A phase III trial in ovarian cancer was allowed to continue even as the patients who received the experimental study drug were experiencing strikingly inferior outcomes compared with participants on standard therapy. The lack of answers about this trial remains a glaring example of shortcomings in the research paradigm.
Maurie Markman, MD
It has been 9 years since the oncology community learned for the first time at the annual meeting of the American Society of Clinical Oncology (ASCO) about an extraordinary event that challenged the ethical foundation of cancer clinical trials in the United States. That’s when it was revealed that a phase III trial in ovarian cancer had been allowed to continue even as the patients who received the experimental study drug were experiencing strikingly inferior outcomes compared with participants on standard therapy.1,2
Although many asked at the time how the trial could have continued with the safeguards supposedly built into study designs, including federal regulatory oversight of industry-sponsored clinical trials, there has never been a full, publicly disclosed response to these questions.
Now, 9 years later, it is likely that those involved in this debacle assume the episode has been closed and forgotten. That assumption would be incorrect. For some of us in the gynecologic oncology community, the lack of answers about this trial remains a glaring example of shortcomings in the research paradigm.
The study in question was a quite reasonable phase III randomized trial comparing a standard-ofcare arm consisting of either single-agent pegylated liposomal doxorubicin or single-agent topotecan to the experimental agent canfosfamide as a third-line antineoplastic drug strategy in the management of epithelial ovarian cancer.3 On the surface, there was nothing strange or alarming about the purpose of the trial or its apparent design.
However, the study revealed, as reported in an unmanned poster at the 2007 ASCO Annual Meeting, a highly statistically significant inferior survival associated with the canfosfamide treatment arm. The median overall survival (OS) with canfosfamide was 8.5 months compared with a median OS of 13.6 months for the standard care drugs (P = .0001).1
While the OS outcome clearly was most distressing, it was even more disturbing from the perspective of ethical and regulatory oversight of the clinical trial that there was also a strikingly inferior progression-free survival (PFS) for patients randomized to the canfosfamide regimen. The median PFS with canfosfamide was 2.3 months compared with a median 4.4 months (P = .0001) for the control arm.1
So, the very simple but profoundly critical question to be asked is as follows: Since this study was specifically designed as a trial to demonstrate the superiority of canfosfamide compared with pegylated liposomal doxorubicin or topotecan, where was the study’s Data Safety and Monitoring Committee and its independent statistician when the trial began to show an inferior time-to-disease progression for women who were randomized to receive canfosfamide?
Why was the study not discontinued when this negative trend was noted? Or, if not immediately discontinued, watched closely, and then stopped when the trend continued? The study began to enter patients in June 2003 and completed accrual in August 2006. Surely there was sufficient time during the active accrual period to assess and observe this stunningly distressing trial result. How is it possible that this negative trend in time-to-disease progression was not noted before the analysis was presented at ASCO in June 2007? Further, the final study report notes the median duration of treatment for patients on the experimental arm was one-half (65 days) the median duration of treatment for patients receiving pegylated liposomal doxorubicin (125 days) or topotecan (121 days).3
Did no one see these profoundly disturbing results until the abstract was being prepared for submission to the ASCO meeting?
What possible ethically justifiable explanation can be advanced that would have permitted patients (“research subjects”) to continue to be treated with an experimental drug resulting in an inferior survival outcome including PFS or OS?
We had to dig through documents filed in a stockholder lawsuit to find something approaching an answer to these questions. Apparently, officials of Telik, the California-based company developing canfosfamide, contended they were “blinded to all substantive data” about the clinical trial until the studies were concluded in December 2006.4
“While the [data monitoring committees] reviewed the underlying data from the trials on an ongoing basis, their charters expressly precluded them from disclosing any detailed data, such as drug efficacy, to the company,” according to a document filed in the case.4
Perhaps, at the time of reporting the study results, any surviving patients who participated in this disaster and the families of all deceased patients were informed regarding what actually happened in the conduct of this trial. Perhaps each involved site’s independent review board whose role was to protect the rights and safety of research subjects was also informed. And perhaps the FDA conducted an extensive review of this highly questionable episode before allowing Telik to resume clinical development of canfosfamide, if the company had been able to do so.5
But there is no evidence that any meaningful efforts were made to explain to the public, patients with cancer, or the oncology research community exactly how such a tragic clinical study-related event could have occurred, what was learned from the episode, and—perhaps most importantly—how such a distressing episode could be prevented from happening in the future. Finally, fully recognizing the study investigators had absolutely no control over the actual conduct of the study or of its ethical oversight, it is more than a little disconcerting that the gynecologic oncology research community as a group including those who participated and entered patients into this trial have apparently had little to say about what happened here.
How can a trial have gone so badly and research subjects apparently been subjected to such harm without this trial being stopped? What assurances do future patients with cancer have that such an event could not happen again? And why have these questions not been vigorously pursued by cancer investigators?
Maurie Markman, MD, editor-in-chief, is president of Medicine & Science at Cancer Treatment Centers of America, and clinical professor of Medicine, Drexel University College of Medicine. maurie. firstname.lastname@example.org.