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Article on Clinical trials - any thoughts?
I had this posted on my journal at http://www.medhelp.org/user_journals/show/111724 - and thought perhaps some of you might want to join the conversation. I figure I would restart this one here where everyone would see it - L
I just read an article on why clinical trials in cancer drug studies fail to move forward - I wonder how much of the reluctance to participate by cancer patients is mirrored in MS or other life-altering diseases? The whole article can be read online at
http://www.nytimes.com/2009/08/03/health/research/03trials.html?pagewanted=1
I would be curious to hear what you think...........
I just read an article on why clinical trials in cancer drug studies fail to move forward - I wonder how much of the reluctance to participate by cancer patients is mirrored in MS or other life-altering diseases? The whole article can be read online at
http://www.nytimes.com/2009/08/03/health/research/03trials.html?pagewanted=1
I would be curious to hear what you think...........
Why antidepressants are no better than placebo
However, this Newsweek article (http://www.newsweek.com/id/232781) argues that the supposed benefits of even the approved antidepressants are dwarfed by the placebo effect.
Sharon Begley asks how the FDA could’ve approved such ineffective drugs. She answers that “the FDA requires two well-designed clinical trials showing a drug is more effective than a placebo. That's two, period—even if many more studies show no such effectiveness. And the size of the ‘more effective’ doesn't much matter, as long as it is statistically significant.” Makes you wonder about some of these MS drugs, such as Ampyra (http://industry.bnet.com/pharma/10006294/acorda-therapeutics-ms-drug-ampyra-could-stumble/), which may also have underwhelming effects.
There is a strong placebo response in a number of conditions, but not generally as high as with antidepressants (for example, the placebo effect for analgesics is around 50%). The placebo effect is not some wimpy thing; “the strength of the placebo response drives drug companies nuts, since it makes showing the superiority of a new drug much harder.” The placebo effect can also be more enduring that it’s often given credit for. Researchers concluded that “the widely held belief that the placebo response in depression is short-lived appears to be based largely on intuition and perhaps wishful thinking.” This makes me worry a little more about my own experience with CCSVI and balloons.
Interestingly, Jonah Lehrer (http://scienceblogs.com/cortex/2010/02/prozac.php) points out that even if antidepressants don’t work against depression, they may have other beneficial effects. Of Prozac, he notes that “scientists have found that the little blue pills modulate the neural pathways of plasticity, up-regulating trophic factors and neurogenesis. Because they make our mind more malleable - and help counter the toxic effects of stress - the drugs have potential implications far beyond the treatment of depression.” So maybe we should all be on Prozac to up our neuroplasticity?
Newsweek also has a nice chart showing some types of conditions that are responsive to placebos and some that are not: http://blog.newsweek.com/blogs/thehumancondition/archive/2010/02/01/the-limited-power-of-placebo.aspx The responsive conditions “tend to be conditions for which the body’s own biochemicals, such as opiates and dopamine, act as natural medications.”
Conditions helped by placebo include:
· Hypertension
· Pain
· Parkinson’s disease
· Psoriasis
· Rheumatoid arthritis
· Ulcers
Conditions not helped by placebo include:
· Atherosclerosis
· Cancer
· Growth-hormone deficiency
· High cholesterol
· Infertility
· Obsessive-compulsive disorder
I wonder where MS falls on this spectrum.
Are doctors misusing the placebo effect?
This Scientific American blog post (http://www.scientificamerican.com/blog/post.cfm?id=beyond-the-sugar-pill-are-doctors-m-2010-02-18) talks about how the context in which a drug is administered affects the power of the placebo effect. Researcher say that the placebo effect is “heavily dependent not just on the existence of possible treatment, but perhaps even more so on the environment in which it is administered.” I’m not sure how you’d ever control for this in trials. The researchers also ask how ethical it is for doctors to try to exploit the placebo effect without telling patients that that’s what they’re doing.
Well, I think I’ve babbled on long enough for today.
sho
However, this Newsweek article (http://www.newsweek.com/id/232781) argues that the supposed benefits of even the approved antidepressants are dwarfed by the placebo effect.
Sharon Begley asks how the FDA could’ve approved such ineffective drugs. She answers that “the FDA requires two well-designed clinical trials showing a drug is more effective than a placebo. That's two, period—even if many more studies show no such effectiveness. And the size of the ‘more effective’ doesn't much matter, as long as it is statistically significant.” Makes you wonder about some of these MS drugs, such as Ampyra (http://industry.bnet.com/pharma/10006294/acorda-therapeutics-ms-drug-ampyra-could-stumble/), which may also have underwhelming effects.
There is a strong placebo response in a number of conditions, but not generally as high as with antidepressants (for example, the placebo effect for analgesics is around 50%). The placebo effect is not some wimpy thing; “the strength of the placebo response drives drug companies nuts, since it makes showing the superiority of a new drug much harder.” The placebo effect can also be more enduring that it’s often given credit for. Researchers concluded that “the widely held belief that the placebo response in depression is short-lived appears to be based largely on intuition and perhaps wishful thinking.” This makes me worry a little more about my own experience with CCSVI and balloons.
Interestingly, Jonah Lehrer (http://scienceblogs.com/cortex/2010/02/prozac.php) points out that even if antidepressants don’t work against depression, they may have other beneficial effects. Of Prozac, he notes that “scientists have found that the little blue pills modulate the neural pathways of plasticity, up-regulating trophic factors and neurogenesis. Because they make our mind more malleable - and help counter the toxic effects of stress - the drugs have potential implications far beyond the treatment of depression.” So maybe we should all be on Prozac to up our neuroplasticity?
