American College of Physicians: Internal Medicine — Doctors for Adults ®

Tuesday, January 12, 2016

A world with no pharmacies

Industry funding of research has always been a rather fraught topic. In the immediate aftermath of what we might reasonably call the “Coca-Cola calorie debacle,” or perhaps “GEBNgate,” it is all the more so. But in this domain, as in so many, the rush to summary judgment (in either direction) obliterates nuance fundamental to real understanding, and obscures a middle path conducive to important and even crucial advances.

Consider, for instance, that were we to take admonishments against industry funding to their logical extreme, 1 thing they would yield for certain is a world with no pharmacies. Virtually everything in the modern pharmacopoeia is a product of industry-funded research.

For some few of you, devoted, perhaps to natural remedies, and thus far spared by happenstance or youth the need for modern medical intercession, a world with no pharmacies may sound good. But most of us, even those of us very devoted to lifestyle as medicine, and very disinclined to take actual pharmaceuticals, have at times unavoidably been their beneficiary. I am, and I have, and thus have cause to be grateful that somebody funded the studies of the drugs I happened to need. So, too, for surgery, the tools of which also advance preferentially through the advent of industry funding.

So here, as in virtually all such scenarios where a complex topic warrants a good scrubbing, we have baby and bathwater in the same tub, and a perilous tendency to overlook the distinction.

Are there important liabilities of industry funding, of pharmaceuticals and anything else? Of course. Interested parties infuse a research agenda with a predictable bias. That bias in turn can corrupt methods from the outset, sometimes rather subtly, and foster the propagation of systematically misleading results.

That is not the only risk. When research costs are covered by private rather than public dollars, the funder might choose to suppress unfavorable findings, or to release findings selectively, or slowly. We might thus wind up with the truth, and maybe even nothing but the truth, but something so far removed from the whole truth as to constitute a falsehood. The famous case of Vioxx is a precautionary tale occupying just such terrain.

But on the other hand, were there no industry funding of pharmacotherapeutic advance, the noteworthy declines in cancer mortality would almost certainly not have been seen. The variety of antibiotics that, thus far at least, defend us admirably against all but the most exceptionally resistant microbes, would not be at our disposal.

Of comparable relevance, funding by the most ostensibly unimpeachable sources is no assurance against just such liabilities. The premier source of biomedical research funding in the U.S., the National Institutes of Health, is by no means devoid of its own native biases, and even potential for conflicts of interest.

Just like any other funder, the NIH favors positive results. The occasional study may be aimed at debunking, but most studies are infused by the hope of positive outcomes. This means that the researchers funded by the NIH are biased as well, hoping to show positive results. There are rather salient reasons why.

For 1 thing, all funders, ultimately, have funders of their own. In the case of NIH, it is the U.S. Congress, processing the money we, the people, provide in our tax dollars. NIH must remake the case for its slice of the pie as the federal budget is renegotiated every year, and breakthrough results certainly help. The expenditure by NIH last year on lackluster results does not help this cause.

Another problem is that our statistical conventions make positive results generally more reliably positive (albeit, far from perfectly so) than negative results are reliably negative. I will spare you the analytical weeds here, and keep it at a very high level: one of the most common explanations for a negative result at odds with hope and expectation is lack of statistical power to find the effect being sought. This, in turn, results from too small a sample.

So, you think, just use a larger sample! Good idea, but human clinical trial costs are related directly to sample size. I have a precautionary tale to tell.

My lab received funding from the NIH some years ago to run the first ever, placebo-controlled, randomized trial of an intravenous nutrient infusion in widespread, but unproven, use for fibromyalgia (among other things). The funding was for a preliminary, rather small, pilot study, with the understanding that the conduct of the trial, and outcome, would determine next steps.

Our treatment group did improve significantly. In fact, the effect size we saw was greater than reported for FDA-approved drugs for the same condition. However, our intravenous placebo produced a very robust placebo effect, so our control group improved substantially as well, albeit less. The result was that the between-group differences favored active treatment, but were not statistically significant. These results were negative, but not reliably so.

This seemed to be a perfect argument for a larger, definitive study. The pilot had proven our ability to apply appropriate methods, and run the study in this challenging population, but left efficacy in doubt. But we could not secure funds for a definitive trial. Reviewers at the NIH simply referred to the “negative” pilot results, and said: no thanks. We struggled to get our results published as well, despite the robustness of the study methods, because journals were no more favorably disposed to such murky outcomes than were funders. We prevailed, but only in a far from top-tier journal.

