Yes, I know readers here are interested primarily in lung cancer, but this is an interesting development in all of oncology, and really all of medicine. It’s reaching a point of ugly warfare between patient advocates and the FDA: as described here, a group called CareToLive, which includes patients and investors, have sued the commissioner of the FDA, the head of the Office of Oncology Drug Products, as well as one of the leaders in prostate cancer research and a medical oncologist at Sloan Kettering Cancer Research Center in New York for obstructing the ability of prostate cancer patients to receive a new vaccine developed to fight metastatic prostate cancer. The actual lawsuit, submitted in Ohio, is available here. It’s a pretty scathing, vicious, and sometimes quite personal tirade against these individuals.
Back in May, the FDA voted against approval of a vaccine against prostate cancer, known as Provenge, made by the Seattle-based company Dendreon. An advisory committee known as the Oncology Drug Advisory Committee, or ODAC, had previously recommended approval of this vaccine, so when the FDA formally ruled against approval and instead said that further information was needed from trials that are ongoing and should be available in the next couple of years. In truth, while I was hopeful to have something new to offer my patients with prostate cancer (which is another significant clinical interest of mine), I didn’t presume there to be a malevolent conspiracy against Dendreon or the prostate cancer community when it wasn’t approved. In fact, the trial on which the approval was pinned didn’t actually show the improvement in progression-free survival that the trial sought to demonstrate, but it did surprisingly show an improvement in overall survival by four months. However, the trial included fewer than 200 patients in total, while larger trials, such as one done in prostate cancer by a company called Novacea that combined chemo with a drug called Asentar (DN-101), a high-dose vitamin D analog, also showed a survival benefit but was felt by the company to be too small to submit to the FDA for approval. And while it hasn’t been featured in discussions, the vaccine procedure, which requires harvesting of immune cells from the patient, conditioning them in a lab, and then re-injecting them in a patient, costs tens of thousands of dollars. Overall, I felt the FDA review of Provenge was far from a slam dunk. This wasn’t a large study, and it wasn’t astoundingly helpful, but it provided encouraging enough results for people to have some hope that this might be approved.
Some experts, including Dr. Scher, the prostate cancer expert from Memorial Sloan-Kettering, were critical of the trial results and thought that the results for Provenge didn’t merit approval based on the borderline data. A letter from him to the FDA was leaked to the public and is available here. I read it and thought he pretty much stuck to evidence and tried to offer complex judgment about an ambiguous topic. It didn’t appear to me that he had an axe to grind. Nevertheless, some prostate cancer advocates were outraged that he advised against approval, claiming that he had conflicts of interest and ulterior motives to prevent the approval of Provenge. At the ASCO meeting that I attended a few months ago, he and another renowned prostate cancer expert allegedly received death threats from the most incensed prostate cancer advocates. They had to deliver their talks from an off-site venue via closed circuit television. It was a sad day in oncology, when a couple of the most respected experts in their fields had to fear for their lives for raising questions about the evidence favoring a treatment.
About the issue of conflict of interest, it’s a thorny one. Like many experts in a cancer field, I receive funding from a few companies for giving lectures, as well as consulting with several in order to review the strengths and weaknesses and future opportunities to develop their agents for the benefit of the cancer community (and also the company). I also lead clinical trials with drugs from multiple companies. I’m quite involved in the lung cancer field, but I’m not one of the top 5 experts in my field, not in the same league with Dr. Scher and others who are singled out here. But I have some conflicts here, because I participated in a clinical trial with Provenge (for earlier stage prostate cancer) and happen to have led a trial of chemo (taxotere) combined with Asentar in lung cancer (abstract here). These are among the less ground-breaking projects I’ve worked on, and I would barely recall them if reporting conflicts of interest on a form. For people like Dr. Scher, who is in great demand from every single company studying prostate cancer, it’s almost impossible not to have conflicts of interest everywhere. Everyone wants to work with the biggest leaders, whether in cancer or Hollywood movies. I’m not saying it’s a perfect system, but it’s hard for the biggest experts to not have a conflict of interest with a huge range of agents and companies.
