Provenge: The Battle for a New Prostate Cancer Treatment
Right now, there is a public drama being played out between the FDA and a company called Dendreon, whose product Provenge is being developed for treatment of prostate cancer. What distinguishes this particular drug approval process is the public nature of the debate, with strongly worded statements from advocates and investors who each have large stakes -- though not necessarily the same stakes -- in the ultimate outcome of the FDA decision.
Before a drug can be sold in the US, it must be approved by the Food and Drug Administration (FDA) as being safe and effective for its stated purpose. As you might imagine, the stakes for a company seeking drug approval are very high. The only hope for a return on their investment in the drug is the ultimate approval, which allows them to market the product.
The FDA approval process begins at the time before major studies are conducted on a drug. The manufacturer will often meet with the FDA, and lay out a series of clinical trials and goals to be met for approval. Usually in cancer medicine, the company and the FDA will negotiate a particular endpoints such as time before tumor progression, or percentage of responses in patients with advanced cancer, or improvement in overall survival. In general, if the subsequent clinical trial meets those endpoints, FDA would consider granting approval.
However, there are additional layers to the approval process. FDA conducts an internal review of the data and also appoints expert panels that advise FDA. Those panel recommendations may, or may not, be honored in final FDA deliberations.
Sometimes the discussions get very complicated and intense. For instance, studies might meet some endpoints (like improving the length of tumor control), but not others (like improving overall survival). In other cases, side effects might emerge which undermine the anticipated safety of the drugs.
FDA, like many regulatory agencies, is relatively short-staffed, and must confront requests from innumerable parties such as drug manufacturers, advisory panels, patient advocates, and others in reaching their conclusions.
Here are several recent newspaper stories on this battle. It will be interesting to see what happens.
Do you think the FDA is right to study this drug further before approving it, or should experimental cancer therapies be fast-tracked through the approval process?
Related Topics:
Technorati Tags: provenge, dendreon, FDA, prostate cancer, vaccine
Before a drug can be sold in the US, it must be approved by the Food and Drug Administration (FDA) as being safe and effective for its stated purpose. As you might imagine, the stakes for a company seeking drug approval are very high. The only hope for a return on their investment in the drug is the ultimate approval, which allows them to market the product.
The FDA approval process begins at the time before major studies are conducted on a drug. The manufacturer will often meet with the FDA, and lay out a series of clinical trials and goals to be met for approval. Usually in cancer medicine, the company and the FDA will negotiate a particular endpoints such as time before tumor progression, or percentage of responses in patients with advanced cancer, or improvement in overall survival. In general, if the subsequent clinical trial meets those endpoints, FDA would consider granting approval.
However, there are additional layers to the approval process. FDA conducts an internal review of the data and also appoints expert panels that advise FDA. Those panel recommendations may, or may not, be honored in final FDA deliberations.
Sometimes the discussions get very complicated and intense. For instance, studies might meet some endpoints (like improving the length of tumor control), but not others (like improving overall survival). In other cases, side effects might emerge which undermine the anticipated safety of the drugs.
FDA, like many regulatory agencies, is relatively short-staffed, and must confront requests from innumerable parties such as drug manufacturers, advisory panels, patient advocates, and others in reaching their conclusions.
Here are several recent newspaper stories on this battle. It will be interesting to see what happens.
- Seattle Times: FDA Sued over Provenge Delay
- Washington Post: FDA Delay in Cancer Therapy is Attacked
- Boston.com: Prostate Therapy's Delay Sets Off a Fight
Do you think the FDA is right to study this drug further before approving it, or should experimental cancer therapies be fast-tracked through the approval process?
Related Topics:
Technorati Tags: provenge, dendreon, FDA, prostate cancer, vaccine
12 Comments:
Nice summary and good question.
In the case of Provenge, the answer is easy: The FDA ABSOLUTELY should approve this drug RIGHT NOW for use. These are terminal, late-stage prostate cancer patients we're talking about with NO other options (any doc worth his salt knows Taxotere is not a viable standalone option, since over 50% of men won't take it and the drug is so toxic it'll actually kill 1-2% of those who take it).
Provenge, on the other hand, has very few side effects, most notably flu-like symptoms for a couple of days. That's it.
The FDA-appointed panel of experts voted 17-0 in favor of the safety of this therapy. You get THAT vote from experts (even conflicted ones) and you've shown great signs of efficacy, you should get approved, NO QUESTION.
