By Ray Moynihan, author, journalist, and senior research fellow, Bond University, Australia
RayMoynihan@bond.edu.au
While Relenza’s benefits are modest at best, its story would make a great Hollywood blockbuster
A drug company executive hailed it as “one of the greatest discoveries of the 20th century” and an Australian politician predicted two decades ago it might be a “breakthrough as significant as penicillin.” The Independent on Sunday in the UK ran a front page story declaring “a cure for flu that actually works,” and Australian tabloids quoted a patient saying that within 24 hours of taking it, “I was completely cured.” Given the sober findings of the recent Cochrane review of the drug,1 and the resources invested in pandemic stockpiles, all this misleading hype about zanamivir (Relenza) now seems obscene. Yet, inside the offices of the world’s most powerful drug regulator, a young biostatistician had concluded 15 years ago that the drug’s benefits were extremely limited. His findings back in 1999 would ignite the fury of one of the world’s most powerful drug companies and set the scene for a case study in failed regulation.
Later overshadowed by its more famous cousin, oseltamivir (Tamiflu), zanamivir was the first in this new class of anti-flu drug, the neuraminidase inhibitors. In the late ’70s Australian scientists working in publicly funded institutes had discovered a molecule common to different strains of influenza, and by 1985 a small biotech company called Biota was created to commercially exploit that discovery. In 1990 an agreement was signed with Glaxo Wellcome, with researchers describing “potent influenza virus . . . inhibitors” that could be the basis of a new drug. By 1999 it was time for regulatory assessment.
On 24 February, members of the advisory committee to the US Food and Drug Administration sat down in a Holiday Inn near Washington, DC to decide whether to approve this new “wonder drug.” Approval was seen by many as a foregone conclusion, as evidenced by buoyant stock prices and reinforced by the upbeat opening presentation from Glaxo representatives, who concluded the drug could reduce the time someone had flu symptoms by up to two and a half days. Australian regulators had already approved it, with a health minister proclaiming an “exciting medical breakthrough.” Biota’s share price was through the roof, and Glaxo had high hopes that the drug would become a blockbuster. But as the morning drew on and the team of FDA reviewers began to present, a reality check was imminent.
An FDA medical officer told the committee of several “concerns” arising from the review of the data. In particular, it was difficult to know the best way to measure the effect of the flu drug on a disease that “resolves completely and permanently in most cases.” Then came the FDA’s statistical reviewer, Michael Elashoff, who questioned not only how well the drug worked but whether it worked in any meaningful way at all.
The statistician famously pointed out that the biggest of the three pivotal trials, conducted in the US, had found no statistical difference from placebo, while two smaller trials elsewhere found modest symptom reduction of 1.5 to 2.5 days. Elashoff also raised questions about the way the company trials had measured the drug’s efficacy, finding the method used could “exaggerate small differences.” Even more worrying, in looking closely at patient diaries, Elashoff discovered that symptoms returned in some trial participants after they’d been classified as having symptoms alleviated, and in the US trial this happened more commonly with the drug than with placebo. “Analysis after analysis,” he told the committee, “you have results that are not significant in North America.” Just before 4 pm, the advisory committee voted by a resounding 13 votes to 4 to reject zanamivir; Glaxo’s share price fell, and Biota’s stock collapsed.
Within days Glaxo launched a fierce lobbying campaign, sending a furious and lengthy letter to the FDA, complaining about the FDA’s presentation, naming Elashoff more than 24 times, and demanding the advisory committee’s decision be disregarded. Within weeks of that letter the FDA management removed Elashoff from reviewing antiviral drugs, and a well placed source told me at the time that the explanation offered was that the FDA wanted a good working relationship with Glaxo.2 Within months FDA appeared to cave into pressure from Glaxo and approved the new drug, bizarrely rejecting the advice of its external advisers and staff. Elashoff , who was effectively punished for telling the truth, had a doctorate in biostatistics from Harvard, had been commended for the quality of previous reviews, and, ironically, would later receive a “special recognition award” from the FDA for his work reviewing zanamivir.
Several years later Elashoff spoke publicly about this tawdry episode on US national television. There was a relentless “pressure to approve” at the FDA, he told the investigative Frontline programme,3 even when drugs had safety or efficacy problems. “There was just an overall expectation from the top” that new drugs would be approved. His comments reinforce widespread concerns about industry funded regulation, with The BMJ running a cover story around this time based on a different drug debacle asking, “Who owns the FDA? The drug industry or the people?”4
Elashoff’s analysis is of course strikingly similar to the Cochrane review of zanamivir, which found a marginal benefit of a possible half day reduction of symptoms and no good evidence it can prevent complications including pneumonia, hospital admission, or death.1 As that review noted, there’s been no publicly funded trial of the drug despite public funds being invested in stockpiling. And as an accompanying editorial noted, the need for more regulatory independence is vital.5 Publicly funded trials and independent regulation—now that would be a real scientific breakthrough.
Notes
Cite this as: BMJ 2014;348:g3611
Footnotes
Competing interests: I have read and understood BMJ policy on declaration of interests and have no relevant interests to declare
Provenance and peer review: Commissioned; not externally peer reviewed.
References
↵ Heneghan C, Onakpoya I, Thompson M, Cohen H, Spencer E, Jones M, et al. Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014;348:g2547.Abstract/FREE Full Text
↵ Moynihan R. A case of hype v hope. Bulletin 1999 Dec 7.
↵ Dangerous prescription: Michael Elashoff interview. Frontline 13 November 2003. www.pbs.org/wgbh/pages/frontline/shows/prescription/interviews/elashoff.html.
↵ Who owns the FDA [cover]? BMJ 2002 Sep 14. www.bmj.com/content/325/7364.
↵ Loder E, Tovey D, Godlee F. The Tamiflu trials. BMJ 2014;348:g2630.FREE Full Text
http://www.bmj.com/content/348/bmj.g3611?sso=
RayMoynihan@bond.edu.au
While Relenza’s benefits are modest at best, its story would make a great Hollywood blockbuster
A drug company executive hailed it as “one of the greatest discoveries of the 20th century” and an Australian politician predicted two decades ago it might be a “breakthrough as significant as penicillin.” The Independent on Sunday in the UK ran a front page story declaring “a cure for flu that actually works,” and Australian tabloids quoted a patient saying that within 24 hours of taking it, “I was completely cured.” Given the sober findings of the recent Cochrane review of the drug,1 and the resources invested in pandemic stockpiles, all this misleading hype about zanamivir (Relenza) now seems obscene. Yet, inside the offices of the world’s most powerful drug regulator, a young biostatistician had concluded 15 years ago that the drug’s benefits were extremely limited. His findings back in 1999 would ignite the fury of one of the world’s most powerful drug companies and set the scene for a case study in failed regulation.
Later overshadowed by its more famous cousin, oseltamivir (Tamiflu), zanamivir was the first in this new class of anti-flu drug, the neuraminidase inhibitors. In the late ’70s Australian scientists working in publicly funded institutes had discovered a molecule common to different strains of influenza, and by 1985 a small biotech company called Biota was created to commercially exploit that discovery. In 1990 an agreement was signed with Glaxo Wellcome, with researchers describing “potent influenza virus . . . inhibitors” that could be the basis of a new drug. By 1999 it was time for regulatory assessment.
On 24 February, members of the advisory committee to the US Food and Drug Administration sat down in a Holiday Inn near Washington, DC to decide whether to approve this new “wonder drug.” Approval was seen by many as a foregone conclusion, as evidenced by buoyant stock prices and reinforced by the upbeat opening presentation from Glaxo representatives, who concluded the drug could reduce the time someone had flu symptoms by up to two and a half days. Australian regulators had already approved it, with a health minister proclaiming an “exciting medical breakthrough.” Biota’s share price was through the roof, and Glaxo had high hopes that the drug would become a blockbuster. But as the morning drew on and the team of FDA reviewers began to present, a reality check was imminent.
