In the December 13, 2007, letter to Rep John Dingell (D-MI), Chairman of the Committee, Congressmen Mike Michaud (D-Maine), Dan Burton (R-IN) and Tim Ryan (D-OH) said they had serious concerns about the FDA's failure "to approve a potentially life-saving therapy for those suffering from advanced prostate cancer."
"We need to ensure that the FDA gets life-saving drugs to the market as quickly and as safely as possible," Rep Michaud said in a statement released to the media.
"Our priority is to ensure the prompt and efficient approval of therapies such as Provenge that could potentially benefit millions of Americans with cancer," he stated.
Provenge belongs to a new class of immunotherapies that is designed to stimulate the body's own immune system to attack cancer cells only, unlike chemotherapy, which attacks both cancer cells and healthy cells.The new immunotherapies pose an imminent threat to the multi-billion dollar cancer research and treatment industry because if they turn out to be as effective as some experts predict, treatments involving radiation and chemotherapy for many diseases could become obsolete.
The FDA's refusal to approve Provenge was extremely upsetting to members of the cancer community who have been closely tracking the approval of this vaccine since October 29, 2004, when the New York Times reported that Dendreon had announced that it had developed "an experimental vaccine extended the lives of men with advanced prostate cancer."
This is supported by the results of a recent trial that reported 34% of the prostate cancer patients who received the vaccine were still alive after 36 months, compared to only 11% of the men who received a placebo.
On February 17, 2005, the Washington Post ran the headline: "Provenge: First Vaccine to Extend Lives for Advanced Prostate Cancer Patients". The article quoted Jamie Bearse, of the National Prostate Cancer Coalition, as stating: "Whenever you have something that comes out that really kind of changes the treatment landscape in the prostate cancer field, it's very encouraging."
Chemotherapy with Taxotere, made by Sanofi-Aventis, is the only approved treatment for late stage prostate cancer patients. Treatment using this drug involves months of infusions and produces severe side effects. Provenge, on the other hand, is administered three times at 2-week intervals, and only one in four patients experiences side effects consisting of mild flu-like symptoms that last a day or two. Further, Provenge keeps working long after each infusion to help the body build up its immune system.
Experts estimate that between 300 and 600 patients a year die from the Taxotere treatment itself, and they say that no patients have died from treatment with Provenge.
The FDA's Office of Cellular, Tissue and Gene Therapies Advisory Committee finally met to review the application for the approval of the vaccine. Specifically, the panel heard testimony from members of the prostate cancer community during an Advisory Committee hearing on March 29, 2007.
Cancer patients testified that the side effects of chemotherapy with Taxotere are so severe that many men refuse the treatment. Put simply, they do not want spend their last years of life living with the debilitating side effects.
They also pointed out that Taxotere was approved when it extended life by only a couple months and that Provenge extends life more than twice as long without the pain or loss of hair, fingernails, vitality, and, importantly, their dignity.
They told the panel that by recommending approval, "you will give up to 50,000 waiting men, maybe more, new hope and new life with an alternative treatment that works."
At the end of the hearing, the panel voted 17-0 that Provenge was safe and 13-4 in favor of it having demonstrated substantial evidence of efficacy. This meant that the drug had met the burden of proof specified in the Food and Drug Administration Modernization Act of 1997, for immediate approval while Dendreon completed its ongoing study of the vaccine.
Under the FDA's risk-benefit balancing test for drugs undertaken pursuant to 21 USC 355(d) as part of the premarket approval process, the FDA generally considers a drug safe when the expected therapeutic gain justifies the risk entailed by its use.
Applying that approach, FDA even has approved cancer treatments that are highly toxic and thus not safe as that term is ordinarily used, but that are, nonetheless, safe in the
relevant sense under the FDCA because the potential benefits to health outweigh the risks. (61 Fed Reg 44,413 (1996)).
Under this balancing test, the experts on the panel voted 17 to 0 that Provenge was safe, so there would be no reason to deny Provenge to cancer patients who are dying.
In determining whether or not the benefits outweigh risks, the FDA also is supposed to consider the availability of other drugs or treatments together with their safety profiles. In February 1996, the FDA Commissioner at the time, Dr David Kessler, testified before the Senate Committee on Labor and Human Recourses and told the panel, "FDA must determine if each new drug or device is safe enough in view of its anticipated benefits and the comparative benefit of other available treatments."
In the case of Provenge, there are no other methods of treatments with comparative benefits to balance against the alternative of certain death.
In their request for a hearing, the lawmakers informed the Committee that a lawsuit has been filed by the Ohio-based nonprofit group, Care to Live, in federal court, accusing the FDA of ignoring conflict-of-interest issues with two advisers who were chosen to sit on the advisory committee that reviewed the application for the approval of Provenge.
