ImClone debacle: what does it mean?

How much credence can we put in clinical trials to determine our treatments?

BY BILL AISHMAN

"A short, convoluted story about sex, intrigue, power, greed, betrayal, wealth, immorality, amorality, lying, cheating, cancer and death. Take it as specific food for thought and analysis as you contemplate the crisis in corporate governance, the melt-down of your 401K, and simultaneously consider entering a clinical trial."

Bill Aishman receives chemotherapy from nurse Rita Burke in a group treatment room at the Carl and Dorothy Bennett Cancer Center in Stamford. His son, Steve, right, who drives from Boston to Greenwich every week to take his father to the center, is documenting his father's treatment in photographs. (Photo: Kerry Sherck/Staff, Southern Connecticut Advocate)

As we watched the stock market meltdown, our own portfolios and 401Ks fade away, the spectacle of corporate governance misdeeds, major accounting irregularities and absurdly extravagant greed became manifest by reports regarding Enron, Arthur Anderson, Global Crossing, WorldCom, etc. - and ImClone. The headlines regarding ImClone, allegations about Martha Stewart, and the early morning arrest of the principals of ImClone all reported corporate governance transgressions and alleged insider trading violations reported in the class of the other financial disasters. But the basic reason for ImClone's meltdown was not financial accounting irregularities -- the irregularities were in the accrual, reporting, and conduct of the clinical trials of Erbitux (IMC-C225). These irregularities are beyond the pale of financial greed -- these irregularities strike at the very heart and lives of all cancer patients, the conduct of clinical trials, and the veracity of the thousands of clinical trial abstracts and reports on which cancer drugs and treatments are based.

ImClone is a major biopharmaceutical company dedicated to developing breakthrough biological oncology medicines. While the company research efforts targeted vaccines, growth factor blockers, and angiogenesis inhibitors, their major effort was development of Erbitux, a highly specific chimerized (a fusion of murine and human macromolecules) monoclonal antibody that binds to EGRF and thus inhibits tumor growth. Multiple abstracts/reports of Erbitux have reported about 23% response rates and the most recent abstract to do so was ASCO 2002 # 536 (44% partial response, with chemo, in colorectal cancer).

But ImClone's Erbitux was in a race with AstraZenca's Iressa as the first signal transduction inhibitor (STI) to be approved as an inhibitor of epidermal growth factor receptors (EGRF). Erbitux is an intravenous MoAB with multiple side-effects; Iressa is a daily oral pill with few side-effects. Iressa was closer to approval and was approved in Japan for treatment of lung cancer on 5 July 2002. Moreover, Eloxatin (oxaliplatin), a direct competitor of Erbitux, was recently approved by the FDA on a fast-track basis.

Notwithstanding multiple favorable trial reports and positive ImClone press releases touting Erbitux as a miraculous treatment for colorectal cancer, trouble was brewing behind the scenes in late summer of 2001. Bristol-Myers Squibb had agreed to pay $2 billion to ImClone for 20% of the equity in ImClone and for rights to Erbitux. But one week before the deal was closed on 4 September, Bristol-Myers had internal reports that revealed the drug to be only half as effective as ImClone was reporting and Bristol-Myers demanded data on the recent trials that were confused between Erbitux as a single agent and in combination with chemo. Notwithstanding this lack of data, the deal was consummated and announced with great fanfare to the investing public. With such a prestigious drug company expressing this confidence in the drug, the ImClone shares rose to $70 by early December but the demanded reports were not submitted to the FDA until 4 December. On 4 December an FDA official told an ImClone executive in charge of regulatory matters that the Erbitux application would be refused.

Moreover, news reports indicate that the FDA told ImClone in August 2001 that there were problems with the trial reports and that the drug showed inadequate responses: no complete responses, no patients went into remission and only 15% had partial responses. ImClone officials were notified unofficially in early December that Erbitux would not be approved.