Vote was 13-4 in favor of the substantial evidence of efficacy (33% of Provenge patients alive at THREE YEARS vs. less than half that for placebo). Life expectancy for this patient population is about 18 months, so Provenge DOUBLED that survival time for 1/3 of those who got it, with essentially NO side effects.
The FDA has NEVER overturned a positive panel recommendation for approval of a therapy in terminal patients. NEVER. And yet, with this strong evidence of efficacy and an unquestionably safe therapy, they want to let another 50,000+ men die while they wait.
Provenge shows exactly the risk-benefit profile that should have garnered immediate approval. Why it didn't is a story that someone needs to write, but it includes a great number of conflicts of interest from two panel members, a historic political fight within the FDA, and a lot of sordid blood money that must be changing hands behind closed doors to deny these men their right to live.
www.arighttolive.com has more.
We believe patients have A Right To Live...don't you?
Thank you for bringing attention to Provenge. As you are aware we are fighting for the rights of prostate cancer patients to receive this safe immunotherapy NOW.
It's the patients who have had their right to life interfered with by those within the FDA who benefited by its non-approval.
Due to political infighting and the ego bruising of certain FDA employees the forgotten patients continue to be denied Provenge and continue to suffer more then they need to.
We have not forgotten them.
Kerry M. Donahue
Counsel for CareToLive, a not for profit corporation
Dr. Burstein, you ask the question:
Do you think the FDA is right to study this drug further before approving it, or should experimental cancer therapies be fast-tracked through the approval process?
With regard to Provenge, isn’t the real question before the FDA not whether the agency has the right to study this drug further, but whether immunotherapy treatments need to be judged by a different standard than chemotherapy treatments?
Sadly, the FDA already knows the answer is yes ---as they were told just that at the NIH/NCI workshop they hosted in February 2007, and were reminded again recently by the NCI’s Dr Jeffrey Schlom:
“Clinical data are providing evidence that patients are living longer following vaccination, de-spite the fact that trials do not show the vaccines can induce the immune system into shrinking tumors,” said Jeffrey Schlom, Ph.D., chief of the Laboratory of Tumor Immunology and Biology at the National Cancer Institute. “The data suggests that the scientific community and regulatory committees ought to rethink the design of clinical vaccine trials and our current approach to measuring the effectiveness of a cancer vaccine.”
And yet the FDA went blindly ahead overuling the conclusions of its own workshop and its own Provenge Advisory Committee where every single member of the AC who had recognized expertise in immunotherapy (and they were from Moffit, MD Anderson, NIH, Harvard, Stanford, UCLA, Duke, U WA) voted 13-4 that there was "substantial evidence" of effectiveness and unanimously (17-0) that there were no safety issues. Not one of the "no" voters on the panel had recognized expertise in immunotherapy. The drug in question was an immunotherapeutic agent.
So if the question is should the FDA have the right to study this drug further --the simple answer, I hope, is no if all the FDA wants to continue to study is why the round ball will not fit into the square hole.
Also troubling for Provenge advocates is an explanation by Dr Mark Thornton, formerly the medical officer in the FDA Office of Oncology Products, and now President of the Sarcoma Foundation of America, on why he believes the FDA did not listen to the majority opinion of its medical panel. Dr Thornton wrote on May 9th, 2007 (Black Wednesday, WSJ On Line) quote:
“Those voting in the minority, very powerful members of the oncology community, (and I would add who had strong financial interests in seeing Provenge disapproved) launched an unprecedented PR campaign accusing those in the majority of incompetence and naiveté in matters relating to cancer products. The arrogance of this campaign overlooked the notion that survival data from immune-based products may be qualitatively different from, and may need to be judged by different criteria than, survival data from chemotherapy drugs.”
I pray Dr Burstein that America's cancer patients, and citizens are not being held hostage at the FDA because of academic turf wars, financial interests or the chemotherapy industry.
kyoto27
Hello Dr. Burstein.
Nice job on your article covering Provenge. There is a Pulitzer prize waiting for journalist/commentators looking into the Provenge saga.
I'm concerned about how the FDA handles its job. We need direct and very bright sunlight into the FDA back rooms.
I know that many people requested that the FDA explain to the people and their medical doctors why it chose not to approve Provenge, even though it was advised by its appointed panel of Oncologists, Urologists, and Immunologists, all experts in the fields of immunotherapy and oncology, that Provenge is unquestionably safe (100% of the experts voted yes on safety) and that there was “substantial evidence” of the drug’s effectiveness as required by FDA regulations (76% of the experts voted yes on substantial evidence of effectiveness).
