FDA "Very Concerned" About Carfilzomib's Safety
U.S. Food and Drug Administration (FDA) staff members appear to have substantial concerns related to the safety of carfilzomib.
The FDA this morning published its internally prepared briefing document for this Wednesday's meeting of the agency's Oncologic Drugs Advisory Committee (ODAC) (see related Beacon news).
At that meeting, the committee will review data related to Onyx Pharmaceutical's (NASDAQ:ONXX) application to have carfilzomib (Kyprolis) approved as a new treatment for relapsed / refractory multiple myeloma.
The FDA report released this morning states that the agency's staff is "very concerned" about "severe toxicities, including deaths" that have been observed in association with the use of carfilzomib.
Because the source of the toxicities is uncertain, and because -- according to the FDA staff -- carfilzomib may not offer an efficacy advantage over existing myeloma therapies, the FDA believes "the risks of carfilzomib may not outweigh its benefits."
Onyx's stock is trading down about 2 percent at midday while the overall stock market is relatively unchanged.
Safety Concerns
In its briefing document, the FDA staff lays out three primary areas of concern related to carfilzomib's safety.
First, the staff notes that a total of up to nine deaths due to heart-related issues occurred during carfilzomib Phase 2 trials involving 526 myeloma patients. Overall, 23 percent of the patients in the trials experienced heart-related side effects of any degree of severity, including congestive heart failure, cardiac arrest, or irregular heart rhythm.
It should be noted that Onyx and the FDA apparently disagree on how many deaths during the carfilzomib trials should be attributed to heart-related causes. Onyx reported only four such deaths in a summary of the trial data it provided the FDA. The agency, however, identified up to five additional deaths that it believes are likely to have been heart-related.
Second, the FDA analysis of carfilzomib trial data reveals that 70 percent of myeloma patients in carfilzomib's trials had lung-related side effects such as shortness of breath, blood clots in the lung, and fluid accumulation in the lungs. Most of the lung-related side effects, however, were mild or moderate.
Finally, the FDA staff report notes that two deaths due to liver-related issues occurred during the carfilzomib Phase 2 trials.
Based on these and other safety-related data, the FDA report concludes that "there are a number of patients with relapsed multiple myeloma who are at high risk of developing life-threatening" heart-related side effects if treated with carfilzomib.
In addition, the FDA report characterizes the lung-related side effects among carfilzomib-treated patients as "significant." It also considers the same to be true -- albeit "to a lesser extent" -- for the liver-related side effects observed during carfilzomib's trials.
The FDA criticism of carfilzomib's safety will come as a surprise to many who have followed the drug during its development. Until recently, discussions about the drug's safety have focused on the levels of peripheral neuropathy (pain and tingling in the extremities) observed among patients taking the drug.
In particular, carfilzomib was believed to cause less peripheral neuropathy than Velcade (bortezomib), a drug similar to carfilzomib that already is approved by the FDA as a treatment for myeloma. As a result, carfilzomib was often characterized as a "safer version of Velcade."
Other Important Aspects Of The FDA Advisory Committee Meeting Materials
The FDA staff report also contains several other items that are likely to receive attention during Wednesday's advisory committee meeting.
In regard to carfilzomib's efficacy, the FDA reports that the overall response rate for the drug is approximately 22 percent. This is the response rate among the same relapsed / refractory patients for whom Onyx would like the FDA to approve carfilzomib.
The FDA staff does have some concerns, however, related to the calculation of this response rate.
One concern is that almost all patients who received carfilzomib during its clinical trials also received relatively small amounts of dexamethasone (Decadron) to counteract infusion-related side effects. Dexamethasone by itself has anti-myeloma properties and is routinely used in combination with other myeloma treatments. Thus, the FDA notes in its report that the agency cannot tell exactly how much of the response rate it has calculated for carfilzomib is due to carfilzomib alone, and how much is due to dexamethasone.
In addition, the FDA report notes that the calculation of carfilzomib's overall response rate is based on a comparatively small number of patients. A total of 266 patients were enrolled in the carfilzomib trial for which Onyx submitted data for review by the FDA. However, only 69 of those patients were unresponsive to, or intolerant of, treatments from among the key categories of already approved myeloma treatments. As a result, the FDA's estimate of carfilzomib's response rate is based on the experience of this relatively small number of patients.
Despite the concerns the FDA expressed about carfilzomib’s safety and efficacy in the agency’s briefing document, the FDA has not built substantial skepticism into the question it has drafted for its advisory committee to vote on at the end of this Wednesday's meeting. The FDA has simply asked the committee to vote on whether the risk-benefit assessment for carfilzomib is favorable for the targeted relapsed / refractory multiple myeloma population.
For additional information, see the FDA briefing document, errata, and draft question (all PDFs) for the FDA advisory committee.
Related Articles:
- FDA Approves Once-Weekly Dosing And Revised Safety Information For Kyprolis
- Once-Weekly High-Dose Kyprolis Yields Deeper Responses And Longer Remissions Than Twice-Weekly Kyprolis (ASCO & EHA 2018)
- Common Measures Of Heart And Blood Vessel Health May Predict Risk Of Heart-Related Side Effects During Treatment With Kyprolis
- Eyelid-Related Complications Of Velcade Therapy: New Insights And Recommendations
- ASCO 2018 Update – Expert Perspectives On The Key Multiple Myeloma-Related Oral Presentations
It is surprising to me that the heart related side effects would come as a "surprise" to individuals following the development. How were they following it? Were they talking to stock analysts? They should have been talking to patients.
