"Over the past five years, the FDA approved sunitinib for the treatment of renal cell carcinoma (RCC) and certain types of pancreatic and gastrointestinal cancers. What the two authors found was a complete disconnect between reported incidences of cardiac toxicities in journal articles on one hand and the FDA’s drug labeling on the other. The labeling raised red flags, indicating that clinicians should be aware of the possible side effects of cardiac damage in patients using the drug. This was a very different picture from what had been presented in the journal articles. “It didn’t make any sense,” said Dr. Witteles. “The labeling warned of a high incidence of heart failure during the clinical trials that was not even mentioned in the journal articles.”
The authors said sunitinib is a good example of how the current method of measuring cardiac side effects during cancer drug trials is inadequate. Although the commentary focuses solely on sunitinib, the authors believe that studies of other cancer drugs have similar methodologic problems and are prone to the same underreporting of side effects."
details here:
http://www.clinicaloncology.com//ViewArticle.aspx?ses=ogst&d=Solid+Tumors&d_id=148&i=ISSUE%3a+June+2012&i_id=859&a_id=21011
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7 posts
• Page 1 of 1
Re: Cardiotoxicity Underreported in Oncology Clinical Trials
Suzierose,
Could this be a problem of Doctors not using drugs for the purpose for which they are approved? For example, Revlimid is FDA approved for relapsed myeloma patients, it is not approved for Induction therapy and it is not approved for maintenance. As we know, it is routinely used for Induction and maintenance. I have also noticed in postings in forums, etc. that Doctors are not making their patients aware of common side effects of the drugs they prescribe. With myeloma therapy I would think we will see more side effects than studies showed because drugs like Revlimid are used for continuos therapy, not for the reason it is approved.
Mark
Could this be a problem of Doctors not using drugs for the purpose for which they are approved? For example, Revlimid is FDA approved for relapsed myeloma patients, it is not approved for Induction therapy and it is not approved for maintenance. As we know, it is routinely used for Induction and maintenance. I have also noticed in postings in forums, etc. that Doctors are not making their patients aware of common side effects of the drugs they prescribe. With myeloma therapy I would think we will see more side effects than studies showed because drugs like Revlimid are used for continuos therapy, not for the reason it is approved.
Mark
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Mark
Re: Cardiotoxicity Underreported in Oncology Clinical Trials
Mark, When you comment about drugs not being used for what they are approved for (is this called 'off label'), would it be safe to assume that some of the myeloma drugs which are firstly approved for relapsed patients, are at a lower standard of safety than those for 'first line' treatment? For example, Revlimid, and also in the upcoming approval process for carfilzomib, the first approval would be for use with relapsed patients. IMO, the use of drugs for maintenance, can overlap with 'relapse' use, since a CR is not always reached before 'maintenance' is begun. That gives oncologists a chance to use a drug that it wouldn't be literally approved for, but for which the condition is similar, if that makes sense. Depending on the country and the terms under which drugs are handled by health authorities, drugs only approved for 'relapse' would not necessarily be available for new patients.
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Nancy Shamanna - Name: Nancy Shamanna
- Who do you know with myeloma?: Self and others too
- When were you/they diagnosed?: July 2009
Re: Cardiotoxicity Underreported in Oncology Clinical Trials
Hi Mark!
While that could be an issue..it is really not the issue being raised in the article.
off label use is ok as long as the doctor is clear what side effects have been seen & reported. What is happening here, the article contends, is that the primary source for that information that doctors are trained to trust, peer -reviewed journals,, are underreporting side effects. Then when the FDA reviews the data and creates a label that DOES.clearly warn of the frequency &severity it is NoT the source that the doc uses & so they continue 2 be uninformed & wrongly believe they HAVE read the BeSt source. After all it is called the "manufacturer,'s " label.. the doc doesn't necessarily recall the FDA are THE safety & regulatory body & that IS their job to do precisely that..tell the data that could be withheld by mfgr's as it could reduce their revenue stream. Because docs may be less likely to prescribe when they weigh risk vs benefits or the time demands & cost necessary when use r not cost - effective due to measures necessary to manage severe or life threatening sside effects...(think $200K SCT due2toxic doses)
IOW 's docs don't necessarily see their peers as having a conflict of interest when they nitially report the data & updates from the trial, the peer is viewed as an unimpeachable source far moreso than ""mfgrs " label
Despite no one regulating what PAID researchers report.