The plaintiffs in the case include dying cancer victims, their family members, and doctors, who are suing collectively as members of Care To Live. The complaint alleges that "prostate cancer patients are living and dying in Ohio and families and doctors in Ohio want this treatment for their family, friends and patients."
It also alleges that one doctor has 12 patients waiting for treatment and a John Doe plaintiff is one of several patients "who may die before he can receive Provenge."
The defendants include FDA Commissioner, Dr Andrew von Eschenbach, Mike Leavitt, Secretary of the Department of Health and Human Services, Dr Richard Pazdur, the head of the FDA's Office of Oncologic Drug Division, and Dr Howard Scher, chosen by Dr Pazdur to serve on the advisory panel to review the application for the approval of Provenge.
In their letter to the House Committee, the lawmakers ask for a hearing to discuss the FDA's role in the Provenge decision and state, "there is reason to believe that serious ethics rules were violated by two FDA advisory panel members in their decision and that those violations played a role in the subsequent FDA decisions to not approve Provenge at this time."
The letter points out that two of the negative votes on efficacy were made by academic oncologists Dr Maha Hussain of the University of Michigan and Dr Howard Scher of the Memorial Sloan-Kettering Cancer Center in New York.
They also note that Dr Scher is the lead investigator for a competing cancer drug made by Novacea and is listed as an adviser to a large venture capital firm that is (or was, at the time of the March 29. 2007, meeting) a major investor in Novacea; that firm is ProQuest Investments of Princeton, NJ.
"We believe the FDA should not be appointing scientists leading the testing of a rival drug for another firm onto an advisory committee evaluating Provenge nor should the FDA appoint an adviser to a large investor such as a competitive firm as a panel member," the lawmakers state.
"Many ethical questions remain about the two panelists who voted no on approving this drug," Rep Michaud said in a statement released to the media.
A Congressional hearing could mean big trouble for the officials involved in this escapade because as of December 1, 2007, investigations of potential criminal misconduct by FDA employees will be conducted solely by the Inspector General for the Department of Health and Human Services without any FDA involvement, according Senator Chuck Grassley, ranking member of the Senate Finance Committee, in a November 29, 2007 press release.
And that would include Dr Scher and Dr Hussain because members of advisory panels are considered "special government employees" of the FDA.
In September 6, 2007 letter, Inspector General David Levinson informed Commissioner von Eschenbach that he will now "independently investigate allegations concerning senior FDA officials and thereby eliminate any conflict of interest - in fact or appearance - created when FDA Office of Internal Affairs (OIA) agents are asked to investigate allegations of misconduct against a supervisory official."
Mr Levinson specifically noted the increased congressional and media scrutiny over allegations of potential criminal violations of Federal conflict-of-interest statutes involving FDA and other officials that led to his office devoting increased attention and resources to ethics issues. "As a result," he informed the Commissioner, "investigators and attorneys have developed significant expertise in handling these complex cases."
Provenge will not doubt qualify as a "complex case" because in addition to being the lead investigator for Novacea's clinical trials for Asentar, a treatment that would compete for treating the exact same patient population as Provenge, Dr Scher also is a member of the scientific advisory board for Novacea.
The lawmakers did not elaborate on Dr Hussain's conflicts but she runs a close second to Dr Scher. She is an investigator for studies on treatments competing with Provenge and her husband owns stock valued at between $15,000 and $300,000 in three competing companies. She is also on an advisory board for Novacea and receives research funding from Sanofi-Aventis, according to faculty disclosures at the University of Michigan.
According to Care To Live, Dr Pazdur chose Dr Hussain and Dr Scher to serve on the panel so that they could persuade the other members to vote against approving Provenge.
However, when that mission failed, a follow-up plan was implemented in which Dr Hussain, Dr Scher and a Dr Thomas Fleming would send letters to the FDA, disparaging the vaccine and urging top officials to basically ignore the Advisory Committee panel's recommended approval.
Under this plan, once the letters arrived, FDA officials would leak the letters to the media, specifically to, "The Cancer Letter," which in turn would publish each one on the Internet roughly a week apart prior to May 15, 2007, when the FDA was required to announce a decision.
Care To Live now has discovered that the FDA not only leaked the letters to the press, but government officials actually had a hand in composing the letters. A document obtained through a FOIA request from the National Cancer Institute shows that Dr Scher's letter had several authors, with the final copy submitted for his approval and signature.
One document, identified as "v3" (version 3) is titled, "FDA Letter Draft" and carries a date of April 3, 2007. The listed recipients are Andrew von Eschenbach, Janet Woodcock and Jessie Goodman.
This draft came from the computer of Dr Alison Martin at National Cancer Institute and shows 13 edits with embedded comments, most if not all of which were adopted or resolved by Dr Scher after he received comments from the other writers.
For instance, in one sentence, he inserted a comment that states: "I thought it might be a nice touch to quote their own guidelines - what do you think?"