Regardless of what happens with the approval process, taking carfilzomib will be an iffy process unless there are no other options available.
Very infrequently does anyone leave a comment about his previous comment. After thinking about what I wrote I feel compelled to do so.
I am not a fan of carfilzomib because of the severe cardiac problem that were triggered when I participated in the trial. However, only 25% of the patients seem to have cardiac side effects. In other patients the efficacy appear to be excellent and the side effects minimal. I want those patients to have the drug.
What bothers me is that the drug may be effective and safe for me as well if it were given at my proper individualized dose level. All the patients in my trial were given the drug at the same dose level. Would it not make sense for the initial dose of a drug with such severe side effects to be started at a lower dose and then increased until side effects kick in? What am I missing?
Surely we don't have to do the "low dose dex" and "reduced dose Velcade" bit every time a new drug is introduced.
What really intrigues me is why a company like Onyx might risk millions and lose the right to sell this drug that could help us all if they would optimize the dosage. I have my ideas but I would like to know what other patient's think.
Perhaps I am just talking to myself...another manifestation of chemo brain.
Hi Gary...that sounds like a good idea. Sorry to hear you had cardiac issues, hope you didn't get serious damage from them. When I took Revlimid, there were differing doses available. My immunological system could not handle even the medium dose (lucky for me it was just for 'maintenance'), and I don't know how patients can manage the full 25mg dosing, but many do, although that just would have 'cratered' me. i wonder how the patients who might be vulnerable to cardiac issues would be differentiated from the rest of the group? Hopefully there might be an answer to that question. Perhaps a cardiologist could venture an opinion. Of course we all want to have drugs available that might help some of the patients, even if not all can benefit.
"In a pivotal clinical trial, 669 multiple myeloma patients were treated with bortezomib or high-dose dexamethasone (17). The incidence of cardiac disorders during treatment with bortezomib was 15% versus 13% in those patients treated with dexamethasone. HF events occurred in 5% of bortezomib-treated patients and in 4% of dexamethasone-treated patients. Two percent of patients in each of the treatment groups developed HF (10,17)."
Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma N Engl J Med 2005;352
"The FDA has simply asked the committee to vote on whether the risk-benefit assessment for carfilzomib is favorable for the targeted relapsed / refractory multiple myeloma population."
Hopefully, the answer is yes. The FDA label should simply state that cardiac monitoring is essential for patients on carfilzomib.
...which they failed to put in the bortezomib label in 2003 when it was approved...and this may account for the caution we are seeing with carfilzomib
as a consequence of post-marketing surveillance showing cardiac issues due to proteasome inhibitors such as bortezomib.
Unfortunately, the problem for carfilzomib is most likely that the FDA is seeing not just the cardiac issue, but also the pulmonary issue and the liver issue, and it's being asked to approved the drug based on a trial that, in the end, has less than 70 patients relevant to the population Onyx wants the drug approved for.
If you read the FDA report, you get the sense that the FDA is simply not happy with Onyx and the way the whole application for carfilzomib has been done. There's a part of the report, for example, where the FDA basically says: Look, we told you guys even before you started your trial to design it better. Plus, how do you think the FDA feels about Onyx after having analyzed the cardiac safety data and finding more issues in that area than Onyx previously reported?
Velcade was approved based on a trial that the FDA judged to have almost 200 relevant patients. When it was approved, neither Thalomid nor Revlimid were approved as treatments for myeloma. Nor were there all the clinical trials available to patients testing new treatments for myeloma like there are now.
I'm not sure anyone can say with certainty which way the FDA is going to go on this new drug application. At the same time, I think it's fairly clear that they're not happy with a number of important issues related to the application.
Now it is as if we were having a court case where the jury will be in deliberation before reaching a verdict. Even though the advisors are instructed to review only the materials submitted by Onyx as part of the application, here is hoping they are influenced by other trial results such as those reported by the University of Chicago during the ASCO meeting this month.
The issues with proteasome inhibitors, whether cardiac, pulmonary or hepatic are a class effect. IOW's bortizomib has the same issues. Proteasomes are ubiquitous throughout the body thus the class side effects when inhibitor. From package label for bortizomib:
"Lung disorders. There have been reports of lung disorders in patients receiving VELCADE. Some of these events have been fatal. Tell your doctor if you experience any cough, shortness of breath (dyspnea), wheezing, or difficulty breathing.
Liver disease. If you have liver problems, it can be harder for your body to get rid of VELCADE. VELCADE has caused sudden liver failure in patients who were taking many medications or had other serious medical conditions. Symptoms of liver problems include a yellow discoloration of the eyes and skin (jaundice) and changes in liver enzymes measured in blood tests. Your doctor will closely monitor you if you have liver disease. In patients with moderate or severe liver disease, VELCADE should be started at a lower dose. Additional dose adjustments may be made based on your tolerance of the drug.
Heart problems. VELCADE treatment can cause or worsen heart rhythm problems and heart failure. Your doctor may closely monitor you if you have, or are at risk for, heart disease. Tell your doctor if you experience chest pressure or pain, palpitations, swelling in your hands, ankles, or feet (peripheral edema), or shortness of breath."
When reading the FDA report there is a sense that the competitors companie are doing whatever they can to create a hurdle for Onyx. After all, the largest market for MM is the relapsed/refractory market not the NDMM patient. The FDA finding additional safety data issue is nothing new, in fact, it is what they do and very common.
