So much for multimodal pain therapy.

A leading proponent, anesthesiologist Scott Reuben, is watching his abruptly damaged reputation. The fraud continued for twelve years, from 1996-2008. More than twenty of Reuben's thirty peer-reviewed articles have been retracted or are being reassessed. It's a black day for peer review. The honor system. And anesthesiology.

What industry critics will do with the scandal remains to be seen. The case could provide fodder for anti-industry politicians intent upon demonizing pharmaceutical research.

For his part, Reuben doesn't appear to be facing legal problems. Or the loss of his livelihood. No one is alleging any patients were harmed under his care. But the longtime Pfizer collaborator is taking a bit of a vacation. He isn't answering email.

Major Mess

To its credit, the Springfield, Mass. branch of the Tufts network, Baystate Health, is answering painful questions.

It didn't employ Reuben; he worked for an independent anesthesiology group. But Baystate acknowledges responsibility for Reuben's research. Its chief academic officer, Hal Jenson, answered questions, somberly recounting the chronology of how the Reuben mess came to light.

Jenson did not hedge his conversation with legal qualifiers such as "allegedly." Instead he spoke crisply and left no doubt Reuben dreamed up clinical data from whole cloth. The scientific community may draw a small measure of comfort from that—no real patients were duped or treated under false pretenses. Reuben's research subjects were all in his head.

The fabrication surfaced during what Jenson termed a "routine" annual review of research covered by the Baystate institutional review board (IRB). For an industry that often chafes at the delays caused by paperwork-clogged IRBs, the detection of a major fraud is a clear victory—a vindication of not rushing. Jenson suggested that no changes to his institution's oversight rules would be needed. The existing procedures eventually summoned the cavalry and stopped the misconduct. "We have a very solid process," said Jenson. "That process worked in finding the fabrication."

'Breach of Trust'

Jenson sounds chastened by the situation: "The one key to the integrity of science is trust. Dr. Reuben broke that trust with colleagues, with the institution. He broke it with everybody who worked in science. My biggest disappointment, beside the immediate finding with the fabrication in publications, is the breach of trust that happened."

Perhaps for legal reasons, Jenson was unable to comment on whether Reuben has confessed. There was no ambiguity about the innocence of Reuben's coauthors. Said Jenson: "In each of those 21 publications, the data was either partially or completely fabricated. The fabrication was solely by Dr. Reuben. There was no indication or evidence that anyone else had knowledge of or participation in the fabrication."

Unchanged Oversight

All of the research appears to have been investigator-initiated or observational—not covered by the investigational new drug (IND) process. "We're not aware of any of this data being used for any submissions to the FDA," Jenson says. "We have notified the FDA of our conclusions. There were no federal or state funds involved with his research." That could reassure taxpayers. It also points toward one remaining source of funding: industry.

Jenson said that as far as he knows, there are no ongoing local, Congressional, federal or FDA investigations of Reuben.

Jenson seems sensitive to the semantics of industry-driven research at Baystate. "I wouldn't say that any of the physicians work 'for' the pharmaceutical industry," he said sternly. But he conceded that an unspecified number of Baystate physicians have direct or indirect industry funding. "Each of those studies is part of the IRB review and also has a scientific review, where the department chair has to ensure the study has scientific merit," he said.

Madoff As Model

Baystate says that its investigation was appropriately paced, giving Reuben an opportunity to answer the allegations, and began in May, 2008. Reuben was put on leave at that time but published his last article (in Anesthesia & Analgesia) in August, 2008. Rumors of a probe seem to have been circulating in the anesthesiology community for a while.

In the interview, Jenson had a subdued and saddened tone. A pediatric researcher, he ruminated about the importance of integrity in any career, in any industry, and accepted tangential comparisons to the $65 billion fraud by Bernard Madoff. "We should all feel betrayed by Bernie Madoff, even if we were not in the financial world," he said. "We should all feel betrayed by Scott Reuben, even if we're not in the medical field. We should all feel the disappointment."

Ethical Impact

The scientific and clinical impact of the withdrawal of Reuben's work from medical journals is not yet clear. But it is fair to describe the anesthesia world as, well, numbed with outrage.

Reuben was an influential voice in the pain management community. Patients around the globe received (or didn't receive) medication based on what other physicians learned in Reuben's peer-reviewed journal articles.

To the extent that harm arose from such treatments, Reuben has no immediate legal liability. But he does have indirect ethical complicity as a scientist who was an advocate for COX-2 inhibitors. Other anesthesiologists will now either replicate Reuben's findings or walk away from multimodal pain therapy altogether.

Multiple Retractions

Pfizer, according to the trade publication Anesthesiology News, tried to down play its relationship with Reuben before the scandal broke into public view. The company once listed Reuben on its speaker bureau but dropped him on an unspecified date. Like its peers, Pfizer visits offices of physicians to inspect or "monitor" the documents of scientists. It's unclear whether the company ever conducted monitoring of Reuben's files. But in this type of research, it probably would not be required to do so under U.S. law or good clinical practice (GCP) guidelines from the ICH.

Of the 21 fradulent articles already retracted, abstracts of five articles explicitly refer to two Pfizer products: Celebrex and Lyrica. In Pubmed, Reuben's name is linked to another seven publications with those drugs. Reuben also studied Vioxx and a variety of opiates.

A Pfizer spokeswoman, Sally Beatty, sent ClinPage an email about the matter. "It is very disappointing to learn about Dr. Scott Reuben’s alleged actions. The withdrawal of Dr. Reuben’s research does not change the risk-benefit profile of Celebrex. The clinical trials that led to the approval of Celebrex’s six pain indications, including acute pain in 2001, did not involve any of Dr. Reuben’s research."

Pfizer's Help

Pfizer says it funded five investigator-initiated research (IIR) grants with Reuben, and defends such research as valid. "Once we agreed to fund these studies," Pfizer said, "Dr. Reuben was responsible for adhering to the strict standards of clinical research, and was fully responsible for all aspects of the research and publication."

Still, academic critics of the industry say many IIR grants are designed not by scientists, but by marketing teams looking for favorable treatment from a gullible tier of medical journal editors a notch or two below the elite publications such as JAMA and the New England Journal of Medicine.

With Baystate's investigation complete, Jenson suspended Reuben from research at Baystate for ten years. Reuben will also be unable to publish or present any scientific data derived at Baystate for a similar period. And Reuben is barred from serving in an educational capacity at the facility.

But Reuben's misconduct has been brought to the attention of the Massachusetts medical board. It's unlikely to impose significant sanctions. U.S. physicians are typically as forgiving as bankers and lawyers when assessing the lapses of peers. Most likely, after the dust settles, Reuben will be allowed to practice again.

Editor's note: After the publication of this story, Baystate alerted us that the independent anesthesiology practice has now terminated Reuben's employment. As a result of that action, Baystate's contract allowed it to strip Reuben of all medical and clinical privileges as of March 19, 2009.

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