Guest guest Posted January 9, 2011 Report Share Posted January 9, 2011 There is a tendency evidenced in government to control what happens to paying for drugs, especially cancer drugs. There is a new effort by the head of Medicare ( Berwick) to limit coverage for cancer drugs. This is similar to the UK's 'NICE' which stands for National Institute for Clinical Excellence. It's charged with denying coverage for drugs based on expense. New drugs are often very expensive. Drug companies want to recoup the $800 million it takes to approve a drug, and they want to make as much money as they can while they hold the patent. The government wants to restrict coverage, to spare costs. This will be the overriding consideration from now on. If CAL-101 and other drugs fall by the wayside, that's just too bad. We Americans have been spoiled by a hands-off policy of drug approval. That's all changed now. Unless a drug is specifically approved for a disease, it might not be paid for. Off-label use may be going away for good. Sat Jan 1, 2011 11:16 am (PST) The problem is much more complicated than this. The FDA approvals are based primarily on not just benefit. The two criteria used are: 1)greater benefit than the currently approved therapies (requires head to head comparisons) 2)unmet medical need (nothing approved to compare with) The FDA has suggested that it will not allow any drugs to be further approved for CLL using the unmet medical need criteria. This is how alemtuzumab and ofatumumab have gained approval. Thus, a trial of drug X in patients who have disease that is refractory to fludarabine, bendamustine, alemtuzumab, and ofatumumab will not lead to approval. Even if this agent (like PCI-32765 or CAL-101) has a 90% rate of clinical benefit / response. Likewise, for some very unexplicable reason, the FDA will not allow multiple drugs to be approved at the same indication. There are 25 different anti-hypertensives and 10 different cholesterol lowering agents. They did not have to prove themselves better than the currently available therapies. Just that they were efficacious. Why not the same thing for oncology drugs? Why can we not just show CAL-101 benefit patients and get it approved? Additionally, the FDA will not approve an agent that is equally effective, but less toxic over the current standard of care. This would require a large study secondary to statistical reasons, but once done, would be a much easier means to approve these new agents. These are just two of the glaring issues where the FDA does not function in a manner that is in patients' best interests. People have been complaining or criticizing the pharmaceutical companies, physicians, etc., but all anyone wants is to get excellent agents to the market as quickly and safely as possible. A less burdensome system would also encourage more novel drug development. It could be a simple as once a drug shows efficacy and safety, that there be programs to allow physicians to use these agents in all patients while closely monitoring further data on safey and efficacy. Would it not be great if anyone who needed CAL-101 or PCI-32765 could get it from their local oncologist? I think this is a good opportunity to build a grassroots effort to change the way the FDA makes these decisions. Let us propose starting a campaign to address these inadequacies in drug development. This is something that CIG is very well situated to spearhead. Let me know your thoughts! Rick Furman, MD Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 10, 2011 Report Share Posted January 10, 2011 The process would not need a randomization between observation and treatment. These are agents that are demonstrating remarkable effects in patients with refractory disease. What the FDA allows in such a situation would be overall survival data, but this would hopefully be a study that would last for years and years. What we need is a change in the response criteria for biologics. This is something that is in the works. Rick Furman, MD > > > > > > > > > > There is a tendency evidenced in government to control what happens > > to paying for drugs, especially cancer drugs. > > > > > > > > > > There is a new effort by the head of Medicare ( Berwick) to > > limit coverage for cancer drugs. This is similar to the UK's 'NICE' which > > stands for National Institute for Clinical Excellence. It's charged with > > denying coverage for drugs based on expense. > > > > > > > > > > New drugs are often very expensive. Drug companies want to recoup > > the $800 million it takes to approve a drug, and they want to make as much > > money as they can while they hold the patent. > > > > > > > > > > The government wants to restrict coverage, to spare costs. > > > > > > > > > > This will be the overriding consideration from now on. > > > > > > > > > > If CAL-101 and other drugs fall by the wayside, that's just too bad. > > > > > > > > > > > > We Americans have been spoiled by a hands-off policy of drug > > approval. That's all changed now. > > > > > > > > > > Unless a drug is specifically approved for a