Special Report The C225 Controversy

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The C225 Controversy: How ImClone's "Hot" New Drug Got Cold Shoulder From FDA This Special Report includes The Cancer Letter's comprehensive FDA: C225 Data coverage of the controversy surrounding the development of the drug Insufficient C225 for colorectal cancer by ImClone Systems Inc. . . . Page 2 Stories in this Report begin with the determination by the Food and Drug Administration that application for the much-hyped drug was ImClone CEO Waksal: “scientifically incomplete" and unsuitable for presentation to the agency's "We Screwed Up" advisory committee on oncology. These articles appeared in The Cancer Letter from Jan. 4 through . . . Page 6 March 8, 2002. The articles begin on page 2. The complete text of the FDA Refusal to File letter appears below. Congress, SEC, DOJ Investigate ImClone ImClone Application "Scientifically Incomplete" . . . Page 9 FDA States In Refusal To File Letter On C225 Our STN: BL 125033/0 Dec. 28, 2001 BMS Seeks To Oust Lily Lee, Ph.D. Waksals, Gain Control ImClone Systems, Incorporated Of C225 Development 22 Chubb Way . . . Page 13 Somerville, NJ 08876 Dear Dr. Lee: Protocol For C225 This letter is in regard to your October 30, 2001, biologics license Tells The Story application for Cetuximab in combination with irinotecan submitted under Of A Flawed Trial section 351 of the Public Health Service Act. . . . Page 15 The Center for Biologics Evaluation and Research (CBER) has performed a preliminary review of your submission and has determined that it is not sufficiently complete to enable a critical medical review. Other Firms Looked As outlined in Title 21 of the code of Federal Regulations Section At C225 Before BMS 601.2(a), “an application for license shall not be considered as filed until . . . Page 20 all pertinent information and data have been received from the manufacturer by the Center for Biologics Evaluation and Research.” This section of the BMS Pumps $200M regulations lists all the information necessary to be submitted by the Into ImClone manufacturer. In addition, the CBER Refusal to File Guidance Document In Peace Deal for Product and Establishment License Applications and the “Guidance . . . Page 21 for Industry: Providing Regulatory Submissions to the Center for Biologics Evaluation and Research in Electronic Format—Biologics Marketing Applications,” provide interpretations of these submission requirements. Because the information in your application is incomplete, it is not being (Continued to page 23) Jan. 4, 2002, Vol. 28 No. 1 Street that the agent had met clinical endpoints, and FDA Says Data Insufficient that the FDA concerns involved documentation that could be reproduced. To Evaluate C225 Application “We feel that this is not a drug that failed to FDA last week declined to review the application meet its clinical endpoints,” Samuel Waksal, the by ImClone Systems Inc. for C225, a treatment for company president and CEO, said at the conference. colorectal cancer patients who develop progressive “However, the company did fail to provide a proper disease following treatment with CPT-11. train of documentation which would allow the agency The agency’s “refusal to file” letter for C225 to accept this filing.” said the data presented by the company were According to Waksal, the agency was unable to insufficient to evaluate the Biologics License assess the patients’ eligibility and their subsequent Application for the therapy. performance in the pivotal trial. In that trial, patients ImClone (Nasdaq: IMCL) planned to present its refractory to CPT-11 were treated with CPT-11 and application for accelerated approval of C225 to the C225. Oncologic Drugs Advisory Committee in February. A copy of the agency’s refusal-to-file letter The drug’s trade name is Erbitux and the generic name obtained by The Cancer Letter indicates that the is cetuximab. problems with the trials were more extensive than the Last fall, Bristol-Myers Squibb Co. bought a 20- absence of the “train of documentation” and involved percent stake in the New York-based biotechnology the structure of the trials. According to the nine-page firm for $1 billion, and co-licensed C225 in a letter: transaction that could add up to another $1 billion if —The company’s pivotal trial was not “adequate C225 is approved. ImClone’s regulatory approval and well controlled.” strategy was in place before the transaction with —The trial was not designed to demonstrate the Bristol, and under the deal, ImClone is responsible contribution of CPT-11 to the regimen. for the filings. —New clinical trials would be needed to provide The FDA letter was dated Friday, Dec. 28, and more robust data documenting response and to was announced after the stock market closed. In a compare the efficacy of the single agent C225 to the telephone conference for the press and the financial combination of C225 and CPT-11. community before the reopening of the market on the —The application does not justify the proposed morning of Dec. 31, ImClone officials assured Wall dosage of C225, and additional pharmacokinetic information is needed.

Member, —The pivotal trial contains protocol violations. Newsletter and Electronic Publishers —Reporting of deaths within 30 days of last Association treatment with C225 is incomplete. The agency World Wide Web: http:// identified 21 patients who died within a month of the www.cancerletter.com Editor & Publisher: Kirsten Boyd Goldberg last treatment with C225, but the company provided Editor: Paul Goldberg narratives for only three of those patients. Editorial Assistant: Shelley Whitmore Wolfe “The exchange between the agency and us is right now a confidential exchange, because we are Editorial: 202-362-1809 Fax: 202-318-4030 working with the agency to try and put together a PO Box 9905, Washington DC 20016 response that allows us to move forward with our E-mail: [email protected] BLA,” Samuel Waksal said to The Cancer Letter. Customer Service: 800-513-7042 “We didn’t release the letter, so whatever you have, PO Box 40724, Nashville TN 37204-0724 you have from an illegitimate source.” E-mail: [email protected] Waksal said the refusal-to-file letter lays the groundwork for the company’s discussions with FDA. Subscription $305 per year worldwide. ISSN 0096-3917. Published 46 times a year by The Cancer Letter Inc. Other than "fair use" as specified “The letter that we got from FDA raises issues,” he by U.S. copyright law, none of the content of this publication may be said. “It doesn’t raise corrective measures. We are reproduced, stored in a retrieval system, or transmitted in any form going to meet with the agency, give them the corrective (electronic, mechanical, photocopying, facsimile, or otherwise) without prior written permission of the publisher. Violators risk criminal penalties measures we are going to use, find out if it’s good and $100,000 damages. Founded Dec. 21, 1973, by Jerry D. Boyd enough, and then we will let you know what they

The Cancer Letter Page 2 n March 8, 2002 say.” believed, obviously, that in-between documentation Regulatory issues notwithstanding, C225 works, was not the gating factor. Obviously, that’s not the Waksal said. case.” Waksal said the company had the data, and “This is an approvability issue; not an acceptance would be able to provide the documentation the agency issue,” Waksal said in an interview. “And the required. approvability issue will be publicly aired at ODAC, When the market opened on Dec. 31, the price and if ODAC feels that we don’t have enough data to of the company’s stock dropped by 19 percent. warrant approvability of this drug, that’s one thing. I The issue of verifying eligibility is fundamental don’t think that they will think that. I don’t think that in clinical trials. “The company said that FDA was anyone believes that this drug doesn’t have dramatic not challenging the response rate, but it may have activity.” been that FDA could not even address that issue until The agency’s decision to refuse the ImClone they got better documentation, so that’s why the submission is likely to have important implications in application wasn’t allowed in the door,” said Mace oncology, observers said. First, the potential of failure Rothenberg, associate professor of cancer research of C225 could impede Bristol’s chances of acquiring at Vanderbilt Ingram Cancer Center, a gastrointestinal a blockbuster drug it needs to replace Taxol, a drug cancer expert who was not involved in development now available from generics. of C225. The FDA action could also mean some tightening “The big issue here is whether they can go back of what so far has been a generous mechanism of and go through the documentation they have, and accelerated approval, based on “surrogate endpoints” include the requested information in the revised BLA that may translate into benefits to patients. Accelerated that will then meet the satisfaction of FDA to allow approval is usually based on nonrandomized phase II filing, or whether that documentation never was trials. obtained in the first place,” Rothenberg said. C225 is a monoclonal antibody that targets the At the conference, company officials said the Epidermal Growth Factor Receptor expressed on the data were available for demonstrating the patients’ surface of some cancer cells. eligibility and performance, and the process would be completed in the next few months. Samuel Waksal “Stunned” Originally, ImClone was responsible for According to the FDA document, ImClone was regulatory filings, while Bristol stood on the sidelines. repeatedly informed about the problems with its This hands-off arrangement has changed, ImClone clinical trials. However, at the company telephone officials said. The biotech company is now working conference, Samuel Waksal said he was unaware of with BMS to respond to the agency’s questions. the problems with the application “BMS is clearly playing an increased role,” “I was rather stunned when we got the letter,” ImClone executive vice president Harlan Waksal said Waksal said at the conference. “I have to tell you, to The Cancer Letter. “We have gone to them to ask this was unexpected. I didn’t have plans to end the for their help and expertise.” year this way.” At the conference, Samuel Waksal described the In an interview, Waksal said he was stunned in interaction between the two companies as “seamless.” part because such letters from FDA are uncommon. “It will be as if its one group [is] moving forward to “A lot of these questions could have been answered rectify all the issues,” he said. during the review process,” Waksal said to The Cancer Many of the questions raised by FDA involve Letter. “Refusal-to-file letters don’t come that often, the operation of the Independent Radiology Advisory and we believe that a lot of the pieces that were Committee, IRAC, assembled by ImClone to review missing would not be something that would constitute patient data from the pivotal trial. a refusal to file.” The committee included two radiologists and two At the conference Dec. 31, Waksal offered oncologists who read the scans to determine the something of a mea culpa for his company’s failure patients’ eligibility and their response to treatment. to anticipate that FDA would require data for assessing The committee members worked independently from each patient’s eligibility and performance. each other, and whenever disagreements arose, they “Obviously, some mistakes may have been had to come to a consensus in assessing each case. made,” Waksal said at the conference. “We had ImClone officials said at the conference that the

The Cancer Letter Special Report n Page 3 committee’s determinations were in concordance with that we have the data available—the data exists in its the determinations of investigators who treated the raw form.” patients at the trial’s 40 sites. The FDA letter states that new studies would be “The concordance of the response rates is very needed. solid, both between the institutions where the studies To begin with, the application does not contain were run and with the IRAC,” Harlan Waksal said at data that isolates the contribution of CPT-11 to the the conference. “However, most important is to combination regimen, the letter states. provide the data in a clear way, so when reviewers According to the agency, the company was told take a look at this information, they can follow the repeatedly that data demonstrating the contribution train of thought, and without any question reach the of each of the agents would be required. same conclusion. Obviously, we did not prepare this “In order for your application to be considered documentation well enough for them to do so. That complete, you were informed during the meeting of train of thought—the ability to take the cases and move Aug. 11, 2000, in our letter of Jan. 19, 2001, and through each one—wasn’t clear enough for the agency during the telephone conference call of Jan. 26, 2001, to accept this filing.” that the application must provide evidence that the addition of a toxic agent (irinotecan [CPT-11]) is Will the Studies be Repeated? necessary to achieve the clinical effect,” the letter To be eligible for the company’s pivotal trial, states. patients had to fail a regimen containing CPT-11. After “The data do not show that the response rate treatment failure was documented, these patients were observed with the combination of cetuximab [C225] treated with a combination of CPT-11 and C225. and irinotecan could not also be observed with single According to a paper presented at last year’s agent cetuximab at the dose and schedule proposed.” annual meeting of the American Society of Clinical The pivotal trial was not “adequate and well Oncology, 22.5 percent of the 120 patients treated controlled,” the letter states. “Because we have achieved an objective response to the two-drug determined that the current study was not adequate regimen. and well controlled and that robustness of the overall Though the trial was designed to assess potential response rate is less than is stated in the study reports, synergy between the two compounds, in an earlier you will need to conduct additional studies to provide meeting with the company, FDA officials said that this evidence.” the trial design makes it impossible to separate the The agency suggested a “randomized, controlled activity of CPT-11 from the activity of C225. trial directly comparing the efficacy of single agent As a result, the company initiated a smaller, cetuximab to the combination cetuximab plus confirmatory trial of C225 as a single agent, company irinotecan in patients who can be documented to be officials said. That trial enrolled 57 patients and refractory to irinotecan therapy,” the letter said. produced an objective response in 6 patients, an 11- “Alternatively, irinotecan therapy could be included percent response rate, the FDA letter said. Patients as a third arm in a study enrolling patients who are enrolled in the confirmatory trial were taken off CPT- not refractory to irinotecan.” 11 regimens, and the trial did not make use of IRAC. Deviations from the protocol are a problem, too, Company data cited by FDA reports that the the letter states. This problem is not limited to the pivotal trial of the two-agent regimen had the 95% question of eligibility. confidence interval of 15.4%, 30.5%. The single-agent According to the agency, one patient was trial had the 95% confidence interval of 4%, 21.5%. declared refractory and enrolled in the trial without a At the Dec. 31 conference, ImClone officials CT scan to evaluate response to CPT-11. No baseline acknowledged the possibility that studies may have scan was performed, and subsequent scans showed to be repeated. no evidence of metastatic disease. “If we cannot provide the evidence in such a The patient ultimately withdrew for reasons way that makes the agency accept the package, then unknown, the letter states. Another patient received the clinical trial is not going to be sufficient for radiation three weeks before enrollment. Still another approval,” Samuel Waksal said. “However, that is not patient was treated with a nonstandard dose of CPT- what we believe is going to happen. Hopefully, we 11 before enrollment. won’t need to prove anything else, because we believe