Dr Scher is referring to his addition of the statement: "Scientific basis for the legal standard, FDA Guidance for Industry; Providing Clinical Evidence of Effectiveness for Human Drugs and Biological Products, May 1998."
He also questioned the language used in a sentence that originally stated: "I am also the PI of the 10 Center Prostate Cancer Clinical Trials Consortium funded by the DOD focused on phase I and 2 trials in this disease."
In the draft copy, Dr Scher inserts a question asking: "Is it really called "10 center..."? If not, I would call it Multicenter ... no one uses the number of centers and I thought it was granting a mechanism eg P10."
Another sentence in the draft states: "FDA doesn't accept secondary endpoints unless primary endpoints are met - is there to be an exception here b/c it is OS? Should be no exceptions because of the complexities - then can name the e.g., heterogeneity, confounders, 2:1, whatever they are."
At this point Dr Scher inserts the comment: "I change my input here - I see that the 2 trials were not confirmatory so don't need to go down the path of secondary endpoints - the primary contradiction is inconsistent results."
Dr Scher's letter was clearly reviewed, edited, and partially authored by officials within the FDA and NCI. But how many people had access to the finalized version is unknown, making it impossible to determine for certain who leaked it to "The Cancer Letter" for publication on the Internet on April 13, 2007. In seeking a hearing, Care To Live is asking Congress to require FDA officials to answer that question once and for all.
According to Care To Live, the desperation evidenced by the efforts to block the approval of Provenge was the result of pressure from investors who had sold the stock short based on insider information that approval would be denied and thus, stood to lose millions if that tip turned out to be false.
A development that instantly raised suspicions came on May 31, 2007, when Novacea announced that it had entered into a partnership with Schering-Plough involving the research and development of its cancer drug Asentar, worth as much as half billion dollars.
Under this deal, Schering would fund the ongoing clinical trials of Asentar for which Dr Scher was the co-lead investigator. The news of the partnership resulted in an 86% increase in stock value for Novacea in one day.
All bets are on Dr Pazdur as the leaker due to his history of similar conduct a few years ago in the ImClone case, where he leaked the fact that the FDA was not going to review the application for the approval the cancer drug, Erbitux, and set off a firestorm of insider trading in December 2001.
Persons in the inner circle of ImClone immediately acted on the tip and sold off large amounts of stock and the company's stock value plunged. The SEC began an investigation within days after the FDA's decision was officially made public on December 28, 2001, and determined that Sam Waksal, one of the owners of ImClone, and his relatives sold over $10 million worth of stock in 48 hours on December 26 and December 27, 2001.
And of course, everybody knows the rest of the story. When the Waksal family started dumping stock, Sam Waksal's broker, Peter Bacanovic, tipped off his famous client Martha Stewart and she quickly got rid her shares.
By January 9, 2002, less than two weeks after the insider trading ended, ImClone had lost nearly $1.5 billion in market value, according to the transcript of a June 9, 2002 Congressional hearing.
Dr Pazdur also used his buddies at the "The Cancer Letter" to make information public in the ImClone case.
It will be interesting to hear what Dr Pazdur has say if Congress holds a hearing on Provenge because the transcript from the ImClone hearing reveals that nobody ratted him out even though several members of Congress directly asked FDA officials, including Dr Pazdur, who leaked the information, and even though that hearing took place 6 months after the fact.
The transcript shows that when asked directly who leaked the information, they all talked in circles in order not to identify Dr Pazdur. For instance, Rep Ernie Fletcher put the question to the whole gang, stating: "Let me ask a question, and I guess this probably goes to Dr. Keegan, but if somebody else has a responsibility, don't hesitate to answer it."
"We got testimony earlier from Mr. Bryan Markison that on December 25, of all days, Christmas, that he received a call from someone, and I don't know that we got that individual's name. But he received a call on December 25 that you all were likely—well, not only likely, but that it was going to occur, that an RTF letter would be issued."
He noted that the official letter that was sent was stamped on December 28, and asked flat out: "Who leaked the information, and is that normal to leak the information, or is that okay to leak the information?"
"It had tremendous impact on the executives, and family, friends, and other folks who ended up selling off a whole lot of stock based on that information," he added.
The closest anyone came to identifying the leaker was when Ms Keegan said, Dr Pazdur says, "we do have the option, and in his Center, he will actually inform a sponsor, a commercial firm, that they would refuse to file the application ahead of issuing the letter."
"There is no prohibition against telling a company that you will refuse to file their application," she stated. "We did not choose to tell them that definitely before we sent the letter, but there is no prohibition against it."
The main problem with this rambling answer is that ImCone's application was not under review by Dr Pazdur's "Center." Ms Keegan office was in charge, and instead of talking in circles, the honest answer would have been for Ms Keegan to say that she did not exercise this so-called "option," but that apparently, Dr Pazdur took it upon himself to exercise it for her.
Of course, that is assuming that she knew he was the leaker.