Point. of fact, inddustry strives to underreport so as not to impede FDA approval
. However, mfgrscannot under report to FDA without risking significant monetary loss...unlike what is printed in. "peer-reviewed"journals. The journals though are AlSO mainly funded by industry via advertising ads for their products just as Industry pays for 90% of drug research in this country..it is lucrative2 be a prinicipal investigator but you are less likely to be retained if you r reporting side effects that reduce chance of approval. Note how even failing or minimimimally effective drugs are commented as " encouraging results " or "not compelling"
When u read trial writeups, those r code words for doubtfully effective & infective, respectively. Docs know that. Patients don't..
When u hear that from researchers or "expert " commmentary...just think ..hmmmm sounds like they r trying to put lipstick on a pig. Cause they are. It sounds nice to mfgrs still creates hope and its not a direct negative...enabling all continue to be on investigator list. Everyone is playing nice in the sandbox.
NIH does not have that conflict. And their data& trials are far more valued, highly regarded& may not appear in the more widely read prestigious medical journals initiall_ simply because there is no conflict of interest nor an outside group that was paid by pharma 2 write, edit, & perform the biostat analysis.
The bigger issue is ethics & how monetary issues impact what is reported from trials. And evenmore important the sources that docs trust most or are most likely to read given their time demands.
The rest of your post is on target. Most would agree that the more stringent criteria for a disease is efficacy in relapsed /refractory population. Such that "off label " use in NDMM pts would likely be more effective if anything.
..
While that could be an issue..it is really not the issue being raised in the article.
off label use is ok as long as the doctor is clear what side effects have been seen & reported. What is happening here, the article contends, is that the primary source for that information that doctors are trained to trust, peer -reviewed journals,, are underreporting side effects. Then when the FDA reviews the data and creates a label that DOES.clearly warn of the frequency &severity it is NoT the source that the doc uses & so they continue 2 be uninformed & wrongly believe they HAVE read the BeSt source. After all it is called the "manufacturer,'s " label.. the doc doesn't necessarily recall the FDA are THE safety & regulatory body & that IS their job to do precisely that..tell the data that could be withheld by mfgr's as it could reduce their revenue stream. Because docs may be less likely to prescribe when they weigh risk vs benefits or the time demands & cost necessary when use r not cost - effective due to measures necessary to manage severe or life threatening sside effects...(think $200K SCT due2toxic doses)
IOW 's docs don't necessarily see their peers as having a conflict of interest when they nitially report the data & updates from the trial, the peer is viewed as an unimpeachable source far moreso than ""mfgrs " label
Despite no one regulating what PAID researchers report.
Point. of fact, inddustry strives to underreport so as not to impede FDA approval
. However, mfgrscannot under report to FDA without risking significant monetary loss...unlike what is printed in. "peer-reviewed"journals. The journals though are AlSO mainly funded by industry via advertising ads for their products just as Industry pays for 90% of drug research in this country..it is lucrative2 be a prinicipal investigator but you are less likely to be retained if you r reporting side effects that reduce chance of approval. Note how even failing or minimimimally effective drugs are commented as " encouraging results " or "not compelling"
When u read trial writeups, those r code words for doubtfully effective & infective, respectively. Docs know that. Patients don't..