The Cancer Letter Page 4 n March 8, 2002 Justification for C225 Dosage Needed It is unclear whether the company would be able “The application does not contain the data to use the same IRAC. requested to support the proposed dose and schedule “We don’t want to call the IRAC back in until for cetuximab,” the FDA letter states. The agency we ask the agency what we need to say to IRAC,” said the issue of dosage is not new. Samuel Waksal said at the conference call. “During the Jan. 7, 1999, meeting, you indicated “Remember, this IRAC has already reviewed these that saturation of tumor occurs at doses between 200 films. They already have seen them. They already to 400 mg/m2, and that a high dose is necessary have their bias. It may be that we need to redo all because the liver and skin, along with the tumor, serve this.” as ‘a sink’ for the elimination of the drug,” the letter After acquiring a stake in ImClone and licensing states. the drug, Bristol paid the biotech company $200 The agency said it didn’t concur with this analysis million. Had FDA accepted the application, the and asked repeatedly for justification of the dose. company would have received another $300 million. “To correct this deficiency, you need to provide Marketing approval would bring in $500 million. Bristol an integrated dataset and analysis of the stands to receive about 40% of the profits on C225 pharmacokinetic profile of cetuximab,” the letter states. over the life of the product. “The analysis should support your statements Bristol bought its stake in ImClone for $70 per regarding the relationship of the proposed dose and share, a considerable premium. Last September, when dosing regimen to clinical safety and effectiveness, the deal was announced, ImClone shares were trading the intensity of tumor EGFR expression and tumor at about $60. A month later, when the deal was burden in patients, and to in vitro and in vivo levels completed, the price of shares dropped to about $50. of cetuximab obtained in subjects receiving the All company stockholders had the opportunity proposed dose and schedule.” to sell their stock at that time. According to company “The safety database is not complete and disclosures, shareholders who cashed in a portion of contains inconsistencies and discrepancies that the stock last Oct. 29 included Samuel Waksal, who preclude an accurate assessment of the toxicity sold 815,000 shares, Harlan Waksal, who sold 775,000 profile,” the letter states. shares, chairman of the board Robert Goldhammer, According to the document, FDA identified 21 who sold 362,000 shares, and board member John patients who died within 30 days of the last treatment Mendelsohn, who sold 90,000 shares. Mendelsohn, with C225. The company provided explanations for president of M.D. Anderson Cancer Center, pioneered three of the deaths. “Narrative summaries are required the preclinical development of C225. for all patients who died during or within 30 days of The C225 application was being processed under administration of study drug or prior to resolution of the FDA Fast Track mechanism. treatment related toxicity,” the agency states. ImClone is about to start a phase III study The letter was signed by Karen Weiss, director comparing the Saltz regimen of CPT-11, 5-fluorouracil of the FDA Division of Clinical Trial Design and and leucovorin with Saltz regimen plus C225 for the Analysis and Kathryn Stein, director of the Division front-line treatment of advanced colorectal cancer, of Monoclonal Antibodies. Both divisions are part of Samuel Waksal said to The Cancer Letter. A pilot the FDA Center for Biologics Evaluation and Research. study for the trial involving 30 patients was recently completed, and the company is starting to accrue Now What? patients for the 1,000-patient study, Waksal said. It will be a challenge for ImClone and Bristol to Also, the company is conducting phase II trials respond to the agency’s concerns by organizing raw of C225 in pancreatic cancer, head and neck cancer data into a format acceptable to FDA, experts say. and non-small cell lung cancer, and phase III trials in “I think FDA is going to want sequential CT combination with chemotherapy and radiation therapy scans that show that the tumor was progressing prior as first-line treatment for head and neck cancer. to study enrollment despite treatment with CPT-11, On Dec. 28, the day ImClone received the and another set of sequential scans demonstrating that refusal-to-file letter, Astra-Zeneca filed a New Drug a subset of patients responded for a clinically Application for Iressa, a small-molecule agent that is meaningful period of time as a result of treatment a potential competitor to C225. with CPT-11 and C225,” said Rothenberg.

The Cancer Letter Special Report n Page 5 Jan. 11, 2002, Vol. 28 No. 2 adopted by ImClone, experts say. The pivotal phase ImClone “Screwed Up,” CEO II trial the company presented as a basis for “accelerated approval” by FDA was testing the Tells Conference; Stock Falls hypothesis that C225 works synergistically with CPT- In his first appearance before investors since FDA 11. said his company’s application for approval of C225 Trials of multi-drug regimens are commonly was unacceptable, ImClone Systems Inc. president conducted by NCI-funded clinical trials cooperative and chief executive Samuel Waksal acknowledged groups. However, group trials are intended to shape having “screwed up.” medical practice, and are rarely used to generate data “What happened was that we put together a faulty for approval of new drugs. By contrast, trials intended [Biologics License Application] package, and we to support FDA approval are usually designed to isolate screwed up,” Waksal said at JPMorgan H&Q health the impact of the new drug. care conference in San Francisco Jan. 7. At the conference, Waksal reiterated his claim ImClone’s stock plunged after the New York- that the company was surprised to receive a refusal based company received a refusal-to-file letter from to file letter, a piece of correspondence that states FDA on Dec. 28. The value dropped again after The that the application is poorly put together and cannot Cancer Letter published portions of the “refusal to be reviewed. file” letter in which the agency asked for additional “FDA didn’t receive or could not comment, on clinical trials of C225 in advanced colorectal cancer any of the clinical information until after they received (The Cancer Letter, Jan. 4). the package on Oct. 31, [2001]” he said. Immediately following Waksal’s remarks at the Generally, the agency offers guidance on the conference, ImClone’s stock dipped again, hitting a structure of the trials long before companies submit low of $31.9 on Jan. 9, then bouncing back to $34.2 applications for approval. FDA officials meet with the following day. Overall, the company’s stock lost companies before clinical trials begin, and at that point 53.7 percent of its value since Dec. 5. the agency reviews the trials for safety and comments The company is facing at least a dozen class on design. action suits filed on behalf of shareholders. The suits Companies are free to disregard the agency’s claim that the management of ImClone (Nasdaq: advice on design, but when they do, they are taking a IMCL) knew, or should have known, that the BLA risk. was in trouble, but didn’t announce this to “Trial design is usually discussed in pre-phase II stockholders. meetings, at the end of phase I,” said a senior “There were a lot of questions that people have pharmaceutical company executive involved in raised in all of this, and they said that we didn’t development of oncology drugs and their approval communicate properly these issues with our “You don’t have to listen to FDA, but you would be a shareholders, and that isn’t the case at all,” Waksal fool not to, if you want to use the trial for registration.” said at the conference Jan. 7. “We’ve been The FDA refusal to file letter said the agency communicating, and communicating accurately all the had reservations about the design of ImClone’s trial. while.” The letter urges the company to conduct randomized Waksal said the principal problem with the BLA trials, offering the company a choice of two designs: was the company’s failure to provide documentation —A randomized, controlled trial comparing demonstrating that the patients enrolled in ImClone’s CPT-11 and C225 with C225 as a single agent in pivotal trial had met the eligibility criteria. patients refractory to CPT-11, or Only advanced colorectal cancer patients whose —A three-arm trial of CPT-11 and C225 versus disease progressed following treatment with a regimen CPT-11 and C225 as single agents in patients not containing CPT-11 were eligible for ImClone trial of refractory to CPT-11. CPT-11 plus C225. C225 is a monoclonal antibody that targets the “Without defining the refractory part of this, you Epidermal Growth Factor Receptor expressed on the don’t have a clinical trial, because it’s not well- surface of some cancer cells. The agent’s trade name controlled,” Waksal acknowledged. is Erbitux, and its generic name is cetuximab. Demonstrating eligibility was indeed a fundamental issue in the high-risk approval strategy

The Cancer Letter Page 6 n March 8, 2002 Blaming the Consultants in the charter for the IRAC,” the letter states. In his presentation Jan. 7, Waksal offered his “However, the license application also contains the version of how ImClone’s trials went wrong. Quintiles Technical Manual, which has a different set The problems were caused by the Independent of criteria for assignment of response It is unclear Response Assessment Committee (IRAC), a group of which criteria were used ” two radiologists and two oncologists who reviewed Also, the application does not contain the the data from the trial’s sites, he said. computer algorithm used to assess changes in the “The data from all of the clinical sites was tumor, the letter states. digitized and transferred to computers where [IRAC] Quintiles Translational is a contract research firm sat with their cursors and reviewed the data in a blinded that conducts clinical trials. It is unclear whether the fashion,” Waksal said. “During that review process, firm was involved in preparing the ImClone BLA. they were meant to document refractoriness. They were meant to measure and annotate every film, and A Series of Mistakes show that these patients were—one—truly refractory, “This is a series of bad mistakes that the and—two—whether or not these were responders. company made from the very beginning of the trial “If there were differences, they were meant to design, right on through to bringing the application to adjudicate between themselves, and they were meant FDA for approval,” Ozer said to The Cancer Letter. to document that adjudication,” Waksal said. “I think they not only didn’t do it right, but they didn’t The committee ended up performing only one realize that they didn’t do it right.” of these functions: documenting response, Waksal said. If the files for each patient enrolled in ImClone’s “They only measured and documented when pivotal trial indeed do not exist at a central location, there was a response rate [Sic.],” he said. “All they they will be difficult to reconstruct, experts say. did with the refractory question was say ‘refractory’ “These are the kinds of things that are always or ‘stable disease.’” difficult to get from sites, even when it’s done This failure crippled the study, Waksal said. prospectively,” said Mace Rothenberg, a “We did not provide that documentation,” he gastrointestinal cancer expert and associate professor said. “It doesn’t exist.” of cancer research at Vanderbilt Ingram Cancer Center. Blaming the review committee is disingenuous, “It magnifies the problem if you try to go back said Howard Ozer, director of Oklahoma University and try to resurrect the scans from long-dead patients,” Cancer Center and Eason chair of oncology and Rothenberg said. “Often, scans are destroyed after hematology. the patient dies. The hard copies contain silver, so “It’s not the IRAC’s fault,” said Ozer, who they are recycled. If you try to get a scan off a reviewed the FDA refusal to file letter for The Cancer computer tape from a few years ago—good luck. It’s Letter. “IRAC would have done whatever they were not an easy matter.” asked to do.” The company would need more than the scans The committee was working for the company, to document that the trial participants were refractory which means that the company bears the ultimate to CPT-11. responsibility, Ozer said. “You have to have dates for the scans, dates for Under normal circumstances, companies employ the treatments, and dosage of the treatments in order experts who make sure that the trials are being to make that judgment,” said Richard Kaplan, a properly conducted. gastrointestinal cancer expert and chief of the Clinical “They would know when IRAC is screwing up, Investigations Branch of the NCI Cancer Therapy and they would immediately report back,” Ozer said. Evaluation Program. “Companies do it in self-defense, so this kind of thing Mistakes in defining eligibility had the potential doesn’t happen.” to bias the study, boosting the apparent activity of The agency’s refusal to file letter indicates that CPT-11 and C225, experts say. IRAC received inconsistent instructions. According to For example, the response rate can be inflated if the letter, at an Aug. 11, 2000, meeting with ImClone, patients whose disease becomes stable on CPT-11 the agency signed off on a set of criteria for assessing are classified mistakenly as having progressive disease response. and receive ImClone’s two-drug regimen. Such “The procedure for this assessment was included patients may actually be responding to CPT-11, after

