Subscribe to RSS feedDoes FDA’s approval of Avastin for breast cancer lower the bar for drug approvals?
On Friday, we posted a press release from Breast Cancer Action (Breast Cancer Action: Patients Lose, Genentech Wins with FDA’s Avastin Ruling) criticizing the FDA’s approval of Genentech’s [NYSE:DNA] Avastin for treatment of metastatic breast cancer. We noted that it was odd that the FDA approved this drug, given that the Oncologic Drugs Advisory Committee (ODAC) had recommended. Applications for drugs to be approved for new uses are first sent to Advisory Committees comprised of physicians with expertise in that speciality (here, oncology). If the Advisory Committee recommends that the drug not be approved, the FDA usually approves it — and if it advises that it not be approved, then the FDA usually doesn’t. As an article in BioWorld Today (FDA Splits with ODAC, OKs Avastin Use in Breast Cancer) describes, the vote of the ODAC was close, but serious concerns were still raised by it:
The approval came as somewhat of a surprise, considering that the FDA usually follows the advice of its advisory panels. Although the ODAC vote on Avastin in breast cancer had been close, at 5 to 4, the panel had raised concerns about trial design, toxicity and survival data.
Breast Cancer Action raised some serious concerns about the FDA’s accelerated approval of Avastin for metastatic breast cancer in its press release which we posted on Friday. Barbara Brenner, Breast Cancer Action’s Executive Director, raises some additional concerns about the approval — not about the drug itself, but about how the drug was approved, and based on what type of clinical trial. In an email to advocates (reprinted here with her permission), she describes the danger:
I want to give folks some context for what happened here, particularly in light of the recommendation of the ODAC some weeks ago that the drug not be approved at this time. BCA encouraged that outcome. See the first story on the home page at http://www.bcaction.org/ for the history.
What happened today is that the Commissioner of the FDA, Andrew Von Eschenbach caved to enormous pressure from industry. Some of you have seen the Wall Street Journal editorial yesterday saying that it would be a “moral tragedy” if the drug weren’t approved because lives were at stake, even though there is no evidence that the drug improves survival. What we know is that the head of Genentech met with the WSJ editorial board last week. And they’ve been dribbling out little bits of data about other trials that also don’t have survival data.
The FDA Commissioner, as you know, is never bound by an ODAC recommendation. In this case, the Commissioner Von Eschenbach is as tied to industry as the rest of the Bush administration is.
As you can see from Genentech’s press release , we are very sad that that industry’s interests have trumped those of patients in the case of this particular drug, and that they have evidently acceded to a lower standard of drug approval — PFS (progression free survival) — instead of overall survival.
But the standard has been changed in another critically important way as a result of today’s decision. Before today, a drug could not be approved for marketing unless it had been subjected to a drug registration trial with standards set by the FDA. This standard is higher than the standard for classical clinical trials, largely because routine clinical trials often mask the true side effects of drugs or are done in populations that are likely to result in overstated benefit.
The decision made today was on the basis not of a registration trial, but of an NCI-sponsored clinical trial, not designed for drug registration. This means that, in the future, other drugs companies will be able to argue to the FDA (probably successfully) that the FDA drug registration standards don’t have to be met, basing approval on clinical trials will be just fine.
As I sat last week trying to figure out why Genentech had not even mentioned the AVADO trial (the one that was designed as registration trial, the results of which were expected in the first three months of this, and were in fact partially released last week, one week before the decision today) in their Avastin presentation to the ODAC in December, I came to a stunning realization: what Genentech was hoping for was a decision that would permit drugs companies to avoid the rigors of registration trials in the future, and rely on clinical trials that are often controlled by industry. And that is what they got with today’s decision.
The bar has been lowered in more ways than we can count. A very sad day for patients.
The BioWorld Today article described above gives some of the history:
In May 2006, Genentech submitted a supplemental biologics license application to the FDA seeking approval of Avastin in breast cancer. But the FDA raised concerns about the underlying data, which had not come from a traditional double-blind, placebo-controlled, company-sponsored Phase III trial. Instead, the sBLA was based on an open-label study, known as E2100, conducted by the National Institutes of Health-affiliated Eastern Cooperative Oncology Group. In September 2006, the agency delivered a complete response letter asking Genentech to audit the E2100 data in the same manner expected of a company-sponsored trial. (See BioWorld Today, Sept. 12, 2006.)
Genentech did as the FDA asked, resubmitting the revised sBLA in August 2007. But a second setback occurred in December, when ODAC narrowly voted against approval. (See BioWorld Today, Dec. 6, 2007.)
