The Perils of Reliance on Industry Funding of Medical Research

John Mandrola, MD


May 20, 2016

...To make change, especially by introducing new methods, ideas, and products.

In medicine, cardiology in particular, innovation largely stems from industry-funded research. This partnership is generally good, but reliance on industry funding for medical research has downsides.

After the Heart Rhythm Society (HRS) and American College of Cardiology (ACC) sessions, I've been thinking about how research funding influences our knowledge base. In the past, I rarely considered what gets studied and how scientific questions are framed.

Then I noticed a trend: cardiology seems to be in an innovation rut. New drugs barely move the absolute numbers; a celebrated new left atrial appendage closure device got approved even though it failed its efficacy end points;[1] and new AF monitoring devices[2]—with no therapeutic end points—are embraced as if they were penicillin. If not for transcatheter aortic-valve replacement (TAVR), cardiology would have little to call truly innovative in recent years.

On Twitter, my friend Dr Saurabh Jha explained this rut as the law of diminishing returns. He makes the point that after sanitation and other basic human needs are met, modern medicine delivers increasingly little to extend the lives of human beings. It's a bit of hyperbole, but he's got a point.

James Fries, a Stanford rheumatology professor, writing in 1980 in the New England Journal of Medicine,[3] noted that mortality rates for those who do not die of premature causes have risen little between 1900 and 1980. In predicting the increased burden of chronic diseases, Fries was prescient. He advocated for improvements in lifestyle so as to compress the time of morbidity before death. The point being: humans have a biologic end point, one that is hard to budge.

Numerous topics from HRS and ACC illustrate how funding of research determines the agenda of clinical evidence. With diminishing returns as a backdrop, it's possible that improving innovation in medicine may require asking different questions.

Exhibit A: One of the most exciting areas in electrophysiology is His-bundle pacing. At HRS, numerous investigators presented encouraging results[4] of pacing on the His bundle. The technique could transform pacing for two reasons: one is that an inexpensive pacing lead connected to a standard generator could provide synchronous biventricular pacing, thereby preventing pacing-induced heart failure. More provocatively, though, His-bundle pacing may be able to reverse bundle branch block (BBB).[5]

Think about that latter statement. If BBB can be reversed, why would we struggle with an LV lead in the coronary sinus if a single lead would do? His-bundle pacing might severely diminish the market for CRT devices.

I spoke with His-bundle-pacing pioneers Dr Gopi Dandamudi (Indiana University, Bloomington) and Dr Pugazhendhi Vijayaraman (Geisinger Clinic, Wilkes Barre, PA); they both want to conduct a multicenter clinical trial comparing His-bundle pacing with CRT. But finding a sponsor has been challenging. Government agencies are stingy with funding, and no device company seems eager to fund a study that could narrow the market for CRT devices.

Exhibit B: At HRS, Melissa Middeldorp (University of Adelaide and Royal Adelaide Hospital, Australia) presented the REVERSE-AF study[6]—an observational cohort study showing regression of persistent AF to paroxysmal AF, not with ablation, but with physician-led lifestyle intervention. REVERSE-AF, like its predecessor studies from the same Adelaide group, LEGACY,[7] CARDIOFIT,[8] and ARREST-AF,[9] make the case that treating lifestyle factors results in dramatic decline in the need for ablation.

Now think about these findings from a research-funding viewpoint. These studies strongly suggest that addressing the underlying cause of the arrhythmia helps patients. Critics of this work say we need a randomized trial. That's true; but which device or drug company will fund a trial in which positive results will lead to less use of their product?

Another area of AF research that makes my point is implantable AF monitoring. Medtronic funded the Crystal AF trial,[10] in which an implantable loop recorder detected more AF than did the straw-man comparator of a single ECG and 24-hour Holter. Medtronic also has the marketing dollars to promote the technology. You see ads in journals and featured sessions at meetings. Despite no outcomes data, loop-recorder implants are taking off—at least in my city, probably yours too.

I'm not against AF monitoring in high-risk patients, but I'd love to see a clinical trial using long-term wearables such as patch technologies or handheld ECGs. But trials don't happen without funding.

Exhibit C: My critique of Watchman (the left atrial appendage closure device) remains. But let's think about stroke prevention in terms of what's known about risk-factor modification. Stroke in patients with AF involves Virchow's triad—endothelial dysfunction, hypercoagulability, and stasis.

Left atrial occlusion devices address stasis in the appendage, but imagine the benefits in endothelial function and hypercoagulability if patients with AF lose weight, get fit, drink less alcohol, and sleep without apnea? In the ARREST-AF substrate trial,[11] Dr Rajeev Pathak (University of Adelaide, Australia) and others showed marked improvements in hypercoagulability, inflammation markers, and endothelial function in patients randomized to lifestyle intervention.

Who will fund the stroke-prevention trial with an arm that delivers improvement in two of the three limbs of Virchow's triad?

Exhibit D: In the HOPE-3 trial,[12,13,14] AstraZeneca helped fund a randomized controlled trial in which lipid-lowering drugs and antihypertensives were studied against no drugs in otherwise-healthy people with risk factors for cardiovascular disease. The statin-arm delivered small absolute benefits.

But HOPE-3 does not answer one of the most commonly asked question in my office: "Doc, do I get the same [statin] benefit with exercise and diet?"

The answer is not known because HOPE-3 and many other similar trials did not add an aggressive lifestyle-intervention arm. If they did, they might have found what the Adelaide group found: high blood pressure, elevated lipids, and diabetes can be treated effectively with fewer, not more, drugs.

I must close with swans—and heavy metals.

Until Australia was discovered, most everyone assumed swans were white. Similarly, until the non–industry-funded TACT trial,[15] which was designed as a chelation-debunking study but instead delivered strikingly positive results in patients with diabetes, mainstream medicine did not consider exposure to heavy metals as a potential risk factor for atherosclerosis. Now, the editor-in-chief of the Journal of the American College of Cardiology, Dr Valentin Fuster, says this about chelation therapy: "Maybe all of us should open our minds."

If chelation-therapy benefit is replicated in the TACT2 trial, we may have found this generation's greatest medical innovation without industry support.

I'm grateful industry has built me new catheters and devices. These are nice. I'm not against continued partnership with industry. We need industry.

More and more, though, the trend of diminishing returns will limit the good that can be done with new drugs and devices. It seems to me the next big leap in medicine will be innovative ways to get humans to help themselves, use less medicine, and perhaps reduce their exposure to toxins.

Who will fund that research?



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