The Cancer Letter Special Report n Page 7 taking a break of a few months, experts say. ImClone stock, of which approximately $150 million Also, physicians had an incentive to put their was tendered by ImClone insiders.” patients on C225, an agent featured on 60 Minutes In addition to buying a 20-percent stake in and on the cover of Business Week. ImClone, Bristol paid the biotech firm $200 million “Here you have an incredibly hyped drug, you when the BLA was filed, and is obligated to pay have patients demanding it, and you have doctors another $800 million if additional milestones are wanting to do the best they possibly can for their reached. patients,” said a member of the FDA Oncologic Drugs It appears that Bristol didn’t anticipate problems Advisory Committee, who spoke on condition that at FDA. his name would not be used. “The end result is that On Sept. 26, 2001, a week after the ImClone it’s very easy to fudge the numbers—little white lies, deal was announced, Collier Smyth, BMS vice really—to try to get your patient on a trial like this.” president for medical affairs, wrote a letter to Several experts were surprised to find that the prominent oncologists: “We are optimistic that C225 response rate reported by the investigators in the will be approved by FDA in the near term, and thus pivotal study was lower than the response rate be available to help oncologists extend and enhance reported by IRAC. the lives of patients with cancer.” The paper presented at last year’s meeting of Bristol didn’t draw on the expertise of its the American Society of Clinical Oncology reported Oncology Advisory Board, a panel of prominent that 23 of the 120 patients treated with CPT-11 and academics, to assess the ImClone data before the deal C225 responded to the therapy. Subsequently, IRAC was completed. The advisory board was briefed on concluded that 27 of the 120 patients had a response. C225 on Oct. 26, 2001. This pushed up the response rate from 19.2 percent According to the agenda of the committee to 22.5 percent. meeting, an overview of C225 data was presented “Outside independent review panels almost by John Mendelsohn, the scientist who led pre-clinical invariably result in lower response rates, often by as development of the agent. much as 50 percent,” said Rothenberg. “Therefore, Mendelsohn is also a member of the BMS it’s surprising that not only did they confirm the advisory board, a member of the ImClone board of response rate, but elevated it.” directors, and president of M.D. Anderson Cancer Center. Who Knew What,When, And How Mendelsohn was followed by Susan Arbuck, Class action suits filed on behalf of ImClone Bristol’s vice president for oncology clinical research, shareholders argue that company executives should who asked the board for suggestions for further have known that the C225 application was in trouble. development of the agent. One of the suits, filed by the law firm of Milberg “We may have been lured into the same sense Weiss Bershad Hynes & Lerach, in the U.S. District of security that Bristol was,” a member of the advisory Court for the Southern District of New York alleges board said to The Cancer Letter. “In retrospect, it that the company issued press releases on the progress doesn’t sound to me as a very accurate portrayal of of its BLA, highlighting “the positive impact that the ImClone’s knowledge base.” drug’s approval would have on the company’s Now, it’s up to Bristol to make sense of revenues.” ImClone’s data, experts say. “I think what Bristol got These statements by ImClone were false and was what in the housing market would be called a misleading, the law firm said in a press release inviting ‘fixer-upper,’” said Ozer. plaintiffs to join the class action suit. “Let’s hope it’s not a tear-down.” “Defendants failed to comply with the FDA’s requirements for filing the [BLA], and defendants knew, or should have known, that their deficient application would be rejected,” the law firm said. The law firm also alleged that “defendants filed their application, despite lacking the skill and expertise to make a proper filing, in order to convince Bristol- Myers Squibb Co. to purchase at least $1 billion in

The Cancer Letter Page 8 n March 8, 2002 Jan. 24, 2002, Vol. 28 No. 4 file” letter, which stated that the company’s clinical House Committee, SEC Probe data on C225, trade name Erbitux, could not be interpreted, and therefore were not suitable for Statements To Shareholders presentation to the agency’s Oncologic Drugs Advisory A Congressional committee last week began an Committee. The company sought accelerated approval investigation of ImClone Systems Inc. In letters dated for a combination of C225 and CPT-11 as a treatment Jan. 18, the House Committee on Energy and for colorectal cancer in patients refractory to other Commerce and its subcommittee on Oversight and regimens containing CPT-11. Investigation asked FDA, ImClone, and its partner A copy of the refusal-to-file letter, obtained by Bristol-Myers Squibb to provide documents related The Cancer Letter, stated that the agency could not to clinical trials of C225. verify that patients enrolled in the company’s pivotal Separately, the Securities and Exchange trial were indeed refractory to CPT-11, and that the Commission began an “informal inquiry” of the New overall structure of the company’s phase II trial made York-based biotechnology company. According to a it impossible to determine how each of the two drugs letter by SEC officials, the agency is probing “possible affected the safety and efficacy of the regimen (The violations of the federal security laws.” Cancer Letter, Jan. 4, Jan. 11). SEC does not announce inquiries or comment The letters launching the Congressional probe on them. However, the agency disclosed the probe in were signed by Energy and Commerce chairman Billy a letter requesting a copy of the Jan. 4 issue of The Tauzin (R-LA), and Oversight and Investigations Cancer Letter. “We are trying to determine whether chairman James Greenwood (R-PA), and addressed there have been any violations of the federal security to FDA acting commissioner Bernard Schwetz, laws,” the SEC stated in the letter dated Jan. 16. “The ImClone Systems President and CEO Samuel Waksal, investigation does not mean that we have concluded and BMS chairman and CEO Peter Dolan. that anyone has broken the law.” The most detailed of the three letters was An informal inquiry, unlike a formal inquiry, does addressed to FDA’s Schwertz. not have the power to subpoena witnesses and “Available information seems to conflict with documents. Attorneys familiar with SEC practice say ImClone’s descriptions of the contents of FDA’s an informal investigation can become formal as soon refusal-to-file letter and its clinical research,” the as investigators encounter a need to subpoena, and in Tauzin-Greenwood letter to Schwertz states. “The some cases, the agency proceeds directly from an RTF letter is not a public document; investors only informal inquiry to filing charges. learned about the details from the excerpts of the RTF The news of a Congressional investigation sent letter reported in The Cancer Letter. Without The ImClone stock into another tailspin. On Jan. 23, the Cancer Letter article, investors would have had to price of ImClone shares hovered around $20 per share, rely on ImClone’s questionable descriptions of the RTF about a third below its value a week earlier. Last letter.” September, Bristol bought a 20-percent stake in the The Tauzin-Greenwood letter noted that by law, company at $70 per share, paying a total of $1 billion. FDA is precluded from disclosing RTF letters and other ImClone is facing over a dozen suits from disgruntled information potentially involving trade secrets to SEC shareholders. or other agencies that are not part of HHS. “For the ImClone Chief Operating Officer Harlan Waksal sake of protecting patients and investors from said the company will cooperate with the deception, we are interested in learning whether FDA Congressional investigation. laws need to be clarified to permit the FDA on its “We were very surprised to hear of that own accord, and in appropriate circumstances, to share investigation,” Waksal said Jan. 23, at a Morgan non-public information with other federal agencies,” Stanley teleconference for investors. “But on the letter states. reflection, it may be a good opportunity for the The Tauzin-Greenwood letter asked FDA to company to go ahead and clear the air on many of the provide information that would allow the committee issues that have been raised, primarily by the media, investigators to determine whether ImClone insiders and picked up by various groups, resulting in various knew that their clinical development program would efforts like this Congressional investigation.” not meet the regulatory standards for accelerated Last month, FDA sent ImClone a “refusal to approval.

The Cancer Letter Special Report n Page 9 “We are interested in learning about the true 100 index. Excitement and confidence in ImClone was nature of the pivotal clinical trial for Erbitux, and reflected in such media reports as a Reuters article in whether ImClone knew or should have known about the Dec. 26, 2001, Los Angeles Times, which the insufficiencies detailed in FDA’s RTF letter,” proclaimed, “Erbitux, a colon cancer treatment from Tauzin and Greenwood wrote. “It is important that ImClone Systems Inc., is set to make one of the the hopes of cancer patients are not falsely raised and biggest splashes of 2002.” that the integrity of biomedical research is maintained.” Therefore, many observers were stunned to learn At the Morgan Stanley conference, Harlan that on Dec. 28, 2001, the FDA had issued a “refuse- Waksal declined to comment on all matters involving to-file” (RTF) letter in response to the ImClone SEC. “We are not privy to FDA policy on sharing submission. The RTF letter, sent in rare cases when materials with the SEC, and as a matter of policy, we a submission is deemed insufficient, is a non-public just don’t comment on discussions with government document containing trade secret or confidential agencies, but we are always happy to provide the SEC commercial information. with any information that it may deem useful to assure According to Adam Feuerstein’s column in that we are in full compliance with SEC regulations,” TheStreet.com, in “its Dec. 31, 2001 conference call, he said. ImClone executives said that FDA regulators sent the RTF letter because the Erbitux application was missing “The Furthest Along Of New Treatments” certain ‘train of documentation’ information needed The text of the Tauzin-Greenwood letter to FDA by regulators to accept the filing. ImClone said it would follows: be able to answer the FDA questions by the end of The Subcommittee on Oversight and the first quarter, leading, hopefully to an approval of Investigations is investigating questions about the Erbitux in the fall.” On the first trading day after the conduct of ImClone Systems Inc. in the development issuance of the RTF letter, ImClone’s shares fell of its colorectal cancer drug, Erbitux (also known as $11.15, or 20 percent, to $44.10 per share. C225 or Cetuximab). On Jan. 4, 2002, The Cancer Letter published ImClone Systems and Erbitux are internationally excerpts of the RTF letter, indicating that the FDA known, having been featured on the CBS program 60 had greater concerns about ImClone’s data than Minutes and the international cover story for the July company executives stated in the Dec. 31 conference 30, 2001, issue of Business Week. One reason Erbitux call with analysts and investors. received such attention is that, according to Business As Adam Feuerstein noted, “if The Cancer Week, this drug was “the furthest along of a handful Letter does have a correct copy of the RTF letter, it of new cancer treatments that precisely home in on a suggests that ImClone executives have not given growth signal found in up to 50 percent of all cancer investors and Wall Street analysts a full picture of the types.” Erbitux problems.” In clinical trials, “the drug demonstrated The Cancer Letter article reported that the RTF remarkable success in causing colon cancer to regress letter detailed a long list of FDA concerns that went in patients who had failed to respond to all other far beyond record-keeping. The FDA was quoted as treatments.” Such promise apparently prompted saying that ImClone’s clinical trial was “not adequate thousands of cancer patients to try to obtain Erbitux and well controlled,” and that additional studies would either through clinical trial enrollment or be needed. Moreover, the letter suggested that the FDA “compassionate use” access. For example, USA Today had warned ImClone starting in August 2000 that its reported that ImClone had received 400 calls a day data would have to demonstrate that Camposar, from patients desperate to get Erbitux outside clinical another cancer drug, was needed along with Erbitux. trials. But the data submitted by ImClone was not In September 2001, Bristol-Myers Squibb bought sufficient to distinguish the effects of Campostar and 20 percent of ImClone for $1 billion, and agreed to Erbitux. Furthermore, the FDA cited protocol pay as much as $1 billion more to obtain the marketing violations in the clinical trial, specifically the fact that rights to Erbitux. On Oct. 30, 2001, ImClone submitted ImClone only reported the deaths of three patients its Biologics License Application for Erbitux. On Dec. who died within a month of their last Erbitux 17, 2001, ImClone was one of seven biotechnology treatment. companies included for the first time in the Nasdaq The FDA found 21 patients who died within a

