In Vivo: 医療用医薬品・医療機器産業の経営層向けニュース
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The US Veterans Administration is attracting more interest from drugmakers seeking to grow their foothold in the lucrative – but scientifically challenging – market for CNS disorders. The allure comes from VA’s strong analytics and data crunching capabilities as well as its investigatory and trial management expertise in high-profile areas like traumatic brain injury, post-traumatic stress and major depression.
The US Veteran's Administration has unrivaled scope in patient data drawn from 20 years of EMR on some 20 million VA patients and is a key partner in the federal government’s Precision Medicine Initiative. Access to these data is particularly valuable to biopharma.
Under new cabinet-level leadership, the VA – which has also just recruited a new chief research officer – is committed to finding new ways to partner with biopharma companies. But, like most of the federal bureaucracy, the devil is in the details.
In Vivo talks to both parties as well as a critical outside stakeholder – the President George W. Bush Institute – to identify logistical and procedural steps to build industry confidence around large-scale clinical projects targeted at major unmet medical needs, not only among the 21 million veterans but in the larger civilian population as well.
So what? As the competition heats up for external assets to fill parched new product pipelines, biopharma companies are being forced to look farther afield for new partners. Many are eyeing the VA, which operates a sizable drug and medtech R&D program in conjunction with the country’s largest provider of integrated patient care.
Biopharma’s inherent shortage of new product leads means that finding a good external research partner has become a strategic imperative. It’s a task made harder by the fact that the dance card of the best players in science is full. So, as the search for that “partner of choice” widens, In Vivo offers up a closer look at the R&D arm of the country’s largest single provider of integrated patient care: the US Veterans Administration (VA).
The time is certainly right. The Office of Research and Development (ORD) has a new chief, Rachel Ramoni, ScD, DMD, who arrived in January with a mandate from President Donald Trump’s choice for Secretary of Veterans Affairs, David Shulkin, MD, to raise ORD’s profile with innovative drugmakers and seek new ways to cooperate, in the best interest of not only veterans but for the wider benefit of the society to which those veterans belong.
With nearly a century of exposure to the health issues of a diverse cross section of the US population, the VA has in-house the attributes of what every commercial biopharma enterprise requires in a potential partner. The list includes basic research and therapeutic expertise in key areas of unmet medical need; extensive information assets, with more than two decades of EMR data covering the cumulative clinical experience of 20 million patients; and a fully networked set of field work capabilities ranging from the conduct of epidemiological and observational studies to management of complex, multicenter clinical trials. Such research is performed by the VA itself and in cooperation with other federal agencies, academic medicine and industry.
All told, ORD manages some 2,000 active projects at more than 100 sites across the country, part of a larger network of 168 regional hospitals and more than 1,000 outpatient clinics run by the Veterans Health Administration (VHA). And because researchers operate within the VHA’s own integrated system of patient care, it can boast of a capability that few other organizations of equivalent size possess: to study, evaluate and treat the course of a disease, from the bench right to the bedside. Nearly two-thirds of ORD researchers are also clinicians who treat patients, which means that scientific insights are tested daily in real-world settings.
Resources are substantial – and may increase under the new administration. ORD funding supports roughly 3,500 professionals across the country with an annual budget of $673 million appropriated by Congress. This figure is considerably enhanced by additional funding from federal and private grants awarded to ORD investigators, from the National Institutes of Health (NIH), US Department of Defense(DOD) and the Centers for Disease Control & Prevention, among others, as well as infrastructure support from VA medical centers, bringing total research spending to $1.8 billion.
Overall, the VA has emerged as an early favorite of a new president skeptical about the federal government bureaucracy. Nevertheless, one lasting point of contention for ORD is the difficulties expressed by biopharma companies in understanding the basics of how to do business with it – where is the relevant contact point for outsiders in a sprawling, decentralized organization? What procedural steps are required to do business with ORD on projects of mutual interest, and how can these interests best be identified? The basic problem, according to industry insiders, is a VA culture that historically tends to see biopharma companies not as innovators, but as vendors engaged in the business transaction of providing medicines as a covered benefit to the veteran population. Industry too shares this problem, due to the sensitivities that company managed market teams have in complicating their commercial relationship with VA formulary administrators, where government ethical and compliance challenges come to bear.
So what’s driving the optimism? Secretary Shulkin. As a past leader of the health care quality movement, his insistence on creating an internal culture of efficiency, accountability and responsiveness is a constant when industry is asked to assess the VA’s current potential as a research partner.