Typically, how the mfgr reports the data and how the FDA 'analysis' views the data are often times at odds, Finding additional safety issues is de rigour. How data is reported has some subjectivity in terms of how it is graded (3 or less) and what it is attributed to. What the FDA noted was that they could not discern how much to attribute to carfilzomib vs. dex due to the trial design. The FDA however, is not involved in how trials are designed other than the standard designs for phase I and II,III approval. Typically, companies have multiple trial designs with placebo arms that are submitted. Onyx is a new kid on the block when it comes to FDA approval process and thus they are encountering 'unanticipated' issues by their clinical research team.
Yes, it is clear that the FDA is not happy but that is common. Regulatory bodies are not necessarily suppose to be happy with mfgr data. It would be interesting to pull up the trial designs that bortizomib used for approval..particularly given the FDA did not require cardiac monitoring. Which is indicative of not knowing what to look at as it was a new therapeutic class and also of possible underreporting of cardiac issues..the cardiac, lung and hepatic issues could have all been label updates post-marketing.
The real issue the FDA has raised is the 69 or ~30% of patients they have identified as not being intolerant of prior therapy.
Onyx if far from the new kid on the block. They already have one drug that's been approved by the FDA (Nexavar) and a follow-up drug that is rather far along in development.
It's also not true that the FDA is not involved in trial designs. With the type of approval process that Onyx is using for carfilzomib, they have had the ability to have extensive discussions with the FDA about the design of the drug's trial.
Finally, it is completely untrue that 'the money' is in treating relapsed/refractory myeloma patients. 'The money' is in treating first line, maintenance, and single-failure patients. There is little to no money in the patient population that carfilzomib might get approval for this round of FDA review. That is why Onyx is trying as hard as it can to build the case in the broader "court of medical opinion" for the use of carfilzomib in early lines of therapy. It's also why the FDA is so concerned about approving the drug based on the available evidence.
If you want the FDA to approve carfilzomib based on 'all the other data that are out there,' then you might as well throw out the FDA approval process. The process was implemented precisely because the government, and the people of this country, want companies to be able to sell prescription drugs only when there is carefully vetted evidence that the drugs are safe and effective.
I always find it amusing (and depressing) how people who, in other situations, love almost every form of regulation government can impose on people and businesses. But, when those regulations affect them, they suddenly change their tune.
Is it just me, or does there seem to be a contradiction among people arguing that carfilzomib should be approved despite the concerns raised by the FDA?
On the one hand, these people want carfilzomib approved because it supposedly is different and better than Velcade. It's supposed to be more effective, have less side effects, it's supposed to be able to treat patients who have failed on Velcade, etc. etc.
On the other hand, when it comes to the safety of the drug, they say: Oh, well, these safety issues are just common issues among the class of drugs that carfilzomib is part of.
Huh? How can you argue, on the one hand, that carfilzomib is different from and better than the main other drug in its class, and then, on the other hand, that argue that it's just the same as the main other drug in its class?
Which is it? The same? Or different?
Hi Everyone...this is a fascinating debate, and too bad it is so real, and not in the realm of science fiction...for all of us are affected by MM, I assume, who take the time and thought to weigh in on it. I found it interesting to note that Velcade was approved in the US in 2003, Suzierose. It wasn't approved in Canada until 2008! So any opinion I have might be subject to a five year 'lag time' I guess. But if you don't mind another opinion, I want to say that the proteasomease inhibitor bortezimib saved my life. I have no doubt in my mind about that. Because it worked fast and effectively, I didn't get too much neuropathy (this was in the days before sub-q velcade, and even before the recommendations of taking it once a week). I did get some neuropathy with it though, and that no doubt was compounded by taking revlimid later on, not to mention the fact that I was sick enough at the time of dx to already have some noticeable neuropathy! So the fact that carfilzomib works quickly also and that there is less neuropathy than Velcade, is, a plus for it. I sure hope that any other safety issues surrounding it can be worked out.
Hi Terry!
The FDA is not raising any safety concerns that are unknown for this class of drugs. Moreover, the FDA has already approved a drug in this class with the very same known safety issues being raised in this thread. That is their job. They have a duty to warn as a consumer regulatory body.
Perhaps, it seems contradictory because of the use of the term better? Different does not necessarily mean better when it comes to drugs.
The argument is not that carfilzomib has greater efficacy, but it is different in terms of how it acts on the proteasome. When it comes to safety, carfilzomib has an equal safety profile as relates to heart, lung, liver issues and a better safety profile when it comes to PN vs. bortizomib.
PN appears to be the only side effect where carfilzomib has demonstrated a better safety profile than bortizomib.
The argument in support of approval is focused on MM patients need therapeutic options, particularly the RR MM pt. Patients who have failed on bortizomib should have additional therapeutic options. The safety issues have consistently been managed by clinicians not by the FDA denying approval when it comes to chemotherapy.
The safety is not being minimized. When you look at all of the chemotherapeutic agents , you will find significant safety issues, overall. Carfilzomib is not raising toxicity issues outside of that, but it is presenting a therapeutic option for patients who may not have one. That is reason for approval.
The argument is not that the drug is better, but that it provides an additional therapeutic option without any greater safety issues than the drugs currently used. No different than penicillin vs amoxicillin. Both have overlap with safety issues and at the same time provide a different therapeutic profile.
The argument about the safety issues is as to how the FDA approval process works. When safety issues are an issue they are put in the label they do not typically result in lack of approval.
For the most part, when it comes to chemotherapeutic agents, all safety issues are handled by labelling. It is not whether there are toxic or life threatening issues for any chemo agent but rather that patients and doctors are INFORMED of those issues.
