gained. According to Atherly and Camidge's analysis, if doctors used enrichment strategies to test patients with certain clinical features that would make them more likely to harbor ALK mutations, that would improve the cost-benefit proposition. But this would also miss patients who could benefit from Xalkori treatment.
According to Doug Ward, VP of companion diagnostics at Roche's diagnostic subsidiary Ventana Medical Systems, depending on pharmaceutical companies to pay for companion testing is not a sustainable model for personalized medicine and it's high time decision makers came together to discuss what's worth paying for in healthcare. "We all have to reduce national healthcare spend globally … but also [we have to] make sure those approaches that are helping patients the most are funded properly," Ward said. "In the end, we believe that … [a] test that identifies patients who truly will benefit from or those that should not get the drug due to safety issues, actually improves the economics of delivering cancer therapeutics into the market. So, there needs to be an approach adopted globally to make sure that diagnostics are properly paid for."
The good news is …
Despite these compounding pressures, or perhaps driven by them – the high rate of attrition, the runaway development costs, the increasingly complex technologies bringing forth unprecedented amounts of data to sift through, the uncertain regulations and the unanticipated reimbursement hurdles – pharma companies are pursuing personalized drug development. Maybe not as fast as some would like, but the field is progressing, and it is undeniable that pharma is trying.
In the realm of complex, common diseases, where molecularly-guided strategies have yet to make their mark, Roche subsidiary Genentech recently reported positive data from a Phase IIb study of the investigational asthma drug lebrikizumab. In the trial, lebrikizumab reduced asthma attacks by 60 percent in patients with high levels of the biomarker periostin compared to 5 percent in patients with low levels of the marker.
Lebrikizumab blocks a cytokine, called interleukin-13 (IL-13), which has been shown in studies to be involved in inflaming the airway passages in asthma patients. But IL-13 is present at such low levels in peripheral blood that it is undetectable even by highly sensitive assays. IL-13 induces the expression of periostin in the lung. The protein can be readily measured in blood and may represent a surrogate marker for the activity of IL-13 in asthmatic patients. In investigating personalized approaches to treat asthma, Genentech researchers and collaborators at the University of California, San Francisco, considered a number of hypothesized blood biomarkers related to the IL-13 pathway, before they settled on looking at periostin levels in patients enrolled in a Phase II lebrikizumab trial.
“This hypothesis that periostin is the best surrogate marker in the blood to measure IL-13 activity in the lung has been around for six or seven years within the company,” said Greg Spaniolo, lifecycle leader at Genentech. “That's incredibly important for internal decision making, to have that prespecified hypothesis,” he continued. “One of the greatest challenges drug development teams have here when they are trying to develop personalized therapies is knowing how much confidence they should have in a finding. We always feel differently about findings [in studies] when they match our prespecified beliefs and hypotheses.”
One positive turn that Avalere's Ramamurthy has seen is that some drug companies are now voluntarily choosing personalized medicine approaches in a smaller subset of patients who experience a robust treatment effect, over pursuing the therapy that's only incrementally better than another marketed drug in a larger, molecularly undifferentiated patient group. "Among big pharma there are those that are coming to this kicking and screaming versus those that are coming to this field as an opportunity to make targeted, effective medicine. There are some companies using personalized medicine to rescue failed or failing compounds … but others are not satisfied with that," he noted.
Ramamurthy has found that some drug makers are willing to forgo pursing a drug that might work fine in 70 percent of the population. Instead, "they are willing to get a claim in a smaller population, in say, 20 or 35 percent of the population, because they see a much bigger response rate in that population," he said.
In the Phase II trial, lebrikizumab was efficacious in the overall, molecularly undifferentiated asthma population. At 12 weeks, lebrikizumab-treated patients had a statistically significant (5 percent) increase in lung function from baseline compared to placebo-treated patients. Regardless, noting that in this study those with high periostin levels had an even greater increase in lung function (8 percent) compared to those on placebo, Genentech moved to advance the drug in this subgroup of asthma patients. It is estimated that approximately 15 million people have severe asthma. According to Genentech, half of those with severe, uncontrolled asthma have high levels of periostin.
