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Wednesday, June 24, 2020

Little chance of proving Covid-19 vaccine effectiveness in UK, says trial leader

Low transmission rates in the UK mean there is “little chance” of trials in the country proving the effectiveness of a coronavirus vaccine, a scientist leading a UK trial has said.
Professor Sarah Gilbert, who is leading the University of Oxford vaccine trial, said that when Covid-19 transmission was high, lockdown was imposed to bring the rate down.
Rates have since dropped, but a sufficient number of volunteers have to be exposed to the virus to see whether a vaccine protects them or not.
However, if their chances of being in contact with an infected person are low, it will take a long time to demonstrate the efficacy of a vaccine candidate.
Prof Gilbert told the House of Lords Science and Technology committee: “Of course, what happened was that because it [transmission] actually increased much more rapidly than anybody thought was going to happen, we had the lockdown, which fortunately reduced transmission.
“Not so fortunate for those of us trying to develop vaccines in the UK, because we now have essentially a very large safety immunogenicity study, running in the UK with little chance, frankly, of determining efficacy.”
She added that the researchers’ approach was to work with multiple different countries in different settings to give them the best chance of seeing efficacy in at least one of those countries.
The committee heard the Oxford team is already running a trial in Brazil because the numbers of transmissions are much higher than in the UK.
“As soon as we get a signal of efficacy and can compare that to the level of immunity that we’re generating, that gives all vaccine developers really helpful information to let them know whether their vaccines are likely to work as well, and whether it will be one dose or two doses, and in older people and in younger people,” she said.
“So the first efficacy signal is going to be really important and as yet we don’t know which country will be generating that.”
Prof Gilbert and Professor Robin Shattock, who is leading the Imperial College London trial, said they were optimistic about their vaccine approaches but cautioned that optimism should be balanced against known risk of success.
Prof Shattock said vaccine success rates “tend to be at about 10% once you start clinical testing”, but added: “I think in the UK we are very lucky that we have two [vaccine] candidates that are already in clinical evaluation.
“We think that probably both of those will work individually
“We also have the opportunity to have a look at them in combination which I probably think nobody else currently globally is thinking about.”
Prof Gilbert agreed with Prof Shattock saying that, if necessary, “we can combine the vaccine to get something that works even better”.
She added: “The aim is to protect the population and that doesn’t mean the vaccination has to be 100% effective – even with a 50% efficacy, we could actually go a long way to protect the population.”

Alternative Payment Models—Victims of Their Own Success?

