FDA Officials Sued Over Conflicts of Interests Part I

Evelyn Pringle October 1, 2007

A lawsuit recently filed in a federal court in Ohio against FDA officials on behalf of terminal cancer patients provides a rare window into the inner workings of an agency hijacked by pharmaceutical industry giants and stacked with insiders by President George Bush to guard against any threat to the profits of his top campaign contributors.

The lawsuit’s complaint describes a conspiracy orchestrated by top FDA officials to basically drive a small company, Dendreon, out of business with the obvious goal of eliminating competition in what has become a thriving new industry involving the treatment of men with prostate cancer.

The complaint gives the details of a step-by-step plot to sabotage the FDA approval process of Provenge, the first-of-a-kind vaccine that can prolong the lives of men with late-stage cancer.

Prostate cancer patients have been waiting for the approval of Provenge for years. The New York Times first reported on a study back on October 29, 2004, the day after Dendreon announced the results that showed that “an experimental vaccine extended the lives of men with advanced prostate cancer.”

The findings also were discussed by Dr Eric Small of the University of California at San Francisco in February 2005, at a meeting in Florida that was co-sponsored by the American Society of Clinical Oncology. Here, he presented the study in which Provenge was given to a group of 82 men whose cancer had progressed after surgery and radiation treatment, and a similar group of 45 men who had received a placebo.

After 36 months, the study showed that 34% of the men who received Provenge were still alive compared to only 11% of the group who received a placebo, or a 23% difference.

On February 17, 2005, the Times reported that the 4.5-month increase in survival that was achieved by Provenge is greater than the roughly 2.5-month benefit shown in clinical trials of Taxotere, a drug from Sanofi-Aventis.

“Taxotere is the only approved chemotherapy for patients, like those in the Provenge trial, whose cancer has spread beyond the prostate gland and is no longer being controlled by hormonal therapy,” the article said.

Dr Small told the Times that Provenge improved survival for all patients, not just those with less aggressive cancers, and said “the treatment was much less toxic than chemotherapy, with the main side effects being flu-like symptoms that last a short time.”

The list of plaintiffs in the lawsuit, first and foremost, includes dying cancer victims, along with their family members and doctors, who are collectively suing as members of a non-profit corporation called CareToLive (CTL).

The plaintiffs allege 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.”

According to the complaint, one doctor has 12 patients waiting for treatment and a John Doe plaintiff “is one of several Ohio prostate cancer patients who may die before he can receive Provenge.”

The named defendants in the case include the current FDA Commissioner, Dr Andrew von Eschenbach, and Mike Leavitt, in his supervisory capacity over the FDA as Secretary of the US Department of Health and Human Services.

And let it be noted that the lead defendant, Dr von Eschenbach, became the FDA Commissioner following a two-month stint by Dr Lester Crawford, only because Lester was booted out of office and found guilty of charges that he failed to disclose his own financial ties to companies regulated by the FDA.

The two other named defendants in the CTL lawsuit are 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 convened to consider the approval of Provenge.

According to the complaint, Dr Pazdur “intentionally violated Federal Regulations” by improperly controlling the make up of the advisory committee and by “applying improper pressure” on panel members and other FDA employees “in an effort to achieve a predetermined outcome of his choosing.”

The plaintiffs allege that when Dr Scher was chosen to serve on the panel, he failed to disclose all conflicts of interest and his own personal interests in urging a decision that Provenge not be approved for men dying of cancer and that Dr Scher acted in “a manner that has callously deprived cancer patients access to a safe and effective immunotherapy.”

It also should be noted that the legal filings show one lone attorney, Kerry Donahue, of the Dublin, Ohio Bellinger & Donahue law firm, up against a “dream team” of attorneys with unlimited access to tax dollars and the full force of the federal government, which includes US Attorney Gregory Lockhart, Assistant US Attorneys Mark D’Alessandro and John Stark, the Director of the Office of Consumer Litigation, Eugene M. Thirolf, along with Andrew Clarke and Daniel Crane-Hirsch, Trial Attorneys from the Office of Consumer Litigation in the US Department of Justice.

According to the lawsuit, the FDA indicated that there were sufficient data submitted from the clinical trials of Provenge to immediately evaluate the product, so Dendreon filed a Biologics License Application in December 2006, which was granted fast track approval designation in January 2007, establishing May 15, 2007 as the date for an FDA decision.

Congress established the fast track approval program to expedite the approval of drugs for terminally ill patients.

In a blatant attempt to corrupt the Provenge advisory panel, Dr Scher was granted a waiver even though he is the chief of genitourinary oncology services of the Center for Prostate Cancer, at the Memorial Sloan-Kettering Cancer Center and the Center has a received a grant for a study from a competing company valued at $100,000-$300,000 and he owns stock valued at between $5,000 and $100,000 in a company that competes with Dendreon.

He also serves as an advisory board member to the venture capital fund ProQuest Investments LP. A 1998 document, entitled “The Opportunity in Cancer: Goldberg’s Variation” says “Prostate cancer will be the focus of the ProQuest Investment LP, a new venture fund founded by Jeremy Goldberg”, and “ProQuest raised $40.5 million in its first closing.”

Dr Scher also is listed on some documents as an officer and member of the board of directors of ProQuest.

However, a later May 2000 document discusses the “Start-Up” issue and says, “ProQuest Investments is a $100 million oncology-focused investment fund, partnered by Jeremy Goldberg and Jay Moorin.”

Under “Companies”, the report lists Dr Scher’s “Memorial Sloan-Kettering Cancer Center”, among many others, but Dendreon is not one of them.

According to May 15, 2006, SEC filings, ProQuest and its principals have a major stake in Novacea. For instance, at the time of the filing, ProQuest Investments II, LP held 1,779,767 shares, ProQuest Investments II Advisors Fund, LP was listed with 75,508 shares, ProQuest Associates II LLC held 1,855,275 shares, and Jay Moorin was listed with 1,910,988 shares.

Dr Scher also is on a scientific advisory board for Novacea and is the co-lead investigator of the company’s Asentar Phase III clinical trial of patients in the same stage of prostate cancer as patients who would be treated with Provenge.

Another conflicted panel member chosen by Dr Pazdur, Dr Maha Hussain, a professor at the University of Michigan, was granted a waiver even though she is the principle investigator for a study funded by a competing company and her husband owns stock valued at between $15,000 and $300,000 in three competing companies.

Under Faculty Disclosure Declarations, Dr Hussain is listed as being a consultant to, and an advisory board member of, Novacea and receiving research funding from Sanofi-Aventis, the maker of the chemotherapy drug Taxotere, the only product on the market FDA approved for the treatment of the cancer patients who would benefit from the approval of Provenge.

Dr Scher is also the lead investigator on a clinical trial investigating Taxotere in treating early-stage prostate cancer – a trial that some experts say would be adversely affected by the approval of Provenge.

Another conflicted member, Dr Savio Lau-Ching Woo, a professor of gene and cell medicine at Mount Sinai School of Medicine, was granted a waiver even though an affected company has patented a gene therapy technology that he invented which is being studied in prostate and other cancers and in the last 12 months Dr Woo has received an amount less than $15,000 from the patent.

Although in the end, the industry plants failed to corrupt the decision of the advisory panel, because the committee said Provenge was safe and that the data submitted show “substantial evidence” of efficacy, the efforts to derail its approval continued and on May 8, 2007, the FDA refused to approve the vaccine.

Instead of approval, the agency issued a Complete Response letter that required Dendreon to provide additional data that could take up to 2 years to accumulate. During that time, as many as 60,000 men will die from prostate cancer – many of whom could have benefited from Provenge.

The most blatant evidence of the conspiracy alleged in the lawsuit emerged in a May 30, 2007 press release, when Novacea and industry giant Schering-Plough announced that they had entered into an exclusive worldwide license agreement for the development and commercialization of Asentar and noted that Novacea was currently conducting a large international Phase 3 trial evaluating Asentar in 900 patients with androgen-independent prostate cancer.

Under the terms of the agreement, all total Novacea will receive close to a half a billion dollars.

FDA Industry Insiders Derail Approval of New Cancer Treatments

Evelyn Pringle October 10, 2007

George W Bush’s FDA, stacked with insiders from the industry that literally carried him to Washington, has stooped to a new low to protect the obscene profits of the multi-billion dollar cancer industry by blocking the approval of a new class of immunotherapies that can extend the lives of dying cancer patients with minimal side effects.

In the May 14, 2007, Wall Street Journal, a former medical officer in the FDA Office of Oncology Products, Dr Mark Thornton, denounced the FDA’s decisions, and stated, “May 9, 2007, should be cited in the annals of cancer immunotherapy as Black Wednesday.”

“Within an eight-hour period that day,” he wrote, “the FDA succeeded in killing not one but two safe, promising therapies designed and developed to act by stimulating a patient’s immune system against cancer.”