Newsweek also has a nice chart showing some types of conditions that are responsive to placebos and some that are not: http://blog.newsweek.com/blogs/thehumancondition/archive/2010/02/01/the-limited-power-of-placebo.aspx The responsive conditions “tend to be conditions for which the body’s own biochemicals, such as opiates and dopamine, act as natural medications.”
Conditions helped by placebo include:
· Hypertension
· Pain
· Parkinson’s disease
· Psoriasis
· Rheumatoid arthritis
· Ulcers
Conditions not helped by placebo include:
· Atherosclerosis
· Cancer
· Growth-hormone deficiency
· High cholesterol
· Infertility
· Obsessive-compulsive disorder
I wonder where MS falls on this spectrum.
Are doctors misusing the placebo effect?
This Scientific American blog post (http://www.scientificamerican.com/blog/post.cfm?id=beyond-the-sugar-pill-are-doctors-m-2010-02-18) talks about how the context in which a drug is administered affects the power of the placebo effect. Researcher say that the placebo effect is “heavily dependent not just on the existence of possible treatment, but perhaps even more so on the environment in which it is administered.” I’m not sure how you’d ever control for this in trials. The researchers also ask how ethical it is for doctors to try to exploit the placebo effect without telling patients that that’s what they’re doing.
Well, I think I’ve babbled on long enough for today.
sho
Well, I know this is an old thread, but since I’ve been thinking about this, I wanted to bring up a few more things about trials and the placebo effect that I think are interesting.
First, certainly many people can tell they’re on the real drug from the side effects (According to http://www.newsweek.com/id/232781/page/2, about 80% of people guess that they’re on the real drug from side effects and also that the worse the side effects are, the more effective the drug turns out to be. “Patients apparently think, this drug is so strong it's making me vomit and hate sex, so it must be strong enough to lift my depression.”). However, it turns out that people who are in the placebo arm also experience side effects, presumably based on suggestion (a variation of the nocebo effect). In trials they are legally obligated to give you a great big long list of possible side effects so people do have some idea what to expect. On the other hand, I was on the real drug in a trial where I couldn’t tell since the drug seemed to have no discernible effects one way or the other; I only know I was on the drug from a blood test. Maybe that’s why the stupid pill didn’t work?
Placebos are getting more effective
Wired has a fascinating article “Placebos Are Getting More Effective. Drugmakers Are Desperate to Know Why” at http://www.wired.com/medtech/drugs/magazine/17-09/ff_placebo_effect “It's not that the old meds are getting weaker, drug developers say. It's as if the placebo effect is somehow getting stronger.”
I thought this story was fascinating: “The roots of the placebo problem can be traced to a lie told by an Army nurse during World War II as Allied forces stormed the beaches of southern Italy. The nurse was assisting an anesthetist named Henry Beecher, who was tending to US troops under heavy German bombardment. When the morphine supply ran low, the nurse assured a wounded soldier that he was getting a shot of potent painkiller, though her syringe contained only salt water. Amazingly, the bogus injection relieved the soldier's agony and prevented the onset of shock.” This led to more rigorous drug testing to try to eliminate the influence of the patient’s expectations on outcomes and the double-blind, placebo-controlled, randomized clinical trial became the gold standard.
The article says that treatments that affect the central nervous system (although here I think they’re talking more about things like antidepressants) are particularly susceptible to the placebo effect. Researchers also found that the geographic location of the trial had a significant effect (for example, some drugs passed muster in Europe but failed in the U.S., which they attribute to cultural differences in the placebo effect) and also that trial observers’ ratings of improvement were not consistent from site to site (which I can see happening easily enough with MS, too; not to mention the influence of the time of day and other factors not usually kept track of). However, there still found some kind of inexplicable “runaway placebo effects.”
For years, the placebo effect was seen only as an obstacle in drug trials or as a psychological sign of weakness and vulnerability rather than as something to be leveraged. However, some researchers have taken a more positive interest in the placebo. The researcher Fabrizio Benedetti has “succeeded in mapping many of the biochemical reactions responsible for the placebo effect, uncovering a broad repertoire of self-healing responses. Placebo-activated opioids, for example, not only relieve pain; they also modulate heart rate and respiration. The neurotransmitter dopamine, when released by placebo treatment, helps improve motor function in Parkinson's patients. Mechanisms like these can elevate mood, sharpen cognitive ability, alleviate digestive disorders, relieve insomnia, and limit the secretion of stress-related hormones like insulin and cortisol.”
The article describes an interesting experiment that compared three groups of people with IBS: one on a waiting list, one who got a sham treatment from a disinterested doctor who made no small talk, and one who got a sham treatment from a doctor who asked questions about their symptoms and was informative and optimistic. The people in this third group did as well as people on the two leading prescription drugs for IBS and the effects lasted for weeks. This suggests that we’d all be better off if more neuros had a good bedside manner and really listened, even if the MS drugs don’t get any better.
The article speculates on reasons for the increase in the effectiveness of placebos. One candidate is the success of big pharma’s direct-to-consumer advertising campaigns.
Placebos can’t do everything and have a bigger effect on some problems than others. “What all of these disorders [depression, social anxiety, etc.] have in common, however, is that they engage the higher cortical centers that generate beliefs and expectations, interpret social cues, and anticipate rewards. So do chronic pain, sexual dysfunction, Parkinson's, and many other ailments that respond robustly to placebo treatment.”
