NEW YORK (GenomeWeb) – The field of personalized medicine has been suffering from a credibility problem. More than a decade after the completion of the Human Genome Project, some are disappointed at the limited number of new life-extending treatments that have resulted from the nearly $3 billion effort. The stewards of the HGP had overpromised what could be gleaned from the human biological blueprint, critics have said, wondering where all the cures are.
In cancer, where much of the treatment advances have occurred to date, researchers are awestruck by the molecular heterogeneity within the same tumor in the same person. Personalized cancer drugs that block specific molecular pathways that tumors use to thrive, appeared at first to melt away patients' tumors, but cancer cells almost always seem to find other ways to re-emerge.
Outside of cancer, the efforts to use genomic data to inform care for autoimmune diseases, cardiovascular conditions, and neurodegenerative illnesses have proven even trickier and are occurring far more slowly. And while genomic tools have pinpointed the causes of exceedingly rare and unsolved conditions, many families continue on their diagnostic odysseys, while others know the cause but lack treatments for their illnesses.
"The problem with personalized medicine right now is that there is not much meat to it," Hank Greely, a law professor at Stanford University, said at the Personalized Medicine World Conference recently in Mountain View, Calif. Greely has spent the past two decades tracking biomedical advances and mulling their legal and ethical impact. "There is not much good, proven, scientific, medical uses for what we're talking about as personalized or precision medicine," he reflected. "And yet, we … sell and we hype as if there is much more."
Shortly after Greely made these comments in California, he received a "cryptic" invitation to attend a meeting at the White House. At that gathering, President Barack Obama unveiled his Precision Medicine Initiative – a proposal aimed at advancing the field through better coordination of the tools, repositories, and knowhow that already exists within public, private, and academic groups.
Under this initiative, the NIH will build a voluntary national cohort of 1 million participants who can contribute a variety of information from their genes, metabolites, and lifestyles. This information will be available to the research community in the hopes that they can use it to advance new treatments. The President has requested $215 million for the project that will be divided amongst the NIH ($130 million), the National Cancer Institute ($70 million), the US Food and Drug Administration ($10 million), and the Office of the National Coordinator for Health Information Technology ($5 million).
Even before details were released, many journalists and opinion writers hyped the initiative and speculated about its makeup and potential impact.
The president pitched his own plan as a way to bolster innovation in the US and keep the country competitive with other nations. "Together, what's so exciting is that, we have the possibility of leading an entirely new era of medicine that makes sure new jobs and new industries and new life saving treatments for diseases are created right here in the US," he said in a speech webcast from the White House. Directed at those that doubt the extent of the HGP's impact on the economy, Obama cited data from an industry-sponsored report that found that every dollar invested in the HGP helped generate $141 in the economy.
Still, what's currently lacking from the bones of the initiative laid out by the White House is the meat. Supporters of personalized medicine and experts in the discipline are thrilled that the president has given a nod in their direction, but they are unsure what this initiative will ultimately look like after it is considered by Congress and the various government agencies start the hard work of figuring out how to execute the president's vision.
As such, it is worthwhile to take a critical look at the stated goals of the Precision Medicine Initiative, and ask if this is the right plan to truly kick start precision care in the country. How much support is truly there for the president's proposal? Are the right agencies being funded to spearhead the program? What are some potential pitfalls for such an ambitious project? And how will we know if the project was ultimately successful?
The right plan at the right time?
To truly glean disease insights from the human genome, what's needed are more sequenced genomes. At a press conference about the initiative, NIH Director Francis Collins suggested that although the cost of whole-genome sequencing has been falling – below $1,000 by some estimates, higher according to others – it is still not low enough for the government to commit to sequencing 1 million people.
So, as costs come down, the Precision Medicine Initiative will try to sequence as many genomes as possible, according to Collins, but in the mean time, also gather data from research projects that have already collected people's genetic information. Nature did an analysis a few years ago estimating that by the end of 2011, there would be approximately 9,000 genomes sequenced in North America and as many as 20,000 genomes sequenced by the Beijing Genomics Institute.
Today, there are many more academic and industry players with the capabilities to conduct whole-genome and exome sequencing, which makes it harder to pin down an estimate of the number of genomes sequenced today. Illumina, a leader in the genome sequencing business, announced last year that based on its customers, there are some 65,000 whole genomes sequenced globally. Based on the number of HiSeq X sequencing systems shipped last year, "we estimate there is additional capacity for hundreds of thousands of genomes to be sequenced each year," a company spokesperson said.