The Cancer Letter Page 10 n March 8, 2002 month of their last Erbitux treatment. According to shares, or just more than 20 percent of each of their the Jan. 8, 2002, New York Times, David Hines, holdings, in the first sale by either executive since the president of the Avalon Research Group, said, “The mid-1990’s. The sales were part of a tender offer by FDA’s communications with the company appear Bristol-Myers at the end of October in connection directly at odds with the statements made by the with the strategic agreement with ImClone. (In contrast company in 2001.” After The Cancer Letter report to the $2 billion agreement with Bristol-Myers for the appeared, the price of ImClone shares fell further to US market, we note that it appears ImClone made open on January 7, 2002 at $34.96 per share. only a $60 million agreement with Merck KGaA for On Jan. 9, 2002, after ImClone had lost nearly the right to market Erbitux outside North America $1.5 billion in market value since Dec. 28 and after and Japan, according to ImClone’s 10-Q SEC filing). the filing of at least 11 federal class action suits, Sam As part of the tender offer, the Waksals and other Waksal, the ImClone president and CEO, attempted insiders—along with all other shareholders—were to explain the company’s situation at the J.P. Morgan allowed to tender shares. However, according to the H&Q Healthcare conference. “What happened was Wall Street Journal, ImClone lent money to insiders that we put together a faulty package, and we screwed so they could acquire shares through the exercise of up,” Waksal reportedly said. The principal problem, options at a time when discussions with Bristol-Myers he said, was the company’s failure to provide “were well under way (having started in May) but documentation demonstrating that the patients enrolled weren’t publicly disclosed.” in ImClone’s pivotal trial had met the eligibility criteria. Along with the Waksals, ImClone extended loans On Jan.11, 2002, the The Cancer Letter to the company’s chairman and another director, published an article on the conference and raised more totaling $35.2 million during July and August. As one questions about Waksal’s explanations of what went observer noted in the Wall Street Journal article, that wrong. For example, Waksal said that the problems select insiders were able to borrow money from the were caused by the Independent Response Assessment company in order to acquire shares “puts shareholders Committee (IRAC), a group of two radiologists and at a disadvantage.” two oncologists, who reviewed the data from the trial’s Given these recent reports, we have several sites. serious concerns. Available information seems to However, The Cancer Letter article cites conflict with ImClone’s descriptions of the contents Howard Ozer, director of Oklahoma University Cancer of FDA’s RTF letter and its clinical research. The RTF Center and Eason chair of oncology and hematology, letter is not a public document; investors only learned who said blaming the review committee is about the details from the excerpts of the RTF letter disingenuous. “It is not the IRAC’s fault,” said Ozer, reported in The Cancer Letter. Without The Cancer who reviewed the RTF letter for The Cancer Letter article, investors would have had to rely on Letter. “IRAC would have done whatever they were ImClone’s questionable descriptions of the RTF letter. asked to do.” The committee was working for the The FDA’s statute and regulations appear to company, which means that the company bears the inhibit the agency on its own from disclosing some, if ultimate responsibility, Ozer said. “They would know not all, of the RTF letter or other similar, relevant when IRAC is screwing up, and they would information to the Securities and Exchange immediately report back,” Ozer said. “Companies do Commission (SEC) when there are concerns about it in self-defense, so this kind of thing doesn’t happen.” the accuracy and completeness of company’s Adding to the controversy are sales of stock by descriptions of FDA actions. We note that Section ImClone executives in the weeks just before FDA 301(j) of the Federal Food, Drug, and Cosmetic Act issued the RTF letter. According to the Jan. 9, 2002, prohibits the “revealing, other than to the Secretary Wall Street Journal, ImClone’s Chief Operating Officer, or officers or employees of the Department . . . any Harlan Waksal, disposed of 700,000 ImClone shares information . . . concerning any method or process on Dec. 6, valued at roughly $71 a share or about which as a trade secret is entitled to protection.” $50 million in total. Therefore, according to FDA’s Regulatory On Oct. 29, 2001, ImClone executives and Procedures Manual, FDA may not share trade secret directors sold a combined 2.1 million company shares information with federal government agencies outside to Bristol-Myers for $150 million. Samuel Waksal sold the Department of Health and Human Services unless 814,674 shares and Harlan Waksal sold 776,450 the submitter of the trade secret consents in

The Cancer Letter Special Report n Page 11 writing. Under 21 C.F.R. section 20.85 any FDA the FDA’s Dec. 28, 2001, refusal-to-file letter. records exempt from public disclosure may be —All records relating to meetings between FDA disclosed to other Federal government departments and ImClone Systems concerning Erbitux. and agencies, except that trade secrets and confidential —All records relating to study CP02-9923, commercial or financial information prohibited from especially the study protocol. Please identify the disclosure by 21 USC 331(j) . . . may be released ImClone official responsible for coordinating with the only as provided by these sections. For the sake of Independent Response Assessment Committee. protecting patients and investors from deception, we Please provide a list of all outside consultants or are interested in learning whether FDA laws need to experts used by ImClone for study CP02-9923. be clarified to permit the FDA on its own accord, and The letter to BMS chairman and CEO Dolan in appropriate circumstances, to share non-public requested the following: information with other federal agencies. —All records relating to communications about We are also interested in learning about the true the FDA’s Dec. 28, 2001, refusal-to-file letter regarding nature of the pivotal clinical trial for Erbitux, and ImClone’s Erbitux. whether ImClone knew or should have known about —A list of the individuals involved in Bristol- the insufficiencies detailed in FDA’s RTF letter. It is Myers Squibb’s (BMS) due diligence review of important that the hopes of cancer patients are not ImClone Systems. Please describe how BMS falsely raised and that the integrity of biomedical organized its due diligence efforts regarding ImClone research is maintained. The available information Systems. demands that this Committee, which is entrusted with —Internal audits, internal investigations, and/or the oversight of public health and consumer protection reports relating to ImClone Systems. laws, get additional information about ImClone and —Did BMS draw on the expertise of its the Erbitux matter. Oncology Advisory Board to assess the Erbitux data In light of these concerns, pursuant to Rules X before the ImClone deal was completed? If not, why and XI of the U.S. House of Representatives, please not? What information did BMS rely on in assessing provide the following by January 31, 2002: the Erbitux data? 1. All records relating to the December 28, 2001 —All records relating to the Oct. 26, 2001, refusal-to-file letter for ImClone Systems’ biological briefing before the BMS Oncology Advisory Board license application for Erbitux. concerning Erbitux. 2. All records relating to meetings between FDA and ImClone Systems concerning Erbitux. 3. All records relating to study CP02-9923, especially the study protocol. 4. All records relating to communications about the biological license application for Erbitux since October 29, 2001. 5. The most current legal analysis of relevant federal statutes and regulations concerning FDA disclosure of non-public information to the Securities and Exchange Commission (SEC). If no such analysis exists, please provide an explanation to the Committee of the circumstances, and for what categories of non- public information, that FDA on its own initiative may provide to the SEC. Please advise the Committee on whether FDA has had contact with the SEC on the ImClone/Erbitux matter and, if there was contact, appropriate details about the nature of the contact. In a separate letter, the committee asked ImClone President and CEO Samuel Waksal to provide the following documents: —All records relating to communications about

The Cancer Letter Page 12 n March 8, 2002 Feb. 8, 2002, Vol. 28 No. 6 The inside players at ImClone profited BMS Demands Resignation handsomely from the transaction with Bristol. The Waksal brothers sold over $150 million in stock when Of Two ImClone Executives the price was high. A summary of trading activity by In an extraordinary ultimatum, Bristol-Myers ImClone insiders can be found on http:// Squibb Co. (NYSE: BMY) demanded resignation of biz.yahoo.com/t/i/imcl.html. A history of trading shows two top executives of ImClone Systems Inc. that from Dec. 5 through Dec. 28, 2001, the day the (NASDAQ: IMCL). company received the RTF letter, the volume of sale According to a press release dated Feb. 5, “Peter of company stock increased, driving down the price R. Dolan, [BMS] chairman and chief executive officer, of the shares. said today that he has proposed steps to fundamentally In a press release dated Feb. 5, Bristol said its restructure the company’s relationship with ImClone.” demands from ImClone included restructuring “certain Though the press release didn’t list Bristol’s economic, financial and other terms of the agreement.” demands, The Wall Street Journal cited Bristol sources These included ceding greater control over driving the stating that the pharmaceutical company is seeking agent through the FDA approval process and “changes removal of ImClone president and CEO Samuel in ImClone senior management effective until FDA Waksal and his brother, Executive Vice President approval of Erbitux.” Harlan Waksal. Also Bristol demanded “expanded rights to Moreover, Bristol wants to take control over ImClone’s intellectual property related to Erbitux and development of the monoclonal antibody Erbitux, also fewer restrictions on the company’s ability to resell known as C225. ImClone shares.” Last September, Bristol spent $1 billion to The Wall Street Journal on Feb. 5 reported that purchase a 19.9 percent stake in Imclone and another Bristol wanted the ImClone Board Chairman Robert $200 million in a first payment for a 40 percent stake Goldhammer to run the company, at least in the in C225. The pharmaceutical company promised to interim. Bristol officials didn’t dispute the article. pay another $800 million if the agent is approved. “If these conditions are accepted, Bristol-Myers The transaction, hailed as the biggest in the Squibb will take the lead in the FDA approval process history of biotechnology, quickly turned sour. FDA and other clinical and regulatory matters related to declined to accept the C-225 application, issuing a Erbitux,” Bristol CEO Peter Dolan said in the press “refuse to file” letter to ImClone, a rare piece of release. “We are taking this action because we believe correspondence that states that the data supporting Erbitux has great potential to treat cancer patients, the application cannot be evaluated, and is not good and we want to move the process forward as quickly enough to be presented to the agency’s extramural as possible.” advisors (The Cancer Letter, Jan. 4, Jan. 11, Jan. ImClone responded with a terse statement: 25). “We have received the proposal from Bristol- As a result of the RTF letter and its subsequent Myers Squibb outlining the terms of a proposed publication in The Cancer Letter, ImClone’s stock restructuring of their relationship with ImClone tumbled, and Bristol’s stake in the company lost over Systems. We will review their proposal and respond 70 percent of its value. Recently, Bristol took a $780 appropriately in due course.” million write-off on its investment in ImClone. Bristol has powerful incentives to start a public The ImClone debacle has become something of brawl with the Waksals, observers said. the biotech industry’s equivalent of Enron. There is To begin with, a fight would differentiate Bristol no shortage of parallels between the two business from ImClone at a time when the C225 debacle is disasters. For one thing, preclinical development of being investigated by the same entities who are probing C225 was spearheaded by John Mendelsohn, president the undoing of Enron: the Securities and Exchange of M.D. Anderson Cancer Center, and a member of Commission, the U.S. Department of Justice, and the the boards of directors of both ImClone and Enron. House Committee on Energy and Commerce and its On the Enron board, Mendelsohn serves on the subcommittee on Oversight and Investigations. Also, audit committee. The ImClone board also includes ImClone is facing about two dozen suits by disgruntled former NCI Director Vincent DeVita, and Arnold shareholders. Levine, president of the Rockefeller University. Also, there is a difference in styles. BMS officials