(to be continued)
First, certainly many people can tell they’re on the real drug from the side effects (According to http://www.newsweek.com/id/232781/page/2, about 80% of people guess that they’re on the real drug from side effects and also that the worse the side effects are, the more effective the drug turns out to be. “Patients apparently think, this drug is so strong it's making me vomit and hate sex, so it must be strong enough to lift my depression.”). However, it turns out that people who are in the placebo arm also experience side effects, presumably based on suggestion (a variation of the nocebo effect). In trials they are legally obligated to give you a great big long list of possible side effects so people do have some idea what to expect. On the other hand, I was on the real drug in a trial where I couldn’t tell since the drug seemed to have no discernible effects one way or the other; I only know I was on the drug from a blood test. Maybe that’s why the stupid pill didn’t work?
Placebos are getting more effective
Wired has a fascinating article “Placebos Are Getting More Effective. Drugmakers Are Desperate to Know Why” at http://www.wired.com/medtech/drugs/magazine/17-09/ff_placebo_effect “It's not that the old meds are getting weaker, drug developers say. It's as if the placebo effect is somehow getting stronger.”
I thought this story was fascinating: “The roots of the placebo problem can be traced to a lie told by an Army nurse during World War II as Allied forces stormed the beaches of southern Italy. The nurse was assisting an anesthetist named Henry Beecher, who was tending to US troops under heavy German bombardment. When the morphine supply ran low, the nurse assured a wounded soldier that he was getting a shot of potent painkiller, though her syringe contained only salt water. Amazingly, the bogus injection relieved the soldier's agony and prevented the onset of shock.” This led to more rigorous drug testing to try to eliminate the influence of the patient’s expectations on outcomes and the double-blind, placebo-controlled, randomized clinical trial became the gold standard.
The article says that treatments that affect the central nervous system (although here I think they’re talking more about things like antidepressants) are particularly susceptible to the placebo effect. Researchers also found that the geographic location of the trial had a significant effect (for example, some drugs passed muster in Europe but failed in the U.S., which they attribute to cultural differences in the placebo effect) and also that trial observers’ ratings of improvement were not consistent from site to site (which I can see happening easily enough with MS, too; not to mention the influence of the time of day and other factors not usually kept track of). However, there still found some kind of inexplicable “runaway placebo effects.”
For years, the placebo effect was seen only as an obstacle in drug trials or as a psychological sign of weakness and vulnerability rather than as something to be leveraged. However, some researchers have taken a more positive interest in the placebo. The researcher Fabrizio Benedetti has “succeeded in mapping many of the biochemical reactions responsible for the placebo effect, uncovering a broad repertoire of self-healing responses. Placebo-activated opioids, for example, not only relieve pain; they also modulate heart rate and respiration. The neurotransmitter dopamine, when released by placebo treatment, helps improve motor function in Parkinson's patients. Mechanisms like these can elevate mood, sharpen cognitive ability, alleviate digestive disorders, relieve insomnia, and limit the secretion of stress-related hormones like insulin and cortisol.”
The article describes an interesting experiment that compared three groups of people with IBS: one on a waiting list, one who got a sham treatment from a disinterested doctor who made no small talk, and one who got a sham treatment from a doctor who asked questions about their symptoms and was informative and optimistic. The people in this third group did as well as people on the two leading prescription drugs for IBS and the effects lasted for weeks. This suggests that we’d all be better off if more neuros had a good bedside manner and really listened, even if the MS drugs don’t get any better.
The article speculates on reasons for the increase in the effectiveness of placebos. One candidate is the success of big pharma’s direct-to-consumer advertising campaigns.
Placebos can’t do everything and have a bigger effect on some problems than others. “What all of these disorders [depression, social anxiety, etc.] have in common, however, is that they engage the higher cortical centers that generate beliefs and expectations, interpret social cues, and anticipate rewards. So do chronic pain, sexual dysfunction, Parkinson's, and many other ailments that respond robustly to placebo treatment.”
(to be continued)
thanks for clearing up my misunderstanding on the adaptive arms - you are great with the explanations.
L
L
Lulu: I'm glad you found the post helpful. So far as I understand it, with the adaptive trials they don't actually change the dosage for individual patients midstream. Rather, they adapt the arms that new patients are put in. For example, in the trial I'm in, 1/3 get placebo, 1/3 get 0.5 mg, and 1/3 get 1.25 mg. They have to decide that upfront and stick with it all the way through, even if someone looking at the unblinded data partway through would know that one of the arms had serious drawbacks. In the adaptive trials, they can shift the percentages or start new arms based on partial data and still end up with statistically sound data at the end.
Patientx: Thanks for your perspective. I'm sorry your experiences with care in clinical trials seem to mirror mine. I don't think anyone is really interested in the continual progression I report, which is frustrating. Not, I guess, that they can do anything. I supposes it's just like regular neuros--the quality of trial set-ups varies.
sho
Patientx: Thanks for your perspective. I'm sorry your experiences with care in clinical trials seem to mirror mine. I don't think anyone is really interested in the continual progression I report, which is frustrating. Not, I guess, that they can do anything. I supposes it's just like regular neuros--the quality of trial set-ups varies.
sho
Your post was very insightful, and you raised some points I had meant to go back and comment on myself (just never got around to it).