We’ll see how this plays out in the courts. I am certainly sympathetic to patients with few options, but I think it’s unfortunate to see factions developing that are moving toward guerilla warfare of patients against the FDA and/or doctors weighing evidence about the value of a treatment. It’s not very different from the recent issues about the drug DCA or the hot debate about CT screening for lung cancer. Perhaps I seem dry and overly clinical in wanting to carefull weigh the facts. Perhaps evidence is a luxury when you’re desperate for options. But I’m saddended to see claws come out, because it shouldn’t be an “us and them” situation. The cancer experts don’t want to keep their patients from getting effective treatments, and I don’t think the FDA does either. They’re trying to walk a fine line between offering useful therapies and not approving harmful and ineffective treatments that need to be recalled later (it’s not like this hasn’t happened in the recent past).
Do people feel that the FDA is overly protective? Do patients feel that expert advisors, the FDA leaders, and the leaders of clinical trials would keep cancer patients from beneficial treatments based on egos and self-interest? Or is a lawsuit like this one misguided?
I promise to get back to lung cancer treatments tomorrow.
posted by Dr. West @ 9:34 pm link to this post
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August 17th, 2007 at 6:34 pm
Found this interesting if general.
http://tinyurl.com/2vp6j3
August 13th, 2007 at 2:15 pm
Dr. West,
In addition to Dr. Beckers points; How development costs are increased with time and if the efficacy requirement’s were to be reduced and more reliance was put on safety then there would be many more drugs being developed by small biotechs whom otherwise would not try to develop those drugs (because of the costs associated with such a long time to develop them)And the issue of efficacy would be solved by competition with improved efficacy being the inevitable result.
Also consider;
From the Cancer Cure Coalition:
“Not only are the FDA’s policies delaying new products from reaching patients but these policies have caused huge increases in medical costs. The required clinical trials cost an average of over eight-hundred million dollars and can take up to ten years before a new drug is approved. Many promising new treatments are abandoned only because of the high cost of the trials. “
http://www.ereleases.com/pr/20070813012.html
Also, I would think that the tax dollars that go into cancer research would go a lot further if we were to create an atmosphere such as Dr. Becker suggested where we would have more competition thus lower prices and better quality drugs. As it is now I think the money is being utilized inefficiently.
Also you must consider that it is the small biotechs which do most of the research and it is the investor which supports that research by buying stock in that company. However when Wall Street does not want to see a small biotech succeed (even if it has a promising drug such as Provenge) It can drastically cripple the biotech to the point that it can no longer continue its development and trials of it drugs. In dendreon case, they had to shelf the very promising breast cancer Immunotherapy Neuvenge.
I hope you are aware what shorting a stock is by now? (google it).
Also If you were to poll investors of biotech stocks on how fair they believe the FDA’s approval process to be I would think that the majority would say that it is hard to tell what the FDA is going to do in many cases. This distrust of the inner workings of the FDA certainly puts more pressure on the federal government to put forth more money into cancer research and subsequently I am sure that (IMO) this money is not being allocated fairly and efficiently.
I would think that although these costs are not directly related to health insurance costs they are indirectly related in some way. There is only so much money and so much you can do with it. The more efficient use of it in one field (development) should certainly lessen the burden in other fields (health insurance).
For more information on Provenge, The FDA, Wall Street corruption and Conflicts of Interest see my blog:
http://provenge.blogspot.com/
And to learn more about the investor side of it all give Investor Village a try:
http://tinyurl.com/2xllag
To learn more about and to support (buy a shirt) the September 18th Rally/Protest at the FDA please go here:
http://www.arighttolive.com/
regards,
CH
August 13th, 2007 at 8:04 am
I would LOVE to be wrong about my concerns. I will definitely read this.
August 12th, 2007 at 10:06 pm
Dr West (and others),
Here is an interesting piece on the economics of
new drugs by Gary S. Becker, Ph.D. , Faster Cures, Professor of Economics and sociology, U. of Chicago.
Dr. Becker contests that :
“Giving people whose lives are threatened by serious diseases greater access to safe, promising (albeit unproven) drugs and other treatments would help their psychological state. More important, it would lower the cost and hasten the development of therapies that could really make a difference.”