Taking her cue from Shulkin, Chief Research and Development Officer Ramoni says collaboration on research and science is one of her first priorities. “We recognize the importance of the consultative process for external partnerships – it needs to be streamlined,” she said in an interview with In Vivo. “By that I mean having a clear, established entry point that any biotech or pharmaceutical company can rely on when they want to work with us.” She also acknowledges that widening the circle of players on research is vital if Shulkin is to meet his objective to raise the standard on health care for veterans against all the negative publicity in recent years concerning the quality of that care.
It’s true that the VA has been slow to emphasize its productive links between veterans, medical research and public health. In a record that extends back to the middle of the last century, VA researchers have notched some notable innovation milestones, including development of the nicotine patch; working jointly with Merck & Co. Inc.to demonstrate the efficacy of its shingles vaccine, Zostovax; and conducting the first successful liver transplant. On the medtech front, ORD researchers are responsible for many of the decades-long advances on prosthetic limbs; ORD was also the driver behind the first implantable cardiac pacemaker. All told, its scientists and investigators have earned three Nobel prizes, seven Mary Lasker awards as well as compiled an extensive record of authorship in peer-reviewed professional journals.
Recently, VA research has emerged as the go-to source for the latest medical insights and evidence on traumatic brain injury; suicide treatment and prevention; and post- traumatic stress disorder (PTSD), which is itself becoming far more prevalent in the civilian population, at an estimated 3 million cases a year. Dr. Judith Bentkover, PhD, adjunct professor at Brown University’s Department of Health Services, Policy and Practice, confirmed this in a December 2015 peer review paper published in the Harvard Review of Psychiatry, which concluded that the VHA model of service delivery on PTSD “offers the best source for developing such capabilities outside the VHA, where a patient-centered research institute or work group devoted specifically to improving care for all PTSD patients is needed.”
It is estimated that as much as 30% of the 21 million US veterans suffer from some form of PTSD, where standard treatment like cognitive behavioral therapy and prolonged exposure therapy, while effective, are not sufficient for many patients. ORD’s partnership with the VA’s National Center for PTSD makes it the acknowledged global leader in research to manage and prevent PTSD, with seven VHA academic centers of excellence located across the country. Of particular interest to biopharma is the announcement in December 2016 of a new PTSD Psychopharmacology Initiative to work jointly with drug companies to identify and test promising candidate drugs to treat this condition.
As chief research and development officer, Ramoni sees her mandate as building on this dense science and clinical architecture to deliver better health outcomes for veterans. A graduate of the Harvard University School of Dental Medicine, Ramoni is also an epidemiologist and expert in bioinformatics, genomics and precision medicine. Prior to joining the VA, Ramoni founded and led from Harvard the Undiagnosed Diseases Network, which, with funding from NIH, coordinates efforts by independent clinical and research experts to identify rare, undiagnosed illnesses using advanced technologies. In addition, she was an early leader in government and private efforts to help health providers share information derived from EMR.
Ramoni’s background makes her a key player in no less than five of Secretary Shulkin’s top 10 priorities for 2017 (see box), covering (1) accountability; (4) infrastructure improvements in the administration of veteran’s health care; (6) coordination of activities with the Department of Defense, where health research is an ongoing focus; (7) interoperability of EMR systems; and (8) prevention of suicide, a political hot button for the VA, which is presently conducting the largest clinical trial ever to test the effectiveness of lithium for preventing suicide. Said Ramoni, “Today, under Secretary Shulkin, every part of the VA is accountable for results. In that regard we have an initiative underway to assess the quality of all the research we are funding, especially as it relates to the end product: what is done with the research we produce? How are we carrying it forward to yield a measurable improvement in veteran’s health? That’s why I am so interested in partnering with the biopharma industry. It widens our horizons around interventions that work in the clinic.”
Alliances with external stakeholders are also a way to de-risk the research process. “The desire to bring forward results that are positive for veterans makes us more conservative about where and how we engage on our own – even if we fail honorably, which is an inevitable fact of life in medicine, it still falls on us to think carefully on how to translate the results to clinical practice. Industry, with its greater tolerance for risk, can help us do that. Our ultimate goal is spreading good ideas more quickly throughout the research community, and thence to the patient,” Ramoni added.
This year, ORD is placing a big bet on precision medicine, where it has been an early leader. The VA Million Veteran Program (MVP), launched back in 2011, is the world’s largest storehouse of genetic health, lifestyle and military exposure data within a closed health care system. It predates former President Obama’s cross-agency Precision Medicine Initiative, and has a goal to understand how genes affect health by compiling blood samples, health and lifestyle questionnaires, and EMR data from the voluntary participation of one million veterans.