As to the question of having placebo arms - I'm of the belief that trials should use an active comparator, rather than placebo. This is what initially scared me away from joining one of the pill trials. Right after I was diagnosed, I decided to do some kind of trial, but everything I read said to get on a DMD as quickly as possible. So, I narrowed it down to trials that had no pure placebo arm. If FTY or BG12 used did not compare to a placebo, I would definitely considered them (though, if I knew then what I know now, I might have chosen differently). You raise an interesting point about placebo-arm trials taking less time and requiring fewer participants. I was always of the opinion that drug makers used placebos instead of a DMD so they could make their drug look better. But even if the reason is that a difference would be harder to see, maybe this is reason enough not to pursue that particular drug. We should get beyond small, incremental advances.
I'm glad that you mentioned the supposed better care that you receive being in a trial. Your experience is similar to mine. I never see the neuro running the trial, and when I go in for my visits, I am always rushed. The examining neuro (different from the study head since it's a blinded trial), seems to have the goal of getting through my exam as quickly as possible. Forget about getting all my questions answered. Now, I have seen accounts by others in clinical trials, and their experiences are completely different. They are never rushed, the neuros take time and sit down with them, and the study head will check in. I guess some of it depends on the study location. And you wrote "to deal with what seems to me to be ongoing progression which never seems to warrant being called a relapse." I feel exactly the same way. When I feel what seems to be a relapse going on, I will call the MS center, both because I'm not feeling well, and I am supposed to report relapses as part of the study. I usually get the feeling that they're not real interested in this reporting. I usually get some answer like, well that's what MS does. Not once have they asked for me to come in for an exam.
As to the question of having placebo arms - I'm of the belief that trials should use an active comparator, rather than placebo. This is what initially scared me away from joining one of the pill trials. Right after I was diagnosed, I decided to do some kind of trial, but everything I read said to get on a DMD as quickly as possible. So, I narrowed it down to trials that had no pure placebo arm. If FTY or BG12 used did not compare to a placebo, I would definitely considered them (though, if I knew then what I know now, I might have chosen differently). You raise an interesting point about placebo-arm trials taking less time and requiring fewer participants. I was always of the opinion that drug makers used placebos instead of a DMD so they could make their drug look better. But even if the reason is that a difference would be harder to see, maybe this is reason enough not to pursue that particular drug. We should get beyond small, incremental advances.
I'm glad that you mentioned the supposed better care that you receive being in a trial. Your experience is similar to mine. I never see the neuro running the trial, and when I go in for my visits, I am always rushed. The examining neuro (different from the study head since it's a blinded trial), seems to have the goal of getting through my exam as quickly as possible. Forget about getting all my questions answered. Now, I have seen accounts by others in clinical trials, and their experiences are completely different. They are never rushed, the neuros take time and sit down with them, and the study head will check in. I guess some of it depends on the study location. And you wrote "to deal with what seems to me to be ongoing progression which never seems to warrant being called a relapse." I feel exactly the same way. When I feel what seems to be a relapse going on, I will call the MS center, both because I'm not feeling well, and I am supposed to report relapses as part of the study. I usually get the feeling that they're not real interested in this reporting. I usually get some answer like, well that's what MS does. Not once have they asked for me to come in for an exam.
Also, another point that you made that jumped out at me was about the inclusion of some many men versus women... It has taken a long time for us to understand that women and men are different in how they react to disease and even longer for the designers of studies to adjust to this difference.
The standards that define coronary events and care were set through trials and studies back in the 50's or so and all of those tests were done on men. It has taken decades for the medical world to recognize that women present with cardiac symptoms in a totally different way....
The standards that define coronary events and care were set through trials and studies back in the 50's or so and all of those tests were done on men. It has taken decades for the medical world to recognize that women present with cardiac symptoms in a totally different way....
Sho,
thanks so much for the thought and effort that went into your response. You obviously have studied the workings of clinical trials in depth and your post here would make a great health page.
I was not aware of the adaptive clinical trial idea and find that one quite interesting - I can understand the need to adapt as the trial proceeds. As they are designed now, once you start on a trial, you stay with the same regimen (unless you opt out).
Clinical trials are so important for us to progress in this search for answers - thanks to you Sho, for being one who is giving of your time, resources and body for this process.
I hope others will join in this important conversation about trials. We all want new options, and need to understand what it takes to get to that point.
be well,
L
thanks so much for the thought and effort that went into your response. You obviously have studied the workings of clinical trials in depth and your post here would make a great health page.
I was not aware of the adaptive clinical trial idea and find that one quite interesting - I can understand the need to adapt as the trial proceeds. As they are designed now, once you start on a trial, you stay with the same regimen (unless you opt out).
Clinical trials are so important for us to progress in this search for answers - thanks to you Sho, for being one who is giving of your time, resources and body for this process.
I hope others will join in this important conversation about trials. We all want new options, and need to understand what it takes to get to that point.
be well,
L
Well, once again I'm too long-winded and I seem to have exceed the character limit, but here the rest of my post...
I was also interested in the end bit where they talk about redesigning a breast cancer trial so they can get results more quickly. A huge problem for MS trials is that due to the slow, heterogeneous course of the disease, large, expensive trials that last for a long time are necessary to get reliable results. The lack of biomarkers for MS is also an enormous obstacle for trials. I have recently been reading some interesting things on “adaptive” clinical trial design where they don’t spell everything out in advance, but instead adapt as they get results going through the trial (See http://pharmexec.findpharma.com/pharmexec/article/articleDetail.jsp?id=352793). These trials are very complicated mathematically. They also assume that you can get results fast enough to adapt and I don’t know how possible that is with the current state of MS research. At the big pharma MS talk, the neuro also mentioned (if I understood correctly) that dosages for MS drugs live or die by their trial doses and even if they don’t hit the optimum, it would be very difficult and expensive to test for alternate doses once the drug comes to market. If adaptive trials could be made to work with MS, they might help with that problem.