Here is his full paper.
http://www.fastercures.org/pdf/BeckerEssay.pdf
BeckerEssay.pdf (application/pdf Object)
August 12th, 2007 at 9:25 pm
Paul,
I understand that in a perfect world cost should not be a factor, and I have no knowledge that it was. I just think it is one more challenge for an agent/approach that is being administered in a palliative setting is so likely to be very, very expensive. People debate whether avastin in lung cancer is worth its cost, even though it has been proven to improve survival in a large phase III trial. Cost is an issue as long as the money spent on a treatment means that there’s less money to spend on other things in health care or elsewhere. This is a different topic that is entirely new issue, but every sentient economist agrees that the US health care system cannot be sustained at this rate, let alone by adding every treatment we can possibly find, no matter what the cost, offered to everybody, forever. To offer incredibly expensive treatments to provide benefits of a few months is in fact making a choice and saying that we will take away from educational spending and federal biomedical research and all sorts of worthy causes. Insurance premiums skyrocket year after year, largely because there are an ever-growing supply of newer, more expensive treatments and diagnostic tests that we refuse to even consider may not be worth the cost.
I am afraid that I or anyone else who even considers limits in the costs of health care risks is perceived as speaking out against motherhood and apple pie. But there are costs that I dare say many patients wouldn’t even consider paying for themselves if a treatment were commercially available but not covered by insurance, but the expectation is that Medicare or private insurance will cover any treatment no matter what the cost and how modest the benefit. I’m NOT talking specifically about Provenge. I’m saying that to contend that cost should never be a factor becomes problematic if you value any other government services being provided in US society other than unlimited health care to insured patients, no matter how little it buys you. We accept no limits like it’s a God-given right, but our society cannot realistically bear to have us put our heads in the sand forever.
-Dr. West
August 12th, 2007 at 7:45 pm
Dr. West,
I understand your hesitation believing the assertions regarding Dr. Scher’s conflicts of interest as it may relate to his inappropriate (and perhaps criminal) participation in the recent advisory panel for Dendreon’s Provenge. Dr. Howard Scher was not only a dissenting voter against the approval of Provenge, but his over the top crusade against Provenge approval was inappropriate and, I believe, due to his huge conflicts of interest that were not adequately disclosed or considered by the FDA. I would like to provide you with some greater detail of Dr. Scher’s conflicts of public and personal interest.
As you know, Provenge received an FDA fast track designation and was brought before the FDA’s own advisory committee. Provenge received a positive 17-0 vote for safety and a positive 13-4 vote demonstrating efficacy. In an unprecedented reversal by the FDA, Provenge was issued an approvable letter from the FDA instead of being granted immediate marketing approval.
I believe that many of the details below will be news not only to you, but also to the FDA and the prostate cancer community. I am particularly concerned about the lack of separation between Dr. Howard Scher, a Government employee for the Center for Drug Evaluation and Research, and his participation in Dendreon’s advisory panel and his financial interests in Novacea, Proquest Investments and the Prostate Cancer Foundation.
What is significant here is the amount of control and influence that Michael Milken possesses over the prostate cancer community and Dr. Howard Scher’s long and close professional relationship to Michael Milken and Dr. Scher’s authority and position within the FDA.
The Prostate Cancer Foundation, founded by Michael Milken, “the Junk Bond King”, in 1993, is one of the largest sources of prostate cancer research funding behind NCI’s Specialized Program of Research Excellence (SPORE) and the Department of Defense’s Prostate Cancer Research Program (PCRP). The Prostate Cancer Foundation has raised over $288 million dollars for prostate cancer research funding since its inception. Dr. Howard Scher has disclosed that he has received material financial support from the Prostate Cancer Foundation and is one of eleven Prostate Cancer Foundation consortium members who review new drugs and determine Prostate Cancer Foundation grants to be awarded. Dr. Howard Soule is Chief Science Officer to the Prostate Cancer Foundation and a ProQuest Investments scientific advisor to the investment company (please see footnote 1). Dr. Jonathan Simons, the President of Prostate Cancer Foundation is also scientific advisor to ProQuest Investments (please see footnote 1). Jay Moorin is a Founding Partner of ProQuest Investments and a board member to Novacea (please see footnote 4). It seems clear that ProQuest Investments operates as an extension of the Prostate Cancer Foundation and Michael Milken. Additionally, half of Michael Milken’s Prostate Cancer Foundation consortium members are DOD PCRP consortium members.
