Washington Editor

WASHINGTON - A congressional investigation into ImClone Systems Inc.'s handling of the cancer drug Erbitux eventually could end in a more transparent FDA.

Initiated by the House Energy and Commerce Committee, the investigation started about six months ago when Samuel Waksal, former CEO of New York-based ImClone, said the FDA issued a refuse-to-file letter for the Erbitux rolling biologic license application because it was missing "the train of documentation leading from the raw data to the conclusions."

If the problem were as simple as some missing material, then why not submit the information and be done with it, Rep. Diana DeGette (D-Colo.) asked Samuel Waksal's brother, Harlan Waksal, last week in an Oversight and Investigations Subcommittee hearing. Harlan Waksal was appointed ImClone CEO about three weeks ago when his brother resigned amid criticism of his business practices. Samuel Waksal, who was charged with conspiracy to commit securities fraud and perjury last week, invoked his Fifth Amendment right at the hearing.

While ImClone does intend to submit reanalyzed data for the approval, it's unclear whether the company will be forced to conduct additional trials in order to get the colorectal cancer drug to market.

But more than that, committee members are trying to figure out if the FDA's secretive approval process was abused or exploited for personal gain by ImClone executives, their friends and family members, and whether useful drugs are being delayed because of flawed development strategies and internal FDA confusion.

"This committee's investigation opens the black box of the FDA process and reveals a drug development and FDA review system that is not serving the interests of the American people," committee chairman Rep. Billy Tauzin (R-La.) said in the hearing last week. "Through this inquiry I hope we can prevent such train wrecks in the future. Drug companies and the FDA should develop approval strategies that work in the patients' interests - not so that companies can hype stock, personally enrich executives and short-change clinical research; not so that the FDA hangs back while a company falls on its face with a high-risk approval strategy as if it's just the company's gamble."

Throughout the meeting, committee members referred to the international attention ImClone and Erbitux received last summer when the CBS News program "60 Minutes" ran a segment on the success of the drug, and when Business Week wrote a cover story on it. The lawmakers maintain that while the Waksals were gaining financially due to the hype, FDA reviewers were finding flaws in the Erbitux application but were prohibited by federal law from discussing the problems publicly. The committee is questioning whether those rules should be changed.

In his defense, Harlan Waksal said the company had nothing to do with the "60 Minutes" segment.

The FDA has confirmed that its decision to grant Erbitux fast-track designation was based on the wrong version of the Phase II study (also called Study 9923). Waksal said a second, or amended, version of the study included additional patients, many of whom were not eligible for the trial.

Furthermore, results of a single-agent study showed enough activity in Erbitux alone to throw into doubt the assumption used for the Phase II study - that the toxic chemotherapeutic, irinotecan, needed to be used in combination with Erbitux for better results, according to the committee. Because of this, the committee investigation found, the FDA needed additional studies to resolve the issue, which would mean a delay in the launch of Erbitux. (See BioWorld Today, June 14, 2002.)

"It appears as though too many people dropped the ball throughout the approval process in this particular case. From the executives and scientists at ImClone who designed the flawed clinical trials, to Bristol-Myers Squibb, ImClone's business partner who was aware of the trial's flaws, including the too-small sample size and enrollment of patients who did not meet the eligibility criteria," DeGette said. "From the FDA's mishandling of the study's protocol design to the issuance of the refusal-to-file letter, sloppy work abounded through this process."

Before apologizing to the committee for setbacks surrounding development of Erbitux and for the patients who may have been affected, Harlan Waksal said the company has been criticized for running small trials and for results that were not proved by the most rigorous testing standards. However, he added that Congress created "fast track" in order to quickly bring drugs to market that had not been through Phase III, but had demonstrated potential for treating dying patients.

But DeGette said Congress did not approve the fast-track process so products could bypass rigorous and sound scientific review. "Unfortunately, there seems to be evidence that this is exactly what happened in the case of Erbitux," she said.

Lisa Cohen, a spokeswoman for DeGette, told BioWorld Today that the committee likely will hold another hearing on ImClone. Also, the committee is investigating businesswoman Martha Stewart, a friend of Samuel Waksal's, who dumped ImClone stock immediately before the FDA rejection was announced.