Julie made a good point about people feeling as if they were “treated as a data point and not as a human being” during a trial. I have had a couple neuros rave to me about the excellent care that patients get during neuro trials. From my perspective, I get a lot of tests for side effects that I wouldn’t otherwise have to spend time on, a bunch of tests to look for progression and a brief neuro exam to determine an EDSS (Expanded Disability Status Scale) score by a neuro to whom I’m not supposed to talk about side effects or symptoms. I hardly see my regular neuro and feel as if I’ve sort of been left adrift to deal with what seems to me to be ongoing progression which never seems to warrant being called a relapse. I don’t really see how this is better care.
If people are interested, there is a nice write-up on clinical trials in MSQR (Multiple Sclerosis Quarterly Report) at http://www.unitedspinal.org/msscene/2009/08/27/understanding-clinical-trials-why-they-are-done-and-what-is-learned/ The NIH also has a page on understanding clinical trials at http://www.clinicaltrials.gov/ct2/info/understand
sho
I was also interested in the end bit where they talk about redesigning a breast cancer trial so they can get results more quickly. A huge problem for MS trials is that due to the slow, heterogeneous course of the disease, large, expensive trials that last for a long time are necessary to get reliable results. The lack of biomarkers for MS is also an enormous obstacle for trials. I have recently been reading some interesting things on “adaptive” clinical trial design where they don’t spell everything out in advance, but instead adapt as they get results going through the trial (See http://pharmexec.findpharma.com/pharmexec/article/articleDetail.jsp?id=352793). These trials are very complicated mathematically. They also assume that you can get results fast enough to adapt and I don’t know how possible that is with the current state of MS research. At the big pharma MS talk, the neuro also mentioned (if I understood correctly) that dosages for MS drugs live or die by their trial doses and even if they don’t hit the optimum, it would be very difficult and expensive to test for alternate doses once the drug comes to market. If adaptive trials could be made to work with MS, they might help with that problem.
Julie made a good point about people feeling as if they were “treated as a data point and not as a human being” during a trial. I have had a couple neuros rave to me about the excellent care that patients get during neuro trials. From my perspective, I get a lot of tests for side effects that I wouldn’t otherwise have to spend time on, a bunch of tests to look for progression and a brief neuro exam to determine an EDSS (Expanded Disability Status Scale) score by a neuro to whom I’m not supposed to talk about side effects or symptoms. I hardly see my regular neuro and feel as if I’ve sort of been left adrift to deal with what seems to me to be ongoing progression which never seems to warrant being called a relapse. I don’t really see how this is better care.
If people are interested, there is a nice write-up on clinical trials in MSQR (Multiple Sclerosis Quarterly Report) at http://www.unitedspinal.org/msscene/2009/08/27/understanding-clinical-trials-why-they-are-done-and-what-is-learned/ The NIH also has a page on understanding clinical trials at http://www.clinicaltrials.gov/ct2/info/understand
sho
Since I am in a clinical trial, I promised to post on this thread, but I never seemed to find the time at a moment when I was sufficiently clear-headed to write anything coherent. I seem to more and more plagued by sleepy brain fog in the afternoons and evenings. I think I need a three-day weekend every weekend.
I thought it was interesting in the article that oncologists take such a financial hit for doing clinical trials instead of chemo, but I don’t have the impression that neuros get that kind of a kickback from the DMD companies. I’m sure they get their share of perks, but even if they do trials, they’re probably still prescribing a lot of DMDs. So I don’t know how much of an obstacle this is in MS. Obviously, there are time and personnel costs necessary for participating in trials, but I wonder if the pharmaceutical companies reimburse some of that (maybe?) and academic MS centers (which is a lot of them) seem to be required to do research by their mission. The place I go is actually trying to increase its participation in clinical trials.
Julie pointed out the time commitment to participate in a clinical trial and this is certainly an obstacle. I live 3 1/2 hours from the place I’m in a study which means I have to take a whole day off work for every follow up, even the short ones. I can only do this because I have a very understanding workplace with excellent (for the U.S.) benefits and time off. The drug company has promised reimbursement for travel time, but it’s been over a year and I haven’t seen a penny yet so I’m not overly optimistic.
Another obstacle is the inclusion and exclusion criteria. The researchers get more reliable results with rigorous inclusion criteria, but if the included population ends up being substantially different from some of the population that uses the drug, they don’t really know what’s going to happen to all those people who are older or younger or have co-morbid conditions. For example, historically, a lot of clinical trials were restricted to men and some of the approved drugs turned out to have unexpected effects in women (see http://www.jci.org/articles/view/19993). Minorities also tend to be underrepresented in clinical trials.
I read somewhere that some surprisingly high percentage of people in MS clinical trials aren’t technically qualified to be there. It’s one of those things that I’ll never find again, but I think it applies to me as I’m pretty sure I’m not technically qualified to be in the trial I’m in (although several neuros have since told me to stay put anyway now that I’m in).
Unlike the cancer trials described in the article, a lot of MS trials still have a placebo arm. There has been debate about whether this is ethical. There are some doctors, like Lulu’s, who think it is unethical to put a patient in a trial with a placebo arm when there are treatments that are known to be effective.