Proquest Investments is a $1 billion venture capital fund that was started in 1998, in large part by Michael Milken, the “Junk Bond King”, with a specific focus on prostate cancer (please see footnote 2). Proquest Investments (and its principals) are major shareholders of Novacea. As with the Prostate Cancer Foundation, Dr. Scher has an instrumental role at ProQuest Investments. Dr. Howard Scher is a scientific advisor for and has been granted an ownership interest in Proquest Investments (please see footnote 1). There are roughly 23 million shares outstanding in Novacea. According to SEC documents filed May 15, 2006, Proquest Investments (or it’s principals) own 1/3 of all the outstanding stock issued in Novacea, a company with a $220 million market capitalization. Below is a table that details ownership in Novacea by Proquest Investments (or its principals).
As of May 15th, 2006
Owner Shares Percentage
ProQuest Investments II, L.P. 1,779,767 8.0%
ProQuest Investments II Advisors Fund, L.P 75,508 0.3%
ProQuest Associates II LLC 1,855,275 8.3%
Jay Moorin 1,910,988 8.5%
Alain Schreiber 1,855,275 8.3%
Total 7,476,813 33.4%
http://tinyurl.com/2sgpgf
Dr. Howard Scher is the lead investigator of their phase III clinical trial for Asentar, an oral treatment for prostate cancer and a direct competitor of Provenge for AIPC patients. Additionally, Dr. Scher is a Novacea advisory board member. As per Novacea’s form 10-K filed with the SEC in April 2007, Novacea’s ability to commercialize Asentar would suffer if marketing approval of Provenge for AIPC were granted. On May 30th, less than 3 weeks after Dendreon was denied immediate marketing approval for Provenge by the FDA, Schering-Plough and Novacea entered into a worldwide development and commercialization agreement for Asentar worth over $450 million plus royalties if all milestones are met as anticipated. Novacea will receive an upfront payment of $60 million, including $35 million as reimbursement for past research and development expenses, a license fee of $25 million, as well as a commitment by Schering-Plough to purchase $12 million of Novacea common stock at a predetermined price within ten days of the closing. Additionally, the agreement provides Novacea with potential pre-commercial milestone payments of up to $380 million, and tiered royalties on worldwide sales of Asentar.
Howard Scher not only reaps large benefits from his consortium activities reviewing the newest research in prostate cancer, but also compensation for conducting clinical trials for such investments, consulting for such investments, and compensation for sitting on Proquest Investment’s scientific advisory board recommending such investments. I suspect Dr. Howard Scher earns far more from these professional relationships than any salary he may draw from the FDA. I think I have highlighted significant examples above of Dr. Scher’s, conflicts of interest and how Dr. Scher, Proquest Investments and Michael Milken appear to benefit and profit from inside information.
There appears to be a related party factor that calls into question Dr. Scher’s true independence as a FDA panel doctor. With such high powered contacts and Dr. Scher’s unmatched power and influence, is there really a level playing field for anyone that doesn’t meet Dr. Scher’s approval, or which Dr. Scher, Proquest Investments (or its principals) does not have a financial interest in? This is an assault on the trustworthiness of the FDA, the SEC and the financial markets in general.
I have highlighted Dr. Scher’s connection to a $1 billion venture capital fund and a long history to Michael Milken. On top of his close professional relationship to these 2 huge financial titans, his wife’s cousin, Barry Lafer, operates a $200 million offshore hedge fund (Lafer Equities).
There appears to be a certain quid pro quo as it relates to Dr. Howard Scher and his professional involvement with Prostate Cancer Foundation and Proquest Investments (and its principals). Often these are not public companies and Dr. Scher’s financial interests, those of Proquest Investments or Michael Milken are not publicly available. Much of these conflicts in ownership do not appear in the public domain until years later when the company files registration statements with the SEC to go public or is perhaps is acquired by a public company. Proquest Investments is a venture capital fund that is not transparent like a common mutual fund and the Prostate Cancer Foundation is a private foundation.