IOW's the FDA has historically approved chemotherapeutic agents with major toxicities by simply providing that information in the label. Physicians are acknowledged as highly trained professionals with the expertise to clinically assess when to use and how to monitor the use of any chemotherapeutic agent to the extent that 'off-label' use is how the vast majority of chemotherapeutic agents are used. The FDA has the duty to warn. The physician has the right to clinical use, knowing those warnings/precautions.
If safety/toxicity were issues for chemotherapeutic agents they would pull all of them off the market.
We are dealing with incurable disease, people's lives are at stake, and that tops the safety issues. Which is very evident when you recognize the high dose chemotherapy that preceeds SCT..fatal doses are administered and then the patient is rescued. If life-threatening events limited chemotherapy drug approval nothing would be approved.
The approval process is about therapeutic options, safety issues are handled by labelling. The FDA's duty is to warn and inform. Not restrict availability of therapy to populations in need. Clinical restriction is based on the physicians judgement.
If we look at bortizomib FDA approval what we have in 2003 is a drug approved with 27% response and the majority of the patients had been on alklylators/mustargen agents and/or had SCT. The entire population was proteasome inhibitor naive.
In contrast, carfilzomib is requesting approval with a 22% response in a patient population that includes prior proteasome inhibitor use. Further, while the FDA says they cannot discern the cardiotoxicity attributable to dex vs carfilzomib..that type of trial design would be unethical today. When bortizemib was approved dex, as a single agent was still a standard of care, today MM patients are not treated with dex as a single agent, thus carfilzomib could not have had an arm that was solely dex.
Carfilzomib has a good chance of approval if the ODAC panel is made up of primarily hem/onc's vs. cardiologists, who seldom treat oncology patients.
Hi Nancy,
You are a perfect example of what I am saying!! You had an additional therapeutic option.
Bortizomib provided you with a response that previously was only seen with far more toxic agents. Carfilzomib, will offer many patients who have relapsed or are refractory to bortezomib an additional therapeutic option with a far better safety profile than the other agents available.
Therapeutic choices with MM are not easy and there is basically no free lunch, (pick your poison) but there should be options and all patients should be informed and know the risks vs. benefits.
What carfilzomib seems to confirm is that as a class of drugs, proteasome inhibitors, have a narrow cardiotoxicity therapeutic window and that is likely true for pulmonary toxicity as well.
JimNY-I hear you on regulation and how some people change their tune when it affects them. As a farmer, I also find it "amusing" that some people will go nuts over the safety of genetically modified food "Frankenfood", but often those same people vote in favor of cloning human embryonic stem cells.
Back to related stuff: price of ONXX is fairly stable so I assume that is a plus for carfilzomib.
Hi Jim,
Onyx, is a new kid on the block, simply in terms of how long they have been in the oncology market. Very briefly as compared to Merck, Genetech, Bristol, or Millenium wouldn't you agree? Nexavar did not seek approval in a competitive market. What were the competing kinases for advanced renal carcinoma in 2005?Thus, the clinical research team did not anticipate the FDA approval process for a 'second agent' in the same class, which is how the trial design for the RR patients did not have a competitive arm. Simply because they based it on the approval process for bortizemib.
Additionally, the longer a mfgr is in the oncology market the more they are familiar with physicians on ODAC. Having extensive discussions with the FDA does not constitute the FDA being involved in COMPLETED trial designs. Onyx, could not go back and re-design the trial. The FDA may have asked for additional information but that would not have changed the trial design.
"Finally, it is completely untrue that ‘the money’ is in treating relapsed/refractory myeloma patients. ‘The money’ is in treating first line, maintenance, and single-failure patients"
Do you have any Numbers to support this assertion?.
The other data "out there' for the class of drugs is an essential part of the approval process, it highlights differences as well as what can be expected. The question is does carfilzomib have a higher safety bar as the second agent in the class or are these safety issues to be expected and the focus needs to be on whether carfilzomib provides patients with an additional therapeutic option, while NO LESS safe?
I have no issue with government regulations. I find them an essential safety net in a capitalistic society where health is a commodity to generate revenues vs altruistic cures.
Nor, have I suggested, implied or inferred that the FDA should overlook safety issues. What I have stated is that safety issues are handled by labelling when it comes to the vast majority of chemotherapeutic agents. The label is the FDA regulatory response to warn and should not be taken lightly. It is there for consumers and physicians to know what to expect regarding safety and toxicity.
I think there seems to be a major misunderstanding of the FDA's role here.
The FDA does NOT just say: This drug is effective; it may not be safe, but it's effective. So we'll let it go to market, and just put lots of warnings in the prescribing information.
The FDA weighs the risk/benefit profile of drugs. That means it takes into account both efficacy AND safety when considering whether to approve new drugs, and whether to allow existing drugs to stay on the market. It doesn't just say: Okay, you're effective, here's your approval ... go get 'em tiger!
This applies just as well to cancer drugs as it does to other drugs. Just the past few months, the FDA advisory committee voted against approval of a new formulation of vincristine ... yes, vincristine, a cancer drug that has been on the market for ages. The FDA has not yet decided on the new drug application, but it has extended the time it wants to take to review the drug. (The proposed brand name for the drug is Marqibo.)
Also, the FDA and manufacturers discuss the design of trials BEFORE the trials are started, and the FDA gives the manufacturer feedback about proposed trials. This is particularly true for drugs like carfilzomib which are granted faster approval times and more consultations with the FDA.