Experts say, the new immunotherapies hold promise for many forms of cancer. “FDA’s hubris will affect the lives and possibly the life spans of cancer patients from nearly every demographic, from elderly men with prostate cancer to young children with the rarest of bone cancers,” according to Dr Thornton.

With the approval of the new therapies, the profits, along with the horrendous side effects of the only treatments now available, could become a thing of the past. “One day current treatment approaches such as surgery, radiation and chemotherapy, which often kill most but not all of a cancer, could be made obsolete by a potent immune response that eradicates the cancer cells and provides subsequent protection against return and relapse,” Dr Thornton wrote.

As such, the new therapies pose a grave threat to the cancer industry as a whole, and the lost profits would not be limited to the sale of products. The pharmaceutical giants have spent a small fortune to gain control of every segment of the industry, from researchers to government regulators, and every year, billions of dollars flow through a nationwide network of research institutions and treatment providers under the guise of finding a cure for cancer.

However, the profits up for grabs have become so enormous that critics say the goal of industry-controlled research is no longer focused on finding a cure for cancer to save lives. Instead, the focus is on thwarting the development and approval of new therapies in order to protect the profits of the treatments already on the market.

The FDA’s refusal to approve Provenge, a new immunotherapy vaccine manufactured by the Dendreon Corporation, has caused major outrage in the cancer community. Provenge supporters have sent thousands upon thousands of letters and other correspondence to the FDA, members of Congress, the Department of Justice and others.

In addition, the Ohio-based non-profit corporation, CareToLive, has filed a lawsuit on behalf of terminal cancer patients seeking a declaratory judgment that the FDA acted “arbitrarily” and “capriciously” by denying patients access to Provenge, in violation of their constitutional right to live.

Dendreon sought approval to treat late-stage androgen-independent prostate cancer (AIPC) patients who have no other options. A study presented to an FDA Advisory Committee at a March 29, 2007, meeting showed that, after 36 months, 34% of the men who received Provenge in a clinical trial were still alive, compared to only 11% of those who received a placebo.

Provenge is designed to stimulate the patient’s own immune system to specifically attack only cancer cells, unlike chemo drugs that attack any fast-growing line of cells.

Patients who qualify for Provenge have already had their prostates removed or have undergone radiation and hormone therapy. Eligible patients receive a one-time round of treatment consisting of 3 visits to a urologist’s or oncologist’s office to give blood, and 3 visits for the blood enhanced with Provenge to be infused back into the body.

On September 10, 2007, CareToLive filed a motion asking the court to issue an order enjoining the FDA from denying the marketing and distribution of Provenge. The plaintiffs charge that within six months, another 15,000 patients will have died waiting for justice.

The memorandum filed with the motion points out that the only available treatment approved for terminal AIPC in the last 42 years is a chemo drug, Taxotere. “The effectiveness of Taxotere,” it states, “is so superficial, and the side effects so severe, that most men decline the treatment, as the risks far outweigh the benefits.”

According to the filing, between 300 and 600 patients per year die from the Taxotere treatment itself. “This is truly amazing,” the memo states, “considering the cost of the treatment and the cost of hospitalization and that the average benefit is an increase in survival of only 2 ½ months.”

In contrast, the Provenge safety profile is so good that nobody has died from it and less than one in four patients experience side effects consisting of mild flu-like symptoms lasting one or two days, the memo notes.

The defendants named in the lawsuit include Mike Leavitt, Secretary of the US Department of Health and Human Services; FDA Commissioner Andrew von Eschenbach; Dr Richard Pazdur, head of the FDA’s Office of Oncologic Drug Division, and Dr Howard Scher, chosen by Dr Pazdur to serve on the advisory panel set up to review the approval of Provenge.

CareToLive is represented pro bono by Attorney Kerry Donahue, of the Dublin, Ohio law firm Bellinger & Donahue, while the FDA officials are represented by a legal team of 11 government attorneys, at last count, funded by tax dollars.

The plaintiffs allege that the defendants engaged in a conspiracy to prevent the approval of Provenge and that Dr Pazdur, “purposely located two conflicted oncologists who he was sure for a variety of reasons would be anti-Provenge and he instructed them to try to derail the approval of Provenge.”

The plaintiffs charge that, by choosing Dr Scher, and also Dr Maha Hussain, to serve on the advisory panel, Dr Pazdur “likely found two of the most conflicted oncologists in the country to sit in judgment of Provenge, and who would both assuredly continue his plot to lobby others at the FDA to vote for non-approval.”

At the behest of Dr Pazdur, and for their own future political and monetary gain, the plaintiffs claim, “these two oncologists did everything they could think of to obstruct and impede the approval of Provenge.”

The waiver of conflicts of interest granted by the FDA to Dr Hussain, which allowed her sit on the panel, reveals that she is the lead investigator on a research contract awarded by a company that competes with Dendreon, and her husband owns stock in three competing companies valued at between $15,000 and $300,000.

The lawsuit alleges that, as part of the conspiracy, on May 9, 2007, the FDA denied terminally-ill patients access to Provenge, even though the FDA Advisory Committee recommended approval, found the vaccine safe by a 17-0 vote and found there was “substantial evidence” of efficacy with Provenge by a 13-4 vote.

In an attempt to derail an approval recommendation by the panel, the plaintiffs claim that, prior to the vote on efficacy, Dr Pazdur and “his co-conspirators changed the statutory question regarding efficacy from ‘substantial evidence’ to ‘absolute certainty’ of efficacy, in an effort to obtain a ‘no’ vote on Provenge.”

However, during the voting, this manipulation was discovered and promptly corrected by the FDA’s Dr Celia Witten and Dr Jesse Goodman, and by an overwhelming majority, the panel voted “yes” to the revised efficacy question.

“It is unprecedented for the FDA to overturn the Advisory Committee on such a positive vote when men are out of options, delaying approval and asking for more trials,” according to CareToLive spokesman Mike Kearny in an August 2, 2007, press release.

“Men are dying now,” he states. “They do not have years to wait.”

In the case of Provenge’s approval, the profits at stake could not be higher. Prostate cancer is the most common non-skin cancer in the US and the third most common cancer worldwide. More than one million men in the US have prostate cancer, with an estimated 232,000 new cases diagnosed each year and more than 30,000 men face death from the disease each year.

As an initial treatment, when diagnosed with prostate cancer, most men have their prostate removed, or undergo radiation, which can lead to various degrees of incontinence and impotence. After the initial treatments fails, hormone therapy is given to block the production of androgens such as testosterone, needed for cancer cells to grow, and some men undergo testicle removal in an attempt to stop the androgens from spreading the cancer.

With AIPC patients, prostate cancer has usually gone into remission and then returned, spreading to other parts of the body including the bones, lymph nodes, bladder, rectum, liver and lungs. All men who do not die of other causes progress to the final stage where the cells no longer respond to hormone therapy. Provenge is intended for use by patients who have already failed other types of therapy.

Because Taxotere is the only approved drug, Sanofi would have suffered the greatest immediate loss had Provenge been approved. According to firm’s 2006 Annual Report, Taxotere was the company’s 4th best-selling product in 2006, and the US is listed as the number one country contributing to sales.

As far as profits per dose, in the February 7, 2007, article, “What Does It Cost to Have Cancer?”, a patient who received the chemo drug for breast cancer in 2006 reported that “each infusion of Taxotere cost over $16,000.”

She also stated: “That’s just for the drug, not administration or anything.”

According to the lawsuit, defendant Dr Scher, Chief Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, is a scientific advisor and lead trial investigator for a competitor of Dendreon called Novacea. Under faculty disclosures at the University of Michigan, Dr Hussain is listed as an advisory board member of Novacea, and she receives research funding from Sanofi.

Dr Scher also has an interest in ProQuest Investments, which stood to reap windfall profits if Provenge was not approved. ProQuest is a venture capital fund established in 1998, in large part by Michael Milken, who was given the nickname “Junk Bond King,” after being indicted on nearly 100 counts of insider trading and sentenced to 10 years in prison, in addition to being barred from the securities industry for life.

The ProQuest fund was established with a specific focus on prostate cancer, and SEC filings show that ProQuest and its principals are major shareholders of Novacea.
Citing documents from ProQuest, the plaintiffs allege that Dr Scher is a “ProQuest Executive” and “member of the Board of Directors”, ProQuest reaps millions of dollars investing in prostate cancer companies based on advice from doctors such as Dr Scher, and ProQuest own stock in direct competitors including Novacea.

Dr Scher receives compensation from ProQuest as a scientific advisor recommending investments and for conducting clinical trials that result from the investments. He also holds an ownership interest in ProQuest.

The lawsuit also alleges that Dr Scher receives research support from the Prostate Cancer Foundation, as well as financial benefits, as one of a consortium of members who reviews new research on cancer drugs to determine which grants should be awarded by the Foundation.