I understand that in the early MS trials, the participants tended to be people with more active and severe disease as they were the ones motivated to join trials with potentially bad side effects. This contrasts with current participants, who tend to have much milder disease, as these are the only people likely to be willing to go in a trial with a placebo arm (well, that and people who have failed the other DMDs, but I’m pretty sure I read that current participants do tend to have milder disease). I wonder if this leads to some differences in results.
There have been some trials without placebos where participants either get (1) a sugar pill and real shot of one of the current DMDs or (2) a real pill and an inert shot. I would think that there would be some difficulties with blinding since the side effects from the current DMDs are fairly obvious. I haven’t particularly noticed any side effects from the drug I’m on, but at my last physical, my PCP looked at my CBC (complete blood count) and was trying to figure out how to ask me if I thought I should consider an AIDS test because my WBC (white blood count) was through the floor. He looked relieved when I told him that it was probably the trial drug, which is supposed to keep the lymphocytes in the lymph nodes so they don’t go to the brain and do mischief there (as a side effect, it also keeps the lymphocytes out of the blood). Anyway, I’m pretty sure I don’t have AIDS as I had to have an AIDS test to get into this trial and the likelihood of my having picked it up in the last year is fairly infinitesimal.
Trials without placebo arms tend to be more expensive (they need more people to prove their point and they also take longer because the difference between the groups is less; they also have to pay for the drug for the placebo arm). Here is how the MSRQ article described below justified placebo arms:
“Trials using placebos are carefully considered and must ethically justify the use of an inactive treatment. On the other hand, using placebos requires fewer subjects and shortens the time frame of the trial, enabling fewer patients to be exposed to potentially ineffective new drugs for a shorter length of time. This occurs since it is easier to see the difference in results of an active drug compared to a placebo than it would be to compare two active treatments. The sample sizes often are 4 times as many patients and thus, up to 4 times the cost. Furthermore, by using a placebo, we get a better idea of just what side effects and serious adverse consequences are due to the active drug compared to consequences of the disease.”
There are risks to trial (or any) drugs, even if they try to minimize them. Two people (maybe three) have died in the trial I’m in, probably for reasons related to the immunosuppressive nature of the drug. The newer drugs, despite being potentially more effective, tend to have worse side effect profiles.
I would think that for all of those reasons, MS trials can have trouble recruiting, especially among people who don’t have severe disease and, therefore, have other options. I went to one of those big pharma-sponsored MS talks and the neuro said that the trials for FTY720/fingolimod (which is what I’m in) have been delayed because they’ve had trouble recruiting enough people. Which means it takes longer to get the drug to market.
I agree with PatientX that there doesn’t seem to be enough ground-breaking research. So much of it is incremental and we need something more dramatic. I also think there’s still too much focus on the autoimmune, inflammatory aspect of MS. There’s a lot of talk about neuroprotection, but I don’t see much concrete coming out of it (or maybe I don’t know where to look). Nor do I think there’s enough work on alternate hypotheses or factors, like the vascular/chronic cerebrospinal venous insufficiency idea (which I talked about at http://www.medhelp.org/posts/Multiple-Sclerosis/Interesting-takes-on-the-etiology-of-MS/show/986162) or HERV (human endogenous retroviruses). Of course, I may be biased, since these neuros keep telling me that the standard immunomodulatory DMDs aren’t likely to help me since I’m apparently not having acute inflammation.
I like this quote from the article, which mentions attacking important problems as a characteristic of successful trials:
“It is not entirely clear why some trials succeed, but researchers say those that do may have some features in common: patients may be like Dr. Fye, with no or few options, so they are easier to recruit, particularly if the drug promises to make a real difference, not just give them a few days or weeks. Successful trials also typically address an important problem, as opposed to a more marginal one, and involve experienced investigators and patient advocates who push for participation.”
I thought it was interesting in the article that oncologists take such a financial hit for doing clinical trials instead of chemo, but I don’t have the impression that neuros get that kind of a kickback from the DMD companies. I’m sure they get their share of perks, but even if they do trials, they’re probably still prescribing a lot of DMDs. So I don’t know how much of an obstacle this is in MS. Obviously, there are time and personnel costs necessary for participating in trials, but I wonder if the pharmaceutical companies reimburse some of that (maybe?) and academic MS centers (which is a lot of them) seem to be required to do research by their mission. The place I go is actually trying to increase its participation in clinical trials.
Julie pointed out the time commitment to participate in a clinical trial and this is certainly an obstacle. I live 3 1/2 hours from the place I’m in a study which means I have to take a whole day off work for every follow up, even the short ones. I can only do this because I have a very understanding workplace with excellent (for the U.S.) benefits and time off. The drug company has promised reimbursement for travel time, but it’s been over a year and I haven’t seen a penny yet so I’m not overly optimistic.
Another obstacle is the inclusion and exclusion criteria. The researchers get more reliable results with rigorous inclusion criteria, but if the included population ends up being substantially different from some of the population that uses the drug, they don’t really know what’s going to happen to all those people who are older or younger or have co-morbid conditions. For example, historically, a lot of clinical trials were restricted to men and some of the approved drugs turned out to have unexpected effects in women (see http://www.jci.org/articles/view/19993). Minorities also tend to be underrepresented in clinical trials.
I read somewhere that some surprisingly high percentage of people in MS clinical trials aren’t technically qualified to be there. It’s one of those things that I’ll never find again, but I think it applies to me as I’m pretty sure I’m not technically qualified to be in the trial I’m in (although several neuros have since told me to stay put anyway now that I’m in).