Recognizing that genomic information by itself isn't a panacea, the Precision Medicine Initiative isn't just focused on churning out genome sequences, but on making better use of already available capabilities and existing research cohorts. Genomic data needs to be considered in the context of other types of information, such as a person's family history, the environment they live in, and the way they live. Researchers need to gather this information on thousands of people and follow them for a long time to figure out how all these different factors together impact the diseases they develop or don't develop.
This is where the president's proposal, if executed the right way, might make a difference, said Amy Miller, executive VP of the Personalized Medicine Coalition, which represents the interests of groups focused on advancing molecularly-informed therapies. "A program designed and led by the government aiming to bring together different stakeholders that already have activities in this area could be very powerful," she told GenomeWeb. "There are a lot of organizations in the US … that might be willing to work together."
In announcing the initiative, government officials leading the project highlighted incorporating data from ongoing efforts such as a longitudinal genomics research study in which the US Department of Veterans Affairs is aiming to enroll one million veterans by 2017. According to the website for the Million Veterans Project, the VA has so far enrolled more than 345,000 veterans, and completed genotyping of 200,000 participants. The VA also has contracts with testing companies to sequence the exomes of a small subset of study participants.
The CancerLinQ effort already underway, spearheaded by the American Society of Clinical Oncology, may also be a fit for the "cancer knowledge network" that the NCI is charged with advancing under the present initiative. ASCO recently announced it would work with data analytics juggernaut SAP to launch the first version of a big data framework later this year that will enable doctors to capture and use real-world patient information from "millions of electronic health records."
The 1 million research cohort could also bring in data from ongoing projects such as Kaiser Permanente and the University of California, San Francisco's effort to gather EMRs, genetic information, and environmental data on 500,000 consenting health plan members. As of 2011, researchers had genotyped 100,000 members. The NIH's Electronic Medical Records and Genomics program – a project that is trying to use EMRs to pinpoint links between genomic information, diseases, and drug response – could be another key resource fueling the Precision Medicine Initiative.
Although the field of personalized medicine lacks large-scale coordination of the kind the Obama plan proposes to undertake, new precision therapies are coming to market. Last year, by the PMC's count, 20 percent of the new drugs approved by the FDA had a biomarker associated with them. "Personalized medicine is at a tipping point," said Miller, who attended the White House event announcing the initiative. "We know drug companies are using genome sequence information in drug discovery right now."
Genentech recently inked two deals, one with Google-backed 23andMe and another with genomics pioneer Craig Venter's latest venture Human Longevity. Through both of these deals, the firm is planning to gather whole-genome sequencing data on thousands of patients and use the information to inform understanding of diseases, as well as its drug development efforts. Pfizer has also netted genomics-focused partnerships with 23andMe, a company that boasts a cohort of 850,000 genotyped customers. Meanwhile, nearly all the top drug firms have molecular diagnostics and genomics expertise in house.
"There is a level of maturity in the field that might allow for this type of program, if indeed it is a coordination piece," Miller said.
The details that divide
In announcing his plan, the president appeared optimistic despite a difficult fiscal climate that he would have congressional support for the $215 million he is asking to launch the effort. "The time is right to unleash a new wave of advances … in precision medicine," he said. "This is how you know the moment is right … there is bipartisan support for the idea here in Washington."
Congress this week just began mulling the President's $4 trillion 2016 budget package. Although the amount requested for the Precision Medicine Initiate represents a sliver of a very large pie, congressional approval isn't guaranteed. Republicans, who now control the House and the Senate, continue to call for the repeal of the Affordable Care Act. In this climate, it's presumptuous to expect that any Obama Administration pet projects will sail through Congress.
According to industry insiders who spoke with GenomeWeb, the White House has been working on the Precision Medicine Initiative since last summer. It seems the idea came from Obama himself. That's not surprising since as a Senator he sponsored the “Genomics and Personalized Medicine Act of 2007," which wasn't ultimately enacted, but contained ideas that have resurfaced under the latest initiative. One proposal from that bill that hasn't been included in the initiative described a system for classifying genetic tests – regardless of whether it was a laboratory-developed test (LDT) or a diagnostic kit – into risk categories, establishing the level of regulatory review required for each category, and determining which agency should have oversight.
It's cool that each of them has realized that this is an important policy area, but I think the politics are going to be pretty intense.
For several years now, the life sciences industry has been at loggerheads about whether the FDA should oversee LDTs or if regulatory responsibilities should remain with the Centers for Medicare & Medicaid Services. Most in the lab industry say FDA oversight would hurt innovation and patients' access to necessary tests, while manufacturers of diagnostic kits and some pharmaceutical companies want a more uniform regulatory framework under the FDA. The debate has worked up to a fever pitch since the agency issued a draft outline of its regulatory plan for LDTs in October.