Enter egregious greed and deception: Dr. Samuel Waksal is a medical research doctor and was the ImClone chief executive. His brother (also a medical/research doctor), Dr. Harlan Waksal, was the chief operating officer. On 6 December, after knowing of the FDA problems, Harlan dumped $44 million of his ImClone stock. On 25 December Bristol-Myers told Harlan that rejection of the drug was "99% likely. Harlan called Samuel and other executives with the news. Samuel transferred 79,797 shares to his daughter and tried to sell the shares on 27 December; he was refused and he transferred them to still another account but a sale could not be made therefrom. His daughter dumped 40,000 of her shares the same day. And the good doctor's father likewise dumped his shares the day before the FDA announcement. Can you connect the dots?

Enter domestic diva Martha Stewart, a long time social friend of Samuel and Harlan (the Waksals had shared as 'friends' in Martha's own initial public offering of Martha Stewart Living Omnimedia, which crashed from $20 to $6/share on news of her alleged insider trading in ImClone). On 27 December she dumped her ImClone shares while vacationing in Mexico. On 28 December the FDA officially notified ImClone of the rejection and ImClone announced the same later in the day. The ImClone shares plummeted.

On 31 December ImClone executives held a series of press conferences and told the investing public that the drug was still a miracle and the FDA rejection was only because of a faulty application and could easily be remedied. But shortly thereafter, the FDA rejection was public. The FDA had found that instead of the company's report of 3 patients who died within one month of receiving the drug, 21 had died. The FDA further found that 25% of the patients enrolled in the trial did not meet the entry criteria (FDA applications require a certain patient cohort). A cancer expert hired by congressional investigators concurred with the FDA that the ImClone Erbitux studies were too flawed to tell if anybody benefited from the drug.

The egregious greed and deception becomes more devastating for cancer patients: Dr. John Mendelsohn allegedly developed C225 in the early 1980s, before he went to M. D. Anderson. In 1996 he became president of MDA and was an advisor to ImClone and later a member of the ImClone Board of Directors. MDA was an arm of the Erbitux trials with a patient cohort of 195 patients. In 1996, Dr. Mendelsohn instituted a policy at MDA that denied a faculty member with a financial interest in a drug to serve as an investigator, or treat a patient with it. Last year he instituted a policy which requires that the president's financial interest in a drug under investigation be included in the patient's informed consent document. Yet neither the public nor trial participants were informed of Dr. Mendelsohn's interest in ImClone until December 2001. He sold $6 million of ImClone shares in December shortly after the FDA heads-up to ImClone officials, one month before the stock melted down. Can you connect the dots? Obviously, MDA denies any wrongdoing by any of their staff or the institution.

How is this tangled, convoluted story of corporate intrigue, greed and alleged insider trading related to prostate cancer? I believe that the ImClone story is not just another run-of-the-mill crisis of corporate greed and financial accounting irregularities that cost thousands of investors/employees billions of dollars -- I believe that it was overt acts by medical research doctors resulting in a grossly immoral injustice to the thousands of cancer patients, and to medical science on which our lives depend.

I am confident that the ImClone scientific debacle is not the general rule in scientific research; but I have to wonder how many of the 3,038 abstracts reported in ASCO 2002 and the multitude of reports in peer-reviewed journals are intentionally manipulated and flawed for economic gains at the expense of cancer patients? © Bill Aishman

NOTE: I am not a doctor and cannot render medical advice. I am not a medical researcher. I am not a reporter or connected in any manner to any media entity. I am a prostate cancer patient and I performed this layman's analysis for my own informational purposes. I make no claim that this analysis is definitive or complete. The above is my interpretation, analysis, and opinions of the following references:

REFERENCES

1) Erbitux defined: www.imclone.com/imc-c225.html
(2) Pollack A; The New York Times; 6 July 2002.
(3) The New York Times; 14 June 2002, pp. C1.
(4) ibid.; 15 June, pp. C1.
(5) Neergaard L; The Associated Press; Congress probes ImClone downfall; 14 June 2002.
(6) Houston Chronicle; 1 July 2002, Vol. 101, No. 261.
(7) The New York Times; 15 July 2002, pp. C1.
(8) CNNMoneline: 25 January 2002.
(9) New York Post, 12 August 2002; pp. 6.
(10) The New York times, 13 August 2002; pp. C1.

Bill Aishman's article first appeared on
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