On page 6 of the FDA's carflzomib briefing document, the FDA says that it gave the following feedback about the carfilzomib trial design before the trial started: "You have not addressed the availability of other drugs which have received regular approval for MM (multiple myeloma) such as melphalan and carmustine. Whether the results of a single arm trial will support accelerated approval will also depend on the magnitude of response, duration of response, and the risk-benefit assessment."
As for Onyx being some tiny minnow, new-kid-on-the-block company ... Onyx has a stock market value of $3 billion. It has a drug on the market -- Nexavar -- that was approved just two years after Velcade was approved, and now has global sales that are about two thirds those of Velcade. It also is just about to file a new drug application for another new drug.
In terms of what parts of the myeloma "market" are the most important, I believe I saw the information in a financial report related to either J&J, Celgene, or perhaps both. I remember it distinctly because it surprised me, but it made sense after I thought about the typical age of myeloma patients, the distribution of patients by risk, how long response to therapy usually lasts, and so on.
Hi Suzierose...thanks for your reply. I do feel fortunate to have had really effective treatment which I am sure helped me out a lot because it got the 'M' protein nos. down quickly. Of course, as you know, I went on to other treatments too, to 'consolidate' the whole kettle of fish, but I really thank the Velcade for taking me so much closer to good health again. I hope you have the same experience with the carfilzomib treatments...I am pretty sure you would not 'consolidate' it with an ASCT, and hope it holds you on it's own! Best wishes to you too, and I really think that this debate is turning up a lot of information!
"The FDA does NOT just say: This drug is effective; it may not be safe, but it’s effective. So we’ll let it go to market, and just put lots of warnings in the prescribing information."
False.
That is precisely the purpose of labelling. ACCESSS is the goal, not denying therapy based on toxicity for incurable diseases. Let's be clear, we are talking incurable disesase.
Labelling does state the drug is effective. Now here are the safety precautions,you the physician get to use your medical expertise/judgement about use. Where are you deriving your understanding,? We are talking chemotherapy not any other disease drug therapy and when it comes to chemotherapy that is precisely what occurs. What the FDA does for the class of drugs for an incurable disease is different when it weighs risks vs benefits vs. an agent for diseases that are incurable. Get your facts straight. Focus on the therapeutic group. ACCESS is the key. Should we deny those patients dying, with no other option a choice?
The FDA does not discuss clinical trial designs BEFORE trials are designed. There are standard trial designs for phase I, II, and III.
The FDA has standard trial designs that any mfgr can refer to as recommended, those do not impact COMPLETED trials. Seeking fast track approval has nothing to do with trial design and everything to do with greater therapeutic impact. Carfilzomib was not granted fast track approval. What mfgrs do is look at trial designs that DID receive fast track approval. If you have data that shows otherwise, please share. The statement you provide is about fast track approal AFTER the data was submitted, not PrIOR! The data you provide was feedback AFTER the trials were presented for fast track approval.
What Onyx's stock value is, is irrelevant to the criteria I gave about new kid on the block. This is not a financial issue, unless you gamble on health a a commodity. You want to talk finance, go right ahead, my focus is access for those patients who need it!
You have provided no data to support your assertion that the NDMM is a bigger market than the relapsed market. Even your own statement "single failure therapy" included failed therapy.
Suzierose,
I'm happy to stick to the facts.
Fact #1: Carfilzomib's trial design was discussed with the FDA before the trial was started.
Here is the information about the carfilzomib Phase 2 study which is the basis for Onyx's new drug application:
http://clinicaltrials.gov/ct2/show/NCT00511238
The information states that the trial was started in August 2007
In its briefing document, http://goo.gl/844wx , the FDA staff states (p 6) that it provided feedback about the design of this trial at two meetings, one in an "End of Phase 1 (EOP1)" meeting in March 2007, and another in an "End of Phase 2 (EOP2)" meeting in November 2008. As the FDA staff explains:
"During the EOP1 and EOP2 meetings in, the FDA provided the following advice to the Applicant regarding their proposal to use a single arm Phase 2 study (Study 3) in heavily pre-treated patients with multiple myeloma to support a request for marketing application via the accelerated approval pathway:"
"The determination of what constitutes available therapy for a particular population is made at the time of the regulatory action on an NDA. You have not addressed the availability of other drugs which have received regular approval for MM (multiple myeloma) such as melphalan and carmustine. Whether the results of a single arm trial will support accelerated approval will also depend on the magnitude of response, duration of response, and the risk-benefit assessment."
Fact #2: The FDA cares about efficacy and safety when it comes to all drugs, including cancer drugs.
In some ways, this is self evident from the fact that the FDA is asking the advisory committee to address the question: "”Is the risk benefit assessment favorable for the use of carfilzomib". If it didn't care about the safety of the drug, all it would do is ask: "Is carfilzomib an effective treatment for ..."
But we get more concrete. The FDA just turned down the new drug application for Merck's bone cancer drug ridaforolimus:
http://www.reuters.com/article/2012/06/05/merck-results-idUSL3E8H5AQM20120605
If you go and read about it, specifically the data that was presented for it at the advisory committee meeting where it was reviewed, you'll find that it statistically demonstrated efficacy. But the FDA decided not to approve the drug because it (apparently) feels the efficacy was not clinically meaningful enough to justify the potential safety risks associated with the drug.
So efficacy is not the be all and end all for the FDA, even when it comes to cancer drugs.
I'm not saying that's the way it should be, but it's apparently the way it is.