E2100 had randomized 722 previously untreated breast cancer patients to receive Avastin plus paclitaxel chemotherapy or paclitaxel alone. The study met its primary endpoint of improving progression-free survival (PFS): patients receiving Avastin achieved a median PFS of 11.3 months compared to 5.8 months for the control arm. However, there was no statistically significant difference in median overall survival, with the Avastin group surviving 26.5 months and the control group surviving 24.8 months, leading ODAC to debate the clinical merits of PFS.
The panel also raised questions about the design of E2100 once again and voiced concerns about adverse events. Six deaths were found to be ‘definitely or probably’ caused by toxicity related to Avastin, and 71.1 percent of patients in the Avastin arm experienced severe adverse events, compared to 51 percent in the control arm.
But between ODAC’s negative decision and the FDA’s positive one, data from a new Phase III trial became available. Known as AVADO, the trial was sponsored by Roche and properly designed. The randomized, double-blind, placebo-controlled Phase III study compared Avastin plus docetaxel chemotherapy to placebo plus docetaxel in the first-line treatment of 736 patients with locally recurrent or metastatic HER2-negative breast cancer. Avastin was administered at 15 mg/kg or 7.5 mg/kg every three weeks, and both doses resulted in a statistically significant improvement in PFS. [PAL Ed.: But not in overall survival, as Breast Cancer Action also pointed out in the trial upon which the approval was formally based] (See BioWorld Today, Feb. 14, 2008.)
Although the AVADO data were not officially included in the Avastin sBLA, Genentech submitted them to the FDA for consideration. That may have helped to sway the agency’s decision to go ahead and grant accelerated approval.
In its news release, Genentech said that converting its accelerated approval into a full approval will be dependent on an FDA review of the full AVADO data as well as data from a Genentech-sponsored Phase III trial known as RIBBON I. Initial RIBBON I data are expected later this year, while overall survival data from AVADO are expected around mid-2009.Genentech also plans to provide the FDA with data from three additional randomized trials that are either ongoing or planned.
So the question remains: Will FDA’s approval of a new indication based on a trial that was a not traditional double-blind, placebo-controlled, company-sponsored Phase III trial pave the way for the loosening of standards on what data the FDA will accept for approvals? Does the FDA’s overruling of its own advisory committee make it likely that the FDA will ignore its advisory committee recommendations more often? And what does the FDA’s approval of a drug based on a secondary endpoint like progression-free survival when the drug failed to meet the primary endpoint of overall survival bode for the future?
Got thoughts on these questions? Post ‘em in the comments.
June 5th, 2008 at 6:02 PM
Provenge and Our F.D.A.’s Etiology For Not Being Approved
Terminal patients are those who are not expected to live due to usually illness such as advanced prostate cancer (cT3). If the patient has 6 months or less to live, those patients are considered terminally ill. Regardless, if a patient is terminal, they are without a cure or tolerable treatment for their illness. Since such patients will likely die in a short period of time, treatment options, even if unproven, are often desired by such patients. This is understandable, because at such a severe stage of illness, such as prostate cancer, possible extension of their lives with comfort is worth it to them, regardless of lack of evidence of proof of whatever treatment that may be advantageous to them regarding these issues. The FDA, however, claims authority on the treatment options of such patients, although that administration has proven itself over the years to be rather inadequate with its frequent drug recalls and black box warnings, and they do these things only under pressure from the public, usually.
Prostate cancer is a rather frequent occurrence- with between 10 to 20 percent of men predicted to acquire the disease during their lifespan, resulting in about 30,000 deaths a year from this disease of the one million men who have prostate cancer in the United States. Furthermore, there are different stages of prostate cancer, and the more severe the prostate cancer cases are which is determined by such methods as bone scans and Gleason’s scores, which is a score that assesses prostate tissue after it is biopsied and if it is determined that the stage of cancer is severe by this and to estimate proper treatment options if proven to be malignant. Typically, the initial suspicion of prostate cancer is determined by the results of what is called a PSA blood test, as PSA is a protein produced by prostate cancer cells. If the PSA blood test is above normal limits, a prostate biopsy is performed to determine and confirm not only the presence of cancer, but also the severity of the disease on such a patient.