The program is a “living” entity, not just a collection of historical records, as participants’ health information is continuously updated through the EMR as well as through the survey record of lifestyle and behavior issues. “There are significant opportunities in population health, because of the access we have to this very accessible, defined group,” says David Atkins, MD, director of health services and development, ORD. “We are not just collecting biological specimens, but other things going on in people’s lives, too. This interaction between genes and the lifestyle environment is likely to power some highly useful observational studies to support better and more efficient spending within the VA health system overall.”
A precision medicine study launching in the 2017 fiscal year, called PRIME (Precision Medicine in Mental Health Care), will test the clinical value of pharmacogenomic testing in mental health. Says Atkins, “There are genetic tests on the market today that have some predictive value around the metabolism of certain SSRI drugs. The study could help clinicians in choosing a specific drug appropriate to the individual patient rather than working on the basis of trial and error, which is a common challenge with SSRI therapies.”
Late last year, MVP enrollment, distributed across 52 medical centers, passed the 500,000 mark. It is well on its way to reach the goal of a million participants by 2020. Some $30 million is allocated under the VA draft budget for FY 2017 to maintain the pace of enrollment. To expand the accessibility and range of the MVP data for use in research, ORD is in the final stages of creating a joint program with the Department of Energy (DoE) called MVP CHAMPION – Computational Health Analytics for Medical Precision to Improve Outcomes Now. CHAMPION will give researchers access to DoE’s advanced high-capacity computing networks to gain fresh insights from the MVP data pool. Prostate cancer has been proposed as the first target of this partnership.
Genetic sequencing with DNA information drawn from the samples is being applied to drive current and future research in a range of illnesses affecting the veteran population, including cancer, heart and kidney disease, and mental illnesses such as PTSD. VHA medical centers in San Diego and New Haven, CT, are using the platform to study possible genetic pathways to PTSD. The data should shed more light on the neurobiology behind PTSD, leading in turn to possible drug treatments involving behavior modification.
Another precision medicine initiative is the Applied Proteogenomics Organizational Learning and Outcomes consortium (APOLLO) partnership between ORD, the National Cancer Institute (NCI) and the DOD. It is the first federal system attempt to screen, on a routine basis, individual patient tumors for gene and protein information to define a customized plan of treatment. Data generated will also be applied to general clinical practice, including early detection of cancers, matching patients to clinical trials and the development of standard treatment guidelines. Launched last year, the project is focusing initially on patients with lung cancer at VHA and DOD medical centers.
“This is a partnership with real potential in giving clinicians the ability to find out which is the best drug to work for an individual patient,” Atkins told In Vivo. “Each of our three entities is contributing intellectual capital and technical services. The next step is figuring out how to fund the actual trials, and with whom – it could be an area of interest for the biopharma industry.”
In addition, ORD has inked a partnership with IBM Watson Health to use super-computing’s deep learning capacity to interpret the results of tumor sequencing to recommend therapies and help place the right human subjects in clinical trials.
In Vivo discussions with big pharma majors at a January 12 consultative meeting on partnering chaired by Secretary Shulkin with the President George W. Bush Institute revealed that a principal interest is the richness – the sheer heterogeneity – of all these data compiled by ORD. The industry perception is reinforced by Christopher Bever, MD, a neurologist and director, ORD biomedical and laboratory research, who noted, “The rap on VA research is that veterans don’t resemble the general civilian population. In fact, the opposite is true.” (See sidebar, "VA Research: Can The Military Help Score A Match With Industry?")
His point is that veterans are actually a bit ahead of the latter on the demographic and health status curve. Veterans tend to express the same conditions as the rest of the population. They are aging, ethnically diverse, suffer from chronic care co-morbidities and often have some mental health issues. Minorities are slightly more represented here than in the general population, while women constitute a small but fast-growing cohort – about 6% of the total. “Our data base is also more concentrated on sick patients rather than the healthy, who by and large don’t need to be studied except as a comparator. So we can draw attention to that veteran with high blood pressure who also suffers from diabetes along with mild anxiety or depression. In terms of trial recruitment, our pool of veterans has the most numbers and depth in the experience of disease, compared with other systems and sources.”
Finally, the VHA, as an integrated health network that follows the patient from first diagnosis to cure, is able to cover data gaps that often prevent researchers from drawing richer insights beyond a baseline conclusion. Says Atkins, “We own the clinical care of those patients; it’s full-profile longitudinally. Only Kaiser Permanente comes close to matching that. The major PBMs and insurers can’t, because of data churn due to the frequent turnover in covered lives. We see it as an appealing credential for us when external stakeholders evaluate a potential research partner.”