Such is the peril of pilot studies and negative results: One may not be able to say whether there is a true lack of effect, or merely lack of evidence of effect. In the case of intravenous nutrients for fibromyalgia, the result was a very unfortunate dead-end, leaving the matter unresolved to this day.

There is yet another problem with federal funding. While individual grants receive excruciating review, there is concern that the overall allocation of biomedical research dollars may be misdirected. This concern has been voiced by colleagues in Preventive Medicine, and echoed by none other than a Nobel Prize-winning, former NIH director.

In addition, politics may introduce bias directly. Colleagues directly affected tell me that during the Bush years (the second Bush), NIH grants addressing harm reduction strategies, such as needle exchange, were summarily rejected on ideological grounds, despite their clear, epidemiologic promise.

There is one more handicap to NIH, or other federal agency funding: these sources are none too enthusiastic about any proprietary advance, and tend not to fund studies of same. But what if there is legitimate hope that a proprietary, branded app, technology, device, program, algorithm, or even food has specific, favorable health effects? The only likely source of proof one way or the other is funding from the intellectual property owner, because no one else is apt to pay.

Having received funding from the NIH, the CDC, private foundations, and industry sources over the years, I can attest to personal bias in every instance, i.e., with every study, my team and I were “hoping” for a particular outcome. Why on earth would we even bother to do a study (they are rather tedious to design, fund, and run) if we didn't care about the outcome? The answer is, we wouldn't; no one would. As soon as one does care about the outcome, bias is inescapable.

But that is biased preference. Biased methods, in contrast, are avoidable, or nearly so. Methods, then, and safeguards against bias in the study protocol, are the more robust measure of a study's merits than the funding source, or the native preferences of funder or investigators.

We actually have a very good template in place for the research equivalent of having our cake and eating it too, i.e., allowing for industry funding and protecting against systematic distortion. That template is the very matter with which we began: funding of drug studies. The for-profit pharmaceutical companies pay these (often colossal) bills, but the FDA standardizes the criteria. A variation on that same theme could work for all industry funded research.

My initial, fairly obvious standards for industry-funded research include:

1) the customary defenses against bias and confounding, whenever practicable: randomization; double blinding; concomitant control

2) contractual protection of the right to publish, independent of study outcomes

3) complete research team autonomy with regard to study management

4) complete research team autonomy with regard to data analysis, interpretation, and manuscript preparation

A final consideration might be disclosure at the time of publication regarding satisfaction of these criteria. Funding sources are already disclosed routinely. We might add, without much fuss: “This study does/does not satisfy Standard Criteria for Research at Low Risk for Undue Influence by the Funding Source.” The papers that did should be more trusted, and indeed published preferentially, as compared to those that did not. The same check list could be applied to all entries at

To the best of my knowledge, every research contract at my lab over the past 20 years has met the criteria above. As a result, we certainly have published industry-funded studies with negative results the funder did not love.

Absent industry funding, research in pharmacotherapeutic advances would be set back decades. I think few propounding the perils of industry funding, of which there clearly are, pause to consider what its abolition would mean to the offerings of any modern pharmacy; they would be all but annihilated. One might even argue that the problem is less industry funding, and more the lack of a level playing field. The pockets of some funders, namely those who deal routinely in patents, are much deeper than those of others, and this in turn produces a distinct lack of parity in the capacity to generate evidence. When evidence-based medicine becomes revenue-based medicine, we all have a problem.

That problem will not be solved by summary judgments, dismissive of such subtleties. We have in our culture, arguably, killed expertise. We do the same to dialogue at our peril.

Use of the word “conflict“ has become an almost reflexive disparagement of industry funded research; a meme, of sorts, invoked presumably to highlight one's own virtue. Those addressing the matter thoughtfully, however, have begun to note that such funding may portend confluence rather than conflict, and the distinction should be made.

That distinction can be all but self-evident. Coca-Cola, clearly, should not be subsidizing our understanding of “energy balance.” Trade organizations representing nuts, or produce, or oils funding legitimate examinations of specific health effects of their products, or wearable health tech companies funding studies of their proprietary offerings, are another matter. But for the confluence of their interest and funding, research in such areas may simply lag behind.

Propriety can lead to credible funders, and clear criteria for research findings we can trust. Sanctimony leads reliably only toward the domain of history's greatest blunders.