Yet fortunately, and as you will read, innovation still exists in medicine. A few years ago, a small Biotechnology company called Dendreon was working on a conceptually new treatment for the worst prostate cancer patients, and this treatment therapy created by Dendreon was named Provenge. Provenge is the first immunotherapy biologic treatment for the progressed prostate cancer patients, and has proven to be a very novel and innovative treatment option for advanced prostate cancer patients who are terminally ill. Usually, these patients are unresponsive to usual treatment methods for prostate cancer, and are left with chemotherapy as their only treatment option at such a traumatic stage of prostate cancer. Understandably, most patients at this stage refuse treatment entirely, largely due to the brutal side effects of such chemotherapy treatments as taxotere. The immunotherapy method developed by Dendreon required the removal of white blood cells of the diseased patient and, after altered, are re-injected into this patient now designed to attack what is called PAP, which is on prostate cancer cells only. This treatment required only three such injections in a period of six weeks. This resulted in life extension twice that of chemotherapy treated prostate cancer patients of this severity, 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.
Fortunately, as the years passed, Provenge, by 2007, had convinced others of its safety and efficacy in its benefit for severe prostate cancer patients. This caused great joy to such patients and their families. Perhaps greater elation was experienced by the caregivers and specialists of such a disease, such as Urologists and Oncologists who treat such patients. While Provenge was on fast track status at this time at the FDA, the FDA panel thankfully recommended with clarity the approval of Provenge based on its proven and substantial efficacy and safety demonstrated in its performance in past trials. The FDA announced this to the public in the early Spring of 2007, I believe.
Now for the bad news: With great shock and surprise, the FDA agency rejected the approval of this great treatment for very sick patients due to, they said, ‘lack of data’ in May of 2007. This contradicts their favorable opinion of Provenge weeks before delivering this terrible news. Especially when one considers the FDA Commissioner is a prostate cancer survival himself!
Soon after this judgment was passed by the FDA, conflicts of interest were discovered by others. For example, a member of the FDA agency who was evaluating Provenge, Dr. Scher, was found to have a financial commitment to a future competitor of Provenge that was being produced by a company called Novacea, and this company had signed a co-promotion agreement with Schering with this similar prostate cancer drug being developed by this company. Dr. Scher never disclosed this conflict during the approval process of Provenge. As it turns out, this anticipated prostate cancer drug made by Novacea was discovered to have serious flaws, and Schering pulled out of the agreement with Novacea. In addition to this incident and before May of 2007, baseless letters were anonymously delivered to the FDA stating negative qualities about Provenge that were without Merit and speculative claims about the treatment. Yet overall, the disapproval by the FDA of Provenge angered many, and a newly formed advocacy group called Care to Live filed a lawsuit against the FDA for their clear lack of protocol or knowledge about such complex treatment agents as Provenge at the end of last year.
Terminal patients, I surmise, desire comfort during their progressive disease that has placed them in the last chapter of their lives, and certainly should have a right to choose any treatment that possibly could benefit them. At this stage of such a patient, one could argue, safety of any treatment option is not of concern to these patients, because they are going to die anyway. Yet the FDA, with reckless disregard and overt harshness for these very ill patients, ultimately harmed others more by not approving Provenge with deliberate intent.
The FDA does in fact presently have the ability to grant what is called conditional approval for such treatment methods as Provenge, and why they have not expanded this approval process to all terminally ill patients remains completely unknown. What is known is that they are harming those they pledged to protect so long ago by depriving such patients in need of treatment, as no other options are viable presently that are as safe and effective with great tolerability associated with Provenge. So now the FDA appears to be a bought, corrupt, and incompetent administration without loyalty and dedication to the public and its health. This needs to be corrected in any way possible for the lives of others. A terminally ill patient has a personal right to obtain and access such treatments upon their own volition as well as the discretion of their doctor, just as a terminally ill patient is granted an individual right to die, if they choose to do so. It is an individual decision in such cases that should be void of interference from others.
“Facts do not cease to exist because they are ignored.” — Aldous Huxley
Dan Abshear
July 11th, 2008 at 3:23 PM
Beginning in the 1970, biopharmaceuticals were being researched for conceptual production in those places once called academic institutions, and conducted basic research to identify new product candidates applying a great amount of research. The same protocol is applied with biopharmaceutical companies today.
The first biopharmaceutical ever was synthetic insulin called Humulin made by Genetech in 1982 utilizing what is called rDNA technology, which also is used to produce human growth hormones. Later the rights were sold to Eli Lilly for this insulin. Biopharmas are distant and covert relatives of big pharma, yet become intimate with them more often now than ever before due to dry pipelines of big pharma- GSK and Roche in particular, yet most big pharma examine acquisition of biopharma companies for assured profit more than any other reason, they may speculate. Big pharma has a clear need to diversify which has created alignments with biopharmaceutical companies to create a pharmatech of sorts with the resources from both big pharma and biopharmaceutical companies. Furthermore, big pharma likes the fact that there is no design to produce biogenerics along with another fact that biopharmaceutical companies historically are fast growing companies of a different ethnicity of their own.