When u hear that from researchers or "expert " commmentary...just think ..hmmmm sounds like they r trying to put lipstick on a pig. Cause they are. It sounds nice to mfgrs still creates hope and its not a direct negative...enabling all continue to be on investigator list. Everyone is playing nice in the sandbox.
NIH does not have that conflict. And their data& trials are far more valued, highly regarded& may not appear in the more widely read prestigious medical journals initiall_ simply because there is no conflict of interest nor an outside group that was paid by pharma 2 write, edit, & perform the biostat analysis.
The bigger issue is ethics & how monetary issues impact what is reported from trials. And evenmore important the sources that docs trust most or are most likely to read given their time demands.
The rest of your post is on target. Most would agree that the more stringent criteria for a disease is efficacy in relapsed /refractory population. Such that "off label " use in NDMM pts would likely be more effective if anything.
..
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: Cardiotoxicity Underreported in Oncology Clinical Trials
Hi Mark
Oops scanned 2 fast didn't see all youu wrote on adverse events 's (AE)
Regarding AE warnings ...patients need to ask. Every person is responsible for what they consume. Doctors may tell patients but.may not so as to minimize the power of suggestion.which is why it is vitally important to be informed. Select a doctor that you trust & who is open & forthcoming when you have questions vs being omniscient.
Gaining FDA approval for drugs is costly. Thus off -label use is beneficial 2 patients&mfgrs. Off label use can result in mfgr learning where it is cost effective 2 do a trial and at same time patient gets effective therapy even when off -label while there is limited liability 2 docs or mfgr 4 off -label use. That is because when the regulation was passed it deferred to the expertise of medical opinion when it came to deciding whether the drug should be used for that particular patient or patient population based on the clinical expertise of the physicians. The vast majority of.chemotherapy is off -label use.
Regarding long term AE's.. Yes cummulative dosing can uncover AE 's not seen in clinical trials due to small patient populations as well as limited co -morbidities in trials.
However this is true for virtually all drugs even when given as indicated..because the goal of the trial design,again, is to limit /exclude variables that would impede FDA approval.
What this means in reality is that until the drug is in widespread use in diverse patient populations no one will know the true cummulative AE profile. This typically takes on average about 5 years & means label changes post-marketing by FDA should not be taken lightly & that is especially true if the change is less than 5 years as all AE reporting is completely voluntary.
ADverrse events like Leukemia & SPM post HDT are particularly good examples of this in both the allo & auto SCT populations due to long term effects of highly toxic doses (HDT) the actual therapy that precedes SCT rescue...
Oops scanned 2 fast didn't see all youu wrote on adverse events 's (AE)
Regarding AE warnings ...patients need to ask. Every person is responsible for what they consume. Doctors may tell patients but.may not so as to minimize the power of suggestion.which is why it is vitally important to be informed. Select a doctor that you trust & who is open & forthcoming when you have questions vs being omniscient.
Gaining FDA approval for drugs is costly. Thus off -label use is beneficial 2 patients&mfgrs. Off label use can result in mfgr learning where it is cost effective 2 do a trial and at same time patient gets effective therapy even when off -label while there is limited liability 2 docs or mfgr 4 off -label use. That is because when the regulation was passed it deferred to the expertise of medical opinion when it came to deciding whether the drug should be used for that particular patient or patient population based on the clinical expertise of the physicians. The vast majority of.chemotherapy is off -label use.
Regarding long term AE's.. Yes cummulative dosing can uncover AE 's not seen in clinical trials due to small patient populations as well as limited co -morbidities in trials.
However this is true for virtually all drugs even when given as indicated..because the goal of the trial design,again, is to limit /exclude variables that would impede FDA approval.
What this means in reality is that until the drug is in widespread use in diverse patient populations no one will know the true cummulative AE profile. This typically takes on average about 5 years & means label changes post-marketing by FDA should not be taken lightly & that is especially true if the change is less than 5 years as all AE reporting is completely voluntary.
