A dust storm is being kicked up following the announcement at the annual meeting of the American Society of Clinical Oncology of the early suspension of Johnson & Johnson’s drug trial testing its prostate cancer drug, aribraterone (Zytiga).
The trial was suspended by J & J’s Data Safety Monitoring Board (DSMB), a committee that operates in secret. The DSMB determined that the data showed that the drug reduced the spread of prostate cancer by 57%, and that the results hinted, but didn’t prove, that Zytiga was extending the men’s lives by a startling 33%.
But the decision to suspend the trial is viewed as highly questionable, raising disturbing questions about the role that marketing played–especially in light of the fact that Zytiga’s patent is due to expire in 2017.
Could marketing considerations have been the determining factor leading to the suspension of the trial, thereby promoting its (unproven) superiority?
Wall Street analysts wasted no time in trumpeting the news to their clients as a positive for J & J and a negative for its rival Dendreon.
The Zytiga trial enrolled 1,088 men around the world who had prostate cancer that had spread, but who hadn’t yet turned to chemotherapy. The patients, at 151 clinical sites in 12 countries, had no visible symptoms or only mild symptoms of their disease. They were randomly assigned to get Zytiga or a placebo.
Forbes science reporter, Matthew Herper, notes: “lately DSMBs have been deciding to stop trials early an awful lot, causing some statisticians to worry that they are too eager to deliver early results. Stopped-early studies proved the benefits of Viread for preventing HIV infection, Afinitor in breast cancer, Viread for preventing HIV infection, Crestor for preventing heart attacks and strokes, Revlimid for use in multiple myeloma after a stem cell transplant, Sutent in treating the rare form of pancreatic cancer that afflicted Steve Jobs, and studies of Lotrel and Norvasc, both blood pressure drugs, just to name a few.”
He further informs us that DSMBs “are often recruited by companies themselves, [and] are making decisions “driven by marketing considerations” and the desire to get drugs to market faster and not their obligation to society.”
DSMBs were established as independent monitors of clinical trial data in real time–data to which they alone are (presumably) privy. DSMBs were introduced as a safeguard to protect the safety of human subjects while maintaining the integrity of the blinded study. DSMBs are empowered to suspend a study for ethical reasons–when the evidence demonstrates unambiguously that one treatment is overwhelmingly superior for survival to the other.
As with pretty much every aspect of clinical trials, the integrity of the entire process is muddied by those with high financial stakes in the endeavor. Those stake holders control the protocol design and time frame, the selection of the research centers and the investigating scientists, the number and selection of patients, the data and data monitoring boards. Absolutely nothing is left to impartial evaluation or oversight. Indeed, “Michael Meyers, the J&J executive in charge of Zytiga, said that the DSMB makes only recommendations, and that the sponsor – the company – makes final decisions.”
Likewise, GlaxoSmithKline and Merck were intimately involved in the deliberations of their DSMBs involving the diabetes drug Avandia (GSK) and the cholesterol drug Vytorin (Merck).
To paraphrase a Mae West quip in response to an admirer who exclaimed, “Goodness, what beautiful diamonds…” to which Mae West famously responded:
“Goodness had nothing to do with it.”
Ethics had nothing to do with these suspensions.
On Saturday, a researcher from the University of California, San Francisco, stood in front of a crowd of doctors at the year’s biggest cancer conference and presented stunning results from a company-funded study of a new Johnson & Johnson drug, Zytiga. The study tested the pill, already approved for men who have received chemotherapy for prostate cancer, in those with an earlier stage of the disease. It slowed the spread of their cancer by 57%. Even more tantalizingly, the results hinted, but didn’t prove, that Zytiga was extending the men’s lives by a startling 33%.
Immediately after the data were presented, statistician Susan Halabi from Duke University took the stage to discuss the study – a job she’d been given by the American Society of Clinical Oncology, which runs the conference. She raised real concerns about how confident doctors could be about Zytiga’s benefit. The Zytiga clinical trial had been stopped too early, she said, and that meant that right now it might be giving an impression that the drug is more effective than it actually is. It would also make it difficult to prove Zytiga extended these men’s lives once and for all. In an interview, she said that the decision to give placebo patients the drug “sacrificed” the trial. “This decision,” she said, “is irreversible.”
Why did the Data Monitoring Committee (DMC) recommend unblinding the study based on an interim analysis?
That was the question that Susan Halabi, associate professor of biostatistics and bioinformatics at Duke University, sought to answer in her excellent discussion of Ryan’s presentation. Given the complexity of the statistical issues in question, and the difficulties of questioning the decision to end the study early, Halabi gave a very fair review of the issues.
The COU-AA-302 trial had several planned interim analyses, with clearly defined criteria that would show, based on how much study data was available, whether the drug was effective or not.
Halabi presented the COU-AA-302 overall survival data in the context of the O’Brien-Fleming boundary, that graphically represents a curve, one side of which the drug is judged to be “ineffective,” the other side “effective.” Based on this analysis, abiraterone was “ineffective.” But as Halabi went on to say, it was extremely close to the boundary. In that case, why would the independent data monitoring committee (DMC) choose to unblind the study at the time it did the analysis, rather than wait a little longer until statistical significance might be reached?
The judgment of the DMC has to be questioned. The decision to unblind the study means that the “interim” data presented by Ryan is effectively the final data for the randomized trial. Unblinding a study introduces biases, which essentially turns a well-controlled randomized study into an observational one. As Halabi noted in her presentation, the “follow-up data will be biased due to confounding,” —which means other factors besides abiraterone could be influencing whether patients live longer in one group or another. By halting the study early, patients in the placebo group are now being switched over to abiraterone, which makes the comparison between the drug group and the placebo group less clear. Statistically, the COU-AA-302 data only shows a “trend to overall survival,” said Halabi.
The DMC’s decision to terminate the trial early has led to the trial’s failure to show a statistically significant survival advantage. Would it have required long to wait to show overall survival? Probably not. The interim analysis that Ryan presented was based on 43 percent of the expected overall survival events (333 deaths of trial subjects). This took place in the fourth quarter of 2011. The next interim analysis was planned for the second quarter of 2012 based on the expectation that 425 deaths (55 percent of the expected death events) would have occurred. Halabi told me after her presentation that it was highly likely this interim analysis would have crossed the O’Brien-Fleming boundary, and shown a statistically significant overall survival advantage for abiraterone in chemotherapy-naïve patients.
The early interim analysis of the COU-AA-302 trial is an opportunity missed to show an unequivocal survival advantage for abiraterone in the pre-chemo setting. The study failed to show overall survival and no matter what the positive PR spin is put on the data, it is unlikely that the study will ever show statistically significant overall survival for abiraterone. On some level this must be regarded as a failure of drug development. Ending studies in this way does a disservice both to medicine and the men who participated in the trial.