Clinical Trials Funded By The VA Office Of Research And Development Cooperative Studies Program
Given the high expectations the VA now attaches to its research agenda, ORD is officially off the fence when it comes to working with private industry – “it’s an unambiguous yes,” says ORD chief Ramoni. Nevertheless, potential industry partners must navigate a series of steps to formalize the arrangement and meet departmental compliance rules designed to protect veterans. A drug company comes to ORD with a proposal for a trial project, based on scientific contacts with ORD investigators who share an interest in finding something out. Discussions to identify commitments from each party on topics like protocol development then take place under sponsorship of ORD’s Cooperative Studies Program, (CSP), which then leads to negotiation of a formal Cooperative Research and Development Agreement (CRADA). If the project is financed from the ORD budget, then ORD is responsible for conducting an independent scientific peer review and managing the overall study. Funding is then provided to VA investigators managing the project; no money from a company changes hands.
If the CRADA involves a financial contribution by the industry partner, the company must work through a network of federally financed non-profit companies (NPC) that operate in ways similar to an independent foundation. The NPCs are located in proximity to clinical investigators at the major VHA medical centers. “In both cases, it’s an arms-length financing arrangement that limits the possibility of conflicts of interest,” says Bever.
ORD acknowledges that the onus is on biopharma companies to take the initiative in seeking out a partnering deal with the VA. In that regard, it’s often hard for executives to know where to start. Another issue is negotiation of a CRADA for industry-sponsored trials is typically required for each trial location, which in effect means drafting multiple CRADAs to support a single multicenter investigation. The National Association of VA Research and Education Foundations, the VA Non-Profit Office and the VA General Counsel, working with private industry, have developed model agreements for basic scientific research, data collection, material transfer, exclusive and non-exclusive licensing agreements, Phase-IV clinical trials, principal investigator initiated research and investigational device studies. “In effect, it’s a group of master CRADAs covering all elements of a project. Standardizing this approach will pay a large dividend in terms of speed and efficiency,” Ramoni told In Vivo. “It’s another of my priorities for 2017.”
Her message to In Vivo readers is that partnering with industry is done for the best of reasons: to get emerging treatments to the patient, as quickly as possible.
Another outreach project is building a publicly accessible database covering the activities of ORD’s in-house and contracted researchers and their specific areas of expertise. “The goal is if industry or another external stakeholder is looking for an investigator with clinical trial experience in MS, then you could check the database and quickly find someone to reach out to,” Atkins said. The database project has been contracted out but has encountered some technical glitches that ORD is trying to work out. The hope is this tool will also be ready sometime this year.
Atkins says an easy way for biopharma to assess the VA partnering landscape is to participate in ORD’s annual “Industry Day.” The most recent, held in September 2016, brought nearly a dozen biopharma companies together with ORD senior staff to present their views on PTSD and review the current state of play, with the aim to determine how company participation might advance the development of more effective treatments. The discussions, which included the participation of executives from Janssen Pharmaceuticals Inc., Otsuka America Inc. and Shire PLC, helped drive the decision to launch the PTSD Psychopharmacology Initiative to conduct studies on new drugs to help veterans in coping with the condition, using data from the MVP and other clinical information sources in the ORD network. (See sidebar,"Partnering With The VA: Otsuka’s Opt-In Agenda.")
The first step is crafting a series of protocols to help structure the research partnering. A RFP document was tabled on December 20, 2016, calling for applications to initiate and/or participate in clinical studies, from industry as well as qualified VA investigators. Reviews are now underway. The potential of the anesthetic drug esketamine, now being tested separately for treatment of suicidal behavior during major depressive episodes, for application against PTSD as well, is but one of many opportunities being considered. “This kind of drug-related research is a complement to the predictive tools we have developed separately, through big data applications, to identify veterans at highest risk of suicide. The tools are now being applied directly at the clinical level – another example of how we traverse the divide between research and practice,” Atkins said.
Overall, both the VA and many in industry are convinced the time is right for industry to reach out to the veteran community and its researchers to create new precedents in advancing mental health. The VA now has a high-profile in that it’s seen as one area where bipartisan cooperation around policy is still possible. Shulkin, a recognized independent innovator in quality care delivery and Trump’s only cabinet-level holdover from the Obama era, can work both sides of the aisle in Congress – a good credential for biopharma’s own efforts to keep R&D in medicine focused on the patient, not politics
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