The Cancer Letter Special Report n Page 13 surely cringed on Dec. 31, as Samuel Waksal, “While the stock is not likely to react well to the addressing investors, claimed to be “surprised” to public display of discontent between the parties, the receive the RTF letter, when in fact the text of the dispute is in our view a ‘sideshow.’ In our view, letter states that the agency repeatedly criticized the ImClone stock will recover or wane depending upon structure of the company’s clinical trials. which way the regulatory process goes for Erbitux. In a subsequent statement, Waksal announced “We continue to believe that Erbitux is an to Wall Street that his company “screwed up” the effective cancer drug, and will ultimately win FDA pivotal clinical trial testing C225 and CPT-11 in approval. What is unclear is the timing of this event. colorectal cancer patients whose disease progressed Our prior notes state that we believe this could happen on other regimens containing CPT-11. by mid-2003. Under last year’s deal, ImClone was in charge “The dispute between BMS and ImClone does of the trials and the FDA submissions, but following not currently change this view,” Hecht wrote. the RTF letter, Bristol scientists started to work side- The acquisition agreement signed by the two by-side with ImClone to reconstruct the files of companies last September contains a termination patients who took part in the pivotal trial, to determine clause, which states, among other things, that Bristol whether they met the eligibility criteria. has a right to end its relationship with ImClone if “any Soon after that process began, Bristol took a of the representations or warranties [by ImClone] $735-million write-off on the ImClone investment, fail to be true and correct.” and acknowledged that additional write-offs may follow. Bristol officials have good reasons to regret the unusual structure of their investment deal with ImClone. In a departure from standard practice in corporate acquisitions, the pharmaceutical company purchased the ImClone stock at a premium price directly from the shareholders, and not from the company, said David Hines, president of Avalon Research Group Inc. Had the stock been purchased from ImClone, most of the proceeds would have been sitting safely in a money market account. As it stands, Bristol’s money has gone to all four winds. “Bristol struck a historically bad deal when it agreed to buy $1 billion of ImClone stock at $70 from ImClone shareholders, and not directly from ImClone, the company,” Hines said to The Cancer Letter. By going on the war path, Bristol may ease the questioning of its scrutiny of ImClone’s data before concluding the deal, observers say. “It seems that Bristol performed shoddy due diligence, failing to pick up faulty and incomplete data,” Hines said. “It only makes sense that Bristol will seek to remedy this embarrassing and costly mistake.” Merrill Lynch analyst Eric Hecht said ImClone officials have no reason to cave to Bristol’s ultimatum. “We do not see any reason why ImClone would succumb to these demands since they are outside the terms of the contract,” Hecht wrote. “BMS has also not stated on what basis they believe they are entitled to these changes.

The Cancer Letter Page 14 n March 8, 2002 Feb. 15, 2002, Vol. 28 No. 7 cut of proceeds from C225. Also, the findings provide Review Of ImClone Protocol a context for interpreting recent attempts by the pharmaceutical company to assume full control over Concludes Approval Unlikely development of the compound and interaction with The data from the controversial trial of C225 FDA. and CPT-11 cannot be reshaped into a format that Bristol employs many first-rate experts in clinical could convince FDA to approve the monoclonal trials who had the training and experience to catch antibody, said three independent experts after the problems noted by the reviewers. reviewing a copy of a protocol ImClone Systems Inc. Though the anatomy of Bristol’s decision to used to test the regimen in advanced colorectal cancer. commit to ImClone and C225 remains unknown, A copy of the proprietary protocol was obtained sources familiar with the transaction say Bristol’s by The Cancer Letter. The reviewers were: business leadership was bullish on the deal. “It seemed —Howard Ozer, director of Oklahoma this was a big product, and there was a lot of pressure University Cancer Center and Eason chair of oncology to get the deal done,” said one source. and hematology. The problems noted by the reviewers were —Otis Brawley, professor of medicine, oncology, fundamental: and epidemiology at Emory University Winship Cancer —The entry criteria on the study were so vague Institute and a member of the FDA Oncologic Drugs that it can’t be determined whether all the patients in Advisory Committee. the trial are indeed refractory to prior therapy. —Mace Rothenberg, Ingram associate professor —The Independent Response Assessment of cancer research at Vanderbilt Ingram Cancer Center, Committee is not mentioned in the protocol. Its who was the principal investigator in two phase II formation following an Aug. 11, 2000, meeting with studies that were part of the Pharmacia application FDA officials was part of the attempt by the company for accelerated approval of CPT-11 for advanced to change the objective of the trial retroactively. colorectal cancer in 1996. —Converting a run-of-the-mill trial to a The reviewers were given copies of the protocol registration trial is problematic, since a registration and the refusal-to-file letter in which FDA notified trial requires greater documentation on patients. ImClone that its application for approval of C225 does —The original protocol sought to enroll 49 not contain enough information to be reviewed (The evaluable patients with progressive disease and an Cancer Letter, Jan. 4, Jan.11, Jan. 25, Feb. 8). The equal number of patients with stable disease. Yet, reviewers were not paid. while the trial was underway, the company altered it The protocol describes a phase II study to test to include 120 patients with progressive disease. the hypothesis that CPT-11 and C225 could shrink “It is not clear whether the data presented to tumors in patients whose disease progressed or FDA encompassed both the stable disease and remained stable on regimens containing CPT-11. The progressive disease groups, or whether it represented protocol was later converted into what the company an expansion of the progressive disease cohort,” hoped would be a registration trial. Rothenberg wrote. The reviewers’ critiques focused on different “This is an important point, since the protocol- problems with the protocol. However, all three agreed specified analysis is based on an intention-to-treat that the trial can’t be expected to produce data to analysis, which would include both the stable and support either a full or an accelerated approval by progressive disease groups,” Rothenberg wrote. “If FDA. the data presented to the FDA was comprised of only “Overall, this is a protocol that asks the wrong the subset of patients with progressive disease, then questions, and then is not tightly written and efficient,” this should be considered a subset analysis, no matter Brawley wrote. “The protocol generates far more how large the subset ended up being. While questions than it could ever answer. It is a blueprint encouraging, subset analyses are never definitive. They for the production of vague findings.” are best used to help in the design of follow-up studies The reviewers’ comments raise questions about that address that question specifically and the rigor of due diligence review Bristol-Myers Squibb prospectively.” conducted prior to paying as much as $2 billion for a The company wrote the protocol, sources said. 20-percent share in ImClone and about a 40-percent Widely respected oncologists presented the

The Cancer Letter Special Report n Page 15 findings at annual meetings of the American Society “A poorly designed trial is a house of cards, of Clinical Oncology in 2000 and 2001. These lacking a foundation that will eventually make the physicians had good reasons to regard this as a determination of the drug’s efficacy difficult, if not reasonable phase II, hypothesis-generating trial. More impossible,” Pazdur said to The Cancer Letter. important, the trial gave their patients access to a “With poorly designed trials, truly effective drugs sought-after therapy. may not reach the market in a timely fashion, and The authors of publications resulting from trials everyone loses: the sponsor, FDA, and, mostly sponsored by pharmaceutical companies are chosen importantly, the American patient.” on the basis of prominence or because of the number of patients they enroll. Leonard Saltz, an oncologist Meeting With FDA Scheduled For Feb. 26 at Memorial Sloan-Kettering Cancer Institute, was ImClone and Bristol are scheduled to meet with named lead investigator on the trial in the spring of FDA on Feb. 26. Based on the reviews of the protocol, 2000, after most of accrual was completed, sources they would be unwise to hold their breath for a said. favorable outcome. “There is nothing wrong with conducting a trial Meetings of this sort give hapless sponsors the in which you are going to test the question that patients opportunity to petition for a reconsideration or to who are refractory to CPT-11 will now respond to a hammer out a plan for returning to the agency with combination of CPT-11 and C225,” Ozer wrote. better data. “That’s a perfectly fine hypothesis, but I don’t think Bristol and ImClone will not come to this FDA would ever have suggested that this trial would appointment arm-in-arm. The companies have been support approval of a new drug.” locked in an extraordinary public feud, which involves officials firing off letters and making them available No Binding Agreement With FDA to the press. Drug companies have to comply with FDA The battle began on Feb. 5, when Bristol determinations on safety of clinical trials, but when it Chairman and CEO Peter Dolan demanded that comes to design, the agency’s role is advisory. ImClone step aside and allow Bristol to take over the Under a program called Special Protocol dealings with FDA. Dolan also asked for a bigger Assessment, FDA can enter into binding agreements percentage of proceeds from C225, cancellation of with companies on trial design, but no such agreement $800 million in milestone payments, and temporary could have existed between ImClone and FDA. removal of ImClone’s two top officials, President and Agency officials declined to comment on the CEO Samuel Waksal, and his brother, Executive Vice C225 application, but agreed to discuss the protocol President Harlan Waksal. assessment program, which has been available since In a letter dated Feb. 12, Robert Goldhammer, 1997. Under that program, the agency can assess chairman of ImClone’s board, rejected Bristol’s whether phase III protocols meet “scientific and demands. regulatory requirements.” The letter states that a committee of the board “Having agreed to the design, execution, and “has concluded that there is no need, nor would it be analyses proposed in protocols reviewed under this in the best interests of ImClone Systems’ stockholders, process, the agency will not later alter its perspective to renegotiate the terms of our existing partnership on the issues of design, execution or analyses, unless arrangements with Bristol-Myers Squibb.” public heath concerns unrecognized at the time of the Dolan responded on the same day. “Clearly, we protocol assessment under this process become have a fundamentally different view of the serious evident,” the regulations state. issues created by the FDA refusal-to-file letter, Companies that request protocol assessment meet subsequent events, and the appropriate course of action with FDA as they are concluding phase II trials, and, to take, including who should lead the effort going once again, before going into phase III. forward,” he wrote. “We want to spend the time up-front to help Dolan’s letter describes Bristol’s efforts to sponsors design trials rather than in a salvage operation resurrect C225 and the wrangling between the two at the end of a poorly designed trial,” said Richard companies: Pazdur, director of the FDA Division of Oncology “As you know, since the FDA’s issuance of that Drug Products. letter, Bristol-Myers Squibb has provided significant

