The ongoing fallout from the withdrawal of rofecoxib in 2004 continues to expose the core values of the international research community to debate. In the second of a two part series, David Brill looks at the safeguards being put in place to prevent it from happening again, and finds out how Southeast Asia can play its part in helping to restore the damaged reputation of medical research.
When the integrity of medical science is threatened, “patients, clinicians and researchers are all at risk of harm, and public trust in research is jeopardized,” wrote the editors of the Journal of the American Medical Association in an editorial last year. “Ensuring, maintaining, and strengthening the integrity of medical science must be a priority for everyone,” they concluded. [JAMA 2008; 299(15):1833-1835]
The trigger for this call to action was the publication of two new papers shining yet more light into the uncomfortable darkness surrounding the withdrawal of rofecoxib. With every painful new insight revealed by the ongoing litigation process – these latest revelations alleged the ghostwriting of manuscripts and the questionable presentation of mortality data in key clinical trials – the restoration of this integrity seems an ever-more distant target. [JAMA 2008;299(15):1800-12; JAMA 2008;299(15):1813-7]
The task is one that faces the entire medical profession, but for Professor Jeffrey Drazen, editor-in-chief of the New England Journal of Medicine (NEJM), it has taken on a particularly personal significance. The journal became an unwitting accomplice in the rofecoxib affair when it published the Vioxx Gastrointestinal Outcomes Research (VIGOR) study – later to be tainted for its omission of three late-breaking myocardial infarctions. [N Engl J Med 2000;343:1520-8; N Engl J Med;2005 353:2813-4] The saga, he says, has “changed the rules” for medical journal editors.
The NEJM, for its part, is fighting on several fronts to ensure the objectivity of the research contained within its pages. Along with other major medical publications, the journal now stipulates that clinical trials be registered in an international database – a requirement which prevents the changing of protocols mid-trial and creates an internationally-harmonized norm, Drazen says. The editors have also learned to demand personal accountability for the data, request longer adverse event reporting, and be more aggressive about querying authors when they feel that there are discrepancies, he adds.
Drazen believes, however, that the long-term solution to the rebuilding process lies out of the hands of the journals and at the very heart of medical research training. “People need to understand that you’re not here to make the boss happy – you want to report the truth,” he says. “In all research we need to teach this culture that [focuses on] getting it right, not just getting it published. Publishing papers is a way to gain fame and reputation, but if you publish a lot of papers that are wrong you’ll start off on a high but you’ll crash.”
The damage to the reputation of medical research has perhaps been most keenly felt in the US, but for Southeast Asia the stakes are equally high. As the region continues to promote itself as a biomedical research hub, financial and commercial interests in its countries grow, and the potential for disaster increases. And with the shadow of Dr. Hwang Woo Suk, the discredited South Korean stem cell scientist, still looming large, the need for adequate ethical safeguards in the region is beyond question.
Singapore, for one, appears already to be taking action to ensure the future integrity of its research. Ethics feature prominently in the nation’s Good Clinical Practice (GCP) Guidelines, a cornerstone of all research conducted in the country, and are also moving up the agenda at the Yong Loo Lin School of Medicine, which in September 2006 became the first medical school in Southeast Asia to open a dedicated academic center for biomedical ethics. At the national level, approval for clinical trials must be gained from the Health Sciences Authority, which scrutinizes all proposals before granting the required certificate.
Much of the responsibility for protecting the integrity of research, however, still lies at the doorsteps of the individual centers and their institutional review boards. Professor Fong Kok Yong’s role, as chairman of division research, is to promote and encourage research at Singapore General Hospital (SGH) – just one of several research centers in the country which prides itself on its publication output. He says that he is happy with the ethical safeguards that are presently in place, but stresses that it is an ongoing, “lifelong” process to instill the appropriate values in SGH’s researchers.
“Medical school is a good start but lectures are just laying some of the foundations,” he says, noting that researchers continue to learn from their peers through an informal mentorship network. The hospital has also been strengthening its educational agenda – offering additional courses and seminars which, Fong says, have been received with enthusiasm by researchers. A recently launched 2-day workshop, focusing on the ethics of GCP and involving speakers from both academia and industry, was heavily oversubscribed, he notes. SGH also implemented a “whistleblower” policy in 2007 to help protect the integrity of its research – allowing researchers to report fraudulent activities without fear of reprisals, and enabling an independent investigation to be undertaken.
Fong adds that it is important to maintain a balance where the frontiers of knowledge and technology can continue to be pushed but without sacrificing patient safety in the process. “As in all things in science, to compete is good, but we don’t want people to compete at all costs. At SGH I think there is a balance – we want to emphasize that it’s not so serious that if you don’t publish you will perish,” he says.
Although Southeast Asia has so far been spared the type of incident where patients are put at risk, the research community here must continue to strengthen its defenses, according to Dr. Thiru Thirumoorthy, a former director of the Singapore Medical Association’s Centre for Medical Ethics and Professionalism. He believes that the rofecoxib story should serve as a wake-up call for the rest of the world, and draws attention to the wider ethical issues of conflicts of interest and the relationships between doctors and pharmaceutical companies.
“Of course the pharmaceutical industries are much bigger in the US so they have greater stakes, but this is by no means purely an American condition,” he says. “The lesson to learn is for us not to reach this point. We should have already put up our barriers much earlier.”
Thirumoorthy believes that in Singapore, in general, the relationships between academia and industry are relatively well moderated at present, but notes that in the absence of definitive evidence the community should remain on guard against complacency. “The first question we need to ask is do we have a problem and is it severe enough for us to do something more? At the moment there is no obvious evidence that it has reached a stage of an exploitative nature. There may be incidences that we do not know of but until such time we should continue to work on education and enforcing guidelines to improve the situation.”
Ultimately, however, only time will tell whether the global medical community is doing enough to protect itself, and whether the public’s faith in medical research can ever be fully restored. Despite the profession’s best attempts to tighten its defenses, it may simply be a matter of time until its values are once again left cruelly exposed.
“We’re doing our best to try to keep people honest but I’d be a fool to say that it won’t happen again,” concludes Drazen. We’re protecting against things that happened in the past but somebody will be creative and come up with something new and there’s nothing you can do about it. If someone wants to cheat badly enough, they’ll succeed.”
Professor Jeffrey Drazen was in Singapore as part of the National University Health System’s Distinguished Editors Series.
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