It is also, predictably, parent to hypocrisy when the thing you assert with self-righteous zeal is wrong, becomes the very thing you need. I have yet to meet anyone with acute ureteral colic, or pancreatitis, holding forth in the Emergency Department about who funded the trials of the drugs they need. Their message tends to be much more primal: Help me!

We generally can do so, and industry funded research is much of the reason. In a world with no pharmacies, we would look on at such misery rather helplessly. We should take steps to foreclose on true conflicts in research. But we should allow for confluence, too, and keep the pharmacies open.

This post by John H. Schumann, MD, FACP, originally appeared at GlassHospital. Dr. Schumann is a general internist. His blog, GlassHospital, seeks to bring transparency to medical practice and to improve the patient experience.

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Members of the American College of Physicians contribute posts from their own sites to ACP Internistand ACP Hospitalist. Contributors include:

Albert Fuchs, MD
Albert Fuchs, MD, FACP, graduated from the University of California, Los Angeles School of Medicine, where he also did his internal medicine training. Certified by the American Board of Internal Medicine, Dr. Fuchs spent three years as a full-time faculty member at UCLA School of Medicine before opening his private practice in Beverly Hills in 2000.

And Thus, It Begins
Amanda Xi, ACP Medical Student Member, is a first-year medical student at the OUWB School of Medicine, charter class of 2015, in Rochester, Mich., from which she which chronicles her journey through medical training from day 1 of medical school.

Ira S. Nash, MD, FACP, is the senior vice president and executive director of the North Shore-LIJ Medical Group, and a professor of Cardiology and Population Health at Hofstra North Shore-LIJ School of Medicine. He is Board Certified in Internal Medicine and Cardiovascular Diseases and was in the private practice of cardiology before joining the full-time faculty of Massachusetts General Hospital.

Zackary Berger
Zackary Berger, MD, ACP Member, is a primary care doctor and general internist in the Division of General Internal Medicine at Johns Hopkins. His research interests include doctor-patient communication, bioethics, and systematic reviews.

Controversies in Hospital Infection Prevention
Run by three ACP Fellows, this blog ponders vexing issues in infection prevention and control, inside and outside the hospital. Daniel J Diekema, MD, FACP, practices infectious diseases, clinical microbiology, and hospital epidemiology in Iowa City, Iowa, splitting time between seeing patients with infectious diseases, diagnosing infections in the microbiology laboratory, and trying to prevent infections in the hospital. Michael B. Edmond, MD, FACP, is a hospital epidemiologist in Iowa City, IA, with a focus on understanding why infections occur in the hospital and ways to prevent these infections, and sees patients in the inpatient and outpatient settings. Eli N. Perencevich, MD, ACP Member, is an infectious disease physician and epidemiologist in Iowa City, Iowa, who studies methods to halt the spread of resistant bacteria in our hospitals (including novel ways to get everyone to wash their hands).

db's Medical Rants
Robert M. Centor, MD, FACP, contributes short essays contemplating medicine and the health care system.

Suneel Dhand, MD, ACP Member
Suneel Dhand, MD, ACP Member, is a practicing physician in Massachusetts. He has published numerous articles in clinical medicine, covering a wide range of specialty areas including; pulmonology, cardiology, endocrinology, hematology, and infectious disease. He has also authored chapters in the prestigious "5-Minute Clinical Consult" medical textbook. His other clinical interests include quality improvement, hospital safety, hospital utilization, and the use of technology in health care.

Juliet K. Mavromatis, MD, FACP, provides a conversation about health topics for patients and health professionals.

Dr. Mintz' Blog
Matthew Mintz, MD, FACP, has practiced internal medicine for more than a decade and is an Associate Professor of Medicine at an academic medical center on the East Coast. His time is split between teaching medical students and residents, and caring for patients.

Everything Health
Toni Brayer, MD, FACP, blogs about the rapid changes in science, medicine, health and healing in the 21st century.

Vineet Arora, MD, FACP, is Associate Program Director for the Internal Medicine Residency and Assistant Dean of Scholarship & Discovery at the Pritzker School of Medicine for the University of Chicago. Her education and research focus is on resident duty hours, patient handoffs, medical professionalism, and quality of hospital care. She is also an academic hospitalist.

Glass Hospital
John H. Schumann, MD, FACP, provides transparency on the workings of medical practice and the complexities of hospital care, illuminates the emotional and cognitive aspects of caregiving and decision-making from the perspective of an active primary care physician, and offers behind-the-scenes portraits of hospital sanctums and the people who inhabit them.