Among drug developers, Roche has been the most vocal in terms of its goal to make personalized therapies a large part of its business. CEO Severin Schwan famously said a few years ago that 60 percent of drugs in the firm's pipeline are being advanced with a companion test in order to make them more effective. But along with its precision medicine success stories – Herceptin (trastuzumab), Perjeta (pertuzumab), Kadcyla (ado-trastuzumab emtansine), Zelboraf, and Tarceva (erlotinib) – there have been some disappointments, as well. For example, the anti-angiogenic drug Avastin (bevacizumab) has proven a particularly hard nut to crack in this regard, and despite searching, Genentech hasn't uncovered predictive markers for the agent in breast or brain cancer patients.
Healthcare stakeholders across industry, academia, and government have never been good at sharing their lessons from failed projects. Perhaps spurred by the complexity that genomic data has introduced to the drug development process, life sciences players seem more willing to share data in public databases and engage in collaborative learning projects. For example, instead of giving up and tossing the program, even though Avastin failed to show a survival advantage in newly diagnosed glioblastoma patients, Genentech researchers have agreed to share data with independent investigators to try to learn more about the effect of the agent in these patients with limited treatment options.
Collaborative efforts like this and the NIH's Clinical Genome Resource (ClinGen) will be key to improving collective understanding within the life sciences field of the relationships between genomics and diseases, particularly since greater use of advanced sequencing technologies is revealing increasingly rare variants with uncertain links to disease. By launching ClinGen, the NIH is hoping to build a public, annotated database of variants across the human genome using standardized classification methods. The database, which is supported by $25 million in NIH funding, currently lists nearly 80,000 submissions on more than 18,000 genes.
Well-anotated, public databases can also fuel molecularly targeted drug development in the way that Eric Lai, head of pharmacogenomics at Takeda Pharmaceuticals, has proposed (see details in first part of this two-part feature). The Multiple Myeloma Research Foundation launched the CoMMpass trial last year in which researchers plan to collect detailed clinical and genomic data from 1,000 patients over a five-year period after initial diagnosis. The information collected in this trial will be stored in a database that will be accessible to drug industry partners and the research community in the hopes of accelerating development of multiple myeloma treatments.
Pharmaceutical firms are also working toward solutions to tackle reimbursement issues limiting access to molecular testing. In partnership with the French National Cancer Institute, Pfizer is participating in a program that aims to test melanoma, lung, and colorectal cancer patients routinely for eight biomarkers associated with these diseases and predict their ability to respond to various therapies. Under this initiative, all NSCLC adenocarcinoma patients will be tested for ALK mutations – around 10,000 patients per year – to determine their eligibility to receive Pfizer's ALK inhibitor Xalkori. Similarly, in the UK, Pfizer and AstraZeneca are involved in the £5.5 million ($9.2 million) Stratified Medicine Program, which has taken on the challenge of figuring out how to disseminate molecular testing to patients within the National Health Service.
These efforts in France and the UK to perform centralized multi-gene panel testing highlights the fact that as more therapies are molecularly targeted, pharma companies will not only be competing for patients but for tissue they can analyze for markers in their drug trials. Particularly for diseases like lung cancer, where administration of the targeted agent depends on molecular analysis of the tumor tissue, there is often not enough tissue to conduct multiple single-gene tests in search of the right drug. As such, the one-drug-one-test model currently prevalent in the personalized medicine space will eventually have to give way to panel testing.
“Lung cancer is a heavily molecularly segmented disease, whereby some of the molecular segments are rare and found at a frequency of only 1 percent. In these instances, even if there is a drug that targets that segment of the population, it is difficult to screen and identify patients eligible for that treatment,” said Anne-Marie Martin, who leads GSK's molecular medicine unit, as well as the firm's precision medicine and diagnostics team in oncology. “It is becoming apparent that the marketplace is not going to be able to support five or six different FDA approved assays for the same biomarker, particularly when they're not going to be used for the most part by the majority of labs because labs tend to use their own laboratory-developed tests.”