The Cancer Letter Page 16 n March 8, 2002 resources and support to ImClone in an effort to that would convince FDA to approve C225. Bristol, respond to the FDA’s concerns. These resources and ImClone—or whoever is in charge—will now have to support have been provided to ImClone even though conduct a randomized phase III trial that would we have no contractual obligation to provide them. compare a CPT-11-containing regimen with a C225 Indeed, our agreement expressly provides that the regimen. initial Biologics License Application filing is ImClone’s This protocol is confusing with respect to responsibility. eligibility requirements. You can’t see what the “ImClone management has advised us that they ultimate denominator is. Who is in this trial? How intend to take the lead at the FDA meeting on Feb. they actually define refractory and stable disease is 26. Given the potential importance of this drug to fuzzy. They do have good criteria for defining response critically ill cancer patients, we will continue our to their combination of drugs, but there is very little voluntary efforts to collect the CT and MRI scans about eligibility specifics. and radiographic and other clinical data that we have If I were a physician entering a patient on this been collecting in anticipation of the FDA meeting on trial, I wouldn’t know what to do to assess whether Feb. 26, and to provide that information to ImClone. the patient is refractory or stable. I wouldn’t know We will continue to provide ImClone with our views how to demonstrate that my patient is really and on the best approach to take with the FDA on Feb. honestly progressing on CPT-11. 26. We also plan to attend the Feb. 26 FDA meeting. I can see how you could have reasonable “I must consider the best interests of Bristol- disagreements on the definition of progressive disease, Myers Squibb Company and its shareholders. but that’s why you need a definition. If you have a Accordingly, we are considering our business and legal definition, you will not have a disagreement. If you options with respect to our relationship with ImClone, don’t define it, then different investigators will define but will wait until after the FDA meeting to determine it differently. Ordinarily, you would see this very what further actions we may take.” clearly defined in a protocol. Retrospectively reconstructed data from a flawed Without a definition of refractory disease, a trial are extremely unlikely to convince FDA to change patient on this protocol could go immediately from a its mind on C225, reviewers said. CPT-11-containing regimen to this experimental “An audit of all existing data may be the only regimen of CPT-11 and C225. way to be absolutely certain about the validity of the For example, a patient could be entered results to date,” Ozer wrote. “Such an audit could at immediately following the second cycle of CPT-11, least salvage the trial and test the original hypothesis. which just might be the cycle that elicited the response. However, it will not provide grounds for approval of You would not then know whether the patient is C225 as a treatment for advanced colorectal cancer.” responding to CPT-11 or C225. Rothenberg agrees. “The bottom line is that a The original goal was to accrue 49 progressive phase III trial that included a C225-alone treatment disease patients and 49 stable disease patients. arm would have provided a clearer picture of the Ultimately, ImClone says 120 progressive disease impact of C225 in patients with refractory colorectal patients were accrued. To go back retrospectively and cancer,” he wrote. add more patients with the stratification for refractory Spokesmen for ImClone and Bristol did not disease already poorly defined makes the data even respond to a request for a detailed discussion of the more fuzzy. protocol with The Cancer Letter. The science is not difficult at all. Any good institution could design this sort of trial. It just needs Retrospective Data Clean-Up good peer review. If a fellow brought this to me, I’d say there is nothing wrong with this trial design for Can't Help C225 Phase II Trial; testing this hypothesis, but the eligibility criteria would Protocol Far Too "Fuzzy" have to be cleaned up. I would tell that fellow that he Howard Ozer, director of Oklahoma University or she needs to finish this protocol by defining the Cancer Center and Eason chair of oncology and eligibility criteria. hematology: I would, first of all, eliminate the stable disease I can’t see how anyone can retrospectively clean population. I am not sure why that’s there. Then I up the data from this trial and make it part of a package would spell out a rigorous definition of refractory

The Cancer Letter Special Report n Page 17 disease, and I would require that patients have a respects it reflects the thinking of “the old school of minimum number of courses in order to be oncology” in which it was believed that a drug that documented as refractory. causes tumor to shrink is good and definitely means Because the sites are likely to vary in their the patient lives longer. The profession has gotten definition of refractory disease, the company put beyond that; there are a number of diseases where together an independent review committee, IRAC the concept has not proven true. The question one (independent response assessment committee). They should ask in a trial to gain approval is, “Does were trying to put some kind of an overall quality treatment with the drug improve the quality or the control on the protocol, but this is a retrospective quantity of the patient’s life?” manipulation, and that’s inappropriate methodology A small phase II trial to assess response is useful in clinical trials. and should be done, but to justify a larger phase III A retrospective analysis introduces a bias. In this trial comparing the accepted standard treatment with case, it’s equivalent to introducing a sliding scale an experimental treatment. An alternative approach grading system after you’ve given a test to a class in patients with disease refractory to standard therapy and found that only 20 percent passed, and now you would be to do a phase II trial with rigorous quality go back to fix it by assigning a sliding scale and letting of life measures. If one can prove that the drug 50 or 70 percent—whatever your target number is— decreases pain, discomfort and other morbidities of pass the test. That’s fine when you are grading students metastatic disease refractory to other treatments, then in a school. It’s not so fine when you are trying to one has made a true contribution. The quality of life find out whether a drug actually works better than component of this protocol was without the rigor the standard therapy. necessary to prove the treatment improves quality of There is nothing wrong with conducting a trial life. in which you are going to test the question that patients The trial as written would have been an “OK who are refractory to CPT-11 will now respond to a phase II study,” if it were performed in a single combination of CPT-11 and C225. That’s a perfectly institution by one specific principal investigator, who fine hypothesis, but I don’t think FDA would ever saw all the patients enrolled.The major difficulties with have suggested that this trial would support approval a multi-institutional trial, as written, include the fact of a new drug. that the inclusion and exclusion criteria are vague, to Had the response rate in this trial been 80 say the least. There are broad criteria as to what is a percent, I am certain that FDA would have continued patient who has stable or progressive disease, while to work with them. But that, clearly, was not the case. getting 5-FU and CPT-11. If indeed the true response rate to C225 in CPT- Very detailed exclusion criteria are necessary 11-refractory patients is 20 percent, then that’s indeed when running a clinical trial in a number of institutions, a very significant result. Unfortunately, given the trial because a number of doctors will be reading these design based on flawed eligibility requirements, that criteria and trying to apply them. Indeed the fact that result remains suspect. this drug received a lot of hype and positive press An audit of all existing data may be the only means a physician hoping to do the best for his or her way to be absolutely certain about the validity of the patient might use the vagueness of the inclusion and results to date. Such an audit could at least salvage exclusion criteria to their advantage enrolling patients the trial and test the original hypothesis. However, it the authors of the trial would have excluded. will not provide grounds for approval of C225 as a There is, of course, the question, “Why include treatment for advanced colorectal cancer. the individuals with stable disease in the clinical trial?” In my opinion, there are two trials in this protocol. A ImClone Protocol Generates trial of patients with nebulously stable disease while on 5-FU and CPT-11, and a trial of patients with More Questions Than Answers nebulously progressive disease while on 5-FU and Otis Brawley, professor of medicine, oncology, CPT-11. This might be called “stratifying” in an and epidemiology, Emory University Winship Cancer extremely loose employment of the word. Institute: The study of a stable disease cohort is actually a The problem with this protocol is that it asks the study biased against the CPT-11 and C225 wrong questions necessary to gain approval. In many combination. It is difficult to argue that a patient with

The Cancer Letter Page 18 n March 8, 2002 stable disease on a 5-FU and CPT-11 regimen would CPT-11 and had 49 percent shrinkage of tumor could have benefited if they have stable disease on the new have been eligible for this trial. experimental regimen. Also, stable disease and A mere 1 percent additional shrinkage in tumor progressive disease are possibly very different diameter following treatment with C225 plus CPT-11 diseases. Hence, again the argument that they would have converted this patient with “refractory” described two different trials in one protocol. disease into a “responding” patient. It should be noted that pretreatment evaluation It is not clear whether the data presented to FDA doesn’t specifically require an x-ray, a CT, or MRI encompassed both the stable disease and progressive scan to establish tumor size. The protocol doesn’t disease groups, or whether it represented an expansion specifically state that all imaging studies, both those of the progressive disease cohort. done before and after conclusion of treatment, would This is an important point, since the protocol- be forwarded to centralized reviewers. It is unclear specified analysis is based on an intention-to-treat who was to make the call of response, stable disease, analysis, which would include both the stable and or disease progression in the original protocol. The progressive disease groups. If the data presented to Independent Response Assessment Committee the FDA was comprised of only the subset of patients eventually used to evaluate responses is not mentioned with progressive disease, then this should be in the original protocol. In an ideal study, three considered a subset analysis, no matter how large the radiologists would be engaged prospectively to assess subset ended up being. While encouraging, subset before- and after-treatment films, as patients analyses are never definitive. They are best used to completed the trial. help in the design of follow-up studies that address The radiologists should separately see the films that question specifically and prospectively. from just prior to administration of study treatment There is an inherent contradiction in the way and the data and films that are used after completion patients with stable disease are treated by the protocol. of study treatment. Each radiologist would At entry, patients with either stable or progressive individually decide what the response is. Any disease on CPT-11 were considered to be “refractory” differences of opinion among the radiologists should to therapy and therefore eligible for this trial, implying be carefully noted and discussed. lack of benefit from single agent CPT-11. However, Overall this is a protocol that asks the wrong once on C225, patients without progressive disease questions, and then is not tightly written and efficient. could continue to receive therapy, implying that those The protocol generates far more questions than it could patients with stable disease were deriving benefit from ever answer. It is a blueprint for the production of therapy. This is internally inconsistent. vague findings. It appears that sequential scans demonstrating stable or progressive disease on CPT-11 were required Phase III Trial Would Give for patients to be eligible for this study. These scans Clearer Picture Of C225 Role are of critical importance because of the non-controlled nature of this phase II trial. Since each patient’s Mace Rothenberg, Ingram associate professor response to combined CPT-11 and C225 therapy was, of cancer research at Vanderbilt Ingram Cancer Center: ultimately, going to be compared to the response (or The protocol, as written, is comprised of two lack of response) that that patient had had to prior groups of patients: one with “stable disease,” and one CPT-11 therapy, retention and review of those scans with “progressive disease” following treatment with by the IRAC would be essential for demonstration of CPT-11. Biologically, these could represent two very the impact of the CPT-11 and C225 combination. distinct groups. It’s hard for me to imagine that this study was Those with progressive disease must have greater intended for use as a registration study. I think that it than or equal to 25 percent increase in tumor is more likely that the sponsor considered the results dimensions and are a fairly homogeneous group. On so compelling that it was decided to proceed directly the other hand, stable disease encompasses patients to registration without performing additional studies with anywhere from a 49percent shrinkage to a 24 that would have addressed some of the key questions percent enlargement in tumor dimensions. This is a that remained. These questions include: much more heterogeneous group of patients. For —Must C225 be administered in combination example, a patient who had received two cycles of with CPT-11 in this setting, or would similar results

The Cancer Letter Special Report n Page 19 have been obtained with C225 alone? Feb. 22, 2002, Vol. 28 No. 8 —Were adequate phase I studies done to ImClone Offered C225 Deal determine the appropriate dose of C225 to be used in this setting? To Seven Firms Prior To BMS —Why weren’t baseline scans demonstrating A Congressional committee investigating stable or progressive disease on previous CPT-11- ImClone Systems Inc. and its development of C225 containing regimen retained and reviewed by the asked seven pharmaceutical companies to turn over IRAC? records related to discussions of strategic partnerships —Why wasn’t the study conducted exclusively with ImClone. in a more homogeneous patient population, such as According to the letters dated Feb. 19, the seven those with progressive disease on or shortly after single companies had considered licensing C225, a agent CPT-11? monoclonal antibody also known as Erbitux, prior to —What happened to the quality of life data that ImClone’s $2-billion deal with Bristol-Myers Squibb the protocol required? Co. The bottom line is that a phase III trial that The letters were addressed to the chief executives included a C225-alone treatment arm would have of Pharmacia Corp., Merck & Co., Eli Lilly & Co., addressed many of these questions and provided a Johnson & Johnson, Chiron Corp., Amgen Inc. and clearer picture of the impact of C225 in patients with Abbott Laboratories. refractory colorectal cancer. “In response to an inquiry from Committee staff, ImClone Systems provided a list of companies with whom ImClone Systems discussed a strategic partnership relating to Erbitux prior to the tender offer by BMS,” said the letters signed by Energy and Commerce Committee Chairman Billy Tauzin (R-LA), Ranking Member John Dingell (D-MI), Oversight and Investigations Subcommittee Chairman James Greenwood (R-PA), and Subcommittee Ranking Member Peter Deutsch (D-FL). “To assist our understanding in the ImClone matter, please provide the following by Feb, 28: all records including internal audits, investigations, and/ or reports relating to ImClone Systems,” the letters said. Last September, Bristol-Myers Squibb paid $1 billion for a 20-percent stake in the company and $200 million in the first milestone payment for a 40-percent stake in C225. Bristol committed to pay another $800 million in milestone payments if the drug is approved. This appears unlikely any time soon. On Dec. 28, ImClone received a Refusal to File letter from FDA, stating that the application cannot be reviewed. On Feb. 26, BMS and ImClone official are scheduled to meet with FDA to discuss the potential for salvaging the application. Last week, The Cancer Letter published a review of ImClone’s protocol for the pivotal phase II trial of C225 and CPT-11. After reviewing the protocol, three independent experts said that the trial cannot be expected to support approval of a new agent by FDA.

