Funding the Future: How Industry Support for CV Trials Could Evolve

When the 5-year results from the controversial EXCEL trial were published earlier this year, it revived an old and divisive stent-versus-surgery debate but it also rekindled questions about how clinical trials are funded. In addition to concerns over trial endpoints and reporting, some physicians complained that EXCEL and other device trials like it can’t be trusted because of the role of the manufacturer in funding the research.

The pros and cons of commercial funding in clinical research are well documented, and endless ink has been spent examining the ties between investigators and sponsors and the impact on clinical trials. But what’s the alternative? In a year when so many other aspects of cardiology practice and research have been upended, is it possible to picture medicine without company dollars flowing into the research enterprise? A world where large-scale, government-funded trials are the norm rather than the exception?

Richard Kovacs, MD (Indiana University School of Medicine, Indianapolis), immediate past president of the American College of Cardiology (ACC), said the COVID-19 pandemic has revealed that cardiologists and other researchers are particularly adept at responding to the moment, even as their worlds were turned upside down. The vast majority of COVID-19-related research, including studies looking at the virus’ effects on the heart and vascular system, happened without drug and device company funding, he said.

“It didn’t require an industry sponsorship to bring together collaborators from all over the world,” Kovacs told TCTMD. “We did it very quickly on Zoom out of necessity. We were linking to our colleagues in China, in Italy, in Spain, and in Latin America. One role of industry in the past has been to unite us internationally but we learned to do that on our own.”

He also pointed out that “industry” in the past referred to the top three or five pharmaceutical companies, but that’s no longer how drugs are developed. There are hundreds of small, innovative companies pushing new products forward, and when they achieve some sort of success in early clinical trials, they then get snapped up by the major firms. Kovacs acknowledged, however, that large-scale clinical trials needed to bring new products and devices to market depend upon industry funding—a sentiment echoed by several cardiologists, some of whom have been vocal about industry’s undue influence.

“I don't think there's any alternative funding source to develop new drugs and new devices,” David Brown, MD (Washington University School of Medicine, St. Louis, MO), told TCTMD. “I mean, the [National Institutes of Health] is really not interested in late-stage development trials of drugs or devices.”

Andrew Foy, MD (Penn State Health, Hershey, PA), likewise, can’t envision a future where cardiology isn’t driven by company-funded clinical research. “I think industry plays an important role,” he said. “I don't think that we'd be where we’re at if we were relying on only publicly funded science. But it's interesting to think about. You know, would we be better off or worse? I think it would be better from the standpoint of not having so much of the incrementalism, which I think keeps costs up, but at the same time, I don't think we would have as many genuine advances as we do either.”

Khurram Nasir, MD, MPH (Houston Methodist, TX), thinks companies within the nascent “digital technology” industry will soon be spoken of alongside powerhouse pharmaceutical and device companies. He predicted to TCTMD that health systems and payers—all of which are moving towards value-based purchasing in asking how to best keep people healthy—will provide the bulk of funding.  

“When we think about industry, we have historically thought about pharmaceuticals and devices, but a greater adoption of digital solutions is knocking on the door,” said Nasir. “The pandemic has really accelerated their uptake because the payers and providers have been forced to start thinking outside their comfort zone and ask how we can reach out to engage our patients safely and more efficiently.”

Does Size Matter?

Speaking with TCTMD, Sukhjinder Nijjer, MBBS, PhD (Imperial College Healthcare NHS Trust, London, England), noted that in other medical specialties without extensive industry input, such as nephrology or respiratory medicine, the research studies that do emerge are dramatically smaller. “It tells you straight away that without industry support for these kinds of things, you don't get the big studies,” he said.

In the US, the NIH is currently investing $40 billion annually in medical research, with half of that money awarded to institutions for basic science research. The estimated funding awarded for cardiovascular research in 2019 was roughly $2.4 billion. In the United Kingdom, there are several large charities and research bodies, such as the Medical Research Council, Wellcome Trust, and the British Heart Foundation, and all provide funding for clinical research, although the amount provided is relatively small, said Nijjer.

But that money only goes so far, and competing for the limited grant money is an incredibly competitive, cutthroat process, he said.

“The total number of studies being funded is relatively small and those studies generally tend to be mechanistic studies that are less likely to move the needle in terms of clinical practice and guidelines,” said Nijjer. Much of that work is less likely to be featured as major studies at big conferences although it may be featured in the smaller sessions, he noted. 

“Now, if you look at what happens in the cardiovascular space, say at what’s presented at TCT or EuroPCR in the interventional space, the studies presented in the major late-breaking sessions are clearly biased in favor of industry-supported studies,” he continued, a factor largely due to the fact that these studies are larger. “This is also true in the non-interventional space, for pharmaceuticals or drug studies. I know it’s very popular at the moment to paint interventionalists as some form of biased group of individuals, but I would say non-interventionalists have just as many biases. They all have their fiefdoms to hold onto.”