"Believe it or not, the LDT issues at the FDA are quite relevant to pharmacogenomics and lots of personalized medicines, so that needs to be sorted out sensibly," Russ Altman, director for the biomedical informatics training program at Stanford University, told GenomeWeb. Altman is a scientific advisor at Personalis, a company that provides DNA sequencing data and interpretation to researchers. Personalis performs its testing in a CLIA-certified lab.
Under the Precision Medicine Initiative, the $10 million in funding to the FDA is intended to enhance the "regulatory structure needed to advance innovation in precision medicine," specifically for next-generation sequencing tests. While the president's plan doesn't take on the LDT debate directly, some might view the Administration as tacitly supporting the FDA's controversial move to regulate LDTs. The guidance was held up at the Office of Management and Budget for some time, and industry insiders have said that the Administration timed its release (before the mid-term elections) to minimize partisan backlash for FDA's plan.
But the LDT regulatory controversy has attracted congressional attention, and there are personalized medicine-focused initiatives underway within the US House of Representatives and the US Senate. A few days before the president announced his plan, legislators in the House Energy & Commerce Committee released a 400-page draft legislation that included proposals for advancing innovative drugs and tests. Under that effort, members of Congress said they were also thinking about how to regulate genomic tests, specifically LDTs, and planned to issue legislation on the topic in the future.
"I think we can't ignore the fact that medical device regulation doesn't necessarily fit lab tests used to personalized care and that needs to be altered," PMC's Miller said. But since Congress is thinking about how to tackle some of the more divisive issues in the life sciences field, she hoped that the president's initiative and congressional efforts will "come together in a good way."
"The president’s initiative is consistent with the bipartisan legislative package already under development to promote precision medicine," Sheila Walcoff, CEO of the consulting group Goldbug Strategies and a former FDA and HHS senior official, told Genomeweb. "But it is unlikely that the appropriation process will produce funding exactly as proposed by the president since Congress will need to consider and carefully allocate scarce discretionary funds across the range of bipartisan objectives for these programs."
Ultimately, Congress may take a different approach toward LDT regulation and favor its own personalized medicine proposals, and this might temper legislators' willingness to back the Precision Medicine Initiative. "Republicans might hate the fact that this came from the president," said Robert Cook-Deegan, director of the Center for Genome Ethics, Law and Policy at Duke University. While the Precision Medicine Initiative might provide an opportunity for bipartisanship, he noted there is the chance that Congress might want to "get the credit" for affecting positive change in the personalized medicine space.
"I don't think anyone knows how this is going to play out," said Cook-Deegan. "It's cool that each of them has realized that this is an important policy area, but I think the politics are going to be pretty intense."
Among interested stakeholders, the Precision Medicine Initiative has raised a number of questions regarding its implementation. Given that the 1 million patient cohort is the centerpiece of the project, Stanford's Greely wondered how participants' consent will be procured, particularly since most of the volunteers will be brought in from different projects around the country.
The president has assured that protecting volunteers' privacy will be a top priority, and he invited legal experts and biomedical ethicists to the White House, such as Greely and Cook-Deegan, to underscore that point. "I hope NIH will take very seriously the president's language," Greely said. "My main concern is that a lot of people are going to be included in this research and they had no idea that they were going to be agreeing to be part of this. When you're stitching together older cohorts, I get nervous about that. [The NIH] needs to make sure that the rights, interests, wishes, concerns, fears and hopes of those million people are adequately respected and reflected in what's done."
Under the initiative, the ONC has $5 million to establish privacy requirements and facilitate data sharing across EMRs. Currently, many large healthcare providers use EMR systems from Epic. These Epic systems "turn out to be not so much a language but a language family," Greely said. "So, Kaiser Permanente's Epic, Stanford's Epic, and the Palo Alto Medical Clinic's Epic, they are all Indo European languages. One of them is English, one is Russian, and one is Greek."
Altman agreed that any amount of money to ONC to ensure interoperability standards between EMRs will be money well spent. Figuring out the technical barriers to storing genomic information is another must for Altman. In order to make the critical gene-disease associations, researchers need high-quality phenotypic data. At the moment, well-defined phenotypic data is precisely what's lacking from many genomics resources, so the planners of the initiative will also need to address this hurdle, Altman added.
"If this data is any way siloed and not available for research and discovery that would be hugely disappointing," Altman said, noting that the powers that be surely know all the details that need ironing out. Still, as a member of a committee that advises NIH's Collins, he said he will be raising these issues at the next meeting.
Greely would also liked to have seen the administration propose funds for studying why genomic testing, even when there is strong scientific evidence backing it, isn't paid for by payors, and as a result isn't used by doctors. Variations in genes that code for CYP450 enzymes, for example, have been well established in studies to impact the metabolism of numerous commonly prescribed drugs. Still, very few healthcare providers test for these markers before administering treatments. "Why hasn't this happened and how can we make it happen?" Greely asked.