The Cancer Letter Page 20 n March 8, 2002 March 8, 2002, Vol. 28 No. 10 immediately receive $140 million in cash and another Waksals Keep ImClone Jobs, $60 million a year after signing the revised agreement. Under the original agreement that was announced last BMS Pumps $200M Into C225 September, ImClone stood to receive $300 million for Bristol-Myers Squibb Co. has abandoned its submitting an acceptable application to FDA. effort to jettison two top executives of ImClone The deal follows a meeting between FDA and Systems Inc. and watered down its demand to lower officials of the pharmaceutical companies involved in the payments for C225, a monoclonal antibody for developing the monoclonal antibody. At the Feb. 26 late-stage colorectal cancer. meeting, the companies sought FDA guidance on A new agreement between the two companies salvaging ImClone’s botched clinical development gives Bristol greater control over the development of program that resulted in a Refusal to File letter from C225, trade name Erbitux, and cuts at least $100 the agency (The Cancer Letter, Jan. 4). million from the total $2 billion price of the agent. In Issues related to development of C225 have exchange for winning concessions in future earnings, triggered investigations by the Department of Justice, Bristol agreed to pump $200 million in cash into the Securities and Exchange Commission, and the House New York-based biotechnology firm over the next Committee on Energy and Commerce (The Cancer year. Letter, Jan 25). The deal, announced March 5, concludes two Discussions between FDA and drug sponsors months of scuffling between Bristol and ImClone slammed with RTF letters are rarely bird-dogged by executives. While Bristol didn’t walk away from the the press. However, the case of the much-hyped C225 deal, as it threatened to do, the pharmaceutical was different. A television news team and print company has committed more cash to a risky, poorly reporters were staking out the FDA Parklawn building run venture. Should the C225 program fail now, Bristol for the Feb. 26 meeting. will have lost $1.4 billion. The two-hour meeting between FDA and “We are confident that we will now be able to pharmaceutical company officials was cordial and low- move forward in our partnership with ImClone key, sources said. Agency officials agreed to review Systems for the development of Erbitux,” Peter Dolan, the protocol from a randomized phase II study of Bristol chairman and CEO, said in a joint statement C225 being conducted in Europe by Merck KgaA. with ImClone. “As the world leader in oncology, we That study is enrolling 225 patients refractory to CPT- are looking forward to playing an expanded clinical 11 in the two-arm trial comparing single agent C225 and strategic role related to the Erbitux development or C225 plus CPT-11. program, working in close collaboration with the Merck, based in Darmstadt, Germany, has an ImClone Systems team.” agreement with ImClone to develop the agent in The revised deal leaves ImClone President and Europe. Under the 1998 licensing agreement, the CEO Samuel Waksal and his brother, Executive Vice German company has to provide its clinical data to President Harlan Waksal, in their jobs. However, a ImClone. long-time Bristol executive Andrew Bodnar will be The Merck protocol was not discussed in detail put in charge of a joint team running clinical and at the meeting with FDA, sources said. Experts in regulatory development of Erbitux. Bodnar is a senior clinical trials say the study appears to have low power vice president of medical and external affairs at Bristol for a randomized trial. Still, at least on the surface, and a member of the ImClone board of directors. the study appears to be roughly what the agency If the drug is approved, ImClone’s share of North described as appropriate for this indication. American sales will be capped at 39 percent, regardless According to the FDA Refusal to File letter dated of sales volume. Under the original deal, the ImClone Dec. 28, 2001, ImClone would be expected to conduct share went up as volume increased. additional studies. The agency suggested a In another change, Bristol will no longer be “randomized, controlled trial directly comparing the obligated to pay ImClone $500 million on approval of efficacy of single agent [C225] to [C225] plus [CPT- C225 by FDA. Instead, the pharmaceutical company 11] in patients who can be documented to be refractory will pay $250 million for approval of the first to [CPT-11] therapy.” Alternatively, FDA suggested indication and $250 million for approval of the second. a three-arm trial comparing C225 and CPT-11 as In exchange for these concessions, ImClone will single agents with a combination of the two agents in

The Cancer Letter Special Report n Page 21 patients not refractory to CPT-11. endorsement of its data on the editorial page of The ImClone sought accelerated approval based on Wall Street Journal. a single-arm phase II trial that was originally designed The Feb. 27 editorial said that despite compelling as a hypothesis-generating study measuring tumor anecdotal accounts of patient benefit, and shrinkage in CPT-11-refractory colorectal cancer notwithstanding involvement of cancer luminaries in patients receiving a combination of C225 and CPT- the company trial, “FDA declined even to review 11. ImClone’s application, leading to allegations that An independent review of the ImClone protocol ImClone executives had misled investors about the demonstrated, among other things, a lack of detailed status of the drug. inclusion criteria (The Cancer Letter, Feb. 15). Also, “Well, we’ve had a good look at the leaked letter ImClone officials acknowledged that the BLA didn’t detailing the FDA’s reasons for rejecting ImClone’s contain patient files that could allow the agency to study, and we’d say it says more damning things about analyze the data for every patient. the agency than it does about ImClone,” the editorial After receiving the RTF letter, Bristol and continued. “To be sure, it goes into detail about patient ImClone have reconstructed the files for almost all data it wishes ImClone had provided. But the bottom patients, sources said. Though the conclusions of this line is a demand for additional studies ‘directly audit were not discussed at the meeting, such comparing the efficacy of single agent [Erbitux] to retrospective analysis can be useful in generating the combination of [Erbitux] plus irinotecan.’ hypotheses, but can’t be used as a substitute for “In other words, although the FDA granted fast- prospective clinical trials, experts say. track approval review to Erbitux last year, it apparently Now, it appears that ImClone and Bristol will never had any intention of approving the drug based ask FDA to consider Merck’s data in conjunction with on the kind of study it knew ImClone was doing. whatever information can be salvaged from the U.S. Moreover, the FDA now wants critically ill patients trial. to endure a study to test Erbitux alone, even though “Based on concerns raised by the FDA regarding ImClone has good reasons to believe the drug is twice its U.S. phase II clinical study, ImClone Systems as effective when used in combination with a discussed an approach to provide the FDA with data traditional chemotherapy agent. Isn’t there some from a European clinical trial currently being enrolled famous medical oath about doing no harm?” by Merck KGaA in conjunction with reanalyzed The FDA letter said ImClone was repeatedly clinical data from ImClone Systems’ U.S. phase II warned that the data from its trial would not support clinical trials,” the Bristol and ImClone said in a joint approval. statement issued after the meeting. The text of the FDA Refusal to File letter to Merck is aiming to complete the colorectal cancer ImClone begins on page 1 of this Special Edition of trial within a year. Participants in the meeting didn’t The Cancer Letter. discuss the potential for filing a Biological License Application with FDA in any indication beyond colorectal cancer, sources said. C225 is in phase II trials for head-and-neck cancer in the U.S. and in Merck-sponsored phase III European trials for this indication. Though the Feb. 26 meeting can be described as inconclusive, it has produced at least an appearance of an approval strategy. This was enough for investors to bid up the price of ImClone stock from $15.52 per share on Feb. 26 to $28.25 per share on March 4. Following the news of a peace treaty with Bristol, ImClone stock was traded at about $28.45 on March 7. ImClone has to clear many a hurdle to prove that Erbitux works. However, the company has obtained the next best thing to FDA approval: an

The Cancer Letter Page 22 n March 8, 2002 FDA: Flaws Of C225 Trial b. The application does not contain the data requested to support the proposed dose and schedule Were Repeatedly Discussed of Cetuximab. During the January 7, 1999 meeting (Continued from page 1) you indicated that saturation of tumor occurs at doses filed as a biologics license application. between 200 to 400 mg/m2 and that a high dose is We are refusing to file this biologics license necessary because the liver and skin along with the application under 21 CFR 601.2(a) for the following tumor serve as “a sink” for the elimination of the reasons: drug. We noted at the time our lack of concurrence 1. The application is scientifically incomplete in with this assessment and asked that you provide the that it does not contain the data needed to evaluate data to support this statement. During the August 11, the clinical effectiveness of your product. 2000 meeting you maintained that the dose and dosing a. The application does not contain data that regimen selected in the clinical investigations was isolates the contribution of irinotecan to the based upon the pharmacokinetic data that ensured combination regimen. In order for you application to maximum receptor saturation; we asked that you be considered complete, you were informed during provide the data. In our January 19, 2001 letter, you the meeting of August 11, 2000, in our letter of January were to submit data to support the selected dose of 26, 2001, that the application must provide evidence Cetuximab and during the March 27, 2001 meeting that the addition of a toxic agent (irinotecan) is you were requested to provide tumor saturation data necessary to achieve the clinical effects. Based on in the BLA. the summary information provided, and assuming that To correct this deficiency, you need to provide the results can be confirmed, the data do not show an integrated dataset and analyses of the that the response rate observed with the combination pharmacokinetic profile of Cetuximab. The analyses of Cetuximab and irinotecan could not also be should support your statements relationship of the observed with single agent Cetuximab at one dose and proposed dose and dosing regimen to clinical safety schedule proposed. Your report on study CP02-9923 and effectiveness, the intensity of tumor EGFR indicates that an objective response was observed in expression and tumor burden in patients, and to in 27 or 120 patients who received Cetuximab plus vitro and in vivo levels of Cetuximab obtained in irinotecan (95 percent confidence interval of 15.4 subjects receiving the proposed dose and schedule. percent, 30.5 percent). Conversely, your report for c. You have not provided data to confirm that study CP02-0141, states an objective response was all subjects enrolled in CP02-9923 were unresponsive observed in 6 of 57 patients treated with Cetuximab or refractory to irinotecan. As discussed during the alone (95 percent confidence interval 4 percent, 21.5 August 11, 2000 meeting, documentation of irinotecan percent). failure is crucial to show that the results observed in You must provide evidence in support of this the trial could to be achieved by continuation of application, which isolates and establishes the irinotecan alone and thus confirm the benefit provided individual contributions of irinotecan and Cetuximab. Cetuximab. The application does not contain the “Because we also have determined that the current documentation for the independent review by the study was not adequate and well controlled (as Independent Response Assessment Committee (IRAC) discussed below) and that robustness of the overall of the CT scans confirming irinotecan failure for all response rate is less than is stated in the study reports, patients in the study CP02-9923. Specifically, there you will need to conduct additional studies to provide is no documentation that a review of these films was this evidence.” The most appropriate clinical study conducted, no identification of the lesions that were design for this purpose is a randomized controlled trial assessed and there is no listing of summated or directly comparing the efficacy of single agent individual tumor lesion measurements based on Cetuximab to the combination Cetuximab plus radiographs obtained prior to and after irinotecan irinotecan in patients who can be documented to be treatment. Therefore, we cannot verify how the IRAC refractory to irinotecan therapy. Alternatively, determined that subjects were eligible for enrollment irinotecan therapy could be included as a third arm in in CP02-9923. We also note that the number of a study enrolling patients who are not refractory to subjects meeting the criteria proposed in the request irinotecan. for accelerated approval and in you proposed