While industry is heavily involved funding cardiovascular research, there are upsides to that model. Nijjer pointed out that when he first started practicing as a cardiologist, TAVR for the treatment of symptomatic severe aortic stenosis didn’t even exist.

“TAVR is something that was conceived by interested physicians, but without industry. This would have just been a small niche thing that a few guys who would have been deemed eccentric were doing,” he said. TAVR took off “because industry saw this potential and then they pushed, and if it wasn't for the drive of the market, TAVR probably would not exist at all. It just wouldn’t. And you can look at multiple medical technologies that don't necessarily generate a new market, or in which there isn't this concept where you can drive physicians to do something, and those technologies don’t advance. There’s loads of technologies where iterations have moved at a glacial pace.”

He pointed to the evolution of pressure wires for use during coronary angiography, which has been relatively slow-moving for 15 years. Fractional flow reserve (FFR) studies have come and gone but companies didn’t put much iterative effort into the technologies, wires, and consoles, and as a result, the field stagnated. Adoption of a data-driven technology didn’t grow, but instead there was a push to stent, regardless of physiology, because there was an established market. In general, he said, companies won’t put money into research and development until there is a proven market for new products.

Defending Industry-Funded Trials

Juan Granada, MD, chief executive officer of the Cardiovascular Research Foundation, which coordinated the data analysis, angiographic core laboratory, and clinical events committee for EXCEL,  knows there are critics of the current funding model. But he pointed to the current pandemic as evidence supporting industry involvement in clinical research.

“The reason why companies were able to aggressively develop a vaccine during this pandemic is because of their ability to take risk, their ability to put dollars at risk, their ability to move fast, and their ability to innovate and push progress forward,” he told TCTMD. “I honestly don't really see a future without the private sector. To rely on universities and not-for-profit organizations, or even the government, to essentially create a new technology, a new development? Yes, it sounds nice, but it's completely unrealistic.”

Granada understands the argument that positive results from industry-funded trials could potentially appear clouded by the role of the sponsor, but he stressed that even with industry funding, regulatory agencies, specifically the US Food and Drug Administration, act as the ultimate safeguard for ensuring quality trials.

“You can say whatever you want about a trial that has been funded by industry, but the FDA is a tough filter,” said Granada. “These protocols, the data and results, are evaluated in depth by groups of people that are highly qualified. Even for the trials funded by industry, the data is analyzed independently. For people to think that a company is going to go and influence a group of biostatisticians, who analyze and report the data, is not what happens. There are a lot of controls put in place to ensure that the data is actually clean.”

Kovacs agreed, noting that while private enterprise is regarded as being “nimbler” than government when it comes to finding solutions to problems, the space is tightly controlled. “Even in terms of how they're investigating things, they have regulatory agency-defined endpoints and safety monitoring, among other things,” he said. “The pharmaceutical and device industry is a heavily, heavily regulated industry, for many good reasons, and it does inhibit them in ways many don't recognize.”

When cardiologists take to social media to discuss a study’s merits and shortcomings, the exchanges can be heated, but Foy doesn’t think the cardiologists, in general, are particularly distrustful of data derived from studies funded by drug and device companies. All clinical trials, regardless of their funding source, will be judged on their strengths and weaknesses, he said. However, Foy noted that at his institution, where he mentors younger physician-scientists, a major emphasis is placed on obtaining independent and external funding. And that funding, he said, is valued more than industry funding.

If industry funding were completely removed, Nijjer imagines that studies would shift from large clinical trials to something akin to the efficient, low-cost SWEDEHEART registry-based model for collecting data. However, that model is possible in Sweden because all hospitals who care for patients with ACS, and those who provide coronary angiography, PCI, or cardiac surgery, participate in the registry. Such integration doesn’t exist in the US, nor does it even exist across hospitals in a single city.   

“You may be able to do it in a network of hospitals in a medium-sized city but it’s harder in some bigger places,” he said. “If you look at London, we've got some big hospitals with huge prestige, and yet they're not linked and it is not common for them to share data or information. The real push will need to come from the British Cardiovascular Society and British Cardiovascular Intervention Society to develop registry platforms where everyone can share their data. It does happen already but in a purely registry format and the data can be incomplete. To take it to the next level, with national registry randomization like in SWEDEHEART, you need a whole new system, mindset, and culture.”

Publish or Perish (Your Expense Budget)

To TCTMD, Nijjer notes that the top-tier journals are also part of the medical-industry complex because they have a financial incentive to publish industry-funded research, particularly those “needle-moving” randomized trials. Indeed, Nijjer was hard-pressed to name a major cardiovascular clinical trial that had been published in the New England Journal of Medicine that did not have industry backing.  

“There’s a huge drive for them to accept these papers because they want the big studies that have razzmatazz, that people will be interested in downloading and industry will pay for preprints,” he said.