Over 20 biopharma drugs were approved in 2005, I believe. They grew almost 3 times as much as big pharma recently. Last year, biopharmaceutical companies made close to 80 billion in sales as well. Over 20 biopharmaceutical products are blockbusters by definition. They are overall very effective treatments for very difficult diseases to manage, as they target specific aspects of certain diseases, which limits side effects experienced by the patient placed on therapy with a biopharma drug. Unlike traditional drug development, biopharmaceutical companies first seek disease targets by genetic analysis and then search for a way to manipulate this target in a very specific way. The biopharmaceutical companies typically have a high profit margin and their products. Also, these products are biologically synthesized and do not cross into the bloodstream.
There are about a dozen f different classes or mechanisms of action of biopharmaceuticals that have about a half of dozen different types of uses that is always increasing, as lablel alterations of biopharmas are requested soon after the approval of a particular medication by this method that is allowed for further exploration of potential additional uses of thier new drug which, like other biopharmaceuticals, work in novel ways. Some cause apoptosis, or cell death of specific tumor cells. Some cause angiogenesis to occur, which means they cut off the blood supply to tumors. Then some biopharmaceuticals have multiple modes of action that benefit certain patient types and their diseases greatly, as with most biopharma products, the safety and efficacy is evident and reinforced with clinical data and eventual experience with the biopharmaceutical that is chosen to be utilized. And this clinical data is of a different method as well. Patients in the clinical trial are profiled, which allows better interpretation of this clinical data on their products.
Some biopharmas are more noteworthy than others, such as Enbrel, which was originally created for the many forms of RA- arthritis caused by the patient’s immune system attacking their bodies. At one point, demand exceeded supply for this drug, as the efficacy and safety was evident and demand was unexpected by the manufacturer, so Enbrel was sought out by doctors and patients both due to the clinical data verifying the efficacy and benefits of the drug. Relief from the pain and decreased quality of life was the primary motivation for patients seeking this particular drug. Enbrel was approved in 1998 and produced from what are called monoclonal antibiodies, which is one of several ways in which biopharmaceuticals are produced. In fact, some call the 1990s the biopharmaceutical decade.
Partnering of biopharmaceutical companies and larger pharmaceutical companies began during this decade in large part. Or a big pharma company will acaquire a biopharmaceutical company for complete ownership and bypass what would otherwise be a symbiotic relationship in that big pharma can provide the resources and connections necessary to launch and grow a particular biopharmaceutical drug, with the return on this investment being speculated revenue generated from what should be eventually a blockbuster biopharmaceutical.
The country of Belgium provides the most biotech products to the biopharmaceutical companies in the United States, which leads the industry in the world, with more than 70 percent of both revenues and research and development expenditures. Canada is ranked number two in this area, I’ve been told.
Some biopharmaceutical drugs are more profitable than others as well. Biopharmas compose around 10 percent of the pharmaceutical market presently, I understand. And with the government health care programs being the largest U.S. payers for pharmaceuticals, Medicare pays 80 percent of the cost of biopharmaceuticals. One other controversial, yet profitable biopharma class is known as EPOs, with names like Procrit and Epogen, and are indicated for anemia that is experienced in patients on dialysis or who have cancer in particular. Doctors are monetarily incentivized to exceed dosing requirements of these agents for their anemic patients, but this excess causes premature deaths and accelerated cancer progression for the patients that are over-dosed in this way. Once this tactic was exposed, there are now limitations regarding the amounts authorized to be given to particular patients placed on these EPOs. They are in the class of hormone biopharmaceutical drugs, which is another type of several classes of biopharmaceuticals, and they reduce the need for blood transfusions as they increase RBC proliferation.
While biopharmaceuticals are very efficacious and safe, as well as having therapeutic and diagnostic benefits for the very sick, the cost of them is outrageous, some have said. Genzyme has one biopharma product that costs a half a billion dollars a year. Yet most biopharmaceuticals cost around 100 grand a year for therapy that provides with some only limited life extension or survival rate of these patents that is only a few months. Furthermore, with cancer drugs, they are used together with chemotherapy for their treatment regimens, so there is no real improvement in the quality of life of some patients on biopharmaceuticals, considering the devastating side effects of chemo treatment. In addition, Co-pays financially drain such patients and their families, yet there is no other choice for therapy because of the avoidance in the creation of generic biopharmaceuticals, for example. Oncology, by the way, is the primary commercial focus of biopharmaceutical companies now and in the immediate future, so maybe competition will be a cost advantage to such patients in time.