On the subject of what part of the myeloma "market" is bigger, I already have said that I don't have the relevant data at my fingertips. But why is the burden of proof on me? You are the one who first suggested that "the big companies" are trying to keep Onyx from gaining access to the most lucrative segment of the myeloma "market".
And, along the way, please note that, when you made that argument, you were the first person to bring economics and finance into this discussion.
I have a feeling that what all this means is that Carfilzomib may be denied the fast track approval. That does not mean it will not be approved but will have to go through the standard route requiring more detailed phase 3 tests. That of course all takes years.
There have not been any new approved novel agents since Velcade and Revlimid were approved by the FDA some 7 to 8 years ago. I think as patients in the MM community that is disconcerting. We need more options and are frustrated at how long it takes to get new drugs on the market to fight this incurable disease.
Having said that I don't want the treatment to be worse than the disease. We need to know that he drug is both safe and effective given the likelyhood of its extreme cost and known side effects.
Ron
Hold on here folks! The tone and choice of nuance by both susierose and JimNY is antagonistic, accusatory, and basically unhelpful. It sounds to me like a pissing contest! We all need to live by the Golden Rule. May all be kind to each other! The FDA is an important agency, certainly not beyond financial influences and bias, but crucial in protecting the public as well as evaluating novel pharmacological therapies. The challenge and opportunity of MM and other serious illnesses is shared by all of the Beacon readers. We do not choose it, but we do choose how we respond to it.
May all beings be happy and content, may all beings be safe and free from harm, may all beings be healthy and strong, and may all beings live in ease, and be liberated. Take a deep breath and relax for true inspiration. That will help all of us. Thank you!
Jim,
I am not sure why but clearly you are taking umbrage at some perceived issue I have not raised. Perhaps, it is as simple as not understanding what the standard Phase I, II, and III FDA trial designs are? Please note that what you cut&pasted states the feedback was at the end of each phase. Again, that feedback is not designing a trial. It does provide guidance on what type of information the FDA could seek, not will seek, but could seek. Additionally, it is encompassed by my prior statement that the FDA has standard Phase I, II and III trial designs for drug approval. Secondly, it is standard for a second drug in a therapeutic class to show efficacy vs. the standard of care along with therapeutic/safety benefit over (if so) the first drug in the class, which the latter is typically viewed as being the prototype for the drug class. I'm not sure why you are so at odds with what is basically long standing and well known FDA drug approval processes. It also appears that the feedback from the FDA was about an accelerated approval vs normal approval process based on what you cut&pasted and therefore the feedback addresses what is typically provided in the normal review process. Not designing a trial.
At no time have I stated that the FDA does not care about safety and toxicity. What I have consistently and repeatedly stated is HOW they do so. And that is via the label. The FDA does not generally deny access to drug therapy when there are safety issues, based on a class effect, such as those raised here. Somehow you misconstrued that as them not caring and that is not what was stated. In order to put that in context, I provided additional examples of drugs with safety issues to demonstrate what generally occurs. Again nothing there about FDA overlooking safety issues. Additionally, I highlighted chemotherapy because it has some of the most severe and toxic safety issues of any drug class, and I hoped you would see that safety issues are not necessarily cause for denying FDA drug approval. Drugs with life threatening safety issues are approved and the cautions, warnings about using the drug are all placed in the label. Nothing there about what the FDA 'just letting drug go to market', but clear examples of what they actually do. Why you take issue with that I do not know. especially as I have clearly identified that as their role and stated several times I support that and explained how it is handled by FDA. It's not an efficacy issue.
Perhaps, this is as simple as your being unaware of how the FDA addresses safety issues even when they are life-threatening. Perhaps, you believe that putting warnings, precautions in the label is not sufficient and therefore somehow perceive that as overlooking the safety issues. That is not the case. My posts are saying HOW safety issues are addressed the majority of the time even when they are severe and life-threatening and the approval of the majority of chemotherapeutic drugs illustrates that most clearly. I certainly never said that efficacy was the be all and end all either, why you have a penchant to misconstrue I do not know.
My focus was on approving a drug that offers another therapeutic option for patients and HOW the FDA addresses issues of safety traditionally, that were raised here, by what they regulate go in the manufacturers label. O, that's right, I also cut&pasted bortezomib's label as well to factually support that.
Perhaps, you were alarmed at the safety issues personally and had an emotional response to those facts.
But nothing I said minimized the safety issues. Rather, I placed them in context of the other drug in the class and showed how that was typically handled by the FDA.
"But why is the burden of proof on me?"
Um, because you said it was completely untrue.
"you were the first person to bring economics and finance into this discussion."
Really, Jim..did you just go nanner nanner?
Guess Jan is right about the sound.
Look, the last 3 threads on carfilzomib raised economics and finance. Market share, finance and stock price speculation seem to go hand in hand with the approval process.
..bye Jim...
I'm hoping the FDA approves Carfilzomib. I'm almost half way through Onyx's Phase III clinical trial for relapsed patients who have had at least two other treatments, and it has worked well for me. Since being diagnosed with MM in the fall of 2008 I've been treated with thalidomide, velcade, and two bone marrow transplants (autologous). Each worked well initially but relapse followed a few months later. My initial response to Carfilzomib was not completely positive. I spent the first week of June and the first week of July 2011 hospitalized due to high fever. The dosages of carfilzomib and revlimid were both reduced by a third and I've had no problems since. Although I'm not in remission my M protein is below 100 and I'm feeling well with almost no side effects. I'm having monthly cardiac, liver tests to watch for complications and all have been negative. My only complaint is cramps caused by the dexamethasone I take every Thursday, but I'm getting control of that with extra calcium and magnesium. Carfilzomib has worked for me to this point and as one who may be running out of options i'm hoping this option is available for me and for others down the road. As mentioned earlier in this thread, not all treatments will work equally for all patients - this really goes without saying - we need all the options available. But we also need good science behind the treatments. It's a matter of life - death and quality of life. So far I've been very blessed to have carfilzomib as an option.