The PCF, also founded by Mr Milken, is one of the largest sources of funding for the National Cancer Institute and government research programs. A following of the tangled web involved in the PCF reveals that Dr Jonathan Simons, President of the Foundation, Dr Stuart Holden, Medical Director, and Dr Howard Soule, an Executive Vice President of the Foundation, are all scientific advisors to ProQuest.

Another research arm found to be infested with several of the same insiders is the Prostrate Cancer Research Program, within the Department of Defense, which since 1997 has been appropriated a total of $730 million by Congress. According to a PCRP report, “Today, the PCRP is the second leading source of extramural prostate cancer research funding in the United States.”

The PCRP funds a Clinical Consortium Award to support the creation of a major multi-institutional clinical trial resource, “to speed development of novel therapeutics that will ultimately decrease the impact of the disease.”

Here, too, Dr Scher is listed as the leader of the consortium, and the list of participating clinical sites and lead investigators includes none other than Dr Hussain. Dr Simons is listed as developing new clinical therapeutics for late-stage prostate cancer, but a review of upcoming research listed in the report shows immunotherapies are not in the cards.

These consortium members are invaluable to the industry and investors due to their unique access to insider information about clinical trials and influence over the FDA approval process. Evidence of this claim came on May 30, 2007, less than 3 weeks after approval for Provenge was denied, when Novacea announced an agreement with Schering-Plough worth over $450 million, in which Schering agreed to jointly fund and develop Asentar, a competing prostate cancer drug, for which Dr Scher happens to be the lead investigator.

“The partnership leverages Novacea’s existing capabilities with Schering-Plough’s experienced development, regulatory and commercial teams and will provide Novacea with an opportunity to support the commercialization of Asentar in the United States,” John Walker, company chairman and interim CEO, stated in a May 30, 2007 press release.

A May 2000 ProQuest document provides insight about the investment firm’s interest in Asentar’s success and states: “ProQuest Investments is a $100 million oncology-focused investment fund, partnered by Jeremy Goldberg and Jay Moorin.”

Mr Moorin owned 1,910,988 shares of Novacea stock at the time of a May 15, 2006, SEC filing, and the ProQuest document mentions an investment from Domain Associates, “whose general partner, Jim Blair, has also worked with the fund to plot its strategy.”

As it turns out, Mr Blair and Mr Moorin were both members of Novacea’s board of directors when the Schering deal was set up. However, apparently their services are no longer needed, because on August 30, 2007, Novacea announced the resignation of James Blair and Jay Moorin, effective September 4, 2007, and September 19, 2007, respectively.

All that said, it does not take a financial genius to figure out that this whole deal could have gone up in smoke had Provenge been approved, because there would have been a drastic drop in the enrollment of late-stage cancer patients in clinical trials as soon as they learned that there was a new vaccine that could not only increase their survival rate but allow them to live out their final days without the agonizing side effects of chemotherapy.

Provenge’s approval also would have caused many patients currently participating in trials to drop out. Novacea’s 2006 Annual Report filed on April 2, 2007, less than 2 months before the Shering announcement, warned that the “clinical development and regulatory approval processes inherently contain significant risks and uncertainties.”

The report shows Novacea was going broke trying to keep the Asentar trials running, with research and development expenses associated with the drug of $12.9 million for the year ended December 31, 2006, up from $7.3 million for the year ended December 31, 2005.

The $5.6 million increase was due primarily to the Phase 3 Asentar trial, and the filing warns that Novacea could experience many delays in getting its product to market due to problems in trials including, “patient enrollment may be slower than expected at trial sites due to factors including the limited number of, and substantial competition for, suitable patients with the particular types of cancer required for enrollment in our clinical trials”.

It also notes that there “is a limited number of, and substantial competition for, suitable sites to conduct our clinical trials; clinical trial sites may terminate our clinical trials”; “patients and medical investigators may be unwilling or unable to follow our clinical trial protocols;” and “patients may fail to complete our clinical trials once enrolled.”

In addition, another ongoing trial is evaluating Asentar as part of a combination therapy for AIPC patients with Sanofi’s Taxotere. If safety or efficacy issues arise with Taxotere, the annual report warns, Novacea could experience significant regulatory delays, and the clinical trial may need to be terminated or redesigned.

Even if Asentar were to receive FDA approval, Novacea would continue to be subject to the risks that could arise with Taxotere or that Taxotere may be replaced as the standard of care for AIPC. “This could result in Asentar ™ being removed from the market or being less commercially successful,” the report states.

Ironically, in one of 3 derogatory letters sent to the FDA urging the non-approval of Provenge leaked to the media following the failed efforts to rig the advisory panel vote, Dr Scher discussed the same fatal effects that the approval could have on the research industry. “An approval recommendation has far reaching implications beyond making the product available that the data simply do not support or justify,” he wrote.

Approval would provide the Agency’s endorsement of Provenge as a “standard of care” for men with AICP, he said, and by extension, elevate Provenge “to a position of being the new ‘control’ arm for future randomized phase 3 trials that are being designed for the regulatory approval of any new experimental agent or approach.”

In other words, all the billions of dollars invested in the clinical trials now underway, or set to begin, conducted in hopes of gaining FDA approval for a new ACIP treatment, could go right down the drain if Provenge is approved as the first-line treatment for this patient population.

Dr Scher is probably more aware of this fact than anybody. On February 26, 2007, MedPage Today reported that in a satellite symposium titled, “Improving Upon Current Standards: The Integration of Novel Therapies in the Treatment of Androgen-Independent Prostate Cancer,” sponsored by Novacea, Dr Scher said Taxotere-based combination therapy is being investigated in a dozen clinical trials for ACIP patients, and he reported receiving grants and research support from both Novacea and Sanofi.

FDA’s Refusal to Approve New Cancer Vaccine – The Plot Thickens – Part II

Evelyn Pringle November 29, 2007

On November 26, 2007, CareToLive, the non-profit corporation that is suing FDA officials on behalf of terminal prostate cancer patients over the decision not to approve Provenge, a new life-extending prostate cancer vaccine, announced that a judge had dismissed the lawsuit.

The attorney for CareToLive, however, said an immediate appeal would be filed in the 6th Circuit Court in Ohio where the case will be heard by a 3-judge panel. “CareToLive will keep fighting to the Supreme Court if need be,” attorney Kerry Donahue says.

In its press release, CareToLive’s spokesperson, Melody Davis states: “Men are dying while a safe, effective treatment languishes outside of their grasp.”

The group also is vowing to put more pressure on lawmakers to investigate the Provenge debacle. “Congress needs to wake up and hold hearings immediately!” Ms Davis states.

“The evidence clearly shows our government violated these men’s right to live,” says Mike Kearney, a CareToLive board member.

“They can say it, explain it, and infer it any way they want, but the truth is they allowed over 16,000 men to die since May 8th without treatment while other men profited handsomely during their demise,” he states in the group’s press release.

Because the FDA refused to approve Provenge, prostate cancer patients and advocacy groups have organized public rallies in major cities, taken out a half-page ad in “The Washington Post”, placed ads on the sides of Washington, DC buses, and written thousands of letters and e-mails, lobbying Congress to hold hearings on the matter in an all-out effort to get the vaccine approved for dying prostate cancer patients.

“We are going to stand up for these men’s rights,” Attorney Donahue states in the press release.

Scott Riccio, founding member and lobbyist for another advocacy group, “A Right To Live,” who organized a rally at the FDA headquarters with CareToLive, also says his group will continue to focus on efforts aimed at Congress to hold public hearings.

A sign-on letter is available on the CareToLive web site at http://caretolive.com/ for people who want to join the effort to get Congress to investigate the FDA’s handling of Provenge.

Provenge is an active cellular immunotherapy designed to direct the body’s immune system to attack only cancer cells, in contrast to chemotherapy, which uses drugs to kill not only cancer cells but also other rapidly growing cells, while causing horrendous side effects.

Dendreon, a Seattle-based biotech company, makes Provenge. The only other treatment approved for late stage prostate cancer patients who would benefit from Provenge in more than 40 years, is the chemotherapy drug Taxotere (docetaxel) sold by Sanofi-Aventis.

A mere 3 injections of Provenge at 2 weeks intervals offers men with prostate cancer the chance to significantly prolong their lives without the negative effects that many months of chemotherapy can have on their quality of life.

On March 29, 2007, an FDA Advisory Committee (AC) reviewed Dendreon’s Biologics License Application (BLA) for Provenge. The AC’s 17 members voted to recommend immediate approval. Specifically, it voted 17-0 that the vaccine was safe and 13-4 that it demonstrated “substantial evidence” of efficacy, the Congressionally mandated standard.

In large part due to the fact that the FDA had never before refused to follow an AC panel’s recommendation to approve a cancer treatment for a patient population facing imminent death, doctors, patients, and the public at large believed that Provenge would be approved by May 15, 2007, and that a whole new era of immunotherapies for the treatment of many types of cancer would follow.