Among the NOs, Dr. Sher and Dr. Hussain.
Provenge achieved a 200% increase in overall survival measured at 3 years... (which means three times BTW) with multiple recipients alive and well over 6 years later.
27,000 men with end-stage prostate cancer will die needlessly early (some will die needlessly period) each year the Provenge is delayed by the FDA.
If FDA found the clinical trial data submitted by Dendreon (Provenge producer company) to be insufficient, why did it even submit the data to a panel of experts for their opinions?
Some of those doctors that voted "NO" as to the effectiveness evidence even had letters (urging the FDA NOT to approve Provenge) "leaked" to the media. They were Dr. Sher and Dr. Hussain. I let you judge on the ethics of this behaviour.
On May 30, 2007, news was that Schering-Plough Corp. said it had agreed pay Novacea Inc. up to $440 million for rights to develop the smaller drugmaker's prostate cancer treatment, causing Novacea shares to double.
Both Dr. Sher and Dr. Hussain are Novacea consultants.
Do you think Schering-Plough would have paid $60 million immediately and an additional $380 million to Novacea if Provenge was on the market?
Why the FDA - for the first time in its history - did not approve a drug deemed safe and effective by its own panel?
How is that Dr. Sher and Dr. Hussain - with their obvious and enormous conflicts of interest - took part in the panel?
Who did choose Dr. Sher and Dr. Hussain?
We already have proof that Provenge works (two phase III trials). Many people are going to die due to the delay. Who is accountable?
Why isn't this revolutionary and extremely safe treatment available NOW?
I can't imagine the motives are about monetary gains. Otherwise, here is the Pulitzer. That would be huge.
I wish you all the best.
Dr. Burnstein, Thanks for shedding light on the Provenge situation. Immunotherapy is the biggest threat ever faced by the oncology community and they are doing everything they can to stop or at least slow its adoption. I attended a local ACS sponsored meeting where two prominent oncologists talked about new developments in treating prostate cancer. Neither would talk about Provenge when I asked even though it is the most promising treatment option for late stage patients. I hope that the effort continues to get the word out to the patients and their families. They are the ones who are losing the most.
demo
Yes, Provenge should have been approved! The appointed panel voted 14-3(substantial evidence of eff.) and 17-0 (safety). IMHO the reason it was not given full approval was.. MONEY, POWER, GREED, BIG CHEMO PHARMA, Hedge FUNDS short dndn shares stood to lose many hundreds if not billions of dollars if it was approved on schedule! IMHO the DOJ and Congress needs to do a full investigation into the FDA and the SEC needs to look into the short sellers hedge funds and how they knew that after the AC panel voted to approve they increased their short position by over 10 million shares to ~38 million shares shorted!!!! Was there a leak from someone inside the FDA to them that a APPROVABLE LETTER was to be delivered to Dendreon??? As for Mr. Scher why did he not claim all of his COI's on his signed waiver to be on the panel??? Did he break the law??? If he has why has nothing been done about it? With the help of the SEC,DOJ and the current lawsuit against the FDA the true reason Provenge was not given FULL APPROVAL or at least a CONDITIONAL APPROVAL will be brought to light and Provenge will be made available to all AIPC men!
No, the FDA need not study Provenge further. It is an immunotherapeutic that was unanimously (17-0) found to be safe (even the FDA accepts its safety), and its side effect profile is much more benign than the chemotherapy alternatives.
All the Advisory Committee members having recognized expertise in immunotherapy found the data to show "substantial evidence" of efficacy, and the vote was 13-4 on that question. National Cancer Institute experts likewise examined the data and, according to their July 1, 2007 article in Clinical Cancer Research, found that Provenge affords a statistically significant survival benefit.
Data that is good enough for the true experts in the relevant field (immunotherapy) who were assembled by the FDA, and good enough for the NCI, ought to be good enough for the statisticians at the FDA, especially for an end-stage disease where there is no good alternative and where the data eliminate safety as a concern. Afterall, the purpose of having advisory committees is to examine the data in the proper context. If that weren't so, there would be no reason to have advisory committees; a computer could make the decision.
Tens of thousands of AIPC patients will needlessly die early while 2-3 years pass for the acquisition, analysis, submission, and FDA-analysis of additional survival data of a study still being enrolled. Provenge was derailed because of turf battles inside the FDA, an anachronistic adherence by a few there to statistical purity (that ignores science and patients more than it serves those ends) and some outside financial interests.