Hey guys,
Thank you very much for your deep analysis.
But for me the only point is:
"In regard to carfilzomib’s efficacy, the FDA reports that the overall response rate for the drug is approximately 22 percent. (for relapsed / refractory patients)." So is this adding something meaningful to our hope ?
On a slightly different track, I brought this up at my appointment yesterday, and asked if they'd been seeing similar concerns in the CRD trial I'm on for newly diagnosed patients. We brought up the information on the trial, and to date they've had no heart related issues attributable to the Carfilzomib. We speculated that perhaps the issues with relapsed patients may be that those patients tend to be older, and have already been subjected to previous lines of treatment that may have weekend their systems. We also discussed respiratory issues, and there are some moderate side effects noted, mostly dealing with shortness of breath.
Tiziano,
I have many times thought similarly to you. I see the reports of this drug or that drug showing promise in treating myeloma, then when I get into the article find that the repsone rates are in the 10-20% range and think "this shows promise?". But if you think about it, this indicates there's 1 out of 5 people that might otherwise have no option, so it meaingful to them. My problem is I (and probably most others) keep wanting to see new drugs coming out that are offering 80-90-100% response rates.
Kevin J
Regarding your "perhaps the issues with relapsed patients may be that those patients tend to be older", from a statistical point of view, I should relapse in a (median) time of 30 months (or a few more) that means about 50 yrs of age. So I'LL not be so old.
Moreover I wish you at least 10 years of good health(I think a very good result), BUT just looking at your nice picture of young man, I hope that, should you ever relapse, you could still be young and I hope you will not depend on Carfilzomib to deal with it. (I beg your pardon to virtually refer to you personally, it is just to make an example)...
Anyway the point for me is that we need smthing to face relapse, that is a common problem, not a special problem regarding a little group of elderly patients.
Hi Kevin!
One other thing that could be occuring regarding cardiotoxicity in the RR patients vs age is that the population includes patients who have received high dose chemotherapy as a prior treatment. HDT causes long lasting major organ damage which could have made these patients more susceptible to heart/liver/lung issues when on proteasome inhibitors.
This would also account for not seeing the cardiotoxicity/pulmonary issues in the NDMM population.
Suzierose,
How would you account for the results of this NIH study on blood cancer patients that used HDT?
"Most survivors beyond 5 years had an excellent performance status with no difference in physical and mental health and higher HRQL scores (P = .02) compared with population norms."
http://www.ncbi.nlm.nih.gov/pubmed/20302959
How would patients with long lasting major organ damage have a better health related quality of life (HRQL) than population norms?
Mark
Being a MM patient, I thought I had the inside tip on ONYXX and so I sold the stock at 42 on tuesday. Trading was stopped yesterday. Today it opened at 62. I've never been happy to lose money in the stock market but I'll take it!
I may be wrong, but if carfilzomib helps only 22% now, I would think it will be tried in different combinations with other therapies and be found to help more people. (cocktail theory)
Suzie--you sure harp against the stem cell transplants. My organs test out perfectly fine after two SCT's last year and two rounds of VDPACE. My two MM buddies had similar therapies and similar results as myself. Maybe HDT causes some organ damage to some of us, but I'd be willing to bet for most of us that is not true. (that's a rhetorical bet, on real bets I always lose)
Mark--you beat me to it. Thanks for link.
Hi Stan,
You write:
Suzie–you sure harp against the stem cell transplants.
Is that how you perceive it as 'harping' against cell transplants? SCT are not what I am critical of. I am critical of HDT. The fact that you believe that it is about SCT simply underscores that you think somehow that SCT is therapy. It is NOT. Each of the statements I made is about HDT. NOT stem cell transplants since those are not therapy but merely how the toxic life threatening outcome of HDT is managed.
Perhaps, I should say...Stan you sure are delusional about stem cell transplants being therapy and as a result you have failed to discern that being rescued with a SCT is the issue.cause you want to hold on to the wholly false belief that using a SCT to save you from dying when it is not.
you write:
My organs test out perfectly fine after two SCT’s last year and two rounds of VDPACE.
Long term organ damage is a common problem...due to HDT not SCT's. At some point perhaps you will understand that HDT is the therapy NOT the SCT. Additionally, the operative word is 'long-term' damage.
What that means, not to 'harp' is that the damage does not show up right away. You will find many studies in the forum that attest to that. Perhaps, those clinical outcomes will not come across as 'harping' but as the very real and factual outcomes due to HDT.
Every patient gets to decide what they choose. Don't let the 'harping' facts get in the way. Just be informed.
On another note, you likely would not have lost that money had you bet on the FDA doing what they traditionally do, and that is put the warnings and precautions in the label, vs. not approve the drug.
Hi Mark!
"Therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML) after high-dose chemotherapy (HD-CT) and autologous stem cell transplantation (ASCT) for malignant diseases have become an important problem. The actuarial risk has varied, but has often been high if compared to the risk after conventional therapy. Prior chemotherapy with large cumulative doses of alkylating agents is the most important risk factor."
http://bloodjournal.hematologylibrary.org/content/95/11/3273.long
https://docs.google.com/viewer?a=v&q=cache:x9Ji28h-QWgJ:www.biomedcentral.com/content/pdf/1471-2407-11-260.pdf+MDS+post+breast+cancer+therapy+incidence&hl=en&gl=us&pid=bl&srcid=ADGEEShjguOBh2xzPp_TEksuZHNhnzZE5-ct41eB-Ug4Kj7LTWIiqMVq1JTRQjNIy4Dny_0Maf3loW75GyzB9ax_ZEcURB9_S2atI_HQKFjYWs0SA-dbFXY0BPktSa9BzzYp_MamfEi5&sig=AHIEtbRWHH56ypbJQCQjw5zqu0s8uki-Ww
Secondary cancers post HDT with akylators and is real.
Hi Suzie,
If you look at other posts I've made in the past, you would know I feel it is important for patients to understand HDT is doing the work of the SCT. I've stated several times that the word "transplant" seems like a misnomer to me. It should be called a "rescue".
You are the most prolific writer on this website. And you obviously know a lot. Therefore your posts carry a lot of weight, especially to those newly diagnosed patients who are trying to figure out a plan.
So I cringe when I hear you opine on the toxicity of these treatments, as if those of us who choose HDT (I'd guess 90% of us), are not too wise. And I'd hate for that to influence new comers to choose the Steve Jobs approach to fighting cancer.
I apologize for using the word "harp".
Since you appeared to have known what the FDA was going to do, you could have made a bundle of money yesterday.
Oh, here I am again, online. My family has noted that the Beacon has become a bit of an 'obsession' for me, but it is a very interesting area of study, especially when your treatments have worked for you well, as mine have. I learn an awful lot from reading the info on this site. After awhile, I began to recognize people by their postings, and find out a bit about their personalities too! I checked again with my oncologist this week at my 3 month checkup to make sure I had no discernible chromosomal abnormalities that would make my 'journey' of treatments more difficult. I do not have those,and my myeloma is still 'inactive', so how lucky I am!! I have the greatest sympathy and I would hope empathy for those who may be on a rockier path that the one I have had to take. Like more than one friend told me 'You have been to hell and back!". Maybe it was the hair loss, maybe it was the fractures, whatever...they could see the struggle I had undergone, and they could also see how I got through it. But anyhow, we all have differing health profiles, and it is really all quite personal , and for some of us to share on line with others is mostly helpful I think. Of course people can get a little over wrought, or stressed out at times, during their treatments...that is normal. I think we have to be gentle in our approaches to others too!
BTW, I dabble in buying and selling stocks, a hobby i have had for maybe 15 years now. I could never find anyone here who dealt with pharmaceutical stocks...it's all oil and gas here. From reading the Beacon, I have learned a lot about the pharmaceuticals...the stock movements are even mentioned in the articles printed here by the Beacon journalists. So that has also been very interesting and even profitable sometimes! Thanks everyone! AND have a lovely weekend, and enjoy the summer too.
Hi Stan,
I feel that when it comes to MM therapy, all of the choices have toxic side effects, some more toxic than others. I will take a break, from all the 'safety concerns'.
I appreciate your feedback.
Risk vs benefits of therapy is all the gambling I can handle right now...I wish it was only money but its mortality.
Hi Everyone,
I have read all your comments. I just want to say that my husband went through a Stem-Cell Transplant 2005 after which he had many side effects. First he had to get all his blood levels back up, we were in the hospital for 3 weeks. When they gave my husband the book on side effects, one was death. Now I'm sure anyone can imagine how that would make one feel. But he went through it and recovered well. He was off treatment for two years. He relapsed and his Oncologist prescribed Velcade & Prednisone. He was doing well but he developed Neuropathy and was prescribed pills for it which helped him a little. Just last week he changed from Velcade by IV to injection in his stomach. So far he does not have as much pain by getting it this way and it's giving him less & less pain. I could go on & on but I must say thank God there is Research out there to keep giving us hope. It is a big hill to climb.
God bless us all
Ena Martin
Suzierose,
They say imitation is the sincerest form of flattery. You are now being quoted by myeloma patients on other blogs. Check out what "Southern Yankee" wrote in the comments section.
http://multiplemyelomablog.com/2012/06/transplant-timing-questions-continue-to-top-my-most-commonly-asked-question-list.html
Your influence is growing! I have seen people quote Nick from Nicks Myeloma Blog almost verbatim before in the Forum. I think you are now the 2nd most influential myeloma patient. I guess I will have to do a better job of convincing you that Allo transplants are a good thing so more patients will consider them!!!
Mark
Mark - You are correct as the language I used on Pat's blog was inspired by SR. To me "words mean things" and I think it's important that we describe procedures/treatments accurately and I applaud SR for her efforts in trying to make that happen.
--Steve
Hi Mark & Southern Yankee
Thank you so much for your positive feedback. I had no idea that I was having that type of influence. It was not a goal.
My only goal has been to make sure patients are informed. I am sorry and apologize to any who feel thta has made then feel their choices unwise. I do not feel any choice is unwise. I simply want to make sure patients are informed about the choices they make.
Your posts have made me willing to continue to contribute as I was doubting that my posts were helpful.
I knew they were opposing the prevailing view that SCT was therapy, but I believed that patients wanted to know what the true choice was that they were making. There are no good choices in MM but knowing what your choices means and WHAT you are choosing, to me, makes a difference.
I now know from Stan's feedback, folks do not see it as helpful.
I will do what we all hope our MM cells do...become quiescent.
I've always believed that knowledge is power....guess I was wrong.
Big thanks to you both!
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