The US health care system requires major changes to make health care more affordable and higher quality. In the decade since passage of the Patient Protection and Affordable Care Act (ACA), alternative payment models have become central to this effort. These models are designed to replace existing fee-for-service payments with a reimbursement structure that provides incentive for high-quality and cost-effective care—so-called value-based care. The Centers for Medicare & Medicaid Services has introduced several alternative payment models, each with a particular focus, such as Comprehensive Primary Care Plus for primary care and the oncology care model for patients with cancer.
Whether the shift to alternative payment models has been a success or failure is a matter of intense debate with substantial implications for future policy directions. Yet there is a paradox. Individual demonstration projects have not reported significant success. However, overall health care spending as a share of gross domestic product (GDP) has plateaued at just less than 18%, below the 20% predicted by the US Department of Health and Human Services (HHS) Office of the Actuary and the Congressional Budget Office (CBO).1 This in part may reflect that the economy has expanded at a rate faster than predicted. Nevertheless, the flattening of real per capita Medicare expenditures since the passage of the ACA is evidence of cost control.2 How can these contradictory findings be explained?
Three Explanations for the Paradox
The ACA established the Center for Medicare and Medicaid Innovation (CMMI) to design and test new payment and care models, which it did at a rapid pace and on a large scale during the past decade. The ACA required the introduction of accountable care organizations (ACOs)—consortiums of physicians, hospitals, and other clinicians designed to reduce spending and improve quality by coordinating care. Today, 1 of every 3 traditional Medicare beneficiaries is enrolled in an ACO. From 2012 to 2017, HHS introduced major payment reform initiatives for primary, specialty, and hospital care and greater than 40% of Medicare payments are now value based.
The Secretary of HHS can scale models tested by the CMMI if they reduce spending while maintaining or improving quality. Hence, the center rigorously evaluates alternative payment models. However, at least 3 main factors help to explain why these individual model evaluations may underestimate the true effects of alternative payment models on health spending.
First is psychological change among clinicians and health care organizations. In 2015, then-HHS Secretary Burwell signaled that delivery system reform was inevitable. Anticipation of ACA-driven expansion of value-based payment may have catalyzed a change in psychology and approach among clinicians and health care entities, and produced practice pattern changes and efficiency gains that decreased spending regardless of alternative payment model participation.
Second is peer network effects. When a clinician’s or health care organization’s neighboring practitioners or medical centers practice differently, they may be influenced by this other behavior. Clinicians and health care organizations observing colleagues or peer organizations engaging in novel, value-oriented behavior may pursue similar efforts. Commercial insurers, now responsible for 60% of ACO contracts, also expanded value-based contracting to align incentives with Medicare’s alternative payment models, further contributing to network effects. This could have accelerated shifts in practice patterns.
Third is control group contamination. Because the CMMI has implemented a large number of models in a short period, it has become practically impossible to ascertain the influence of any single model. Although formal accounting of the degree of contamination across dozens of programs is not yet available, it is likely to be large, supported by reports that more than 350 000 clinicians were exempt from MIPS (Merit-based Incentive Payment System) because of participation in alternative payment models.3 Thus, it is likely that clinicians and health care organizations affected by 1 or more models may be counted in the control group of another model, yielding smaller estimates than true alternative payment model effects.
Therefore, it may be that after enactment of the ACA, alternative payment models catalyzed broader systemwide control of health care spending that is not detectible in any individual model evaluation but is observed in both the flat per capita Medicare spending and flattening of national health expenditures as a proportion of GDP.
Empirical Data on the Shifting Baseline
The plausible influences of these 3 explanations—psychological changes, peer networks, and control group contamination—may be assessed by examining the secular trend in the control groups used in single-model evaluations. If the control group spending consistently decreased in evaluations of different alternative payment models spanning types of participants (eg, primary care practices, hospitals) and types of spending (eg, total spending per patient, total spending on clinically defined episodes of care), it would suggest underlying changes separate from any particular alternative payment model.
Assessment of peer-reviewed, systematic evaluations of prominent alternative payment model programs that reported Medicare spending trends reveals patterns in the control group spending trend. Despite expectations of an increase in spending based on CBO and HHS projections, there was a consistent “bending of trend,” reflecting slowing of spending growth or actual spending declines in the control group for 7 of 8 studies evaluated (eTable in the Supplement). For the 5 reports in which an absolute decrease in control group spending was reported, the decrease in spending ranged between 1.7 and 7.0 percentage points, with greater decreases in the control group in more recent years.
Consequently, alternative payment model participants were evaluated against a spending baseline that was decreasing. The changes in control group spending would make it more difficult to detect the effects of single alternative payment models. This is an important point; if the trajectory of lower spending in the control group was directly or indirectly a result of the alternative payment model movement, it could lead to systematic underestimation of the effects of individual alternative payment models.
There are alternative explanations for these observations, but they are improbable. Some might argue that the problem is related to inaccurate health expenditure projections. This explanation seems unlikely. For years, projections have been relied on by health economists, insurers, and the government for estimating spending and savings from various policies. These estimates have been accurate. A 2016 systematic review of HHS projections since 1998 confirmed accuracy across 1-, 2-, or 10-year forecasts to within 1%.4