One of the projects investigating the use of a comprehensive genomic testing platform is the Lung Cancer Master Protocol. Friends of Cancer Research and multiple drug partners will use a next-generation sequencing panel from Foundation Medicine to stratify squamous cell lung cancer patients into various therapeutic arms in the Phase II/III study.
“I think there is willingness on the part of the FDA and those of us who are living and breathing the development of precision medicines, to find a way to advance the development of companion diagnostics that incorporates the use of next-generation sequencing technologies,” said Martin, who was part of the GSK team that developed two new personalized melanoma drugs, Mekinist (trametinib) and Tafinlar (dabrafenib).
There is even the rare example now when a drug company, without any financial incentive or even any personalized drug products in its pipeline, has funded a genotyping effort to advance knowledge and research about a disease. Biogen Idec is footing the bill for 5,000 hemophilia patients to get free genetic testing that will better characterize their disease. Meanwhile, the National Hemophilia Foundation and other groups are storing the de-identified genotype and phenotype information in a repository to support research to improve understanding of this genetic disorder that impacts between 18,000 and 20,000 people in the US.
The willingness to back this project came from Glenn Pierce, chief medical officer of Biogen Idec's hemophilia subsidiary, who was born with the disease and has long advocated improving genetic testing access for patients. In the US, largely due limited insurance coverage, approximately 20 percent of hemophilia patients get genotyped, which can cost between $500 and $3,000 depending on the testing technology used. In the early 2000s, when Pierce was president of the National Hemophilia Foundation but before the first human genome was sequenced, he attempted to push through as part of an appropriations bill language that would have provided funding to genotype hemophilia patients.
“Although it wouldn't have been that much money, it still was more than could be managed in terms of a line item,” he recalled. So, when he came to Biogen Idec, he spearheaded this genotyping project, with his employer's full support. “In the greater scheme of things, this is not that expensive of a program to fund,” Pierce said. “When you're looking at an orphan disease, one that's as rare as hemophilia, individual treatment centers can't do it. Even a consortia of five or 10 centers don't have the ability to fund it. So, it just seems like the right thing to do.”
Hemophilia is a bleeding disorder that occurs in patients with mutations in either the F8 or F9 genes that lead to a deficiency of the blood-clotting proteins Factor VIII and Factor IX, respectively. Changes in the F8 gene are responsible for hemophilia A, while mutations in the F9 gene cause hemophilia B. By collecting genotype-phenotype information in this database, the collaborators are hoping to advance knowledge about this rare illness – around 1 in 5,000 males are born with hemophilia A, and 1 in 25,000 men are born with hemophilia B. Researchers want to figure out, for example, why two patients with the same genotype have different responses to the clotting factor concentrate they're treated with – one developing antibodies against it and the other responding well. Why do two patients with the same genotypic defect have different bleeding rates? Or why two patients with the same genotype and the same bleeding rate have varying levels of joint damage?
These unexplained phenotypic differences among hemophilia patients will be critical to answer before drug developers can even begin to think about advancing personalized drugs for the disease. In fact, while Biogen Idec is a leader in developing hemophilia treatments, there is no investigational agent in the company's pipeline that can immediately benefit from the data being collected in this repository. But Pierce hopes that this resource can begin to move the field closer to the personalized medicine era.
“The idea behind this wasn't to develop a system that only we would have access to, so that five or 10 years down the road, we would get some advantage. That would be doing a huge disservice to the community,” he said. A future where every person's molecular information is a key part of his or her care may still be many years away. Yet, the type of investment Biogen Idec is making, be it in a rare disease and precompetitive setting, signals that industry is preparing for that future, whenever it comes.
Investing in a database of this kind “requires some long-term vision for where a therapeutic area is going to be in five years, 10 years, or even 15 years,” Pierce said. “It's conceivable looking at this bank of samples that five, 10 years down the road, one may be able to ... identify individuals who are at very high risk for one complication or another. And once you've done that, then you have the ability think about … personalized medicine.”