Reimbursement is another challenging area in the personalized medicine field, but one that the Precision Medicine Initiative is silent on. Molecular diagnostic shops have long complained that reimbursement levels don’t capture the value that their tests add to healthcare, particularly when a test is required to figure out which patients should get a drug. Recently, some labs have even complained that Medicare reimbursement levels are too low to cover the cost of performing some molecular tests.
"I think a lot of other agencies are pretty important" when thinking about how to deliver on precision medicine research, Cook-Deegan said. "I think CMS is hugely important." In his view, however, Congress has deliberately starved the agency of funding to keep it from doing research. "It strikes me that you need to understand the system of healthcare delivery before you can make good policy decisions," he said.
Another agency not mentioned in the initiative is the CDC. "The CDC had a whole genomics program that is now a tiny shadow of its former self," Cook-Deegan said. "The future of precision medicine does involve a fair amount of public health."
CDC's Office of Public Health Genomics (OPHG) was established in 1997 to implement evidence-backed genomics interventions for preventing chronic and infectious diseases. In 2011, the CDC announced it was slashing funding for this program by 90 percent. Subsequently, a report issued by public health leaders in the country pointed out that while the government funds basic genomics research and some translational studies, there hasn't been enough investment in developing databases for tracking public health or investigating connections between genetics and environmental factors.
OPHG Director Muin Khoury wouldn't comment on the president's initiative, but said that his group has long emphasized that for precision medicine to be broadly implemented "a public health perspective is needed." Meanwhile, he pointed out that Congress has funded the Advanced Molecular Detection Initiative, which uses sequencing and bioinformatics tools to study the genomics of microbes and try to detect disease outbreaks faster. This program is critical in light of the Ebola crisis.
"We talk about precision medicine as if it's the end all for trying to figure out how to use genomic technologies," Khoury said. "But there is another angle to this, and that is how do we use those tools to track what's happening at the population level and predict outbreaks earlier."
Beyond the hype
The Precision Medicine Initiative is coming on the heels of the NIH's cancellation of the National Children's Study (NCS) – a project that had ambitions to study the long-term environmental and biological factors that impact the health of 100,000 children. The study, which the government launched in 2005 to much drumbeating, was cancelled in December after spending $1 billion. This has raised questions about the NIH's ability to lead large-scale, longitudinal studies and align the interests of disparate stakeholders.
The NIH is aware of the shadow the children's study has cast on its capabilities. "The NIH has an extensive, successful history of conducting and supporting cohort studies," NIH spokesperson Renate Myles told GenomeWeb. "The NCS is the exception and provides important lessons."
Myles pointed out key differences between the Precision Medicine Initiative and the NCS. For example, the infrastructure for the NCS had to be designed from scratch. "At the same time, planning for the NCS was ad hoc, rather than a priori, and that allowed it to change directions along the way," she said. "Because there was no clear agreement among scientists on what the NCS should do, it gradually grew to try to do too much." The lack of focus that contributed to the study's failure is avoidable for the President's initiative, Myles assured, "and we will apply these lessons learned as we develop the precision medicine cohort."
"Importantly, NCS was conceived well before computing and mobile health technologies were sufficiently developed," she continued. "The facilitating technologies made possible by advances over the past 15 years in basic research, including genomics, molecular biology, mobile health engineering, and bioinformatics is what makes now an opportune time to initiate an ambitious research endeavor like the Precision Medicine Initiative."
As researchers in the personalized medicine field await a more fleshed out plan, perhaps their biggest question is how those in charge of the project will measure success. A "research effort to revolutionize how we improve health and treat disease," sounds great, but how can we tell if the revolutionaries are winning?
Although Miller hasn't heard any metrics for success articulated yet, getting genomics information into EMRs would be a big win, she said. Before the initiative was announced, Greely noted at the meeting in California that the "pay off" for personalized medicine has always been about five years away, largely due to the fact that the science has been more complicated than initially thought. So, he is hoping the project will produce stronger gene-disease and gene-drug associations that have better evidence supporting their use in healthcare.
He recognized the irony that two days after he criticized the precision medicine field at the PMWC, he was invited to the White House for what is being upheld as one of the seminal moments for the field. Obama's mention of this initiative during his State of the Union Address is already being compared to President John F. Kennedy's 1962 speech in which he put forth the goal of sending an American on the moon within a decade. "The Precision Medicine Initiative is not going to decrease the hype," Greely said. "But I do think it has a decent chance of increasing the reality."