Another possible explanation is that financial uncertainty from changes in the US economy led patients to use less health care. However, this is not supported by the evidence, which indicates that Medicare patients have not reduced their demand for health services.5 As a further possible explanation, perhaps Medicare payment reductions explain the observed declines in spending. Yet a 2012 CBO analysis projected that savings from these reductions would be $35 billion annually, approximately 1% of national health expenditures.6 A 2014 Kaiser Family Foundation analysis concluded that a large portion (38%) of the gap between projected and realized spending remained unexplained after accounting for CBO projected savings from the ACA, payment reductions in the Budget Control Act of 2011, the slowing of prescription drug price growth, and other policy changes. Payment reductions alone cannot explain the gap. Policy interventions such as alternative payment models have surely played some role in this unexpected slowdown in spending growth.
Policy Implications of a Changing Expenditure Baseline
When the future of alternative payment models and the best ways to improve affordability and quality of health care are considered, it may be necessary to reexamine whether greater interest should be given to micro causal effects of individual models or to the combined macro effects of policy changes on the trajectory of US national health expenditures.
To truly quantify the national system-level change would require augmenting existing methodological approaches. This may require greater comparisons of Medicare with “closed” systems such as Kaiser Permanente or the VA (taking care to recognize that some clinicians simultaneously practice outside of these systems) or greater efforts for rigorous cross-national comparisons.
Moving forward, these findings also may have implications for alternative payment model design in general and control group selection in particular. It may be useful to treat alternative payment models more experimentally from the onset, focusing mandatory models in specific geographic areas while limiting overlap and contamination. Stratification based on participation in existing models, combined with randomization in the event of overlap, could help isolate effects. Randomization at the organization level and within volunteer cohorts also could help ensure robust controls that better isolate the effects of a model against a neutral backdrop.
The slowing or declines in spending in control groups reported in alternative payment model evaluations are important and suggest that it is premature to call alternative payment models a failure. Conversely, through the rapid implementation of broadly transformative models, the Centers for Medicare & Medicaid Services may be a victim of its own success, with broad secular changes prompted by policy undercutting individual program results. Given that few, if any, alternative strategies to decrease health care spending are supported by robust evidence, and that alternative payment models have not led to worsening quality or higher spending, these models remain an attractive option that policy makers should exploit.
Article Information
Corresponding Author: Amol S. Navathe, MD, PhD, Division of Health Policy, University of Pennsylvania, 423 Guardian Dr, 1108 Blockely Hall, Philadelphia, PA 19104 (amol@wharton.upenn.edu).
Published Online: June 22, 2020. doi:10.1001/jama.2020.4133
Conflict of Interest Disclosures: Dr Navathe reports receiving grants from the Pennsylvania Department of Health, Hawaii Medical Services Association, Anthem Public Policy Institute, Commonwealth Fund, Oscar Health, Cigna Corporation, Robert Wood Johnson Foundation, Oschner Health System, United Health Group, Blue Cross Blue Shield of North Carolina, and Donaghue Foundation; receiving personal fees from Navvis Healthcare, Agathos, University Health System (Singapore), Singapore Ministry of Health, Elsevier Press, Navahealth, Cleveland Clinic, and the Medicare Payment Advisory Commission; serving as a board member without compensation for Integrated Services Inc; and receiving equity from Embedded Healthcare outside the submitted work. Dr Emanuel reports receiving speaker’s fees from Tanner Healthcare System, Mid-Atlantic Permanente Group, American College of Radiology, Marcus Evans, Loyola University, Oncology Society of New Jersey, Good Shepherd Community Care, Remedy Partners, Medzel, Kaiser Permanente Virtual Medicine, Wallace H. Coulter Foundation, Lake Nona Institute, Partners Chicago, Pepperdine University, Huron, American Case Management Association, Philadelphia Chamber of Commerce, Blue Cross Blue Shield Minnesota, UnitedHealth Group, Futures Without Violence, CHOP, Washington State Hospital Association, Association of Academic Health Centers, Blue Cross Blue Shield of Massachusetts, American Academy of Ophthalmology, Lumeris, Roivant Sciences Inc, Medical Specialties Distributors LLC, Vizient University Healthcare System, Center for Neuro-Degenerative Research, Colorado State University, Genentech Oncology Inc, Council of Insurance Agents and Brokers, Grifols Foundation, America’s Health Insurance Plans, Montefiore Physician Leadership Academy, Greenwall Foundation, Medical Home Network, HFMA, Ecumenical Center–UT Health, American Association of Optometry, Associação Nacional de Hospitais Privados, National Alliance of Healthcare Purchaser Coalitions, Optum Labs, Massachusetts Association of Health Plans, District of Columbia Hospital Association, Washington University, Optum, Brown University, America’s Essential Hospitals, National Resident Matching Program, Shore Memorial Health System, Tulane University, and Oregon Health & Science University. He also reports being a venture partner with Oak HC/FT, a firm that invests in health services but not pharmaceuticals or devices; and being on the board of 2 start-ups, Village MD and Oncology Analytics.
References
1.
US Congressional Budget Office. The Long-term Outlook for Health Care Spending. 2007.
2.
Emanuel  EJ, Gluck  AR, eds.  The Trillion Dollar Revolution: How the Affordable Care Act Transformed Politics, Law, and Health Care in America. PublicAffairs; 2020.
3.
Verma  S. Quality Payment Program releases 2017 Physician Compare data and sees increases in clinician participation rates and success for 2018. CMS blog. July 11, 2019. Accessed June 16, 2020. https://www.cms.gov/blog/quality-payment-program-releases-2017-physician-compare-data-and-sees-increases-clinician
4.
Getzen  TE.  Accuracy of long-range actuarial projections of health care costs.   North Am Actuar J. 2016;20(2):101-113. Google Scholar
5.
Holahan  J, McMorrow  S; Urban Institute.  Slow Growth in Medicare and Medicaid Spending per Enrollee Has Implications for Policy Debates. Robert Wood Johnson Foundation; 2019.
6.
Elmendorf  DW. Letter from the Congressional Budget Office. July 24, 2012. Accessed June 14, 2020. https://www.cbo.gov/sites/default/files/43471-hr6079_0.pdf 