This may explain, in part, the rise of simultaneous publications at major medical meetings. Increasingly, the biggest trials—which often means industry-funded research—presented in the big late-breaking sessions, are also simultaneously published. At the American Heart Association (AHA) 2019 Scientific Sessions, for example, GALILEO and RECOVERY were both published in NEJM. Interestingly, ISCHEMIA was not published at the time of the AHA presentation, although it appeared in NEJM several months later. At the European Society of Cardiology (ESC) Congress 2019, there were more than 50 simultaneous publications in medical journals, including BIOSTEMI and ENTRUST-AF PCI in the Lancet and AFIRE in NEJM. At the ACC 2019 meeting in New Orleans, the low-risk TAVR studies both ended up in NEJM. 

Because of this tight connection, Brown believes the medical journals could play a bigger role going forward in regulating the influence of industry in research. For starters, they could refuse to publish an article where the industry sponsor has had any say in study design, analysis, or preparing the manuscript for publication. Additionally, Brown said he’d like to see more transparency going forward, with companies publishing a detailed breakdown of how much money the company spent on the trial and where it went, including the amount awarded to the research organization running the study.

“It would be nice if [companies] had to publish the budget as an appendix to the article,” said Brown. “Why does that need to be a closely held secret? The companies that are publicly traded, they have to divulge that information to their shareholders, but they just divulge the top-line number. Somewhere in there should be an accounting of the spending.”

Nijjer suggested a spending cap on industry funding might be useful, noting that the money spent on clinical trials is enormous. As one of the researchers for DEFINE-FLAIR, a study run by the Biomedical Research Centre at Imperial College London and sponsored by Philips Volcano, Nijjer said they were accused of conducting an extravagantly expensive study that wasn’t really necessary for clinical practice. Yet the total cost of the trial was just £6 million.

“We ran that study in an incredibly tight, efficient manner,” said Nijjer. “It can be done if you’re forced to do it. I think we need to maybe curtail some of that excess in industry-sponsored studies.”

Going Forward

All of the physicians who spoke with TCTMD had ideas for how the field could evolve, even as they acknowledged that industry dollars are here to say.

Foy pointed to the “incrementalism” that includes me-too drugs and small iterations to existing devices, such as small tweaks or design changes to drug-eluting stents. Some of the clinical trials funded by industry resulting in these products are less about advancing patient care in terms of reducing the risk of death or hospitalizations and more about benefiting the sponsor and its shareholders, he said.

Doing away with those, he said, would potentially leave only the better-quality trials without obvious biases. “They would likely be more definitive in terms of outcome measures,” Foy said. But making that kind of switch comes at a price, he said. “There would definitely be fewer trials, I don't think there's any doubt about that, and as a result of there being less, the field would be progressing slower. I think you certainly have to balance those two things out.”

For Granada, there is still room for improvement, and he cited open access as a critical necessity so that outside researchers can see and analyze data independently, which would obviate the kind of attacks the EXCEL investigators have faced. He would also like to see improvements in the design of clinical trials so they include endpoints meaningful to patients, as well as improvements in trial processes and study methodologies.

On the whole, Granada said, interventional cardiology is a data-driven field, one that has advanced cardiology by demonstrating the safety and efficacy of a number of technologies used today. It’s not constructive, he added, when scientific discussions on social media devolve into attacks on the sponsor or the clinical trial organization.

“I see this a lot on social media, which has allowed a lot of people from different fields and different areas to depart from the truth without really having a solid basis for their arguments,” said Granada. “I really believe, for myself and my colleagues in our field, we don’t want to see data that’s polluted or corrupted to move the needle in terms of guidelines.”

Beyond the guidelines are the patients themselves who stand to lose or gain when trials are stopped early due to lack of funds, or research questions aren't pursued because there’s no profit to be made.

Brown pointed out that while the vast majority of clinical trials in cardiovascular medicine are funded by industry, many pharmaceutical drugs brought to market have been developed with the help of government-funded basic science work. The public, he said, helped pay for these innovations and they shouldn’t be forgotten, especially those who can’t afford these new drugs.

“There should be a way as a condition of licensing intellectual property that was developed at the NIH to at least guarantee funding for people that don't have insurance,” he said. “Three to five times a week, I'm prescribing medications, whether it’s a NOAC, Entresto, one of the injectable PCSK9 inhibitors, or an SGLT2 inhibitor, to patients who, when they get to the pharmacy, can’t afford it. You know, that should not happen.”

A pledge where all companies that have benefitted from taxpayer-funded research dollars committed to providing treatment to those who can’t afford it should be part of any approval, said Brown.

Nasir, in the same vein, pointed out that the pharmaceutical and device companies are starting to tune in to the idea that bringing a new product to market isn’t effective if people can’t access or afford it. He speculated that one way to ensure equality would be to tie reimbursement to the patient’s ability to pay for treatment.

“Coming up with a new medicine or new therapy, even if we do that, the end goal will not be the same unless we acknowledge social inequities and social risk and find ways to address it,” said Nasir.