Thursday, April 16, 2009

Provenge: The Real Impact of IMPACT

It appears as though Dendreon put out some long-awaited good news on the Provenge therapeutic prostate cancer vaccine.

The vaccine intended for men with advanced prostate cancer “met” its primary endpoint of overall survival in the 512-patient IMPACT study, according to the company. The primary endpoint was a 22% reduction in risk of death compared to placebo, according to previous disclosures.

“The magnitude of the survival difference observed in the intent to treat population resulted in the study successfully achieving the pre-specified level of statistical significance defined by the study's design,” the company said in a statement.

“Survival is the gold standard outcome for oncology clinical trials, and overall survival was the primary endpoint of the IMPACT trial. The positive results from this landmark study provide confirmatory evidence demonstrating that treatment with PROVENGE may prolong survival,” according to Dendreon CEO Mitchell Gold.

That’s essentially all the public will get until April 28 when the full study is released at the American Urological Association meeting in Chicago.

Despite the lack of real clarity, investors made some big bets on the results. Volume went from 12,775,310 shares on April 13 to 65,410,443 shares at close on April 14. The stock went from $7.30 a share to $16.99—and reached a high of $22.10—over the same period, according to Google Finance.

Based on our conversations over time with a number of people familiar with this therapy, we’re withholding judgment on the approvability of Provenge until the full results are out and we can understand why a drug that missed it’s primary endpoint twice, hit it a third time.

Let’s just say the burden of proof on Dendreon will be quite high.

Provenge represents the first in a new class of active cellular immunotherapies that “engage the patient's own immune system against cancer,” in the company’s own words.

Dendreon says that because the study results meet the criteria of a special protocol assessment agreement with FDA, the company will file an amended BLA in the last three months of the year to gain market approval.

“The successful outcome from the Phase 3 IMPACT study provides validation of the long-pursued goal of harnessing the human immune system against a patient’s own cancer,” Gold said in the statement.

It’s statements like this from company CEOs of high profile therapies that always raise a red flag to us. We’ve seen and heard far too many stories that are similar to Provenge where a combination of hopes and dreams and fevered market speculation can sometimes lead in exactly the wrong direction. Those experiences are cause for caution when trying to bet on FDA approval of the cancer vaccine.

Remember, in October 2008, the IMPACT study interim results showed the vaccine failed to meet the primary endpoint of overall survival—Provenge demonstrated a 20% reduction in risk of death but was short of the 22% mark.

If after the details of the study and the data are released, and the results are compelling, it will be a great victory for Dendreon, its CEO Gold, and a motivated and mobilized patient advocacy community intent on seeing the therapeutic vaccine get to market.

But we’ll have to wait until April 28 at least. In reality, we’ll have to wait for FDA to comb through the data before we know for sure. And until then, we’re managing expectations.


Anonymous said...

Jan-2007: FDA accepts BLA for Provenge, and positive recommendations from ost of the advisory recommendors with the FDA. FDA suggests priority review, with approval likely, as viewed by others, in May of 2007.

May-2007, suprisingly FDA tells Dendreon it wants more results and information, yet nothing specific.

Dec-2007: congressional probe due to the Provenge delay and the conflicts of interests with the advisory committee members.

The rest:

A fundamental aspect of constitutional due process…..

Published on:

The Unreachable Availability of Provenge

Terminal patients are those who are not expected to live, usually due to an illness such as advanced cancer. Typically, a cancer patient is considered terminally ill if it appears he or she has 6 months or less to live. Cancer patients who are terminally ill, without cure or tolerable treatment, with the expectation that they will die soon, may seek and desire even unproven treatment options.
Understandably, for patients at a severe stage of illness, such as advanced prostate cancer, possible extension of life with comfort is worthwhile regardless of lack of evidence of proof that the treatment will indeed provide those benefits.
The FDA claims authority over the treatment options of such patients. Yet in recent years the FDA, with its frequent drug recalls and black box warnings –usually imposed only under pressure from the public — has proven itself to be rather inadequate. The FDA may not be an ideal judge of treatment options for very sick patients.
Individuals should be the deciding factor in selecting their treatment course along with their health care provider, and not an unreliable FDA.
Prostate cancer is the second most common cause of cancer death in men, with between 10 to 20 percent of men predicted to acquire the disease during their lifespan, resulting in the USA in about 30,000 deaths a year from this disease. The more aggressive and advanced prostate cancer becomes, as determined by measures such as Gleason score and methods such as bone scan, the harder it is to treat the patient.
Yet innovation still exists in medicine. A few years ago, a small biotechnology company called Dendreon was working on a conceptually new treatment for prostate cancer. They called it Provenge.
The immunotherapy method developed by Dendreon requires the removal from each diseased patient of some white blood cells (part of the immune system). These are reinjected into the donor patient after being processed by a method designed to make the cells attack a target found only on tumors — in this case a chemical called PAP, which is over-produced by prostate cancer tumors.
As developed in the race to make Provenge the first immunotherapy biologic treatment for progressed prostate cancer patients, Dendreon commenced clinical trials on patients who, no longer responding to standard available treatments, had no approved option remaining except for a chemotherapy called Taxotere. At such a traumatic stage of prostate cancer, many patients, foreseeing brutal side effects from Taxotere, refuse treatment entirely. As tested in clinical trials, Provenge requires just three injections in a period of six weeks.
Provenge received Fast Track status from the FDA because initial evidence indicated potential benefit for terminal patients. Dendreon proceeded to gathered evidence of the safety and efficacy of Provenge as a therapy of benefit for severe prostate cancer patients. Clinical trial results indicated that men with advanced prostate cancer who were treated with Provenge obtained life extension twice that of patients receiving chemotherapy, and without the concerning side effects of chemotherapy.
The medical community and survivors of prostate cancer were elated and waited with great anticipation for access to this treatment method. Patients and their families expressed great joy. Caregivers and specialists such as urologists and oncologists who treat such patients were no less elated. In March 2007, an FDA panel recommended with clarity the approval of Provenge based on its proven and substantial efficacy and safety, as demonstrated in its trials.
Now for the bad news: to great shock and surprise, the FDA agency rejected the approval of this great treatment for very sick patients. They announced this rejection, due to, they said, ‘lack of data, ’ in May of 2007. This decision contradicted their own experts’ favorable opinion of Provenge weeks before delivering this terrible news. Especially on considering that the FDA Commissioner is a prostate cancer survivor himself, many found this ruling completely unbelievable.
Soon after the FDA passed this judgment, others discovered conflicts of interest. In particular, one of the oncologist’s specializing in prostate cancer who helped evaluate Provenge on behalf of the FDA agency, Dr. Howard Scher, was found to have a financial commitment to a future competitor of Provenge that was being produced by another biotech company called Novacea. This company had signed a co-promotion agreement with a major pharmaceutical company, Schering, to provide support for development of this competing therapy for advanced prostate cancer.
Dr. Scher never disclosed this conflict during the approval process of Provenge. As it turned out, eventually, Novacea’s drug was discovered to have serious flaws, and Schering pulled out of their agreement with Novacea.
In addition, in an incident between March and May of 2007, baseless letters were anonymously delivered to the FDA stating negative qualities about Provenge, claims which critics believe were without merit, speculative and even fabricated.
Overall, the FDA’s refusal to approve Provenge angered many, and a newly formed advocacy group called Care to Live last year filed a lawsuit against the FDA charging clear lack of protocol or knowledge about such complex treatment agents as Provenge.
Terminal patients, I surmise, desire comfort during the progressive disease that has placed them in the last chapter of their lives. They certainly should have a right to choose any treatment that possibly could benefit them. Most are willing to assume any risks of unapproved, yet potentially beneficial treatments such as Provenge. Because they have a terminal illness, for these patients possible benefits clearly take priority over safety issues of unapproved treatments.
The controversy could be concluded by a terminal patient’s signing a waiver of some sort, perhaps, stating that they are responsible for the consequences of an unapproved treatment regimen such as Provenge. Yet the FDA, with reckless disregard and overt harshness, denied what likely was a great treatment method for these very ill patients. Considering the available data on Provenge, granting approval, especially for terminal patients, would seem completely rational.
The FDA does in fact presently have the ability to grant what is called conditional approval for such treatment methods as Provenge at this time, and why they have not remains completely unknown. What is known is that they are harming those they pledged to protect so long ago. The FDA ultimately harmed others more by not approving Provenge- nor offering any exceptions for cancer patients in this extreme situation.
I would go as far as to say that the FDA appears to be a bought, corrupt, and incompetent administration without loyalty and dedication to the public and its health. In view of the FDA’s past failures with regard to drugs belatedly taken off the market and the increasing need to label other approved drugs with black box warnings, individuals should be the deciding factor in selecting their treatment course along with their health care provider, and not an unreliable Administration.
“Facts do not cease to exist because they are ignored.” — Aldous Huxley

Dan Abshear

Anonymous said...

Ramsey: For such an expert on FDA and the industry, why act surprised that earlier trials may not have met their endpoints.

You write that it is hard to understand why Provenge missed it’s primary endpoint twice earlier, but hit it on its third trial. Are you kidding?... poor trial designs and a host of many other factors lead to many trial failures for many drugs, including a signinficant number of drugs currently on the market.

I would agree that something smells funny with Provenge and the campaign the company has unleashed with patient advocacy and etc. But don't sentence this drug to death for failing to meet endpoints in earlier trials... unless you want to put all other drugs that have been approved on trial as well.

Ramsey Baghdadi said...

Anonymous commenters: These are great comments. Please keep them coming.

Anonymous said...

Obviously you don't really know much about Provenge - or you pretend not to. The primary endpoints it has missed were other biomarkers, not survival. The reason why the first BLA was turned down was because Dandreon tried to use the survival data retrospectively. That's why the press release emphasized 'survival as the gold standard' and 'this was a prospective study'. Interim survival (20%, just short of the magic number 22%) was bound to increase in the final results as it did in previous trials.

Maybe nobody really knows what's going on in the molecular/physiological level, but what matter is it's safe and it prolongs the patients lives. That's how penicillin was found.