An FDA medical officer told the committee of several “concerns” arising from the review of the data. In particular, it was difficult to know the best way to measure the effect of the flu drug on a disease that “resolves completely and permanently in most cases.” Then came the FDA’s statistical reviewer, Michael Elashoff, who questioned not only how well the drug worked but whether it worked in any meaningful way at all.
The statistician famously pointed out that the biggest of the three pivotal trials, conducted in the US, had found no statistical difference from placebo, while two smaller trials elsewhere found modest symptom reduction of 1.5 to 2.5 days. Elashoff also raised questions about the way the company trials had measured the drug’s efficacy, finding the method used could “exaggerate small differences.” Even more worrying, in looking closely at patient diaries, Elashoff discovered that symptoms returned in some trial participants after they’d been classified as having symptoms alleviated, and in the US trial this happened more commonly with the drug than with placebo. “Analysis after analysis,” he told the committee, “you have results that are not significant in North America.” Just before 4 pm, the advisory committee voted by a resounding 13 votes to 4 to reject zanamivir; Glaxo’s share price fell, and Biota’s stock collapsed.
Within days Glaxo launched a fierce lobbying campaign, sending a furious and lengthy letter to the FDA, complaining about the FDA’s presentation, naming Elashoff more than 24 times, and demanding the advisory committee’s decision be disregarded. Within weeks of that letter the FDA management removed Elashoff from reviewing antiviral drugs, and a well placed source told me at the time that the explanation offered was that the FDA wanted a good working relationship with Glaxo.2 Within months FDA appeared to cave into pressure from Glaxo and approved the new drug, bizarrely rejecting the advice of its external advisers and staff. Elashoff , who was effectively punished for telling the truth, had a doctorate in biostatistics from Harvard, had been commended for the quality of previous reviews, and, ironically, would later receive a “special recognition award” from the FDA for his work reviewing zanamivir.
Several years later Elashoff spoke publicly about this tawdry episode on US national television. There was a relentless “pressure to approve” at the FDA, he told the investigative Frontline programme,3 even when drugs had safety or efficacy problems. “There was just an overall expectation from the top” that new drugs would be approved. His comments reinforce widespread concerns about industry funded regulation, with The BMJ running a cover story around this time based on a different drug debacle asking, “Who owns the FDA? The drug industry or the people?”4
Elashoff’s analysis is of course strikingly similar to the Cochrane review of zanamivir, which found a marginal benefit of a possible half day reduction of symptoms and no good evidence it can prevent complications including pneumonia, hospital admission, or death.1 As that review noted, there’s been no publicly funded trial of the drug despite public funds being invested in stockpiling. And as an accompanying editorial noted, the need for more regulatory independence is vital.5 Publicly funded trials and independent regulation—now that would be a real scientific breakthrough.
Notes
Cite this as: BMJ 2014;348:g3611
Footnotes
Competing interests: I have read and understood BMJ policy on declaration of interests and have no relevant interests to declare
Provenance and peer review: Commissioned; not externally peer reviewed.
References
↵ Heneghan C, Onakpoya I, Thompson M, Cohen H, Spencer E, Jones M, et al. Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014;348:g2547.Abstract/FREE Full Text
↵ Moynihan R. A case of hype v hope. Bulletin 1999 Dec 7.
↵ Dangerous prescription: Michael Elashoff interview. Frontline 13 November 2003. www.pbs.org/wgbh/pages/frontline/shows/prescription/interviews/elashoff.html.
↵ Who owns the FDA [cover]? BMJ 2002 Sep 14. www.bmj.com/content/325/7364.
↵ Loder E, Tovey D, Godlee F. The Tamiflu trials. BMJ 2014;348:g2630.FREE Full Text
http://www.bmj.com/content/348/bmj.g3611?sso=
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