However, on May 9, 2007, the media reported that FDA Commissioner Andrew von Eschenbach had set a new precedent by refusing to approve Provenge for men with end-stage prostate cancer and issuing a Complete Response (CR) letter to Dendreon requesting more data that could take until 2010 to provide.

The CareToLive lawsuit alleges that Dr Richard Pazdur, director of the FDA’s Office of Oncology Drug, intentionally placed Dr Howard Scher, a researcher and oncologist at Memorial Sloan-Kettering Cancer Center, and Dr Maha Hussain, a researcher and professor at the Comprehensive Cancer Center, at the University of Michigan, on the Provenge AC panel in attempt to rig the votes against Provenge because he knew they stood to benefit significantly from a decision not to approve the vaccine.

Importantly, when they participated in the AC, both Dr Scher and Dr Hussain were acting as special government employees, positions that requires an additional moral and ethical duty on their part in the eyes of the public.

After failing to sabotage Provenge during the public hearing, Dr Scher and Dr Hussain wrote letters to the FDA, filled with misinformation to improperly lobby FDA decision-makers and place public pressure on them to withhold approval of Provenge.

Adding to the conspiratorial atmosphere surrounding the two letters, as well as a similar letter sent to the FDA by Dr Thomas Fleming, is the fact that all three letters were leaked for publication on the internet to “The Cancer Letter”, a non-peer-reviewed industry newsletter, with obvious calculated release dates of 1-week apart.

The significance of leaking insider FDA information to the public on whether or not a drug will be approved cannot be over-stated. FDA officials and advisory panel members have the ability to effect billions of dollars in profits and stock value.

CareToLive and other advocacy groups are demanding an investigation to determine who at the FDA leaked the letters to the media. Sources familiar with the case say the likely culprit is Dr Pazdur as he was the FDA official responsible for leaking insider trading information in the ImClone cancer drug case that landed Martha Stewart in prison for 5 months after she sold off her stock based on a tip that originated with Dr Pazdur and then lied to the Feds about her reasons for doing so.

Acting on Dr Pazdur’s tip, in telling family members and friends to dump their stock in the days before the official FDA decision was released, also earned Sam Waksal, the co-founder of ImClone, a 7 year prison sentence.

According to CareToLive, it’s “inconceivable” to argue that it could be a coincidence that Dr Pazdur picked two doctors who would both personally benefit from the non-approval of Provenge, who both acted as expected at the hearing considering their conflicts of interest, and then wrote similar letters to the FDA that were leaked to the same publication.

Never in the history of the FDA have two expert panel members with extreme conflicts of interest worked in conspiracy with one another to attack a product after the public hearing was over, according to a November 9, 2007 brief filed by CareToLive.

On May 29, 2007, just three weeks after Dendreon received the CR letter from the FDA, the competing cancer drug company Novacea announced a funding deal with Schering-Plough worth close to a half a billion dollars in which Schering agreed to jointly fund and develop clinical trials for the cancer drug Asentar combined with Sanofi’s Taxotere.

The day the news was released, Novacea’s stock value rose 86%.

Shortly after the announcement of the Novacea-Schering deal, it became known that Dr Scher was a lead investigator for the clinical trials financed by Novacea and Schering on treatments with Taxotere and Asentar, in direct competition for the same prostate cancer patients that would benefit from Provenge.

On July 26, 2007, Rory Kearney, President of CareToLive, filed a Citizen’s Petition with the FDA to request reconsideration of the agency’s failure to approve Provenge and pointed out that Dr Scher had cashed in on Wall Street “when the competing company he works for received $440 million.”

“That deal” the Petition states, “would not have happened if Provenge had properly been approved.”

Reports that Dr Hussain serves as a consultant and advisory board member to Novacea also emerged soon after the Schering deal was announced.

In the company’s press release, Novacea reported that the ongoing Asentar Phase 3 trial was on track and the firm expected to complete enrollment by the end of the year. The approval of Provenge would have caused major complications for the enrollment of prostate cancer patients and if Provenge were to become the new “standard of care”, it would represent an imminent threat to the cancer research industry as a whole.

For successful enrollment in clinical trials, researchers need a steady flow of patients with specific types of cancer and the competition to find these patients is fierce.

It’s especially difficult to enroll patients who are facing death because a trial may be testing a new treatment against a placebo, which means trial participants have to be told up front that they might not receive any treatment.

And even when enrollment is successful, many trials last years, and there is always the threat of patient dropout if side effects occur or if a promising new treatment such as Provenge becomes available.

For the most part, the current trials for late-stage prostate cancer involve chemotherapy and many terminally ill men do not want to spend their last days experiencing the horrible side effects associated with chemo.

The lengthily trail of conflicts of interest that lead to the gang who succeeded in stopping the approval of Provenge is easy to track on the internet. The top recipients of cancer research funding in the US include Dr Pazdur’s previous employer of 11 years, the MD Anderson Cancer Center at the University of Texas, along with Dr Scher’s employer, the Memorial Sloan-Kettering Cancer Center, and Dr Hussain’s Cancer Center at the University of Michigan.

Prior to his appointment as leader of the National Cancer Institute in 2001, the current FDA Commissioner, Dr von Eschenbach, was executive vice president and director of prostate cancer research at the MD Anderson Cancer Center.

Before Dr Pazdur and Dr von Eschenbach left MD Anderson, Dr John Mendelsohn was their boss as President of the Center Dr Mendelsohn in fact, is said to be the guy who recommended Dr von Eschenbach to Bush for the top position at the National Cancer Institute.

At the same time, Dr Mendelsohn was also a member of ImClone’s board of directors and a board member at Enron, another infamous firm that was busted for insider trading around the same time as ImClone.

Congress held hearings on the ImClone debacle in June and October of 2002, and during testimony, it came out that Dr Mendelsohn had made over $6 million in 2001 by selling ImClone stock without informing cancer patients enrolled in clinical trials at MD Anderson that he was a major stockholder in the company that would benefit from the trials.

When lawmakers tried to question him about the Enron fiasco, Dr Mendelsohn said he was there to talk about ImClone not Enron.

Dr Scher, Sloan Kettering and MD Anderson also benefit financially from the Prostate Cancer Foundation. According to the group’s Federal Tax Form 990 for 2006, Sloan Kettering and MD Anderson received the largest share of money awarded in 2004, 2005, and 2006. The Foundation’s 2005 Annual Report shows their total grants through 2005 equaled about $33 million, far surpassing funding to any other research centers.

Dr Scher serves on the panel that decides who will receive research grants and funding.

The Foundation was founded in 1993, by junk bond king Michael Milken, who served time in prison for securities fraud. The individual who helped Mr Milken establish the Foundation is Dr von Eschenbach, according to the transcript of a September 22, 2004 web conference posted on WebMd.

At the time of the web conference, Mr Milken reported that since 1993, the Foundation has helped fund 1100 research studies in dozens of clinical trials. Dr Hussain is a Consortium Clinical Investigator, according to the group’s 2005 Annual Report.

The Prostate Cancer Research Program is the leading source of government funding for prostate cancer research in the US. Since 1997, a total of $730 million has been appropriated for the Program, including $80 million in 2006.

The Program awards research and training funding, and one such grant, the Clinical Consortium Award, supports the creation of a major multi-institutional clinical trial resource and Dr Scher leads this multi-institutional consortium. The participating clinical sites and lead investigators include none other than Dr Hussain and the University of Michigan Comprehensive Cancer Center, according the Program’s government reports.

Less than a month before the Provenge AC panel held the public hearing, on February 26, 2007, Ed Susman reported in MedPage Today, that Taxotere-based combination therapy was being investigated in a dozen trials, quoting investigators who said there were four phase III Taxotere-based combination trials and eight phase I and II trials.

Mr Susman also noted that in a symposium titled, “Improving Upon Current Standards: The Integration of Novel Therapies in the Treatment of Androgen-Independent Prostate Cancer,” sponsored by Novacea, Dr Scher described a number of the trials.

At the end of the article, MedPage lists Dr Scher as reporting only that he receives grants and research support from Novartis, Novacea, Bristol-Myers Squibb and Sanofi-Aventis, which minimizes the fact that he is involved in most of the clinical trials discussed.

Dr Scher also benefits from financial interests in ProQuest Investments. The firm’s main focus is on prostate cancer therapies and since 2003, ProQuest has invested heavily in Novacea. Dr Scher sits on the firm’s Board of Directors, and is a member of its scientific advisory board.

In addition to being a consultant and advisory board member of Novacea, Dr Hussain’s Michigan University faculty disclosures list her as receiving research funding from Sanofi-Aventis. The University’s 2005-2006 Annual Report says she is a clinical investigator “with a particular focus on prostate and bladder cancer” and “serves as principal investigator of three national NCI-sponsored phase II and phase III clinical trials.”

