Washington Editor

WASHINGTON - Members of a House subcommittee on Thursday were pointing their fingers in all sorts of directions, looking for someone to accept blame for the debacle surrounding ImClone Systems Inc.'s investigational cancer drug, Erbitux.

But Samuel Waksal, the former CEO of ImClone arrested on insider trading charges in New York Wednesday, was in no position to take the blame in front of the Energy and Commerce Subcommittee on Oversight and Investigations.

In fact, when Rep. James Greenwood (R-Pa.), the subcommittee chairman, asked Waksal if he'd placed more importance on personal profiteering than on patient health in the development of Erbitux, Waksal invoked his Fifth Amendment right and promptly left the room.

The Securities and Exchange Commission has charged Waksal with conspiracy to commit securities fraud and perjury. He was arraigned Thursday and released on a $10 million bond that included a $5 million up-front cash payment.

In Samuel Waksal's place, his brother, Harlan Waksal, who was appointed CEO of the New York-based company just a few weeks ago, spent a couple of hours trying to walk congressmen through the clinical trial and FDA approval process.

The House Energy and Commerce Committee initiated an investigation of ImClone's business transactions and development practices related to Erbitux (cetuximab) several weeks after the FDA issued ImClone a "refuse-to-file" letter on its rolling biologics license application for the drug touted as a breakthrough in cancer treatment. The drug is a monoclonal antibody designed to target and block the epidermal growth factor receptor and treat irinotecan-refractory colorectal cancer. (See BioWorld Today, Jan. 3, 2002, and Jan. 22, 2002.)

The Waksal brothers, particularly Samuel, caught the attention of the SEC, the Justice Department and the committee when a few family members and friends dumped large chunks of ImClone stock just before the FDA issued its RTF letter around Christmas.

Furthermore, some committee members believe the Waksals were bragging too much about the potential of Erbitux, causing ImClone's stock to shoot up. All the while, the FDA was going through ImClone's BLA and reportedly identifying problems with Erbitux.

Committee members seemed stumped Thursday by information uncovered in their own investigation that indicates ImClone may have misled the FDA about the protocol in the Phase II study used as the basis for the fast-track application. The FDA and ImClone discussed the protocol in a meeting Aug. 11, 2000, more than a year before Bristol-Myers Squibb Co., of New York, signed on as ImClone's partner in a deal worth $2 billion. (See BioWorld Today, Sept. 20, 2001.)

The committee said ImClone gave the FDA two versions of its Phase II study (also called 9923). The second version - used in ImClone's BLA submission - was amended and included some patients who were not eligible for the trial.

But when the FDA granted Erbitux fast-track status in January 2001, the agency based that decision on the first version.

"Our investigation tells us that the FDA was relying on the wrong version of the study when it made its decision for fast track," Rep. Bill Tauzin (R-La.), said to Harlan Waksal. "Our investigation tells us that no one at ImClone corrected this mistake. Why wouldn't you correct this and get this drug approved?"

In response, Waksal said the FDA had the same version as ImClone.

"It surprises me that they think we would try to mislead them," he said.

Furthermore, he said, the differences between the original trial and the amended version were not great. "The protocol was amended slightly," he said. "It was modified, but the FDA knew that."

Regarding the ineligible patients who enrolled in the trial, Waksal said those types of problems are fairly common in the drug development process. Besides, in the ImClone trials, patients classified as ineligible fell into that category because of abnormal liver tests.

"Let me say that with the benefit of 20/20 hindsight, we now know that we could and should have done a better job in putting together our application package," Waksal said. "Many of our critics have suggested that our pivotal trial was too small and that our results were not proven by the most rigorous testing standards. But I would remind those critics that Congress explicitly created fast track to bring drugs to market that have not been through the rigors of a Phase III test."

So who's to blame?

When Tauzin couldn't get the answer he was looking for from Waksal, Rep. Ernie Fletcher (R-Ky.) put a similar question to Laurie Smaldone, senior vice president of global regulatory sciences for Bristol-Myers.

"With all the experience that Bristol-Myers has in drug development and getting drugs through the FDA, why didn't you notice a problem?" Fletcher asked. "Do you think this is the FDA's failure or ImClone's failure to follow protocol and not be up-front with the FDA?"

Smaldone responded that she could not answer such a question.

Indeed, when the same was asked of committee investigator Raymond Weiss, a consultant in oncology and clinical professor of medicine at the Lombardi Cancer Center at Georgetown University Medical Center in Washington, he said he couldn't answer such a question, either.

He did say he believes Erbitux is an "interesting" drug, but not a breakthrough or blockbuster. "I think Bristol-Myers Squibb thought they were getting a diamond, but got zirconia," Weiss said.

While the response rate, or shrinkage of tumors, in the first study was 12.5 percent, said a Bristol-Myers independent investigator, the response rate in a smaller, 57-patient study was 10 percent, or six responses out of 57 patients.

Nevertheless, Erbitux has not been turned down by the FDA.

Waksal told the subcommittee that ImClone intends to submit additional data to the FDA in combination with data from a trial being conducted by partner Merck KGaA, of Darmstadt, Germany. (See BioWorld Today, May 23, 2002.)

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