ADverrse events like Leukemia & SPM post HDT are particularly good examples of this in both the allo & auto SCT populations due to long term effects of highly toxic doses (HDT) the actual therapy that precedes SCT rescue...
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: Cardiotoxicity Underreported in Oncology Clinical Trials
Nancy S,
Hope you are doing great today. I was really referring to the length of time patients (particularly here in the US) stay on therapy. For example, you used Revlimid for one year as maintenance. Most of the trials used to gain FDA approval used 8 cycles (months). If you had a major side effect that the studies did not report you would have a legitimate complaint since you used it for approximately the time period the studies used for FDA approval. I do not think the patients that stay on the drugs long term should complain if there are more side effects than the studies show since the drug is not being used for the time frame it is approved for use.
I just saw this long term study with patients that did not have access to novel agents. I thought this was rather encouraging since the novel agents should greatly improve this. This is a European study and the results are more encouraging than the MD Anderson study we were discussing in the other thread.
"Twenty three per cent of the patients undergoing up-front single or double ASCT without novel agents were alive after 10 years from start of treatment, with 25% of patients remaining relapse free. Attainment of CR+nCR was the leading independent variable predicting for long-term OS. Prolonged survival after relapse was a contributing factor to long-term OS."
https://www.eventure-online.com/eventure/publicAbstractView.do?id=194187&congressId=5650
Mark
Hope you are doing great today. I was really referring to the length of time patients (particularly here in the US) stay on therapy. For example, you used Revlimid for one year as maintenance. Most of the trials used to gain FDA approval used 8 cycles (months). If you had a major side effect that the studies did not report you would have a legitimate complaint since you used it for approximately the time period the studies used for FDA approval. I do not think the patients that stay on the drugs long term should complain if there are more side effects than the studies show since the drug is not being used for the time frame it is approved for use.
I just saw this long term study with patients that did not have access to novel agents. I thought this was rather encouraging since the novel agents should greatly improve this. This is a European study and the results are more encouraging than the MD Anderson study we were discussing in the other thread.
"Twenty three per cent of the patients undergoing up-front single or double ASCT without novel agents were alive after 10 years from start of treatment, with 25% of patients remaining relapse free. Attainment of CR+nCR was the leading independent variable predicting for long-term OS. Prolonged survival after relapse was a contributing factor to long-term OS."
https://www.eventure-online.com/eventure/publicAbstractView.do?id=194187&congressId=5650
Mark
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Mark
Re: Cardiotoxicity Underreported in Oncology Clinical Trials
Hi Mark, I am doing GREAT today. It doesn't get much better than having Father's Day, one of my daughter's birthdays and her upcoming wedding in two weeks. Thus you will have to excuse me if I am not focussing all that well on anything else (thinK MOB scene ... mother of the bride). I am so darn grateful to be here because whatever treatments I took ...can't even express it in words!!
ANyhow, I agree with you on the length of treatments, and I also wonder how it pans out if drugs are used 'off label'. I don't think that happens much in Canada, since our drugs are tightly controlled by Cancer Boards, although I did note the 'off label' use of sub-Q Velcade inBritish Columbia a few months back, in a post. Oh well, really I am just a patient, and not being actively treated right now either, so there is lots I don't know, that's for sure.
Have a great day, to all reading and Happy Father's Day to all of you Dads too!!
ANyhow, I agree with you on the length of treatments, and I also wonder how it pans out if drugs are used 'off label'. I don't think that happens much in Canada, since our drugs are tightly controlled by Cancer Boards, although I did note the 'off label' use of sub-Q Velcade inBritish Columbia a few months back, in a post. Oh well, really I am just a patient, and not being actively treated right now either, so there is lots I don't know, that's for sure.
Have a great day, to all reading and Happy Father's Day to all of you Dads too!!
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Nancy Shamanna - Name: Nancy Shamanna
- Who do you know with myeloma?: Self and others too
- When were you/they diagnosed?: July 2009
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