Under disclosures for program faculty listed in October 2006, for a CME seminar titled, “Prostate Cancer: Beyond First Line Hormones,” Dr Hussain reported financial relationships to include serving on an advisory board and as a consultant to Novacea and receiving research funding from Sanofi-Aventis.

Dr Hussain’s disclosures related to serving on the advisory panel show her husband owns stock valued at $15,000-$300,000 in three companies that compete with Provenge.

And for what its worth, a web site sponsored by the Huffington Post on campaign contributions shows that during the 2004 Presidential election cycle, Dr Hussain, who received her medical education in Bagdad, Iraq, gave George W Bush $2,000. Her husband also gave Mr Bush $2,000, and Sal Jafar, described as a self-employed physician and listed at the same address, gave the Republican National Committee $2,050.

In his letter that was leaked to the press, Dr Scher spelled out the threat that Provenge posed to the cancer research industry when he noted that the FDA’s approval would provide the endorsement of the vaccine as the “standard of care” and raise it “to a position of being the new ‘control’ arm for future randomized phase 3 trials that are being designed for the regulatory approval of any new experimental agent or approach.”

So, in layman’s terms, if Provenge became the new “standard of care,” any new therapy for late stage prostate cancer may need to be tested against Provenge for FDA approval.

On November 5, 2007, definite signs indicating that one of the main sources of income for Dr Scher and Dr Hussain might soon run dry appeared in the media after Novacea announced that the company had ended its Phase 3 clinical trial of Asentar after the Data Safety Monitoring Board found a higher death rate in patients who received Asentar.

The study was comparing the benefits for late stage prostate cancer patients of weekly chemotherapy with Asentar plus Taxotere against the current standard of care of Taxotere alone. To date, more than 900 of the planned 1,200 patients were enrolled in this study at multiple centers in countries that including the US, Canada, Germany, and Central Europe.

According to Novecea’s November 12, 2007 SEC filing, the company has “ended and suspended enrollment in clinical trials for our lead product candidate, Asentar�, and we cannot give any assurance that it will receive regulatory approval or be successfully developed or commercialized.”

Under the section titled, “Risks Related to Our Business,” the company points out that the firm has never shown profits and possibly never will now. “We have incurred losses since inception and anticipate that we will continue to incur losses for the foreseeable future. We may never achieve or sustain profitability,” it states.

Had Provenge been approved, the entire chemotherapy research industry that has proven to be so profitable for so many entities over the past 2 decades may have collapsed like a house of cards.

And the same goes for the chemo cartel because infusions of chemotherapy drugs represent the primary source of income for most oncologists. In 2005, cancer doctors billed about $4.4 billion for chemotherapy and drugs used to treat anemia caused by chemotherapy, with Medicare covering 80% of the bill, according to a report by Alex Berenson in the June 12, 2007, “New York Times”.

If the FDA had approved Provenge and word got out that a new 3-infusion vaccine was available that extended survival far longer than chemo with minimal side effects, no prostate cancer patients would have been willing to spend the little time they had left battling the grueling side effects of months of chemotherapy.

Clearly, Provenge would have been the treatment of choice, had the FDA allowed these dying men a choice.

Three Lawmakers Give Terminal Cancer Patients Early Xmas Gift

Evelyn Pringle December 19, 2007

Three members of Congress recently sent a letter to the House Energy and Commerce Committee calling for a hearing to examine the conflicts of interest involved in the FDA’s decision to deny the approval of Provenge, a new life-extending vaccine for use with terminally ill prostate cancer patients who have no other treatment options.

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.

Congressmen on War Path Over FDA Approval of Ketek

Evelyn Pringle June 2006

French drug giant Sanofi-Aventis has stopped enrolling pediatric patients in clinical trials for Ketek. On June 9, 2006, the drug maker said it halted tests on its own to ensure that trials of the drug complied with FDA requirements.

The company denied that the studies were suspended because of safety concerns. However, the move jives with the recently initiated investigations into the FDA’s collusion with Aventis in the approval of Ketek by two powerful Congressional Committees.

The FDA’s conduct regarding Ketek is under investigation by House Representatives Edward Markey (D-MA), and Henry Waxman (D-CA), senior Democrats on the House Energy and Commerce Committee. On May 1, 2006 the lawmakers sent a letter to the FDA questioning its actions surrounding the approval of Ketek.

In a press release announcing the investigation, the lawmakers said, “though the FDA has consistently assured the public of Ketek’s safety and efficacy, public documents obtained and examined by Reps. Markey and Waxman’s staff indicate that the approval process for this drug was seriously flawed.”

Most recently, on June 8, 2006, the Senate Finance Committee sent a letter to the FDA asking: “Is the FDA considering temporary suspension of these trials until the serious concerns and issues related to Ketek are resolved?”

The company had been testing Ketek for treatment of ear infections and tonsillitis in nearly 4,000 children in the US and a dozen or so other countries. A search of the Clinical Trials.gov web site shows three ongoing trials in the US of children ages 6 months to 13 years, including:

(1) TELI COM – Telithromycin in Children With Otitis Media,

(2) TELI TON – Telithromycin in Tonsillitis, and

(3) Comparative Study to Evaluate the Efficacy and Safety of Telithromycin Given Once Daily Versus Cefuroxime Axetil Given Twice Daily in Children With Middle Ear Infections.

A fourth trial, “TELI TAD – Telithromycin in Tonsillitis in Adolescents and Adults,” involves children 13 and older.

The FDA approved Ketek on April 1, 2004, for the treatment of adults with community-acquired pneumonia, sinusitis, and acute exacerbation of chronic bronchitis.

Over the past several months, several allegations related to the FDA’s approval of Ketek have caught the attention of the Senate Finance Committee Chairman Senator Charles Grassley (R-Iowa).

The Senate Committee has jurisdiction over the Medicare and Medicaid programs and, accordingly, a responsibility to the more than 80 million Americans who receive health care coverage, including prescription drugs, under those programs.

Senator Grassley’s intense oversight of the FDA began in 2004 over the agency’s reluctance to allow information to become public about the risks of pediatric use of SSRI anti-depressants. He has since put pressure on the FDA to make administrative changes to improve its transparency and post-market surveillance of drugs, in addition to introducing legislation to implement these kinds of reforms.

Among the most serious allegations about Ketek is that the FDA approved the drug despite unresolved questions about the drug’s safety and efficacy, with full knowledge that some of the clinical data submitted to support the drug’s approval was tainted by integrity problems. Documents provided to the Senate Committee show that at least one of the clinical trials, Study 3014, was fraudulent.

In April 2001, Ketek’s initial approval came before the Anti-Effective Drugs Advisory Committee to consider whether its efficacy in treating respiratory infections supported its use given the risks of cardiac and hepatic toxicity and vision problems associated with Ketek.

Based on these concerns, the AIDAC recommended that Ketek not be approved and said Aventis should conduct a large clinical study. A letter to Aventis dated June 1, 2001, said in part: “This study should include the monitoring and analysis of all adverse events, with particular attention to hepatic, visual, cardiovascular, and vasculitic adverse events.”

Aventis subsequently hired Pharmaceutical Product Development (PPD) to conduct a study designed to enroll patients with respiratory infections in the offices of more than 1800 primary care physicians all across the country. Subjects were randomized for treatment with Ketek or Augmentin, another antibiotic.

In October 2001, doctors began enrolling subjects and were paid $100 for each patient they signed up, and another $150 when they submitted study results, as well as a final $150 after all questions were resolved, according to the May 1, 2006 WSJ.

The potential for money-making by doctors enlisted for this study was enormous. A fact that obviously did not go unnoticed by certain physicians who signed on to the study.

On July 24, 2002, Aventis submitted the results of Study 3014 to the FDA, but without fully disclosing the study’s integrity problems.

When the AIDAC reconvened to consider the study, the FDA presented it to the panel without disclosing that the agency’s Division of Scientific Investigation and Office of Criminal Investigation were investigating both the conduct and integrity of the study. Without the benefit of this information, the AIDAC voted to recommend the approval of Ketek.

In the end, a March 25, 2004 memorandum, prepared by the Division of Scientific Investigations titled, “DSI Recommendations on Data Integrity,” states that Study 3014 involved “multiple instances of fraud” and that “the integrity of data from all sites involved in [the] study … cannot be assured with any degree of confidence.”

In a press release on May 1, 2006, Senator Grassley said he was concerned about the FDA’s complicity with the drug maker and subsequent failure to ensure the integrity of a pivotal study about the benefits and risks of Ketek. Specific allegations under investigation by the Senate Committee include that FDA management:

(1) accepted the resubmission of a new drug application for Ketek, which included fraudulent data in support of approval;

(2) presented fraudulent study data to an advisory committee tasked with recommending Ketek’s approval or disapproval;

(3) instructed FDA scientists appearing before an advisory committee that they should present fraudulent data because discussing issues regarding data integrity and the conduct of the safety study would not be “productive;”

(4) approved a pediatric clinical trial, involving infants as young as six-months old, despite concerns related to known toxicities, including hepatic, visual, cardiovascular, and vasculitic adverse events; and

(5) continued to knowingly cite the fraudulent study in publicly released safety information on Ketek.

