COMMENTARY

Five Recent Medical News Stories That Invite Cynicism

John Mandrola, MD

Disclosures

September 23, 2016

Cynic: A person who believes that people are motivated purely by self-interest rather than acting for honorable or unselfish reasons

I don't want to be this person. Cynicism is ugly.

But when it comes to the making and translating of medical evidence, five recent events are ugly.

Event Number 1. The Journal of the American College of Cardiology (JACC)recently retracted a paper[1] published earlier this year. This is notable because JACC is cardiology's biggest journal and because retraction is the highest form of scientific punishment.

The retracted paper reported the results of the OASIS trial—a test of whether ablation of atrial fibrillation (AF) using the controversial Topera Physiologic Rotor Mapping Solution was better than conventional techniques.

The OASIS trial results dealt a crushing rebuke for rotor ablation. The proprietary mapping system failed to deliver. The authors of OASIS, led by Dr Andrea Natale, are widely published and influential in the field. Their paper was presented as a late-breaking session of this year's Heart Rhythm Society meeting.

JACC retracted the paper because of irregularities in the randomization process (basically, the editors said OASIS was presented as a randomized trial, but it wasn't) and because patients were recruited before the trial was registered.

Dr Natale countered publicly, saying that industry influenced the decision to retract the paper. In an email to heartwire from Medscape journalist Patrice Wendling, discussing the decision by JACC's editors, Dr Natale said the information contained in letters to JACC were known only to the investigators and industry; "thus, it [was] obvious that these individuals were acting on behalf and in the best interest of the company."

I wrote a column outlining three possible explanations for this event, all of which, in my opinion, are depressing: a seriously flawed trial made it through the editorial and peer-review process of a major journal, or an influential research group were guilty of scientific misconduct, or industry influenced an editorial decision of a scientific journal.

Event Number 2. Another cynicism-inducing paper[2] out this month detailed the finding that the "sugar industry paid for and was closely involved in development of an influential literature review,"[3,4] published by the New England Journal of Medicine in 1967. This review downplayed dietary sugar's links to coronary heart disease while pointing the finger at fat and cholesterol intake."

Authors from University of California, San Francisco analyzed internal documents from the Sugar Research Foundation, the precursor to the Sugar Association, to probe the history of how dietary guidelines were developed. They looked at more than 1500 pages of documents from a range of publicly available sources, including damning correspondence between sugar-industry representatives and Harvard researchers.

Speaking to heartwire , Dr Cristin E Kearns, the lead author of the report, said that if the evidence had been fairly presented, the recommendations would have been to reduce both fat and sugar, not just saturated fat.

 
Think of the people that may have been harmed by substitution of sugar for fat.
 

My friends—this is a big story. Think of the people that may have been harmed by substitution of sugar for fat. Look around at the populace of Western countries.

George Santayana's famous, often misquoted, quote fits: "Those who cannot remember the past are condemned to repeat it."[5]

Event Number 3. The third article[6] that gets me down deals with the problem of medical overuse.

In a structured review of English-language articles on PubMed published in 2015, Daniel Morgan and colleagues identified 821 articles which addressed medical overuse. Their paper, published in JAMA Internal Medicine and available in full text online, identified the 10 most influential of these papers, detailing important types of overuse.

I see overuse too often; it's harmful to patients because it exposes them to more harm than benefit, and it is harmful to society because it wastes resources. At the core of the overuse detailed in this review was poor translation of evidence into practice. Does overuse persist because people are motivated out of self-interest?

Event Number 4. Recent decisions at the US Food and Drug Administration (FDA) suggest the bar for approval of new devices and drugs is too low.

Last year, the FDA approved the Watchman (Boston Scientific) left atrial appendage closure device, which is a plug placed in the left atrial appendage to prevent stroke. Only it doesn't.

In a clinical trial called PREVAIL, the device was tested against warfarin—the standard of care. The trialists set the lowest possible bar for the device; all it had to do was prove noninferiority. It failed. In counting up events, the device proved inferior to warfarin.

 
That an agency charged with judging clinical science considers the opinion of Hollywood actors demeans the process.
 

How did Watchman get approved, then? Advocates for the device used multiple tactics. They combined previous trial data, they "meta-analyzed" multiple studies; they criticized the PREVAIL trial for providing management of warfarin patients that was too good; and they harnessed the power of patient advocacy. The well-known actor Wilford Brimley spoke at the FDA session on behalf of the device. That an agency charged with judging clinical science considers the opinion of Hollywood actors demeans the process.

Event Number 5. And finally, a far worse crisis at FDA came to light on September 19, 2016, when the agency gave accelerated approval to eteplirsen (Exondys 51, Sarepta Therapeutics), the first drug for a rare form of Duchenne muscular dystrophy, specifically patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping.

During the first pass at the FDA, an advisory committee evaluated the data and rejected it by a 7 to 3 margin with three abstentions. The scientific advisors rejected the drug because the trial included only 12 boys and had deeply flawed methodology.

Despite the negative vote, patient-advocacy groups and others pressured the FDA into a second hearing. And now, the agency has gone against its advisors and granted approval. A clinical benefit of eteplirsen, including improved motor function, has not yet been established, and in its approval, the FDA did require that the manufacturer complete a clinical trial to confirm the drug's benefit. The company estimates the cost of the unproven drug will be $300,000 annually.[7]

 
Compassion for patients with rare diseases does not mean we can or should suspend scientific principles.
 

Compassion for patients with rare diseases does not mean we can or should suspend scientific principles. Luciana Borio, MD, the acting chief scientist at the Agency Scientific Dispute Process Review Board, the board that resolves internal disputes at the FDA, wrote that she "does not believe the available data and information support accelerated approval of" the drug."[8]

Ellis Unger, MD, the director of FDA's Office of Drug Evaluation within the Center for Drug Evaluation and Research and the chair of the advisory committee, in an appeal of this eteplirsen decision, exuded both empathy and common sense: "Many of us would wish to approve this drug if we could. DMD is a horrible disease and there are no approved treatments. FDA takes seriously the patient perspective and our mandate to be flexible."[8]

But in this case, Unger explains, "FDA is charged with the responsibility of ensuring that drugs are shown to be effective prior to marketing, based on substantial evidence. If we were to approve eteplirsen without substantial evidence of effectiveness, or on the basis of a surrogate end point with a trivial treatment effect, we would quickly find ourselves in the position of having to approve a myriad of ineffective treatments for groups of desperate patients—in essence, allowing marketing based on desperation, patient lobbying, and the desire and need of hope."[8]

The Sarepta story is terrible because it shows the darkest side of healthcare—one that I see too often: the hijacking of fear and hope in susceptible people in order to foster profits and self-interest of others.

[ Editor's note: The FDA has made a Summary Review of this decision, including documents from FDA's scientists, available in full online.]

Patients and doctors want to approach new developments in science and medical evidence with the belief that it is honest and born from the desire to foster the greater good. We want our default bias to be rooted in a place of benevolence.

Taken together, these five events give me great concern about the profession that is my life's work. I will continue to fight back cynical thoughts, but it's getting harder.

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