On March 29, an FDA advisory committee overwhelmingly determined that Provenge, Dendreon's immunotherapy directed against prostate cells following prostatectomy in advanced metastatic prostate cancer, is safe and has shown substantial evidence of efficacy, the two criteria Congress authorized the FDA to consider in approving drugs. It was therefore a surprise when the FDA announced on May 9 that it would require further proof of efficacy before approval, which may require waiting for clinical trial results that are 3 years away.
This is the first time in memory that the FDA has ever gone against a committee recommendation to approve a drug for a terminal condition. But most importantly, by forcing a delay of 3 more years to confirm something that already has a 99% chance of certainty, this decision will condemn tens of thousands of men to die earlier and unnecessary deaths. If it still insisted on further proof of efficacy, the FDA had the authority to allow marketing immediately with a postmarking commitment to complete the ongoing trial and revoke authorization if necessary, but the FDA did not pursue this possibility. This delay is therefore neither justified nor necessary.
To make the situation even more difficult to understand, there are plenty of cancer drugs in our armatarium that have never demonstrated a survival benefit, or even been tested in randomized controlled trials, prior to approval. Congress could not have possibly meant in establishing guidelines for the FDA that a drug that triples survival after 3 years, that has shown evidence of efficacy in 4 other trials, that has no side effects, and that is superior in all ways to existing drugs, should not be approved!
This (tragic, in my opinion) decision by the FDA may stem from problems in its organization or leadership. The FDA Commissioner, Dr. Andrew Von Eschenbach, said the FDA would be a bridge rather than a barrier to new therapies, and would attempt to get cancer drugs to patients as quickly as possible. In light of the decision to delay Provenge, Dr. Von Eschenback’s statements lack credibility. In addition, two doctors who had been on the advisory committee, despite having financial interests in companies developing more toxic competing therapies, waged an unusual campaign of disinformation against Provenge approval. That a few people can go outside of their predesignated roles at the FDA, hijack the Provenge approval process, and harm thousands of seriously ill patients would be a true travesty.
Sunday, May 13, 2007
FDA fails to think, applies wrong lessons to Provenge
Found this excellent comment at http://www1.investorvillage.com/smbd.asp?mb=971&pt=msg&mid=2125129
The FDA willingly, openly exposed themselves with this decision by employing a less than logical risk/reward model for terminally ill patients. When safety is a near given, the risk becomes almost non-existent. Hence, the reward becomes more practical in terms of application. And in this case for an even better reason - the therapy works and the patients are afflicted with late-stage disease.
The end-point criteria that has been at the crux of the argument would make much more sense for otc products, or safety insufficient therapies, etc. - Marginalizing the condition of advanced prostate cancer, by minimizing the condition with this given peer set, is where the disconnect of logic by the FDA exposes itself and shouts to the rooftops - "we aren't about what we say, we are about what we do, and that is providing chemo agents to this patient class, and chemo agents only." Remember what the response from Hussein was in regard to the patient advocate who asked for a novel alternative for pc patients? "You can have Taxotere."
Let's reverse the scenario of applying the same standards to chemotherapy as are exhibited by Provenge. That association, of course, would really undermine the objective of the chemo-cartel. First of all we know chemo is not "Safe." Secondly the end-point they are so in love with has a major downside as well. Poisoning the patient guarantees that a given tumor will also be forced to deal with poison. Yes, you are almost awarded an automatic outcome of delay in disease progression with the poison, but at the same time you unfortunately have compromised the patient's system/body in other serious regards. Where are the risk/reward leveraged from in that analysis of feasibility?
The cartel has rendered any therapy believed to be "Safe" as also ineffective, simply because the existing standard dictates you must inflict damage to the overall patient to have success with the disease. Any other concept will be regarded as substandard if the given therapy does not retain this denominator, thus no other approach is ever going to provide a parallel outcome, and there is no flexibility / means to incorporate deviation.
The outcome for chemotherapy is championed because a simple observation says "see the tumor is smaller. We know the patient is less healthy, but so is the tumor." We can understand that as an application, but suggesting not poisoning the patient doesn't make sense (with their logic). If the patient can't be poisoned then how can the mechanism be effective on tumor growth?" This is the small circle the cartel stayed well within until they were recently forced to expose their agenda for basic economical survival.
This approach, although a simple and convenient mindset, has allowed the cartel to avoid / forgo the concept that attacking the disease could actually originate in a different form, with a different mechanism and outcome AND methodology for assessing progress, for either patient or disease. The phenomenon of a different class of agent so close to threatening their ideals is what has forced the chemo-cartel into exposing themselves as they have the past month. They deployed their last line of defense even at the risk of exposing their protectionist agenda. I believe they felt that threatened by Provenge and subsequent related therapy. Their offering was simply... Immunotherapy does not work simply because those agents do not work like chemotherapeutic agents.
The FDA willingly, openly exposed themselves with this decision by employing a less than logical risk/reward model for terminally ill patients. When safety is a near given, the risk becomes almost non-existent. Hence, the reward becomes more practical in terms of application. And in this case for an even better reason - the therapy works and the patients are afflicted with late-stage disease.
The end-point criteria that has been at the crux of the argument would make much more sense for otc products, or safety insufficient therapies, etc. - Marginalizing the condition of advanced prostate cancer, by minimizing the condition with this given peer set, is where the disconnect of logic by the FDA exposes itself and shouts to the rooftops - "we aren't about what we say, we are about what we do, and that is providing chemo agents to this patient class, and chemo agents only." Remember what the response from Hussein was in regard to the patient advocate who asked for a novel alternative for pc patients? "You can have Taxotere."
Let's reverse the scenario of applying the same standards to chemotherapy as are exhibited by Provenge. That association, of course, would really undermine the objective of the chemo-cartel. First of all we know chemo is not "Safe." Secondly the end-point they are so in love with has a major downside as well. Poisoning the patient guarantees that a given tumor will also be forced to deal with poison. Yes, you are almost awarded an automatic outcome of delay in disease progression with the poison, but at the same time you unfortunately have compromised the patient's system/body in other serious regards. Where are the risk/reward leveraged from in that analysis of feasibility?
The cartel has rendered any therapy believed to be "Safe" as also ineffective, simply because the existing standard dictates you must inflict damage to the overall patient to have success with the disease. Any other concept will be regarded as substandard if the given therapy does not retain this denominator, thus no other approach is ever going to provide a parallel outcome, and there is no flexibility / means to incorporate deviation.
The outcome for chemotherapy is championed because a simple observation says "see the tumor is smaller. We know the patient is less healthy, but so is the tumor." We can understand that as an application, but suggesting not poisoning the patient doesn't make sense (with their logic). If the patient can't be poisoned then how can the mechanism be effective on tumor growth?" This is the small circle the cartel stayed well within until they were recently forced to expose their agenda for basic economical survival.
This approach, although a simple and convenient mindset, has allowed the cartel to avoid / forgo the concept that attacking the disease could actually originate in a different form, with a different mechanism and outcome AND methodology for assessing progress, for either patient or disease. The phenomenon of a different class of agent so close to threatening their ideals is what has forced the chemo-cartel into exposing themselves as they have the past month. They deployed their last line of defense even at the risk of exposing their protectionist agenda. I believe they felt that threatened by Provenge and subsequent related therapy. Their offering was simply... Immunotherapy does not work simply because those agents do not work like chemotherapeutic agents.
Saturday, May 5, 2007
Big Pharma vs. personalized medicine: Big is not necessarily better
I was at a local biotech conference today and there was a panel discussion on personalized medicine. The speakers, biotech execs and doctors, noted that while there was much interest and even current business from doctors, there has been very little interest in partnerships or acquisitions from Big Pharma. One of the speakers noted that Lipitor has some of the best evidence for clinical efficacy of drugs widely used in medicine, and yet its benefit of reducing risk of cardiovascular events from 3% to 2% still meant that 97% of patients experienced no actual benefit. Personalized medicine in its various forms aims to be more efficient than that. And surprise surprise, big pharma is not interested.
That got me thinking about trial sizes. I think in recent years there has been some expectation inflation, or expectation confusion, when it comes to trial sizes. We have gotten used to trial sizes of 1000-10000 patients run by big pharma companies testing drugs like Lipitor that are meant to be given to lots of people to provide benefits in low-frequency outcomes. When the effect is real, the p value can be very small. When there are few or no side effects in this large population, then everybody is happy, including the biostatisticians, and the drug gets approved. However, a large trial is not an inherent good in and of itself. In fact large trials should be seen as necessary evils, if they end up taking up more time and money than a smaller one. If you were throwing a Japanese-themed dinner party, for example, would you spend the time and money to make twice the amount of sushi you think you need to be 95% sure nobody is left out, or would you make 10 times the amount, just in case the Japanese national sumo team happens to show up?
Much has been made of the fact that trials for Provenge and other immunotherapies have been small. However, not one of the critics who have raised this issue in public (e.g. oncologist Howard Scher and biostatistician Thomas Fleming), seem to have thought about if the benefit of more trials outweigh their harms. They seem to be misapplying anachronistic guidelines suitable for non-customized drugs with small therapeutic windows, e.g. chemotherapy, to a different new situation of personalized medicine. But large trials and biostatistical purity are not requirements for FDA approval. Demonstration of substantial evidence of efficacy is the requirement, and there are no written rules about how that is defined. Lately, large trials have been accepted as useful tools for most small molecule chemicals to arrive at that demonstration. However, if the indication is urgent and your drug is so good that you can see effects in a smaller number of patients, then that satisfies all the clinical and regulatory requirements for approval. That happened with rituximab, which was approved in 1997 on the basis of a 166-patient noncontrolled unblinded Phase II trial. It is happening now with Provenge, where the 3-year survival rate is tripled over placebo. Now larger trials may have gotten smaller p-values, and that's nice, but one has to ask if the intellectual satisfaction of being 99.9% certain vs. being 99% certain is worth delaying drug availability and putting more patients on placebos, which are real and irreversible harms inflicted to patients. Also, one can make the case that continued testing may reveal unexpected side effects, and this is a valid point for non-life-threatening conditions, but again you could take this argument to infinite extremes, and it's perhaps unnecessary to ask for multi-year safety data in a disease with a 1-year life expectancy.
That got me thinking about trial sizes. I think in recent years there has been some expectation inflation, or expectation confusion, when it comes to trial sizes. We have gotten used to trial sizes of 1000-10000 patients run by big pharma companies testing drugs like Lipitor that are meant to be given to lots of people to provide benefits in low-frequency outcomes. When the effect is real, the p value can be very small. When there are few or no side effects in this large population, then everybody is happy, including the biostatisticians, and the drug gets approved. However, a large trial is not an inherent good in and of itself. In fact large trials should be seen as necessary evils, if they end up taking up more time and money than a smaller one. If you were throwing a Japanese-themed dinner party, for example, would you spend the time and money to make twice the amount of sushi you think you need to be 95% sure nobody is left out, or would you make 10 times the amount, just in case the Japanese national sumo team happens to show up?
Much has been made of the fact that trials for Provenge and other immunotherapies have been small. However, not one of the critics who have raised this issue in public (e.g. oncologist Howard Scher and biostatistician Thomas Fleming), seem to have thought about if the benefit of more trials outweigh their harms. They seem to be misapplying anachronistic guidelines suitable for non-customized drugs with small therapeutic windows, e.g. chemotherapy, to a different new situation of personalized medicine. But large trials and biostatistical purity are not requirements for FDA approval. Demonstration of substantial evidence of efficacy is the requirement, and there are no written rules about how that is defined. Lately, large trials have been accepted as useful tools for most small molecule chemicals to arrive at that demonstration. However, if the indication is urgent and your drug is so good that you can see effects in a smaller number of patients, then that satisfies all the clinical and regulatory requirements for approval. That happened with rituximab, which was approved in 1997 on the basis of a 166-patient noncontrolled unblinded Phase II trial. It is happening now with Provenge, where the 3-year survival rate is tripled over placebo. Now larger trials may have gotten smaller p-values, and that's nice, but one has to ask if the intellectual satisfaction of being 99.9% certain vs. being 99% certain is worth delaying drug availability and putting more patients on placebos, which are real and irreversible harms inflicted to patients. Also, one can make the case that continued testing may reveal unexpected side effects, and this is a valid point for non-life-threatening conditions, but again you could take this argument to infinite extremes, and it's perhaps unnecessary to ask for multi-year safety data in a disease with a 1-year life expectancy.
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