disease, it might not > > be paid for. Off-label use may be going away for good. > > > > > > > > > > > > > > > > > > > > > > > > > Sat Jan 1, 2011 11:16 am (PST) > > > > > > > > > > > > > > > The problem is much more complicated than this. The FDA approvals > > are based primarily on not just benefit. The two criteria used are: > > > > > > > > > > 1)greater benefit than the currently approved therapies (requires > > head to head comparisons) > > > > > > > > > > 2)unmet medical need (nothing approved to compare with) > > > > > > > > > > > > > > > > > > > > The FDA has suggested that it will not allow any drugs to be further > > approved for CLL using the unmet medical need criteria. This is how > > alemtuzumab and ofatumumab have gained approval. Thus, a trial of drug X in > > patients who have disease that is refractory to fludarabine, bendamustine, > > alemtuzumab, and ofatumumab will not lead to approval. Even if this agent (like > > PCI-32765 or CAL-101) has a 90% rate of clinical benefit / response. > > > > > > > > > > > > > > > > > > > > Likewise, for some very unexplicable reason, the FDA will not allow > > multiple drugs to be approved at the same indication. There are 25 > > different anti-hypertensives and 10 different cholesterol lowering agents. They did > > not have to prove themselves better than the currently available > > therapies. Just that they were efficacious. Why not the same thing for oncology > > drugs? > > > > > > > > > > > > > > > > > > > > Why can we not just show CAL-101 benefit patients and get it > > approved? > > > > > > > > > > > > > > > > > > > > Additionally, the FDA will not approve an agent that is equally > > effective, but less toxic over the current standard of care. This would require > > a large study secondary to statistical reasons, but once done, would be a > > much easier means to approve these new agents. > > > > > > > > > > > > > > > > > > > > These are just two of the glaring issues where the FDA does not > > function in a manner that is in patients' best interests. People have been > > complaining or criticizing the pharmaceutical companies, physicians, etc., but > > all anyone wants is to get excellent agents to the market as quickly and > > safely as possible. A less burdensome system would also encourage more novel > > drug development. It could be a simple as once a drug shows efficacy and > > safety, that there be programs to allow physicians to use these agents in all > > patients while closely monitoring further data on safey and efficacy. Would > > it not be great if anyone who needed CAL-101 or PCI-32765 could get it > > from their local oncologist? > > > > > > > > > > > > > > > > > > > > I think this is a good opportunity to build a grassroots effort to > > change the way the FDA makes these decisions. Let us propose starting a > > campaign to address these inadequacies in drug development. This is something > > that CIG is very well situated to spearhead. Let me know your thoughts! > > > > > > > > > > > > > > > > > > > > Rick Furman, MD > > > > > > > > > > > > > > > > > > > > > > > > Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 10, 2011 Report Share Posted January 10, 2011 I see. (I didn't mean to suggest the example I provided was the only way.) Another approach might be to test it in a maintenance role following the same induction therapy - Chlorambucil followed by observation versus C followed by the study drug, again with PFS as the primary endpoint (perhaps submitted for accelerated approval based on predefined interim results with longer followup to resubmit for full approval if a survival advantage is proven. A design model for a drug that doesn't induce a standard type of response would be the idiotype vaccine trials for follicular. In that case the study agent was tested for its hoped-for ability to delay relapse. The study failed to show a benefit for vaccine, but the sponsor and FDA did reach agreement about the ability of such a design to win marketing approval if a benefit in PFS was found. I suppose if the chosen population is treatment-refractory CLL it would take less time to demonstrate that the study drug provides benefit based on PFS, but one challenge would be how you define refractory (to what drug and what degree) - particularly for a single arm study, you would have to have confidence about the natural course of the disease untreated -- to serve as a reliable historical control. (Perhaps for participants randomized to observation in such a trial, a cross over could be provided, to mitigate ethical concerns - assuming obervation is acceptable for this group if truly refractory to all standard therapies) Just some thoughts. Karl > > > > > > > > > > > > There is a tendency evidenced in government to control what happens > > > to paying for drugs, especially cancer drugs. > > > > > > > > > > > > There is a new effort by the head of Medicare ( Berwick) to > > > limit coverage for cancer drugs. This is similar to the UK's 'NICE' which > > > stands for National Institute for Clinical Excellence. It's charged with > > > denying coverage for drugs based on expense. > > > > > > > > > > > > New drugs are often very expensive. Drug companies want to recoup > > > the $800 million it takes to approve a drug, and they want to make as much > > > money as they can while they hold the patent. > > > > > > > > > > > > The government wants to restrict coverage, to spare costs. > > > > > > > > > > > > This will be the overriding consideration from now on. > > > > > > > > > > > > If CAL-101 and other drugs fall by the wayside, that's just too bad. > > > > > > > > > > > > > > > We Americans have been spoiled by a hands-off policy of drug > > > approval. That's all changed now. > > > > > > > > > > > > Unless a drug is specifically approved for a disease, it might not > > > be paid for. Off-label use may be going away for good. > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > Sat Jan 1, 2011 11:16 am (PST) > > > > > > > > > > > > > > > > > > The problem is much more complicated than this. The FDA approvals > > > are based primarily on not just benefit. The two criteria used are: > > > > > > > > > > > > 1)greater benefit than the currently approved therapies (requires > > > head to head comparisons) > > > > > > > > > > > > 2)unmet medical need (nothing approved to compare with) > > > > > > > > > > > > > > > > > > > > > > > > The FDA has suggested that it will not allow any drugs to be further > > > approved for CLL using the unmet medical need criteria. This is how > > > alemtuzumab and ofatumumab have gained approval. Thus, a trial of drug X in > > > patients who have disease that is refractory to fludarabine, bendamustine, > > > alemtuzumab, and ofatumumab will not lead to approval. Even if this agent (like > > > PCI-32765 or CAL-101) has a 90% rate of clinical benefit / response. > > > > > > > > > > > > > > > > > > > > > > > > Likewise, for some very unexplicable reason, the FDA will not allow > > > multiple drugs to be approved at the same indication. There are 25 > > > different anti-hypertensives and 10 different cholesterol lowering agents. They did > > > not have to prove themselves better than the currently available > > > therapies. Just that they were efficacious. Why not the same thing for oncology > > > drugs? > > > > > > > > > > > > > > > > > > > > > > > > Why can we not just show CAL-101 benefit patients and get it > > > approved? > > > > > > > > > > > > > > > > > > > > > > > > Additionally, the FDA will not approve an agent that is equally > > > effective, but less toxic over the current standard of care. This would require > > > a large study secondary to statistical reasons, but once done, would be a > > > much easier means to approve these new agents. > > > > > > > > > > > > > > > > > > > > > > > > These are just two of the glaring issues where the FDA does not > > > function in a manner that is in patients' best interests. People have been > > > complaining or criticizing the pharmaceutical companies, physicians, etc., but > > > all anyone wants is to get excellent agents to the market as quickly and > > > safely as possible. A less burdensome system would also encourage more novel > > > drug development. It could be a simple as once a drug shows efficacy and > > > safety, that there be programs to allow physicians to use these agents in all > > > patients while closely monitoring further data on safey and efficacy. Would > > > it not be great if anyone who needed CAL-101 or PCI-32765 could get it > > > from their local oncologist? > > > > > > > > > > > > > > > > > > > > > > > > I think this is a good opportunity to build a grassroots effort to > > > change the way the FDA makes these decisions. Let us propose starting a > > > campaign to address these inadequacies in drug development. This is something > > > that CIG is very well situated to spearhead. Let me know your thoughts! > > > > > > > > > > > > > > > > > > > > > > > > Rick Furman, MD > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 10, 2011 Report Share Posted January 10, 2011 These new agents are not yet for people who don't need treatment; they are being given to patients who have failed up-front treatment. These are patients who would be expected to die soon if given no treatment. A trial of the enzyme inhibitors versus observation would not be ethical in this group. Terry Hamblin In a message dated 10/01/2011 21:09:41 GMT Standard Time, karls@... writes: I see. Thank you. In that case, I believe the sponsor should focus on convening independent experts and patient representatives to discuss with FDA what trial design (endpoints, eligibility, response criteria, etc) are needed to demonstrate this kind of response and possible benefit to patients. Showing that a drug can delay (with minimal toxicity) time to progression, for example, could well be persuasive in a population not in need of treatment. I expect that such a study could ethically randomize to the agent versus observation in this setting, because no treatment is needed. A crossover could be allowed - for those who progress in the observation group. Could FDA approve for marketing