Sadly, the medical profession has largely remained on the sidelines while the FDA has gained too much control over patient care. What happened here is a prime example. Physicians are scientists who are supposed to be committed to patient care above all else. Where are you?
Clinical trials conclusively agreed that Provenge has a meaningful impact on survival. The Advisory Panel confirmed this opinion by a vote of 13-4.
The only meaningful objections were as to trial size ... not that trial size has any bearing on the claim of efficacy (a P value is a P value regardless of trial size). The small trial size brings up safety concerns as you have to fish with a wide net to find what adverse side effects might be out there.
However, when comparing to Taxotere, the current standard, which is known itself to kill 1-2% of the patients it supposedly treats ... that argument dies on the vine pretty quickly.
Accordingly, the panel voted 17-0 that Provenge was safe.
The denial of Provenge was a sad event not just for prostate cancer sufferers ... but for future progress against all forms of cancer.
Superb article bringing this injustice to the public's attention--Thank You!
Yes, Provenge should receive a Conditional Approval so that those TERMINAL cancer victims--in consultation with their physician's--have the option of this treatment, but especially because more than half of those with this deadly disease will refuse treatment with Taxetore due to the its horrible side-effects and possible death from the treatment--not their disease.
The currently enrolling trial should continue to either prove or disprove the efficacy claims and, as allowed by law, the FDA is able to remove the treatment from public use in the event anything untoward and unexpected arises.
Then, there's the Conflict of Interest (COI) of the 2 vocally negative Panel members... specifically, Howard Scher of Sloan-Kettering.
Scher reported only 3 COI's to the FDA per his filing in late February available at the FDA website which appears to be composed of ownership of 1 stock and 2 competing industry interest.
Internet research shows the following for Scher thus far:
1. NOVACEA: grants & research support; STUDY CHAIR of DN-101; Direct competitor to Provenge
2. GPB BIOTECH: financial conflict of interest per Scher in MedPage
3. PHARMION: financial conflict of interest per Scher in MedPage
4. SANOFI-AVENTIS: grants & research support
5. BRISTOL MYERS SQUIBB: consultant, grants & research
6. MILLENNIUM PHARMCEUTICALS: grant of research support
7. COUGAR BIOTECHNOLOGY: principal investigator; advisory board;
8. INNOVIVE PHARMACEUTICALS: principal investigator
9. INFINITY PHARMACEUTICALS: principal investigator
10. BIOGEN-IDEC: jointly held stock with spouse
11. PFIZER: jointly held stock with spouse
12. GENTA: scientific advisory board (as of March 6, 2007; since removed from web, but cached)
13. DEPARTMENT of DEFENSE: Principal Investigator PC Clinical Trials-P1 and P2
14. PROQUEST INVESTMENTS: consultant, scientific advisory board; Limited Partner FINANCIAL interest
15. MEDIVATION, INC: principal investigator MDV3100
16. AMBRILIA BIOPHARMA INC: Principal Investigator PCK3145, Phase I/II
There appears to be a significant and disturbing difference between his 3 disclosures to the FDA and the alleged 16 COI's found so far on the internet. It seems incomprehensible for someone with the training and education Scher has to "forget" so many apparent COIs… that is simply beyond all reasonableness and suggests intentional dishonesty or deceit.
Even more disturbing is the FDA's Office of Inspector General and others at the FDA to whom this information has been supplied and their apparent failure to investigate these charges that Scher has more COI's than he disclosed to them. When such information is provided and such allegations of potential federal law violation is involved, any ordinary citizen has the right to expect our government to investigate such allegations timely and thoroughly.
As a "temporary government employee" at the FDA, he is obligated, under Federal law, to provide full and complete disclosure. If he didn't, he may have the potential for liability for law violation(s) as well as for providing false data to the FDA under which he secured a waiver in order to participate on the Provenge AC meeting March 29th.
Patients, families, advocates, physicians and others are holding a Rally at the FDA on Sept 18th at 10 a.m. Please come and support cancer victims; details are at http://www.caretolive.com
See you in Washington and Thank You! for bringing this topic further into the public domain!
Hi-
Im in 8th grade. I'm wondering if it would be possible to construct a carniophage-type virus that could be put into a human, and the only way that it could survive is living on and killing cancer mutated cells. If so, im gonna call dibs on the Nobel Peace Prize. (I have to use the title and the money to make my medical journal called THE MD)
thank you for posting that article. now we know. i hope they can find the best medication for prostate cancer.
I think the FDA should approved Provenged, If this medicine proved to cure prostate cancer.
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