Given that the advisory committee had recommended conducting Study 3014 in the first place, theses allegations are “all the more outrageous,” according to Senator Grassley.

The AIDAC members certainly would have been interested to know that the highest enrolling doctors were being investigated and that there appeared to be significant under reporting of adverse events.

For example, the investigator at the highest enrolling site, Dr Ann Campbell, was found to be enrolling patients when the clinic was closed, and patient consent forms had date modifications and signature inconsistencies.

Dr Campbell had a practice in Alabama, that attracted patients by advertising weight-control treatments. “By the middle of January 2002,” according to the May 1, 2006 Wall Street Journal, “she had signed up 287 patients and was receiving enough of the drugs to enroll 30 new people a day, according to emails sent by a PPD employee on Jan. 15 and 17.”

On February 27, 2002, Nadine Grethe, an Aventis manager overseeing the study, got an email from PPD warning that there were possible problems with Campbell including the lack of “proper diagnosis of an appropriate medical condition,” medical charts described as “very limited,” and lab test results that were “suspiciously similar” for multiple patients. PPD also found that many patients signed up during a lunch break when the office was supposed to be closed.

The suspicions were validated on August 29, 2003, in the case of Maria “Anne” Kirkman, MD, aka Maria “Anne” Kirkman-Campbell, DOH Case No 2004-20974, when Campbell was charged in a 21 count indictment in the US District Court for the Northern District of Alabama with 10 counts of using a scheme or fraud to obtain money and property by means of false pretenses and documentation, and 11 counts of knowingly and willingly making and using, and causing to be made and used false writing and document knowing it to contain a materially false, fictitious and fraudulent statement and entry.

The information alleged that Campbell falsified documentation released to a study to establish the safety and effectiveness of Ketek before it could be a approved by the FDA.

Despite all this, when Aventis submitted the results of Study 3014 to the FDA, they included 407 of Campbell’s patients, and “did not alert the Agency to any problems” with Campbell, according to a review of Ketek’s history, safety and efficacy by FDA official, Dr David Ross, on the FDA web site.

Campbell was eventually sentenced to 57 months in prison and was given an additional 3 years of supervised release after the prison term is completed. She was also fined $557,251 and ordered to make restitution to Aventis to the tune of $925,774.

An FDA inspector ended up at Campbell’s office in late 2002, simply by chance because she had enrolled so many patients. The investigator found patients who said they had not received any medication, even though their records said they had, according to Dr Ross. Others patients were being treated for weight loss and not respiratory infections, and some subjects were friends and members of Campbell’s family.

Dr Egisto Salerno was a study investigator in San Diego whose 214 patient recruitment made him the 3rd largest recruiter. Here is part of what was known about Salerno at the time he was conducting the study, according to a report by the Medical Board of California, Department of Consumer Affairs, on March 6, 2006

Petitioner started using cocaine in 1994 on an occasional, recreational basis. His use gradually escalated from occasional use in the mid-1990s to using cocaine every weekend by 2001. He “extended” his weekends to use cocaine by taking time off from his practice on Fridays, and sometimes on Thursdays or Mondays as well. He did not use cocaine before seeing any patients. Petitioner testified his denial of his addictions was so intense he was unaware he was dependent. The use of cocaine became an essential part of petitioner and his wife’s lives.

Petitioner admitted ingested cocaine and drank alcohol Monday morning, April 22, 2002, after which he thought four or five people were inside his home. He armed himself with a loaded .45 caliber handgun. He threatened to kill his wife if she called the police. His mother in law found out what was going on and contracted the police, who responded to petitioner’s home. Petitioner was armed and other weapons n the home, but most of them were antiques. Petitioner was under the influence of drugs and was arrested.

Dr Jeffrey McLeod was another quack who participated in the study from Virginia. On August 24, 2005, the FDA recommended that he be disqualified as a trial investigator and sent him a letter outlining his fraudulent conduct in the Ketek study and said in part:

The FDA’s Center for Drug Evaluation and Research believes that you have repeatedly or deliberately violated regulations governing the proper conduct of clinical studies involving investigational new drugs as published under Title 21, Code of Federal Regulations (CFR, Part 312, and that you submitted false information in a required report to FDA or the sponsor.

The FDA told McLeod: (1) You failed to obtain informed consent from seven subjects; (2) For six subjects you provided consent documents that were signed and dated after they had completed the study; and (3) For 17 subjects you provided documents in which the signatures were backdated to make it appear that informed consents were obtained prior to their enrollment in the study.

The investigation even found that consent forms for 22 of the 23 patients contained a date that preceded the date McLeod received the informed consent templates on March 4, 2002, including 13 documents with his own signature. A member of his staff also told the FDA investigator that McLeod instructed her to backdate the consent signatures.

In addition, the study protocol required clinical lab tests on subjects at visit 1 and 2, but there was no documentation to show that such tests were conducted on 11 subjects.

The protocol required that women of childbearing age have a urine pregnancy test before taking the study medication, but there was no documentation to show that the tests were done on 6 subjects.

The protocol also required McLeod to document adverse events and determine whether any events were of “special interest” as that term was defined in the protocol. The investigator said, that even though records showed that 2 subjects had lab tests to evaluate what was identified on the lab report as a “Cardiac Adverse Event,” the case report submitted by McLeod states that these subjects experienced no adverse events.

For some subjects, McLeod failed to remove the tear-off labels and place them in the Case Report Form so it could not be determined which medication the subjects were given.

Finally, one subject was enrolled despite a documented allergy to the penicillin antibiotic.

Another ace investigator was Dr William Terpstra, of Indiana who had more than 150 patients enrolled in the study. However, an investigation found that he had over 20 violations of the study instructions.

All that said, in April 2006, the results of Study 3014 were cited in an article in the New England Journal of Medicine that claimed Ketek was as safe as other antibiotics. However, five of the 6 six authors had to disclose that they had received consulting fees from Aventis, and that at the time of the study, the 6th author was an employee of Aventis.

In his June 8, 2006, letter, Senator Grassley asked the agency to explain what it is doing to inform parents about the safety issues surrounding pediatric trials of Ketek and pointed out that he had posed the same question to the agency 6 weeks earlier but had not yet gotten an answer.

Lawmakers Demand Answers About Ketek From FDA

Evelyn Pringle June 13, 2006

The FDA has continued to cite a fraudulent study in information released to the public about the safety of the antibiotic Ketek. On January 20, 2006, the agency issued a Public Health Announcement, in response to an article in the Annals of Internal Medicine, where researchers reported three cases of severe liver problems in patients taking Ketek.

The article reported one patient at the Carolinas Medical Center in Charlotte, NC, had died after taking Ketek, another required a liver transplant, and a third patient recovered from drug-induced hepatitis after treatment with Ketek was stopped. The Annal’s report also said that Sanofi-Aventis reported 7 cases of hepatitis or hepatocellular damage in patients taking Ketek in data from Phase III trials.

On June 9, 2006, drug maker Sanofi-Aventis made the announcement that it had stopped enrolling children in clinical trials for Ketek and said it halted tests to ensure that clinical trials complied with FDA requirements. The company did not mention the heat coming from two powerful Congressional Committees.

As it turns out, the cases above are not the only serious Ketek related adverse events that have been reported to the FDA. According to a review by the staff of the Senate Finance Committee, of reports in the Adverse Event Reporting System between July 2005 and September 2005, the most recent 3 month period available, two deaths, 35 liver adverse events, 44 cardiac adverse events, and 80 visual adverse events have been recorded.

Because it is well-known that only between 1% and 10% of adverse events are ever reported to the FDA, the numbers above would have to be multiplied many times over to establish a true accounting of the adverse events associated with Ketek.

Along with the January 20, Public Announcement, the FDA posted a document titled, “Questions and Answers on Telithromycin (marketed as Ketek),” on its web site, that asked, “What information was known about liver problems related to telithromycin prior to approval?”

In response, the FDA said, “Based on the pre-marketing clinical data it appeared that the risk of liver injury with telithromycin was similar to that of other marketed antibiotics.”

Prior to the approval of Ketek, the agency said, the FDA looked extensively at the potential for hepatic toxicity in patients treated with Ketek. The data examined included a 25,000 patient controlled study, as well as information in nearly 4 million postmarketing prescriptions outside the United States.

The release of this public announcement is what initially sent Senator Charles Grassley (R-Iowa), chairman of the Senate Finance Committee, on the warpath. He demanded an explanation as to why the FDA continued to cite Study 3014 without disclosing that the Anti-Effective Drugs Advisory Committee voted to recommend the approval of Ketek, without knowledge that the study was fraudulent.

