NEWS

Erbitux Trial Flawed From the Beginning, Committee Finds

Judith Randal

Until late last year, accelerated U.S. Food and Drug Administration approval of Erbitux for the treatment of advanced colorectal cancer seemed to be in the bag. In hindsight, however, the chances of that may have been remote.

Erbitux is made by ImClone Systems Inc., a small New York City biotechnology firm. On December 28, the FDA told the company that the drug would not get fast track approval because the application the firm had submitted to the agency for that purpose did not contain the requisite information. ImClone initially painted the refusal as the result of easily solved minor problems, thus suggesting that the approval—previously portrayed by the firm as imminent—would be only briefly delayed. (See News, March 6, p. 326.)

Also a factor in the Erbitux story were FDA regulations that forbid the agency from commenting publicly on products it has under review and thus allowed ImClone to issue information about Erbitux without fear of official challenge. Indeed, this gag rule might have continued to protect the company had not a copy of FDA’s letter rejecting the Erbitux approval fallen into the hands of the Cancer Letter, a trade publication that published a report based on it last January.

With that, it became apparent that the reasons for FDA’s refusal to consider ImClone’s application were more serious than the company had let on. As the price of its stock, which had already fallen, tumbled further, the Justice Department and the U.S. Securities and Exchange Commission began to investigate.

But the highest visibility investigation has been in Congress, where the oversight and investigations subcommittee of the House Energy and Commerce Committee took on the job last winter (see box, p. 1825). Although much of the investigation has focused on ImClone’s business practices (most notably on the part of the firm’s former chief executive, Samuel Waksal, Ph.D.), it has also made an effort to get to the bottom of why the clinical trial ImClone submitted to the FDA failed to win the firm approval for Erbitux.

The House subcommittee asked Raymond B. Weiss, M.D., F.A.C.P, a clinical professor at Georgetown University Medical School, Washington, D.C., to review the Erbitux submission from a quality assessment perspective. A practicing medical oncologist, Weiss has extensive experience in monitoring cancer clinical trials and recognizing what can go wrong with them. He was given copies of the trial’s protocol, of which there were two versions (which in itself created some confusion), some patient case reports, and certain other pertinent materials.

Weiss took a hard look at whether the patients admitted into the study—the 9923 protocol—met its entry criteria. In testimony before the subcommittee in June, Weiss confirmed what had previously been reported: that 37 of the trial’s 139 patients—nearly 27% of the total—did not meet those criteria, some for more than one reason.

Weiss called that "incredible," saying that, for clinical trials to be well-conducted, "rates of ineligibility should not be more than single digit percentages." And he termed "incredible" too that 15 of the 37 patients unqualified for the trial got into it not because of inadvertence but because the entry requirements were deliberately waived for them. "Eligibility exemptions are forbidden in all the clinical trials with which I have had experience," he wrote in the report he prepared for the subcommittee.

A further problem Weiss found was that some trial patients had previously been unsuccessfully treated with irinotecan (Camptosar) and were given it again on the Erbitux trial. The rationale was that Erbitux (also known as cetuximab and C225) is a monoclonal antibody that targets the epidermal growth factor receptors on the cell surfaces of solid tumors, so it is believed that it works in a different way than chemotherapy. Accordingly, the question the trial posed was not so much whether Erbitux itself has antitumor activity, but more whether administering it with irinotecan could, synergistically, overcome resistance to chemotherapy.

To answer that question, the trial patients should have been given the same dose of irinotecan and on the same schedule as they had before enrolling in the Erbitux trial, Weiss wrote. Although the trial protocol allowed for modifications in the dosage of Erbitux, it made no such provisions for the use of irinotecan, and so left it up to trial’s participating physicians to decide that for themselves. Therefore, some patients in the ImClone study received irinotecan within the parameters they had previously, but some patients did not, and among them were more than a dozen (at least 17, Weiss found) for whom the chemotherapy dosage was significantly increased.

The result was a seemingly positive effect from Erbitux, but because of the glitch in the trial’s protocol—Weiss called it "a design flaw"—not one that could be quantified. And this was not the only consequence of the mistake. According to Weiss’s report, it was unclear whether—for some patients, at least—irinotecan had contributed anything to the therapy except toxicity. In other words, it was possible that it had had no benefit.

ImClone originally claimed that 22.5% of the trial’s patients had a partial response to the Erbitux-irinotecan regimen. (Partial response was defined as at least a 50% regression of tumors that at the outset of the study were visible and measurable on serial radiographic studies—almost always a CT scan). However, Bristol-Myers Squibb owns a portion of ImClone and has a financial stake in Erbitux, so its scientific reviewers were given access to the data, too. Again, according to Weiss’s testimony, it was their judgment that only 12.5% of the patients had a partial response to the therapy.

Similar complexities have (again according to Weiss’s report) dogged a study that was presented at the annual meeting of the American Society of Clinical Oncology in May in which 57 patients with metastatic colorectal cancer were treated with Erbitux alone.

Leonard Saltz, M.D., of the Memorial Sloan-Kettering Cancer Center in New York, and a Connecticut colleague, Arthur Rosenberg, M.D., who heads the cancer center at Greenwich Hospital, reported that the patients were refractory to irinotecan. But after looking at the data, reviewers from Bristol-Myers Squibb were not persuaded that the study bore that out. In addition, they questioned whether, as the investigators also reported, six of the patients given Erbitux had a partial response. They thought it was only five. (No patient treated with the drug to date has had a complete remission, although one patient had large inoperable tumors shrink to the point where the treating physicians judged them to be resectable. The patient has since died.)

More definitive information about Erbitux’s capabilities may nonetheless become available, though not immediately. ImClone and Bristol-Myers Squibb launched a phase II, open-label study of it in August that will test Erbitux as stand-alone therapy for 250 patients. And the firms recently announced that they have submitted plans to the FDA for two large trials that—because they would be randomized and controlled—could be counted on to find out whether chemotherapy is made more effective by Erbitux.

Then, too, Germany’s Merck KGaA, which has the European rights to Erbitux, has had a trial under way in which some of the patients given the drug have had head and neck cancer and others colon cancer. TheStreet.com, an online investment industry newsletter, recently reported that knowledgeable sources had told it that the results have been disappointing. ImClone released a statement saying, "As our partner Merck KGaA has said, the information in [the story on TheStreet.com] is based solely on unsubstantiated rumor. Merck KGaA has said that the clinical data cutoff for the study is at the end of the year and data analysis is expected in the first quarter of 2003. Any speculation about the results of the data at this time is both premature and irresponsible."


This article has been cited by other articles in HighWire Press-hosted journals:


             
Copyright © 2002 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement