FDA Adds More Heat to the Capsaicin Debate
By Dave R. February 25, 2012
(Look out for changes in policy since February 2012)
Internet links shown in these posts are designed to provide more detailed information if required.
It's a series of events that has become all too familiar to people living with HIV over the years. A promising drug or treatment emerges, either for HIV or an associated illness; the news spreads like wildfire across the Net and people become excited at the prospect of a breakthrough and finally getting some relief. However, the news that something's in the pipeline is just the beginning. Trials need to be organized that can take years to complete and then the drug has to go through assessments akin to the Inquisition before it can be approved.
Depending on your own drug standards authority; it will happen sooner in some countries than others but in the meantime, frustration and pressure will mount on all parties. It pretty much has to be that way and although the American FDA and other international drug approval bodies have made headline-grabbing mistakes in the past, that just makes them, rightly and understandably, even more cautious now.
In a country like the USA, where litigators are hiding behind the furniture, official judgement makers are never going to approve something without being as sure as is humanly possible that they're right. For that reason, they put a series of cast iron parameters in place for drug research and studies and the drug companies had better adhere to them or their product won't stand a chance of getting into the marketplace.
With all this going on in the background, the person with HIV-related problems is waiting and hoping that what they've read about as being the answer to one of their problems, will finally become available. When it doesn't and when it's turned down (especially if it's available in other countries!) he or she will understandably cry foul and mutter about discrimination and political unwillingness. It's not always as simple as that.
Capsaicin extracts, in the form of creams or patches, had been regarded as one of the three proven ways of effectively reducing neuropathic pain for people with HIV and a saturated patch designed to give up to three months relief was widely welcomed. The other proven methods are, strangely enough, smoked marijuana and an experimental and as yet not approved gene therapy, which may give you an idea of how difficult neuropathy is to treat.
More Information: "Cannabis/Cannabinoids/Neuropathic Pain (Part 1)."
However, the American FDA has just denied approval (Feb. 2009) for high-strength (8%) Capsaicin patches, produced by NeurogesX, under the name Qutenza for people living with HIV-related neuropathy, thus creating a significant amount of anger and disbelief amongst the community. The key words are"HIV-related," because these patches are approved for people with post-herpetic neuralgia which is also a form of neuropathy not uncommon amongst HIV patients. The sole patient representative on the FDA panel, Matt Sharp, has written a very informative and well-balanced article on what went on during that process.
More Information: "FDA Pain Patch Decision: Making a 'Sophie's Choice' With People's Lives."
Capsaicin, a derivative of chili peppers, has been used for centuries as a pain reliever in other cultures. The chemical that gives chillies their kick, works as an analgesic. It reduces a neurochemical called substance P, responsible for transmitting pain. The patches are designed to deliver enough capsaicin through the skin, to reduce nerve pain in humans.
For those who are not aware of Qutenza; clinical studies have shown that a single, 60-minute application of a high strength Qutenza patch, impregnated with 8% capsaicin, can provide three months relief from pain associated with post-herpetic neuralgia (PHN), the nerve pain that can occur after shingles. In the UK, the patches were launched in July 2010 for use with people with neuropathy, irrespective of their HIV status and in 2011, in Germany and Austria (Apr 10), and Poland and the Czech Republic (Jul 11) did the same. As early as May 2009, the drug was approved by the EMEA for retail distribution in the whole of the European Union. It makes you wonder what makes things safe in one country and not in another. In the meantime, the FDA in the States was asking for further evidence and further research facts.
More Information: UK Medicines Information: Capsaicin Patch.
However, in the last year, doubts have been appearing in studies and across the Internet, regarding the efficacy of capsaicin patches because of their shaky results in various trials and studies.
More Information: "Red Hot Chili Patches for Neuropathy -- Latest Results."
The issues seem fairly clear but they're unfortunately anything but and whilst it's easy to point the finger at the FDA for prolonging unnecessary suffering, the true fault may lie with the company itself, whose studies and trials may not have been compatible with FDA standards, thus limiting the room the FDA had for a positive outcome. Furthermore, if the FDA is upholding the strict standards required in any scientific trial or study program, we can hardly criticize them for doing what we hope they would do.
Let's look more closely at the details:
The San Francisco pharmaceutical company, NeurogesX submitted what is called an sNDA (supplemental new drug application) to the FDA, hoping to expand the range of patients for whom Qutenza might have beneficial effects. As mentioned previously, it is already approved for post-herpetic neuralgia patients but this approval would include HIV patients with neuropathic problems. It was seeking approval for a 30-minute application of the patch to treat HIV-PN pain. NeurogesX also requested a Priority Review Designation, which is given to drugs that offer major progressive advances in treatment, or provide a treatment that doesn't currently exist. Basically, it reduces the review process from 10 months to 6. This also means that the conditions for such an approval are probably more strictly controlled. As said before, a 60-minute treatment is currently approved for shingles type pain.
What Went Wrong at the FDA Hearing?
On Feb. 9, 2012, the FDA's Anesthetic and Analgesic Drug Products Advisory Committee met to consider NeurogesX's request and based on two major trials, concluded that:
"It would not be in the best interest of these patients for us to approve a product for which substantial evidence of efficacy has not been demonstrated, or one for which the benefits do not clearly outweigh the risks."
That may seem harsh considering the fact that Qutenza is approved for more or less the same condition but under another illness heading in the United States but the FDA could only work according to its own rules and procedures. Basically, the argument presented by NeurogesX just didn't seem strong enough. That said, from what I can gather, panelists were saying off the record that patients could buy the patch, off-label (being approved for shingles pain). By definition, doctors could also prescribe it but the catch is, as always, in the cost. Without approval from the federal body, nobody would get any insurance cover, or even public benefits, for an "off-label" medicine. You only need to look up the costs of these patches to realize that they're just beyond most people's means (and that includes those in work). Whether you see this as grossly unfair, or a question of double standards, it's difficult to hammer the FDA for just doing their job.
The FDA panelists just looked at the evidence that was presented to them and concluded that the effectiveness of the patch compared with non-use was just not proved and outcomes were not reached. They also weren't prepared to accept further company data which used different pain scales, which is hardly surprising if you consider how statistics can be manipulated. NeurogesX may have been wiser to present the full picture without having to request acceptance of post-hoc information and maybe they should have withdrawn the Priority Review designation in order to broaden the time scale and potential evidence base.
There were other problems with the NeurogesX trial designs. They used what they called "an active control" meaning a Qutenza patch with a lower dosage instead of a placebo. This is perhaps understandable when you consider that most drug trials involve the use of placebos to compare and contrast results. In the case of Capsaicin, that's practically impossible because a patient receiving a patch that didn't cause some pain or skin reaction, would immediately know it wasn't the real thing. Using a lower dose patch would provide the necessary redness on the skin and unpleasant burning sensations that capsaicin brings. The problem is that reaction to a lower dose capsaicin patch compared to a high dose version would be so variable that scientific comparisons could hardly be valid. Furthermore, they allowed their trial patients to continue using whatever analgesics and opiates they were taking, which would almost certainly also have an effect on subjective pain outcomes.
You could say that NeurogesX was taking the well-being of their study patients into consideration -- not many people would give up the only medication that lessens their pain, for a lengthy trial period to test another substance's effectiveness against the same pain and the results would be heavily biased by each individual's response. I don't know if NeurogesX could have done anything differently but if they want to convince an unsympathetic panel of a drug's value, they have to play by the accepted rules of trial studies. If not, they may have to spend more time finding another method which is totally objective and trustworthy.
Whether such methods are even possible in the case of neuropathy drugs I don't know. Capsaicin is not to be messed around with. There can be serious adverse reactions, including skin problems and rashes, or blisters, the pain which such a high dose can bring and high blood pressure. You can imagine why the normal placebo trialing will not work here but NeurogesX are surely the experts and should have developed a built-in, 100% verifiable and trustworthy testing system before presenting it to the FDA. Perhaps they imagined that because so many countries and territories had accepted the scientific and trial results as they were that the FDA would step in line. Poor judgement if that was the case!
The final flaw in their judgement may have been choosing to apply for approval of a 30-minute patch instead of the normal 60-minute one. It has to be said that the trials used both 60 and 30-minute versions and even a 90-minute patch (possibly very unpleasant). The decision to go for the 30-minute patch was possibly taken to reduce the capsaicin exposure for the patient but despite company claims to the contrary, the results failed to convince the FDA panel. Apart from that, if a 60-minute application is successfully used to treat post-herpetic neuralgia (shingles) and I'm no expert, why should advanced peripheral neuropathy in the feet, legs and hands require anything less?
More Information: "FDA Committee Rejects Capsaicin Patch for HIV Neuropathy Pain."
Internet links shown in these posts are designed to provide more detailed information if required.
It's a series of events that has become all too familiar to people living with HIV over the years. A promising drug or treatment emerges, either for HIV or an associated illness; the news spreads like wildfire across the Net and people become excited at the prospect of a breakthrough and finally getting some relief. However, the news that something's in the pipeline is just the beginning. Trials need to be organized that can take years to complete and then the drug has to go through assessments akin to the Inquisition before it can be approved.
Depending on your own drug standards authority; it will happen sooner in some countries than others but in the meantime, frustration and pressure will mount on all parties. It pretty much has to be that way and although the American FDA and other international drug approval bodies have made headline-grabbing mistakes in the past, that just makes them, rightly and understandably, even more cautious now.
In a country like the USA, where litigators are hiding behind the furniture, official judgement makers are never going to approve something without being as sure as is humanly possible that they're right. For that reason, they put a series of cast iron parameters in place for drug research and studies and the drug companies had better adhere to them or their product won't stand a chance of getting into the marketplace.
With all this going on in the background, the person with HIV-related problems is waiting and hoping that what they've read about as being the answer to one of their problems, will finally become available. When it doesn't and when it's turned down (especially if it's available in other countries!) he or she will understandably cry foul and mutter about discrimination and political unwillingness. It's not always as simple as that.
Capsaicin extracts, in the form of creams or patches, had been regarded as one of the three proven ways of effectively reducing neuropathic pain for people with HIV and a saturated patch designed to give up to three months relief was widely welcomed. The other proven methods are, strangely enough, smoked marijuana and an experimental and as yet not approved gene therapy, which may give you an idea of how difficult neuropathy is to treat.
More Information: "Cannabis/Cannabinoids/Neuropathic Pain (Part 1)."
However, the American FDA has just denied approval (Feb. 2009) for high-strength (8%) Capsaicin patches, produced by NeurogesX, under the name Qutenza for people living with HIV-related neuropathy, thus creating a significant amount of anger and disbelief amongst the community. The key words are"HIV-related," because these patches are approved for people with post-herpetic neuralgia which is also a form of neuropathy not uncommon amongst HIV patients. The sole patient representative on the FDA panel, Matt Sharp, has written a very informative and well-balanced article on what went on during that process.
More Information: "FDA Pain Patch Decision: Making a 'Sophie's Choice' With People's Lives."
Capsaicin, a derivative of chili peppers, has been used for centuries as a pain reliever in other cultures. The chemical that gives chillies their kick, works as an analgesic. It reduces a neurochemical called substance P, responsible for transmitting pain. The patches are designed to deliver enough capsaicin through the skin, to reduce nerve pain in humans.
For those who are not aware of Qutenza; clinical studies have shown that a single, 60-minute application of a high strength Qutenza patch, impregnated with 8% capsaicin, can provide three months relief from pain associated with post-herpetic neuralgia (PHN), the nerve pain that can occur after shingles. In the UK, the patches were launched in July 2010 for use with people with neuropathy, irrespective of their HIV status and in 2011, in Germany and Austria (Apr 10), and Poland and the Czech Republic (Jul 11) did the same. As early as May 2009, the drug was approved by the EMEA for retail distribution in the whole of the European Union. It makes you wonder what makes things safe in one country and not in another. In the meantime, the FDA in the States was asking for further evidence and further research facts.
More Information: UK Medicines Information: Capsaicin Patch.
However, in the last year, doubts have been appearing in studies and across the Internet, regarding the efficacy of capsaicin patches because of their shaky results in various trials and studies.
More Information: "Red Hot Chili Patches for Neuropathy -- Latest Results."
The issues seem fairly clear but they're unfortunately anything but and whilst it's easy to point the finger at the FDA for prolonging unnecessary suffering, the true fault may lie with the company itself, whose studies and trials may not have been compatible with FDA standards, thus limiting the room the FDA had for a positive outcome. Furthermore, if the FDA is upholding the strict standards required in any scientific trial or study program, we can hardly criticize them for doing what we hope they would do.
Let's look more closely at the details:
The San Francisco pharmaceutical company, NeurogesX submitted what is called an sNDA (supplemental new drug application) to the FDA, hoping to expand the range of patients for whom Qutenza might have beneficial effects. As mentioned previously, it is already approved for post-herpetic neuralgia patients but this approval would include HIV patients with neuropathic problems. It was seeking approval for a 30-minute application of the patch to treat HIV-PN pain. NeurogesX also requested a Priority Review Designation, which is given to drugs that offer major progressive advances in treatment, or provide a treatment that doesn't currently exist. Basically, it reduces the review process from 10 months to 6. This also means that the conditions for such an approval are probably more strictly controlled. As said before, a 60-minute treatment is currently approved for shingles type pain.
What Went Wrong at the FDA Hearing?
On Feb. 9, 2012, the FDA's Anesthetic and Analgesic Drug Products Advisory Committee met to consider NeurogesX's request and based on two major trials, concluded that:
"It would not be in the best interest of these patients for us to approve a product for which substantial evidence of efficacy has not been demonstrated, or one for which the benefits do not clearly outweigh the risks."
That may seem harsh considering the fact that Qutenza is approved for more or less the same condition but under another illness heading in the United States but the FDA could only work according to its own rules and procedures. Basically, the argument presented by NeurogesX just didn't seem strong enough. That said, from what I can gather, panelists were saying off the record that patients could buy the patch, off-label (being approved for shingles pain). By definition, doctors could also prescribe it but the catch is, as always, in the cost. Without approval from the federal body, nobody would get any insurance cover, or even public benefits, for an "off-label" medicine. You only need to look up the costs of these patches to realize that they're just beyond most people's means (and that includes those in work). Whether you see this as grossly unfair, or a question of double standards, it's difficult to hammer the FDA for just doing their job.
The FDA panelists just looked at the evidence that was presented to them and concluded that the effectiveness of the patch compared with non-use was just not proved and outcomes were not reached. They also weren't prepared to accept further company data which used different pain scales, which is hardly surprising if you consider how statistics can be manipulated. NeurogesX may have been wiser to present the full picture without having to request acceptance of post-hoc information and maybe they should have withdrawn the Priority Review designation in order to broaden the time scale and potential evidence base.
There were other problems with the NeurogesX trial designs. They used what they called "an active control" meaning a Qutenza patch with a lower dosage instead of a placebo. This is perhaps understandable when you consider that most drug trials involve the use of placebos to compare and contrast results. In the case of Capsaicin, that's practically impossible because a patient receiving a patch that didn't cause some pain or skin reaction, would immediately know it wasn't the real thing. Using a lower dose patch would provide the necessary redness on the skin and unpleasant burning sensations that capsaicin brings. The problem is that reaction to a lower dose capsaicin patch compared to a high dose version would be so variable that scientific comparisons could hardly be valid. Furthermore, they allowed their trial patients to continue using whatever analgesics and opiates they were taking, which would almost certainly also have an effect on subjective pain outcomes.
You could say that NeurogesX was taking the well-being of their study patients into consideration -- not many people would give up the only medication that lessens their pain, for a lengthy trial period to test another substance's effectiveness against the same pain and the results would be heavily biased by each individual's response. I don't know if NeurogesX could have done anything differently but if they want to convince an unsympathetic panel of a drug's value, they have to play by the accepted rules of trial studies. If not, they may have to spend more time finding another method which is totally objective and trustworthy.
Whether such methods are even possible in the case of neuropathy drugs I don't know. Capsaicin is not to be messed around with. There can be serious adverse reactions, including skin problems and rashes, or blisters, the pain which such a high dose can bring and high blood pressure. You can imagine why the normal placebo trialing will not work here but NeurogesX are surely the experts and should have developed a built-in, 100% verifiable and trustworthy testing system before presenting it to the FDA. Perhaps they imagined that because so many countries and territories had accepted the scientific and trial results as they were that the FDA would step in line. Poor judgement if that was the case!
The final flaw in their judgement may have been choosing to apply for approval of a 30-minute patch instead of the normal 60-minute one. It has to be said that the trials used both 60 and 30-minute versions and even a 90-minute patch (possibly very unpleasant). The decision to go for the 30-minute patch was possibly taken to reduce the capsaicin exposure for the patient but despite company claims to the contrary, the results failed to convince the FDA panel. Apart from that, if a 60-minute application is successfully used to treat post-herpetic neuralgia (shingles) and I'm no expert, why should advanced peripheral neuropathy in the feet, legs and hands require anything less?
More Information: "FDA Committee Rejects Capsaicin Patch for HIV Neuropathy Pain."
Conclusions
This is not the end of the matter. The full FDA may not follow the recommendations of the advisory committee but it more often than not does, so people with neuropathy problems shouldn't expect an early change of heart. Hopefully NeurogesX (Astellas Pharma in the rest of the world) will re-apply for official approval with more finely tuned arguments and the patch will become universally accepted. Decisions will then pass to the patient and the person living with HIV and neuropathy should consider their options carefully and talk to all the relevant specialists before embarking on this treatment.
The idea that one application lasting half an hour or an hour, can bring you three months of relief, is so attractive to people weighed down with pain, that it seems a no-brainer. However, it's not a pain-free process and has possible side effects. Anybody who has tried the capsaicin creams (which are much lower doses) will know what happens when a stray finger touches an eye, a nose, or the mouth -- agony! Rubber hospital strength gloves are essential for a cream application on the feet and even then it's difficult to avoid getting tiny amounts on your fingers. Imagine a patch much, much stronger and you will understand why the application needs to be carried out by a doctor or experienced nurse. Be also prepared for a period of pain for some time afterwards. You should also discuss with your doctor the doubts that are arising as to whether the test results are actually as good as they seem. An oasis looks beautiful in the desert but it still may be a mirage! Then again ... three months relief before the next treatment is necessary -- now that's something I'd sign up for!
This and other posts are based on my opinions and impressions of living with both neuropathy and HIV. Although I do my best to ensure that facts are accurate and evidence-based, that is no substitute for discussing your own treatment with your HIV specialist or neurologist. All comments are welcome.
http://www.thebody.com/content/65941/fda-adds-more-heat-to-the-capsaicin-debate.html
This is not the end of the matter. The full FDA may not follow the recommendations of the advisory committee but it more often than not does, so people with neuropathy problems shouldn't expect an early change of heart. Hopefully NeurogesX (Astellas Pharma in the rest of the world) will re-apply for official approval with more finely tuned arguments and the patch will become universally accepted. Decisions will then pass to the patient and the person living with HIV and neuropathy should consider their options carefully and talk to all the relevant specialists before embarking on this treatment.
The idea that one application lasting half an hour or an hour, can bring you three months of relief, is so attractive to people weighed down with pain, that it seems a no-brainer. However, it's not a pain-free process and has possible side effects. Anybody who has tried the capsaicin creams (which are much lower doses) will know what happens when a stray finger touches an eye, a nose, or the mouth -- agony! Rubber hospital strength gloves are essential for a cream application on the feet and even then it's difficult to avoid getting tiny amounts on your fingers. Imagine a patch much, much stronger and you will understand why the application needs to be carried out by a doctor or experienced nurse. Be also prepared for a period of pain for some time afterwards. You should also discuss with your doctor the doubts that are arising as to whether the test results are actually as good as they seem. An oasis looks beautiful in the desert but it still may be a mirage! Then again ... three months relief before the next treatment is necessary -- now that's something I'd sign up for!
This and other posts are based on my opinions and impressions of living with both neuropathy and HIV. Although I do my best to ensure that facts are accurate and evidence-based, that is no substitute for discussing your own treatment with your HIV specialist or neurologist. All comments are welcome.
http://www.thebody.com/content/65941/fda-adds-more-heat-to-the-capsaicin-debate.html
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