Several years ago, I saw Roy Vagelos, former CEO of Merck, speak to others at Washington University in St. Louis. And during his presentation, he stated something similar regarding the cost of biopharmaceuticals and asked as well about whether or not the value related to the cost of biopharmaceticals appropriate for such a brief life extension of cancer patients in particular, for the most part. An issue or issues are always associated with new paradigms and innovations. Yet there are only a few biopharmaceuticals out of many available with debatable benefits with the high price tag. It ends up being what the market will bear. Yet the real question is the clinical evidence behind biopharmaceuticals: If a biopharmaceutical stops tumor progression without remarkable survival benefits or improvement in quality of life, is the price tag worth it to the patient? Assuring that a logical construct is examined to conclude that such a drug will be of benefit to a very sick patient will or should be the determining factor on the treatment regimen selected for such a patient.
How do these drugs differ from typical drugs that have been made before this advent of biopharmaceuticals? Unlike the small molecule, synthetic, carbon based pharmaceuticals of yesterday, biopharmaceuticals, classified under what is called Red biotechnology due to this being a medical process in the biotechnology world, essentially are larger and very complex modified proteins derived from living biological materials that vary depending on what medication will be manufactured and for what disease state. In fact, it is difficult to identify the clinically active component of a biopharma drug, which is why there is no pathway for generic copies of such drugs, as it would require expensive and meticulous clinical trial processes. Yet recently, a company called Insmed demonstrated bioequivalence to Amgen’s Nupogen that increases whitle blood cells. While there still is no defined pathway for follow-on biologics, this study demonstrated that another biologic drug can show that it is therapeutically equivalent. Insmed’s drug in this study will not be available for marketing until next year or later, though.
Also, a transformed host cell is developed to synthesize this protein that is altered and then inserted into a selected cell line. The master cell banks, like fingerprints, are each unique and cannot be accurately duplicated, which is why there are no generic biopharmas, yet biosimilar drugs are again a possibility, yet it’s in more of a conceptual phase presently, so it seems. So after this insertion, the molecules are then cultured to produce the desired protein for the eventual biopharmaceutical product. These proteins are very complex and are manufactured from living organisms and material chosen for whatever biopharma may be desired to be created. It is difficult to identify the clinically active component of biopharma drugs. So manufacturing biopharmas is a difficult process, and a small manufacturing change could and has raised safety issues of a particular biopharma in development that manufacturing had a manufacturing flaw of some sort. It takes about 5 years to manufacture a biopharmaceutical. And each class has a different method of production and alteration of life forms to create what the company intends to develop. Yet overall, their development methods are rather effective.
Another difference is that biopharmas are regulated under what is called the Public Health Service Act, and unlike the FDA, they authorize the marketing of biopharmaceuticals. The Act’s role in monitoring the promotion of biopharmaceuticals is unknown. Safety protocols regarding biopharmaceuticals are a mystery to me as well. What is known is that biopharmaceuticals have the potential to discover therapies to treat the cause of a particular disease state instead of treating it symptomatically. They set out to solve unmet clinical needs by science that has yet to be proven. Biopharmaceutcals save, enhance, and extend the quality of life of patients with terrible diseases, and over 250 million people have benefited from their products.
Presently, few biopharmaceutical companies are actually profitable. Also, with biopharmaceuticals, some years are better than others from a revenue point of view. Yet like any business, some years are better than others, and biopharmaceuticals are anticipated to offer quite a bit to public health in the future, with a focus on cancer patients in particular.
The cost of developing a biopharmaceutical exceeds a billion dollars, with about a third actually making it to market. The market size of biopharmaceuticals is rapidly approaching 100 billion dollars a year, with average annual growth between 10 and 20 percent. Between70and 80 percent of cancer drugs are prescribed off-label, so it will be interesting on how these drugs will be used in such disease states now and in the future.
Regardless of the challenges that are and will be faced by biopharmaceuticals, I’m pleased to see the results and realization of true innovation in pharmacology by taking a different path of drug development. Furthermore, I believe others should behave in a similar manner and be inspired by the biopharmaceutical companies and what they have done and continue to do for the benefit of the patients.
“The progressive development of man is vitally dependent on invention.” — N. Tesla
Dan Abshear (what has been written is based upon information and belief)
April 18th, 2013 at 11:42 PM
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May 23rd, 2013 at 5:26 PM
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