based on such data? I truly expect so, but the decision (you don't know how persuasive until you test) would depend on the toxicities and the magnitude of the benefit - does it delay PFS for a few months or years ... with consideration of possible offsetting toxicities and hits on quality of life ... as you know (but for the benefit of those following the discussion). Anyhow, my concern is that a valid issue about trial design has somehow morphed into let's trash the FDA and do away with standards for evaluating new drugs. No? I feel strongly about this issue because I've spent the better part of the last 12 years following and sometimes participating in the review process and from that experence I have now much respect for the process, (which I didn't have going in - based on abundant misinformation about FDA on the internet.) For anyone deeply suspicious of the process I recommend that you read carefully the transcipts of any advisory committee review of a cancer drug ... you may disagree with a committee's decision, but I expect you will see that the process has integrity, that the issues are complex, and that patient protection is the primary concern. Karl > > > > > > > > There is a tendency evidenced in government to control what happens > to paying for drugs, especially cancer drugs. > > > > > > > > There is a new effort by the head of Medicare ( Berwick) to > limit coverage for cancer drugs. This is similar to the UK's 'NICE' which > stands for National Institute for Clinical Excellence. It's charged with > denying coverage for drugs based on expense. > > > > > > > > New drugs are often very expensive. Drug companies want to recoup > the $800 million it takes to approve a drug, and they want to make as much > money as they can while they hold the patent. > > > > > > > > The government wants to restrict coverage, to spare costs. > > > > > > > > This will be the overriding consideration from now on. > > > > > > > > If CAL-101 and other drugs fall by the wayside, that's just too bad. > > > > > > > > > We Americans have been spoiled by a hands-off policy of drug > approval. That's all changed now. > > > > > > > > Unless a drug is specifically approved for a disease, it might not > be paid for. Off-label use may be going away for good. > > > > > > > > > > > > > > > > > > > > Sat Jan 1, 2011 11:16 am (PST) > > > > > > > > > > > > The problem is much more complicated than this. The FDA approvals > are based primarily on not just benefit. The two criteria used are: > > > > > > > > 1)greater benefit than the currently approved therapies (requires > head to head comparisons) > > > > > > > > 2)unmet medical need (nothing approved to compare with) > > > > > > > > > > > > > > > > The FDA has suggested that it will not allow any drugs to be further > approved for CLL using the unmet medical need criteria. This is how > alemtuzumab and ofatumumab have gained approval. Thus, a trial of drug X in > patients who have disease that is refractory to fludarabine, bendamustine, > alemtuzumab, and ofatumumab will not lead to approval. Even if this agent (like > PCI-32765 or CAL-101) has a 90% rate of clinical benefit / response. > > > > > > > > > > > > > > > > Likewise, for some very unexplicable reason, the FDA will not allow > multiple drugs to be approved at the same indication. There are 25 > different anti-hypertensives and 10 different cholesterol lowering agents. They did > not have to prove themselves better than the currently available > therapies. Just that they were efficacious. Why not the same thing for oncology > drugs? > > > > > > > > > > > > > > > > Why can we not just show CAL-101 benefit patients and get it > approved? > > > > > > > > > > > > > > > > Additionally, the FDA will not approve an agent that is equally > effective, but less toxic over the current standard of care. This would require > a large study secondary to statistical reasons, but once done, would be a > much easier means to approve these new agents. > > > > > > > > > > > > > > > > These are just two of the glaring issues where the FDA does not > function in a manner that is in patients' best interests. People have been > complaining or criticizing the pharmaceutical companies, physicians, etc., but > all anyone wants is to get excellent agents to the market as quickly and > safely as possible. A less burdensome system would also encourage more novel > drug development. It could be a simple as once a drug shows efficacy and > safety, that there be programs to allow physicians to use these agents in all > patients while closely monitoring further data on safey and efficacy. Would > it not be great if anyone who needed CAL-101 or PCI-32765 could get it > from their local oncologist? > > > > > > > > > > > > > > > > I think this is a good opportunity to build a grassroots effort to > change the way the FDA makes these decisions. Let us propose starting a > campaign to address these inadequacies in drug development. This is something > that CIG is very well situated to spearhead. Let me know your thoughts! > > > > > > > > > > > > > > > > Rick