In a press release on May 1, 2006, Senator Grassley said he was concerned about the FDA’s complicity with the drug maker and subsequent failure to ensure the integrity of a pivotal study about the benefits and risks of Ketek.

On May 16, 2006, he called it “mystifying” that the FDA continued to provide information the agency knew was fraudulent, and said that he’s keeping the pressure on the FDA for more information about the drug’s approval and post-market surveillance. He continues to seek a face-to-face interview with the FDA investigator who discovered the fraud and misconduct in Study 3014.

The study began in October 2001, when doctors began enrolling subjects and were paid $100 for each patient they signed up, and another $150 when they submitted study results, as well as a final $150 after all questions were resolved, according to the May 1, 2006 Wall Street Journal.

On July 24, 2002, drug maker Aventis submitted the results of the study to the FDA, but without disclosing the study’s integrity problems.

When the AIDAC reviewed the study, the FDA did not disclose that the agency’s Division of Scientific Investigation and Office of Criminal Investigation were investigating the integrity of the study.

A memorandum dated March 25, 2004, by the FDA’s Division of Scientific Investigations titled, “DSI Recommendations on Data Integrity,” states that Study 3014 involved “multiple instances of fraud” and that “the integrity of data from all sites involved in [the] study … cannot be assured with any degree of confidence.”

The infractions discovered were not minor. The doctor with the highest number of patients, Dr Anne Campbell, was subsequently charged in a 21 count indictment related to her fraudulent conduct during the study, and in March 2004, she was sentenced to 57 months in prison.

The doctor with the 3rd most patients was in the chronic stage of cocaine addiction and was arrested the same month the study was submitted to the FDA with cocaine in his underwear while holding his wife hostage with a gun.

Another doctor engaged in such blatant misconduct that he was disqualified as an investigator and barred from participating in future clinical studies. Still another investigator with 150 patients was cited with 20 violations of the studies instructions.

“It looks like the FDA caught the drug company red handed,” Senator said in a press release, “and let them get away with it.”

“On top of that,” he said, “the FDA failed to set the record straight and, in fact, continues to cite a discredited safety study as a principal reason to feel okay about using this drug.”

The power struggle between the top dogs at FDA and Senator Grassley has been ongoing for nearly 2 months. In a letter to the FDA on April 26, 2006, Senator Grassley asked the FDA to: “Please explain in detail why the FDA has continued to cite Study 3014 in its safety information for Ketek.”

Senator Grassley said the stakes continued to grow when it comes to overseeing Ketek, because it was being tested in children as young as 6-months-old, and the Senate Committee has received equally serious allegations related to the post-market surveillance of the drug.

For example, in the FDA-approved pediatric clinical trial, known as “TELI COM – Telithromycin in Children With Otitis Media,” despite the known toxicities of Ketek, including evidence of hepatic, visual, cardiovascular adverse events, the FDA was allowing Aventis to experiment on children as young as six-months old.

The Senate panel reviewed a report from the Adverse Event Reporting System that details a suspected visual adverse event in a 15-month old girl participating in the study. According to the report, on 3 occasions the mother observed the girl having staring spells one day after taking Ketek, and one spell lasted for 60 seconds.

The investigator-doctor initially listed the event as related to Ketek and “serious.” However, in addendums to the report, dated months later, the investigator downgraded the event and assessed it to be “non-serious,” not interpreted as a “visual event,” and that a “staring spell is considered unexpected.”

“Given that the Ketek label warns of severe cases of visual problems,” Senator Grassley wrote in the letter to the FDA, “please advise the Committee what action has been taken to fully inform the parents of infants and children enrolled in this study about the risks and benefits of Ketek, including its known liver and visual toxicities.”

In addition, the Senator said he wants FDA staff to make “immediate arrangements” for his staff to review documents and information related to Ketek and Study 3014, including, but not limited to, the administrative files within DSI, OCI, and the Office of Compliance.

“Given the gravity of the Ketek allegations,” the Senator wrote, “I respectfully request that your staff contact my Committee staff by no later than Friday, April 28, 2006, so that my Committee staff may travel to your offices as soon as possible to review the requested administrative files.”

“As Chairman of the Committee,” he added, “I also respectfully request that senior FDA management officials be prepared to brief my Committee staff within three weeks of the date of this letter.”

The FDA’s approval of Ketek is also under investigation by the House of Representative’s Energy and Commerce Committee. On May 1, 2006, Representatives Edward Markey (D-MA), and Henry Waxman (D-CA), the senior Democrats on the Committee, sent a letter to the FDA questioning the approval process for Ketek and the potential dangers involved in conducting clinical trials on children.

In announcing the investigation, the Congressmen issued a press release saying, “public documents obtained and examined by Reps. Markey and Waxman’s staff indicate that the approval process for this drug was seriously flawed.”

Rep Markey said, “I am very concerned that the FDA approved Ketek even though it may be neither safe nor effective, and that FDA has allowed the sponsor to give this drug to children in clinical trials.”

“Recently,” he said, “the GAO found that the FDA does not have a good enough system in place to protect the public from drugs once they are on the market.”

However, he continued, “the Ketek case shows that the FDA may also not be doing a good enough job deciding which drugs should or should not be approved in the first place.”

“We need to look more closely at the Ketek case,” Rep Markey advised, “to determine whether this approval was made in error, and we need to assess whether the Ketek approval process reflects broader systemic problems within the FDA.”

“We cannot allow this critical public health watch dog agency,” he warned, “to become a lapdog for the pharmaceutical industry.”

Congressman Waxman is equally disturbed. “The Ketek case demonstrates the urgent need for reform at the FDA and in the pharmaceutical industry,” he said.  

“FDA approved the drug on flimsy data without resolving the safety issues, and it failed to penalize Aventis,” Rep Waxman noted. “Americans deserve more vigilance from FDA and from the companies that make critical medical treatments.”

“We know drug companies manipulate published studies on their drugs, hiding negative information from physicians,” he added. But here, Aventis went even further he said, by “failing to disclose to FDA grave flaws in a key safety study.”

The Markey-Waxman letter, requests numerous documents and responses to questions on the approval process for Ketek, and other drugs, and states: “The public has a right to know how the FDA reached its decision to approve Ketek and whether they can rely on those conclusions.”

The battle between the FDA and Senator Grassley intensified on June 8, 2006, when he once again wrote to the agency and pointed out that he had asked the exact same questions 6 weeks earlier in a letter but had received no answers.

The Senator said he was repeating his request for answers based on a New York Times article that revealed FDA experts’ concerns about trials involving children and infants.

“The adverse events identified with Ketek are serious ones and the possibility that any six-month old child is being exposed to these kinds of risks unnecessarily is unconscionable,” he wrote to Acting Commissioner, Andrew von Eschenbach.

The New York Times article titled, “Halt Is Urged for Trials of Antibiotic in Children,” reported that this recommendation was made by FDA officials in the Office of Drug Safety and Dr Danny Benjamin, an infectious disease specialist at Duke University, who consulted on the pediatric trials.

According to the Times, an internal review of reports by ODS officials found 110 cases of liver failure or serious liver injury associated with Ketek, since the drug was approved, and most of the events occurred in otherwise healthy people. Twelve adult patients suffered liver failure, including four who died, and 23 others suffered serious liver injury.

A leaked internal FDA memo dated May 16, 2006, says Ketek patients have a higher rate of acute liver failure and deaths than those using other antibiotics.

Based on their review, these agency officials recommended that the FDA “consider forcing Sanofi-Aventis to withdraw Ketek from the market, severely restrict its uses, even in adults, or add a prominent warning to its label about potentially fatal side effects.”

The NYTs also reported that in light of the risk of fatal liver failure, blurred vision and loss of consciousness, FDA official, Dr Rosemary Johann-Liang, questioned the agency’s decision to allow pediatric trials to continue and whether it was even possible to assess blurred vision and loss of consciousness in very young children.

The article said that Dr Benjamin also “concluded that the pediatric trials with Ketek were a cause for concern and ‘hard to support.'”

In a memorandum, Dr Benjamin noted that in up to 87% of the cases, ear infections resolve themselves within a few days without treatment and that tests of an unusually risky antibiotic in infants might only be justified if the infants had already been treated unsuccessfully with safer a antibiotics first.

In his letter, Senator Grassley said: “Now my concerns are even further heightened by the New York Times article on ODS’s assessment of adverse events associated with Ketek and Dr. Johann-Liang’s and Dr. Benjamin’s conclusions regarding the pediatric trials.”

“Let me reiterate,” he wrote, “that more than 6 weeks ago I asked you to advise the Committee of “what action has been taken to fully inform the parents of infants and children enrolled in this study about the risks and benefits of Ketek.”

“Unfortunately,” he said, “I have not received a response to this important question, and I presume that parents who have enrolled their children in the trials have not been advised of anything either.”