Unlike the cancer trials described in the article, a lot of MS trials still have a placebo arm. There has been debate about whether this is ethical. There are some doctors, like Lulu’s, who think it is unethical to put a patient in a trial with a placebo arm when there are treatments that are known to be effective.
I understand that in the early MS trials, the participants tended to be people with more active and severe disease as they were the ones motivated to join trials with potentially bad side effects. This contrasts with current participants, who tend to have much milder disease, as these are the only people likely to be willing to go in a trial with a placebo arm (well, that and people who have failed the other DMDs, but I’m pretty sure I read that current participants do tend to have milder disease). I wonder if this leads to some differences in results.
There have been some trials without placebos where participants either get (1) a sugar pill and real shot of one of the current DMDs or (2) a real pill and an inert shot. I would think that there would be some difficulties with blinding since the side effects from the current DMDs are fairly obvious. I haven’t particularly noticed any side effects from the drug I’m on, but at my last physical, my PCP looked at my CBC (complete blood count) and was trying to figure out how to ask me if I thought I should consider an AIDS test because my WBC (white blood count) was through the floor. He looked relieved when I told him that it was probably the trial drug, which is supposed to keep the lymphocytes in the lymph nodes so they don’t go to the brain and do mischief there (as a side effect, it also keeps the lymphocytes out of the blood). Anyway, I’m pretty sure I don’t have AIDS as I had to have an AIDS test to get into this trial and the likelihood of my having picked it up in the last year is fairly infinitesimal.
Trials without placebo arms tend to be more expensive (they need more people to prove their point and they also take longer because the difference between the groups is less; they also have to pay for the drug for the placebo arm). Here is how the MSRQ article described below justified placebo arms:
“Trials using placebos are carefully considered and must ethically justify the use of an inactive treatment. On the other hand, using placebos requires fewer subjects and shortens the time frame of the trial, enabling fewer patients to be exposed to potentially ineffective new drugs for a shorter length of time. This occurs since it is easier to see the difference in results of an active drug compared to a placebo than it would be to compare two active treatments. The sample sizes often are 4 times as many patients and thus, up to 4 times the cost. Furthermore, by using a placebo, we get a better idea of just what side effects and serious adverse consequences are due to the active drug compared to consequences of the disease.”
There are risks to trial (or any) drugs, even if they try to minimize them. Two people (maybe three) have died in the trial I’m in, probably for reasons related to the immunosuppressive nature of the drug. The newer drugs, despite being potentially more effective, tend to have worse side effect profiles.
I would think that for all of those reasons, MS trials can have trouble recruiting, especially among people who don’t have severe disease and, therefore, have other options. I went to one of those big pharma-sponsored MS talks and the neuro said that the trials for FTY720/fingolimod (which is what I’m in) have been delayed because they’ve had trouble recruiting enough people. Which means it takes longer to get the drug to market.
I agree with PatientX that there doesn’t seem to be enough ground-breaking research. So much of it is incremental and we need something more dramatic. I also think there’s still too much focus on the autoimmune, inflammatory aspect of MS. There’s a lot of talk about neuroprotection, but I don’t see much concrete coming out of it (or maybe I don’t know where to look). Nor do I think there’s enough work on alternate hypotheses or factors, like the vascular/chronic cerebrospinal venous insufficiency idea (which I talked about at http://www.medhelp.org/posts/Multiple-Sclerosis/Interesting-takes-on-the-etiology-of-MS/show/986162) or HERV (human endogenous retroviruses). Of course, I may be biased, since these neuros keep telling me that the standard immunomodulatory DMDs aren’t likely to help me since I’m apparently not having acute inflammation.
I like this quote from the article, which mentions attacking important problems as a characteristic of successful trials:
“It is not entirely clear why some trials succeed, but researchers say those that do may have some features in common: patients may be like Dr. Fye, with no or few options, so they are easier to recruit, particularly if the drug promises to make a real difference, not just give them a few days or weeks. Successful trials also typically address an important problem, as opposed to a more marginal one, and involve experienced investigators and patient advocates who push for participation.”
This is a very important conversation to be holding because advances in treatment can't take place without the clinical trials for new drugs. A cure can't be developed and marketed until it's tested on those of us who suffer from the disease.
The flip side like JJ points out has tons of pitfalls. That giant leap of faith into the unknown is a big step to take when it comes to our health. At least at the present we know our condition and where we might be heading.
Oh wait, this is MS and none of us know where we will end up! LOL
Would it make a difference if we knew our disease course? If we knew we would stay ambulatory and just suffer minor inconveniences vs being in a wheelchair and dependent on others?
I would like to think that clinical trial participants are the explorers - like Christopher Columbus sailing off for the unknown, Madame Curie exposing herself to all that radiation in her lab, or Neil Armstrong taking that giant step for mankind. But it appears the way they are structured the participants are more likely to be the infirm and desperate with no further options in treatment.
The rest of us are stuck in a strange sort of limbo with our treatments - marking time until the next group of drugs come along.
as always,
Lulu
The flip side like JJ points out has tons of pitfalls. That giant leap of faith into the unknown is a big step to take when it comes to our health. At least at the present we know our condition and where we might be heading.
Oh wait, this is MS and none of us know where we will end up! LOL
Would it make a difference if we knew our disease course? If we knew we would stay ambulatory and just suffer minor inconveniences vs being in a wheelchair and dependent on others?
I would like to think that clinical trial participants are the explorers - like Christopher Columbus sailing off for the unknown, Madame Curie exposing herself to all that radiation in her lab, or Neil Armstrong taking that giant step for mankind. But it appears the way they are structured the participants are more likely to be the infirm and desperate with no further options in treatment.