Furman, MD > > > > > > > > > > > > > > > [Non-text portions of this message have been removed] > Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 10, 2011 Report Share Posted January 10, 2011 I am very interested in participating in creating a strong voice for more compassionate and commonsense drug approval policies. It seems that many organizations could get behind this effort, once a mission statement is created. I'm interested in learning more and doing more. Many thanks for your energy towards this! Marietta <snipped by moderator> > I think this is a good opportunity to build a grassroots effort to change the way the FDA makes these decisions. Let us propose starting a campaign to address these inadequacies in drug development. > > Rick Furman, MD Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 11, 2011 Report Share Posted January 11, 2011 To members: It is so hard to read this digest with all of the messages repeated! Can you please delete most of the previous message when you reply? Thank you. Marka Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 11, 2011 Report Share Posted January 11, 2011 Hi Terry, Agree that randomizing to observation has ethical concerns - I suppose the control could also be investigator choice. Again, my main point is the need to focus on trial designs and to have constructive conversations about that with FDA, involving independent experts. I provide examples mainly for observers to show there are many ways to reach the goal of proving a drug works, but it just can't be assumed it works based on mechanisms of action - and that is a good thing for patients, even if not obvious. I know that the previously untreated is an uncommon indication for testing new single agents - but there is some precedent for such design, such as the study of Rituxan at diagnosis, versus observation in newly diagnosed follicular lymphoma who do not need treatment. ....Here the endpoints were time to progression and the softer endpoint, time to first treatment. The intent was not for submission to FDA, but likely to influence clinical practice for an approved drug. It was not convincing result (yet) to many largely because of the toxicities and risks of rituxan when given regularly - and the unknown delayed impact (resistance to R) of regularly schedule R on response to subsequent therapy that typically include Rituxan. However, those issues may be less for the kinase inhibitors, when such agents are not yet part of effective standard protocols? A reason for a pilot studies in that population? ... I couldn't say. Cheers, Karl > > These new agents are not yet for people who don't need treatment; they are > being given to patients who have failed up-front treatment. These are > patients who would be expected to die soon if given no treatment. A trial of the > enzyme inhibitors versus observation would not be ethical in this group. > > Terry Hamblin > Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 16, 2011 Report Share Posted January 16, 2011 Marietta, Feel free to call me about your e-mail. Best after 8 PM Pacific time zone. 1-916-293-8839 Just ask for Leo. My best, Leo In a message dated 1/11/2011 12:42:08 A.M. Pacific Standard Time, mbrill100@... writes: I am very interested in participating in creating a strong voice for more compassionate and commonsense drug approval policies. It seems that many organizations could get behind this effort, once a mission statement is created. I'm interested in learning more and doing more. Many thanks for your energy towards this! Marietta <snipped by moderator> > I think this is a good opportunity to build a grassroots effort to change the way the FDA makes these decisions. Let us propose starting a campaign to address these inadequacies in drug development. > > Rick Furman, MD Quote Link to comment Share on other sites More sharing options...
Guest guest Posted April 21, 2011 Report Share Posted April 21, 2011 Ugh, Buist, ND fda It is not encouraging to me to see this come down in the FDA warning letters: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm251793.htmJudy Quote Link to comment Share on other sites More sharing options...
Guest guest Posted April 21, 2011 Report Share Posted April 21, 2011 Ugh is right! If "The Act" defines a drug as anything claiming to be a "cure, mitigation, treatment, or prevention of disease", even water fits that definition. Good grief. Jana On 4/21/2011 10:04 AM, ladybugsandbees wrote: Ugh, Buist, ND fda It is not encouraging to me to see this come down in the FDA warning letters: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm251793.htm Judy Quote Link to comment Share on other sites More sharing options...
Guest guest Posted April 21, 2011 Report Share Posted April 21, 2011 It is CODEX to the max. *sigh* Buist, ND fda It is not encouraging to me to see this come down in the FDA warning letters: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm251793.htmJudy Quote Link to comment Share on other sites More sharing options...
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