Gut Check
Ryan Madanick, MD, ACP Member, is a gastroenterologist at the University of North Carolina School of Medicine, and the Program Director for the GI & Hepatology Fellowship Program. He specializes in diseases of the esophagus, with a strong interest in the diagnosis and treatment of patients who have difficult-to-manage esophageal problems such as refractory GERD, heartburn, and chest pain.

I'm dok
Mike Aref, MD, PhD, FACP, is an academic hospitalist with an interest in basic and clinical science and education, with interests in noninvasive monitoring and diagnostic testing using novel bedside imaging modalities, diagnostic reasoning, medical informatics, new medical education modalities, pre-code/code management, palliative care, patient-physician communication, quality improvement, and quantitative biomedical imaging.

Informatics Professor
William Hersh, MD, FACP, Professor and Chair, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, posts his thoughts on various topics related to biomedical and health informatics.

David Katz, MD
David L. Katz, MD, MPH, FACP, is an internationally renowned authority on nutrition, weight management, and the prevention of chronic disease, and an internationally recognized leader in integrative medicine and patient-centered care.

Just Oncology
Richard Just, MD, ACP Member, has 36 years in clinical practice of hematology and medical oncology. His blog is a joint publication with Gregg Masters, MPH.

Kevin Pho, MD, ACP Member, offers one of the Web's definitive sites for influential health commentary.

MD Whistleblower
Michael Kirsch, MD, FACP, addresses the joys and challenges of medical practice, including controversies in the doctor-patient relationship, medical ethics and measuring medical quality. When he's not writing, he's performing colonoscopies.

Medical Lessons
Elaine Schattner, MD, FACP, shares her ideas on education, ethics in medicine, health care news and culture. Her views on medicine are informed by her past experiences in caring for patients, as a researcher in cancer immunology, and as a patient who's had breast cancer.

Mired in MedEd
Alexander M. Djuricich, MD, FACP, is the Associate Dean for Continuing Medical Education (CME), and a Program Director in Medicine-Pediatrics at the Indiana University School of Medicine in Indianapolis, where he blogs about medical education.

More Musings
Rob Lamberts, MD, ACP Member, a med-peds and general practice internist, returns with "volume 2" of his personal musings about medicine, life, armadillos and Sasquatch at More Musings (of a Distractible Kind).

David M. Sack, MD, FACP, practices general gastroenterology at a small community hospital in Connecticut. His blog is a series of musings on medicine, medical care, the health care system and medical ethics, in no particular order.

Reflections of a Grady Doctor
Kimberly Manning, MD, FACP, reflects on the personal side of being a doctor in a community hospital in Atlanta.

The Blog of Paul Sufka
Paul Sufka, MD, ACP Member, is a board certified rheumatologist in St. Paul, Minn. He was a chief resident in internal medicine with the University of Minnesota and then completed his fellowship training in rheumatology in June 2011 at the University of Minnesota Department of Rheumatology. His interests include the use of technology in medicine.

Technology in (Medical) Education
Neil Mehta, MBBS, MS, FACP, is interested in use of technology in education, social media and networking, practice management and evidence-based medicine tools, personal information and knowledge management.

Peter A. Lipson, MD
Peter A. Lipson, MD, ACP Member, is a practicing internist and teaching physician in Southeast Michigan. The blog, which has been around in various forms since 2007, offers musings on the intersection of science, medicine, and culture.

Why is American Health Care So Expensive?
Janice Boughton, MD, FACP, practiced internal medicine for 20 years before adopting a career in hospital and primary care medicine as a locum tenens physician. She lives in Idaho when not traveling.

World's Best Site
Daniel Ginsberg, MD, FACP, is an internal medicine physician who has avidly applied computers to medicine since 1986, when he first wrote medically oriented computer programs. He is in practice in Tacoma, Washington.

Other blogs of note:

American Journal of Medicine
Also known as the Green Journal, the American Journal of Medicine publishes original clinical articles of interest to physicians in internal medicine and its subspecialities, both in academia and community-based practice.

Clinical Correlations
A collaborative medical blog started by Neil Shapiro, MD, ACP Member, associate program director at New York University Medical Center's internal medicine residency program. Faculty, residents and students contribute case studies, mystery quizzes, news, commentary and more.

Interact MD
Michael Benjamin, MD, ACP member, doesn't accept industry money so he can create an independent, clinician-reviewed space on the Internet for physicians to report and comment on the medical news of the day.

PLoS Blog
The Public Library of Science's open access materials include a blog.

White Coat Rants
One of the most popular anonymous blogs written by an emergency room physician.

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