The Cancer Letter Special Report n Page 23 indication is unclear, however, it may be substantially (April 12, 2000) and cycle 2 (June 12, 2000). lower than described in your study report. 3) Patient #30618 received weekly Cetuximab 2. The application is scientifically incomplete, doses of 200 mg/m2 instead of 250 mg/m2. because the data provided to evaluate the clinical 4) Patient #59642 had Grade 3 skin toxicity as effectiveness of your product are not derived from per adverse event reporting in the CRF on weeks 2 an adequate and well controlled study. Our preliminary and 3, but Cetuximab dose was not held as specified review of the application has identified deviations from in the protocol. Instead, the dose was reduced to 200 the protocol in a substantial proportion of subjects. mg/m2 on weeks 2,4,5 and 6. Some examples of the types of deviations are provided 5) Patient #01647 had progressive disease at the below. end of cycle 4, as determined by tumor measurement a. Failure to meet protocol-specified eligibility on the CT scan (9/7/00), yet the patient continued to criteria: receive Cetuximab plus irinotecan for an additional 1) As noted in comment 1b, above, you cannot six weeks. provide confirmation that all subjects enrolled were 3. The presentation and organization of data for unresponsive to irinotecan. the primary efficacy analysis in CO02-9923 cannot 2) Patient #20624 received weekly irinotecan be reviewed because of the extent of the discrepancies from 10/14/99 through 12/23/99. This patient had a across datasets, as well as of the missing and incorrect partial response (the total sum of the measurable tumor information. The application does not provide decreased from 10.4 cm3 on 12/02/99 to 4.9 cm3 on sufficient information to allow us to determine whether 01/17/00). This patient with Cetuximab plus irinotecan the discrepancies in response assessments for began on 1/24/00. individual subjects are based upon the use of different 3) Patient #20635 received irinotecan from 11/ criteria for determination of response, errors in 9/99 through 1/26/00. There was no CT scan to computer programs, or data entry, other factors or a evaluate response to irinotecan during this period. The combination of the above. patient was enrolled on 2/28/00. No baseline CT scan a. The application does not adequately document was performed. The CT scan report after one cycle how the IRAC consensus response assessment (used of Cetuximab plus irinotecan on 4/10/00 indicates that to conduct the primary efficacy analysis) was the patient had no evidence of metastatic disease. The determined. These consensus reviews were performed patient continued to receive Cetuximab plus irinotecan when the two IRAC radiologists had inconsistent for an additional five cycles. Interim CT scan reports independent response assessment findings. We note on 5/22, 7/3, 9/19 and 10/30 all indicated absence of that among the 27 responding patients identified by metastatic disease. The patient withdrew consent on the IRAC, there were discrepancies in the response 11/13/00. The reason for withdrawal is unknown. assessment between the two reviewers for 15 patients. 4) Patient #60602 received radiation therapy Specifically, for three subjects, neither radiologist three weeks prior to enrollment. assessed the best response as a partial response and, 5) Patient #60726 received irinotecan from 12/ for eight subjects, one of the radiologists independently 14/99 through 5/31/00. The CT scan report for 6/23/ assessed the best response as progressive disease. This 00 indicates a minor response to irinotecan alone. The consensus finding is logically inconsistent, given the patient was assigned to the stable disease cohort. individual radiologists’ original assignments. 6) Patient #66670 was treated with the incorrect b. During the meeting of August 11, 2000, dose of irinotecan (100 mg/m2 weekly) prior to ImClone proposed an independent analysis of the enrollment. study results as the basis for the primary efficacy b. Deviation from the protocol-specified analysis of this open-label study. The analysis, treatment plan: retrospectively generated but discussed with the 1) Patient #20635 received irinotecan 125 mg/ Agency prior to implementation, was a determination m2 weekly in combination with Cetuximab, but had of response rate based upon the review of patients failed on irinotecan at 250 mg/m2 administered every data by the IRAC and as specified in the IRAC charter. three weeks. The procedure for this assessment was included in 2) Patient #01669 received a loading dose of the charter for the IRAC, along with criteria for 400 mg/m2 of Cetuximab twice, on cycle 1, week 1 response assignment, which was submitted to the IND

The Cancer Letter Page 24 n March 8, 2002 and reviewed by the Agency. However, the license application also contains the Quintiles Technical Computer N algorithm Manual, which has a different set of criteria for Radiologist's overall Radiologist (time- measurable assignment of response, and possibly different response assessment point) response procedures. The role of the Quintiles Technical assessment Manual was never discussed with the Agency. It is unclear if the IRAC members used the Technical 8DPRP Manual as a guide in determining response assignment 1 6DPDS and the application does not indicate which criteria (IRAC charter or Quintiles Technical Manual) were 1RMRP used by an individual radiologist or in the consensus response assessment in assigning response assessment 4DPRP contained in the DOVERRES dataset. 2 4DPDS c. The application contains two datasets for response assignment (DOVERRES and DMEASRES). 3R2 MRP The DOVERRES dataset is stated to be the IRAC radiologist’s overall assessment of response based on We acknowledge your comments of December changes in the sum of tumor area over time, changes 2, 2001, sent by electronic mail, that the discrepancies in evaluable, non-measurable disease over time, and noted above are due to a difference in the criteria for evidence of new lesions. The DMEASRES database disease response in the computer algorithm used to was stated to be derived from a computer algorithm, generate the Measurable Response Assessment using the tumor measurements provided by the IRAC (DMEASRES) as compared to the IRAC charter. computer algorithm using the tumor measurement Without the algorithm, we cannot verify this statement. provided by the IRAC radiologist to calculate the d. The dataset for tumor measurements contains tumor area, the change in tumor area over time, and incorrectly labeled units of measure for some items. this derive a response assessment based upon Tumor measurements made in pixel measurements measurable disease sites alone. However, we note that have been incorrectly labeled in units of millimeters there are discrepancies between the DOVERRES and for measurements of multiple tumor sites. The DMEASRES databases that are logically inconsistent application does not contain the necessary computer and there is insufficient information to determine why program and calibration factor to convert pixel these discrepancies may exist. Specifically: measurements into millimeter values. 1) The application does not contain the computer 4. The safety database is not complete and programs or the computer algorithms used to generate contains inconsistencies and discrepancies that the Measurable Response Assessment (DMEASRES). preclude an accurate assessment of the toxicity profile. 2) The application does not contain the individual The application states that there were 69 patients with radiologist’s comments and findings to support their serious adverse events, 16 patients who were removed overall response assessment. from the study because of adverse events, and 19 This information is necessary to allow us to patients who died within 30 days of the discontinuation understand assessment of those time points where the from the study. Of the deaths within 30 days of individual radiologist’s overall response assessment discontinuation from the study, 16 are listed as due to (DOVERRES) is inconsistent and incompatible with progressive disease, two due to disease-related the computer algorithm generated measurable response complications, and one as a result of intercurrent illness assessment (DMEASRES) for that time point. A (pneumonia and sepsis). We note the following lack summary of the discrepancies between the two of information and discrepancies in the safety database: assessments of responses both ostensibly based on a. We have identified 21 patients who died within the information from the radiologist reviewer, include 30 days of the last treatment with Cetuximab; the following: narratives were provided for only three patients who died within 30 days of discontinuation from the study. Narrative summaries are required for all patients who died during or within days of administration of study

The Cancer Letter Special Report n Page 25 drug or prior to resolution of treatment-related toxicity, patient was hospitalized because multiple entries were regardless of your or the investigator’s assessment of entered and subsequently deleted. The cause of death causal relationship of the death to the treatment. was attributed to disease progression, although there b. The application does not contain information is no CAT scan or clinical documentation. The regarding all hospitalizations that were not specifically application does not contain a narrative description of required in order to administer the treatment. Narrative the case. summaries of all hospitalizations not required by the As a result of this action you are requested to protocol and descriptive hospitalizations per patient resubmit your application in its entirety including the and number of days in hospital should have been information described above. The previously provided. submitted application will be retained and placed in c. There are inadequate descriptions of patients our inactive files in order to maintain an administrative who dropped out of the study. The application does record. not contain summaries of the circumstances and Under section 736(a)(1)(B) of the Federal Food, reasons why six patients withdrew consent. Drug, and Cosmetic Act (referred to hereafter as the d. There are inconsistencies and discrepancies Act) as amended by the Food and Drug Modernization between the CRFs and other portions of the application Act of 1997, the full fee required by subparagraph in a manner which impact on the interpretation of the (A) was due upon submission of your application(s). toxicity profile of the product. The line listings and Under Section 736(a)(1)(D) of the Act, since this other portions of the application should be consistent application has been refused for filing, you will receive with case report forms and should accurately describe a refund of 75 percent of the fee paid under the reason(s) for death and/or termination from study. subparagraph (B). 1) Patient #41729 received four cycles of We have the following comments: Cetuximab and irinotecan, with intermittent Grade 2 5. We note that the pivotal study protocol, CP02- and 3 abdominal pain and diarrhea. One week after 9923, was submitted to the IND on October 7, 1999, the last dose of Cetuximab and irinotecan, the patient one month after accrual had begun on September 9, developed Grade 4 abdominal pain and died 12 days 1999. This is violation of 21 CFR 312.30. Please later (11/12/00). There is no information as to the comment. final cause of death. This patient was listed as off 6. Your report on study CP02-9923 indicates that study due to an adverse event on 11/12/00, the day an objective response was observed in 27 of 120 of her death. In addition, the reviewer notes that the patients who received Cetuximab plus irinotecan (95 narrative of the case does not accurately describe the percent confidence interval of 15.4 percent, 30.5 CRF findings: “ . . . on day 120 11/12/00), the percent). The acceptability of the BLA was predicated abdominal pain was noted to be ongoing and she was on a study with an adequate sample size and clinically discontinued from the study. She had progressive meaningful overall response rate, to show that the disease and eventually died.” effects observed in this single study are acceptable 2) Patient #60605 was hospitalized (on 11/29/ for demonstrating efficacy in a scientifically valid 99) with Grade 4 fatigue, Grade 3 neutropenia, pleural manner, without the need for replication or effusion, tachycardia, diarrhea, nausea, vomiting and substantiation. Based upon the deficiencies in the weakness five days after the second dose of conduct for the study, we do not believe that you can Cetuximab. The patient died eight days after admission document the effectiveness of your product in each on 11/29. The reason for discontinuation from the of the 120 subjects enrolled and treated in accordance study, according to the data listing, was protocol non- with the clinical protocol. Please be aware that compliance. The CRF indicates that the patient was evidence of clinical activity in a smaller patient discontinued from the study due to disease progression population than that enrolled in CP02-9923 or having although no imaging scans were performed. a documented response rate which is substantially 3) Patient #66681 developed progressive fatigue, lower than that stated in the study report, is highly weakness, diarrhea, anemia and neutropenia after three unlikely to be sufficient to demonstrate efficacy doses of Cetuximab. The patient continued to without replication or substantiation. deteriorate and died on 6/9/00, 14 days after the last You may contact the Center in writing if you dose of Cetuximab. It is unclear from the CRF if the wish to request an informal conference to discuss our

The Cancer Letter Page 26 n March 8, 2002 decision to refuse to file this application. Should you have any questions regarding the BLA please contact The Cancer Letter Inc. the Regulatory Project Manager, Ms. Sharon is the publisher of independent Sickafuse, in the Division of Application Review and newsletters in oncology: Policy at (301) 827-5101. • The Cancer Letter: Weekly Sincerely Yours, covering federal cancer policy and Kathryn E. Stein, Ph.D. funding news. Director • The Cancer Letter’s Business & Division of Monoclonal Antibodies Regulatory Report: Monthly Office of Therapeutics Research and Review digest of oncology management Center for Biologics Evaluation and Research and pharmaceutical industry news. • The Clinical Cancer Letter: Karen D. Weiss, M.D. Monthly covering clinical trials and Director other clinical cancer research Division of Clinical Trial Design and Analysis developments. Office of Therapeutics Research and Review • The Cancer Letter Funding Alert: Center for Biologics Evaluation and Research Digest of funding opportunities from NIH, NCI, other federal agencies, and foundations.

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