A request for a Conflict of Interest Waiver was requested by Dr. William Freas, Director of Scientific Advisors and Consultants for CBER, on February 5, 2007. The request was concurred by Vince Tolino, Director of Ethics and Integrity, on February 26, 2007. On March 8, 2007, Dr. Howard Scher was granted a waiver by Dr. Randall Lutter to participate in Dendreon’s FDA advisory panel for Provenge because an individual with lesser conflicts of interest was unavailable. I don’t understand how the need for Howard Scher’s individual services could outweigh the above demonstrated conflict of interest created by the financial interest attributable to Howard Scher. I can’t imagine an individual participant with more financial conflicts of interests sitting on the FDA advisory panel for Provenge. It is my fear that Dr. Scher’s financial interests have come before the best interests of terminal AIPC patients. http://www.fda.gov/OHRMS/DOCKETS/AC/07/waivers/2007-4291-w-07-Sche-208r.pdf
Can there be any question that Dendreon’s FDA determination of Provenge was manipulated? 13 out of 17 of the FDA’s own experts (chosen with bias) agreed that Dendreon had provided enough evidence of effectiveness to approve it. Historically, the FDA has never decided counter to an advisory committee recommendation for marketing approval for a terminal indication. The FDA’s determination counter to the advisory committee’s recommendation to grant immediate marketing approval for Provenge was unprecedented.
Dendreon is on the SEC’s regulation SHO threshold security list and continues to this day to be heavily shorted. Roughly half of the entire float in Dendreon stock is short. The short interest in Dendreon actually increased 50 percent pursuant to the positive recommendation of the Provenge advisory committee meeting. This response by investors is completely illogical unless somebody knew the outcome in advance. How else can anybody explain the means motive and method to this fact? (please see footnote 3)
Huge financial interests are at stake and the positive outcome of a Provenge application could have dire consequences for those who have a short interest in Dendreon stock. Furthermore, Dr. Howard Scher’s partners, Michael Milken and Proquest Investments, have an even larger financial interest in seeing Provenge not approved for terminal AIPC patients. The FDA subjected the terminally ill AIPC patients to more suffering whereby a few would benefit financially.
A full investigation into the matter of corruption within the FDA, and in particular, in the egregious handling of the matter pertaining to the consideration for approval of Dendreon’s Provenge for prostate cancer is needed. Commissioner Andrew von Eschenbach of the Food and Drug Administation was appointed in the aftermath of Commissioner Crawford’s unintentional failure himself to disclose his own financial holdings. I suspect there is much greater detail that is just not available in the public domain.
I also wanted to address your comment in your previous email to me about the cost of Provenge, in which you raised a concern that the cost of the approach may be another challenge. The cost of a drug should have nothing to do with whether or not the FDA receives marketing approval. In the case of Provenge, it is thought that it would be priced between $30,000 and $50,000. I believe Dr. Gold has made only 1 public comment about pricing Provenge. Also consider that Provenge is different from other drugs and vaccines because it is custom made for each individual patient using their own cells. My understanding is that Provenge is expected to cost less than a typical 7 month regimen of Taxotere with hospitalization and a variety of drugs that are commonly administered to lessen the poisonous chemotherapy side effects which include nausea, vomiting, depleted red and white blood cell counts. When all these ancillary costs are considered, Provenge costs less than an average Taxotere regimen and has been demonstrated to be twice as effective at prolonging survival in AIPC patients. Furthermore, over 50% of asymptomatic AIPC patients prefer not to use Taxotere due to its relatively severe side effects.
Taxotere alone: 2.5 months longer survival
Provenge alone: 4.5 months longer survival
Provenge & Taxotere: 13.3 months longer than just Taxotere.
Also of significance, many experts in immunotherapy believe that the sooner you begin immunotherapy, the stronger the immune response. The impressive clinical trial results from stage 4 AIPC patients using Provenge are noteworthy.
I try to live a healthy lifestyle. I exercise, I try to eat well and seldom ever take medication. Having a recognized safe treatment option, like Provenge, that trains my body’s own immune system to fight AIPC is something I would want available to me if I faced death from AIPC. The FDA’s actions needlessly delayed access to a recognized safe treatment for 30,000 men annually.
Footnotes:
1. http://proquestvc.com/scienceadvisory.asp
2. http://tinyurl.com/2w86uo
3. http://www.nasdaqtrader.com/aspx/regsho.aspx
4. http://tinyurl.com/2lfjrz