“If there are no plans to update consent forms and patient brochures at this time,” he wrote, “please provide a rationale for the FDA’s decision.”

Senator Grassley also wants an interview set up with Dr Rosemary Johann-Liang no later than June 28, 2006 and instructed the FDA to make the arrangements no later than June 12, 2006.

“The adverse events identified with Ketek are serious ones,” Senator Grassley wrote, “and the possibility that any six-month old child is being exposed to these kinds of risks unnecessarily is unconscionable.”

Sanofi-Aventis is the world’s third-largest pharmaceutical company with revenue in 2005 of $34 billion. 3.35 million prescriptions for Ketek were written in the US in 2005 amounting to $193 million in sales, according to IMS Health.

No doubt in response to all the bad publicity, sales of Ketek are in a freefall. According to Verispan LLC, a drug tracking firm, in the 22 weeks ending June 2, 2006, the number of prescription written for Ketek dropped 69%.

FDA Hounded Over Ketek Scandal

Evelyn Pringle March 18, 2007

The new drug application for the antibiotic, Ketek, was rejected twice, in 2001 and 2003, before FDA management approved the drug on April 1, 2004, based on fraudulent studies, and over the objections of the agency’s own scientists.

The approval of Ketek, marketed by Sanofi-Aventis, follows a pattern that has emerged since the Big Pharma friendly Bush administration took control of the FDA where the agency has overruled the findings of its own reviewers.

Doctors and patients alike have a paid a heavy price for trusting the FDA’s approval of Ketek. According to a review by the staff of the Senate Finance Committee, of the Adverse Event Reporting System, between July 2005 and September 2005 alone, there were two deaths, 35 liver adverse reactions, 44 cardiac events, and 80 visual events in Ketek patients.

On January 20, 2006, the FDA issued a Public Health Advisory, in response to an article in the Annals of Internal Medicine, that reported 3 cases of severe liver damage in Ketek patients. One died, another required a liver transplant, and a third patient recovered from drug-induced hepatitis after Ketek was stopped. The report also said that Sanofi reported 7 cases of liver damage in patients taking Ketek in Phase III trials.

That said, it took more than year for the FDA to finally ban Ketek for use in two of its 3 approved indications, but the drug is still approved to treat pneumonia. The new labeling warns that cases of acute hepatic failure, including fatal liver injury, have been reported, with some requiring liver transplants, and some occurring after only a few doses.

The new labeling also includes a boxed warning that Ketek is contraindicated in patients with myasthenia gravis, and an update about visual disturbances and loss of consciousness, and a warning about reports of diarrhea, ranging in severity from mild to fatal colitis.

The FDA announced its decision to revise Ketek’s label, on February 12, 2007, a day before a hearing was scheduled to review the FDA’s drug approval policies, to include Ketek, before the House Subcommittee on Oversight and Investigation.

But the attempt to determine why Ketek was approved in the first place, has been an on-going battle. On November 17, 2006, the Senate Committee on Health, Education, Labor, and Pensions, held a hearing on FDA reform legislation, and the approval process for Ketek was discussed.

Jim Guest, president of the Consumers Union, testified about the fraudulent studies submitted by Sanofi, and told the panel, “the FDA found multiple instances of fraud in the company’s clinical trial of about 24,000 patients, some cases of which the maker Sanofi already knew about yet failed to notify the agency.”

Internal emails obtained by Congressional staffers, prove that the FDA was aware of the problems with Ketek before it was approved, and that FDA scientists, Dr David Ross, Dr David Graham, Dr Charles Cooper, and Dr Rosemary Johann-Liang, all warned FDA management about the serious adverse effects associated with the drug.

In fact, on November 23, 2006, Dr Graham sent a letter to the editor in the New England Journal of Medicine, in which he criticized the FDA for refusing to follow the recommendation of a 2001 Advisory Committee which voted against the approval of Ketek primarily because of concerns about liver damage.

According to Dr Graham, an analysis of the FDA’s post-marketing database showed that the rate of acute liver failure was 3.5 to 11 times higher for Ketek compared to other antibiotics on the market, with a reporting rate of 167 cases per 1 million person-years of use, compared to the expected rate of 1 case per 1 million.

Dr Graham noted that, without accounting for underreporting, which can be 10 times higher, this rate is greater than the rate for 3 other drugs that were previously removed from the market because of their link to acute liver failure.

At the recent February 12, 2007, hearing, former FDA scientist, Dr Ross, testified as the safety team leader during the approval process for Ketek, and gave members of Congress some insight into what was going on inside the FDA at that time the drug was approved.

He explained that when the FDA has information that a drug may pose a risk, it weighs the effect of the adverse events against the benefits. The process includes many factors, he said, such as the importance of the drug, the extent of its usage, the severity of the disease treated, the drug’s efficacy, and the availability of other drugs to treat the condition.

“For example,” he explained, “the FDA is more likely to tolerate certain side effects if the drug is the only drug on the market that treats a life-threatening illness than it is when a drug is one of many drugs available for treating a less serious condition.”

In regard to Ketek, Dr Ross testified that the reviewers concluded that none of the safety study data submitted was reliable, but a week later, FDA managers approved it
anyways, “despite knowing that it could kill people from liver damage and that tens of millions of people would be exposed to it; despite FDA knowing that the drug’s maker submitted fabricated data; and despite knowing that Ketek is no better than other antibiotics, and may not even work.”

Dr Ross told the panel that the FDA also allowed Sanofi to experiment with the use of Ketek on children over the protests by reviewers.

Dr John Powers, a physician-scientist who until recently worked at the FDA, also testified that the initiation of a trial with children was inappropriate and unethical because it exposed children to harm without evidence of benefits.

He discussed the effectiveness of antibiotics and said Ketek as a symptom of a much larger problem. He explained that under the Food, Drug, and Cosmetic Act, there must be evidence of effectiveness to justify adverse events. “In the absence of evidence of effectiveness,” he testified, “any adverse effect, no matter how rare, is not justifiable.”

Over the last 25 years, Dr Powers said, the FDA has approved approximately 68 new drug applications for ear infections in children, sinus infections and bronchial infections in patients with underlying lung disease, based on so-called “noninferiority” trials.

An evaluation of previous placebo controlled trials, Dr Powers testified, shows that 12 of 17 studies in sinusitis and 9 of 14 studies in bronchial infections lack evidence of a benefit for antibiotics, and there was no evidence that Ketek is effective at all, and that this was clear when the drug was approved in 2004, he said.

Another witness, Ann Maria Cisneros, formerly worked as a research associate for PPDI, a Contract Research Organization, and assisted in monitoring the Ketek study site of Dr Anne Kirkman-Campbell, who was paid $400 for each patient she enrolled and is now serving a 57 month prison sentence for fraud.

Ms Cisneros testified that Dr Campbell enrolled up to 30 patients a day, often within minutes of each other, and sometimes on days when the office was closed. Dr Campbell even enrolled her entire staff in the study, she told the panel.

Ms Cisneros said, she reported her findings to the Research Organization and Aventis, but nothing came of the matter. “It is my understanding,” she testified, “that when the FDA audited the Kirkman-Campbell site, she was participating in another Aventis clinical trial.”

After Ms Cisneros left her employment at PPDI, she said, she learned that the Campbell site was being audited by the FDA, and that in preparation for the audits, Aventis coached Dr Campbell with leading questions on how to explain away improper conduct. As an example, she said, Aventis would say, “Is the reason you enrolled so many patients in one day because that is when your supply of the drug came in?”

The gross misconduct in the Ketek studies was not limited to Dr Campbell. The doctor with the third most patients was in the chronic stage of cocaine addiction while conducting the study and was arrested the same month his data was submitted to the FDA, while holding his wife hostage with a gun.

Another doctor was disqualified and barred from participating in any future studies, and another was cited for 20 violations of the study’s instructions.

The ability of the Bush administration to muzzle scientific dissent within the FDA may be soon coming to an end. On March 14, 2007, the House of Representatives passed the, “Whistleblower Protection Enhancement Act,” granting federal scientists the right to expose political interference in their research without fear of retaliation and to present their research at conferences and in peer-reviewed journals.

Francesca Grifo, senior scientist and director of the Scientific Integrity Program at the Union of Concerned Scientists, issued a statement praising the legislation and saying:

“Censoring scientists undermines our democracy and threatens public health. One stunning example: Vioxx. Fifty-five thousand Americans died because scientists at the Food and Drug Administration couldn’t speak out. If this law had been in place at the time, those people might still be alive today.”

The muzzling of scientists at the FDA first became evident when Dr Andrew Mosholder found a link between suicide and the use of SSRI antidepressants with children and was not allowed to present his findings at an advisory committee hearing, and when FDA management attempted to stop Dr Graham from testifying at a Congressional hearing about the agency’s mishandling of the Vioxx disaster.