Trial starts with Imperial College London coronavirus vaccine

The first healthy volunteer has been dosed with Imperial College London’s coronavirus vaccine, the second UK-developed candidate to reach the clinical testing stage.
The vaccine – based on a new technology known as self-amplifying RNA – was delivered at a small dose to an anonymous subject at a West London clinic, with no apparent side effects or safety concerns, according to Imperial.
It’s also a major milestone for Imperial’s saRNA approach, which has never been tested in humans before, according to Prof Robin Shattock, who is leading the development of the vaccine.
“We are now eagerly awaiting rapid recruitment to the trial so that we can assess both the safety of the vaccine and its ability to produce neutralising antibodies which would indicate an effective response against COVID-19,” he said.
saRNA vaccines are derived from the genomic backbone of another harmless virus, with the genes encoding the viral RNA replication machinery intact. However the genes that code for viral structural proteins are replaced with a ‘transgene’ directing it to produce vaccine antigens.
In this case, the vaccine uses synthetic strands of RNA based on genetic material from the SARS-CoV-2 coronavirus that causes COVID-19.  Once injected into muscle, the RNA creates copies of itself and instructs the body’s own cells to make copies of the “spike” protein found on the outside of the virus.
The first person in the trial will have a second booster shot within four weeks, and several other subjects will be recruited in the coming days, according to Imperial, which plans to recruit 15 people into the trial in this first phase, and 300 in total.
“We are now poised to test the vaccine in the dose evaluation phase before moving forward to evaluating it in larger numbers,” said Dr Katrina Pollock, the lead investigator in the trial.
If all goes well, Imperial has said that larger phase 3 trials could begin later in the year with around 6,000 healthy volunteers to test its effectiveness, and the vaccine could be ready for widespread use next spring.
The vaccine is being developed with more than £41 million worth of funding from the UK and a further £5 million in philanthropic donations.
It has started testing a few weeks later than another vaccine candidate developed by the University of Oxford and AstraZeneca – ChAdOx1 nCoV-19, now renamed AZD1222 – which uses a viral vector to introduce genetic material from the virus and produce an immune response.
AZ has started a 10,000-patient phase 2/3 trial of AZD1222, with additional studies also in the pipeline.
Earlier this month, Imperial also formed a social enterprise with venture capital group Morningside Ventures – called VacEquity Global Health (VGH) – to develop and distribute its vaccine at “modest cost-plus prices” worldwide.
saRNA has the potential to revolutionise vaccine development and enable scientists to respond more quickly to emerging diseases, it says.
Imperial’s vaccine is the first one to trial saRNA against COVID-19, but other RNA-based vaccines are also in clinical trials for coronavirus, namely Moderna’s mRNA-1273 – already in late-stage testing – and BioNTech/Fosun Pharma/Pfizer’s BNT161.

Novavax to Participate in H.C. Wainwright Fireside Chat Series

Novavax, Inc. (NVAX), a late stage biotechnology company developing next-generation vaccines for serious infectious diseases, today announced that John J. Trizzino, Senior Vice President, Chief Business Officer and Chief Financial Officer, will participate in the H.C. Wainwright Virtual Fireside Chat Series on Thursday, June 25. A topic of discussion will be Novavax’ COVID-19 vaccine candidate, NVX-CoV2373.
Fireside chat details are as follows:
Date: June 25, 2020
Time: 10:00 a.m. U.S. Eastern Time (ET)
Webcast: www.novavax.com, “Investors”/ “Events”, until September 25, 2020

Bayer announces agreements to resolve major legacy Monsanto litigation

Company will make a total payment of $10.1 billion to $10.9 billion (€9.1 billion to €9.8 billion) to resolve current and address potential future Roundup™ litigation
Company also resolves dicamba drift litigation for payment of up to $400 million and most PCB water litigation exposure for payment of approximately $820 million
Funding sourced from free cash flow and Animal Health divestment
Bayer is well positioned to deliver science-based solutions to meet global health, nutrition needs

Tuesday primary results: 3 takeaways for healthcare leaders

Healthcare again was a decisive issue for voters partaking in primary elections June 23.
Three takeaways for healthcare leaders:
1. Out of the six states where primaries were held — Virginia, Mississippi, South Carolina, North Carolina, New York and Kentucky — healthcare played a notable role in Virginia and North Carolina.
2. In Virginia, Cameron Webb, MD, a hospitalist at the University of Virginia in Charlottesville, won the Democratic nomination in the state’s fifth district, which is Republican-leaning. Healthcare is key to his campaign, according to Politico, with a focus on healthcare affordability and inequities.
3. In North Carolina, 24-year-old Madison Cawthorn won a runoff in the state’s 11th district, which leans Republican. The Republican campaigned on addressing healthcare costs, citing his own experience facing $3 million in medical debt after being paralyzed in a car accident.
“I would like to be the face of the Republican Party when it comes to healthcare,” he told the Washington Examiner in May 2020.