The rest of us are stuck in a strange sort of limbo with our treatments - marking time until the next group of drugs come along.
as always,
Lulu
COMMUNITY LEADER
Hi Lulu,
I hate medical trials, yes i understand their need and importance but it can be like playing russian rulet with a bullet that fries your brain, way too many screw ups by the medical world for me to go down that road. None evasive research is different, i've been involved with helping in this way for many years (Autism) but i'm really not comfortable with taking a maybe drug of anykind, i'm not comfortable with the idea that they need desperate enough patients willing to take a gamble on the unknown. It might be selfish to not want to take the gamble, the greater good and all that but i value life and really cant afford to let someone play god with it. But thats me, i'm in a tizz that they are now looking for children for a trial of the pig flu vacine they've just developed in Australia, what if they screw up and where will these medical visionaries be if things go wrong, one thing for sure is that they wont be living with the mistakes, no thats the patients plight. The vissionary dr is back in the lab making a better drug, immune to the damage because they are looking at the greater good, the individual is irrelivant to the equation.
For what its worth, my 2 cents.
Cheers......JJ
I hate medical trials, yes i understand their need and importance but it can be like playing russian rulet with a bullet that fries your brain, way too many screw ups by the medical world for me to go down that road. None evasive research is different, i've been involved with helping in this way for many years (Autism) but i'm really not comfortable with taking a maybe drug of anykind, i'm not comfortable with the idea that they need desperate enough patients willing to take a gamble on the unknown. It might be selfish to not want to take the gamble, the greater good and all that but i value life and really cant afford to let someone play god with it. But thats me, i'm in a tizz that they are now looking for children for a trial of the pig flu vacine they've just developed in Australia, what if they screw up and where will these medical visionaries be if things go wrong, one thing for sure is that they wont be living with the mistakes, no thats the patients plight. The vissionary dr is back in the lab making a better drug, immune to the damage because they are looking at the greater good, the individual is irrelivant to the equation.
For what its worth, my 2 cents.
Cheers......JJ
Patienx is right about clinical trials requiring on the most part that patients live in close proximity to the research centers to even be considered as a participant. The MS trial I was in at NIH had this requirement as well. One of the nurses told me that they had someone contact them from California who said she would pay all her expenses and ensured she would make it to all the follow-up appointments - promised - but they wouldn't take her. That is sad, but it is a reality when you think of how much money these researchers invest in each patient and then maybe having to deal with them dropping out. Distance is truly a barrier with human research and it hurts research in general when these criteria are stringently adherered to with no exceptions.
Another thing that keeps us from participating is that we may not stringently meet the patient "inclusion" criteria. I begged my neuro last month to get me into the oral DMD trial and he told me I didn't meet the criteria of a 2 months since start of symptoms requirement. Where in the world would they find such a patient to meet this criteria? Most people I know, even those who had slam dunk cases, took longer than 2 months before they were diagnosed.
I don't think easing up on the criteria that researhers use is an answer because their who grant or funding depends on the trial being conducted in a particular and stringent manner. If you want clean results that won't be questioned or challenged later, then you have to stick to the rules of the game.
That is the reality of research trials.
Another thing that keeps us from participating is that we may not stringently meet the patient "inclusion" criteria. I begged my neuro last month to get me into the oral DMD trial and he told me I didn't meet the criteria of a 2 months since start of symptoms requirement. Where in the world would they find such a patient to meet this criteria? Most people I know, even those who had slam dunk cases, took longer than 2 months before they were diagnosed.
I don't think easing up on the criteria that researhers use is an answer because their who grant or funding depends on the trial being conducted in a particular and stringent manner. If you want clean results that won't be questioned or challenged later, then you have to stick to the rules of the game.
That is the reality of research trials.
I think the title of this article is misleading. The real problem, I believe, was stated in thew article:
"Even worse, many that do get under way are pretty much useless, even as they suck up the few patients willing to participate. These trials tend to be small ones, at single medical centers. They may be aimed at polishing a doctor’s résumé or making a center seem at the vanguard of cancer care. But they are designed only to be “exploratory,” meaning that there are too few patients to draw conclusions or that their design is less than rigorous.
“Unfortunately, many patients who are well intentioned are in trials that really don’t advance the field very much,” said Dr. Richard Schilsky, an oncologist at the University of Chicago and immediate past president of the American Society of Clinical Oncology.
Others studies, by companies, are designed to persuade doctors to use their drugs.
Still others are testing questions like whether it makes a difference to give a drug every nine days or every two weeks. “These are practical real-world questions,” Dr. Schilsky said. “But they don’t do a great deal to advance the research field. They are not going to provide the next breakthrough.”
Though it's about cancer, I believe it applies to MS. This, and the design of some of the MS studies make them difficult to enroll. For instance, I was begging to get into the Campath trial. No center near me was doing the CARE MS I trial; and you have to be near the trial site because of the frequent visits and possible side effects. Now, I could eventually be eligible for the CARE MS II trial, but it is so narrowly designed, my MS center got dropped as a site because they didn't enroll anyone.
"Even worse, many that do get under way are pretty much useless, even as they suck up the few patients willing to participate. These trials tend to be small ones, at single medical centers. They may be aimed at polishing a doctor’s résumé or making a center seem at the vanguard of cancer care. But they are designed only to be “exploratory,” meaning that there are too few patients to draw conclusions or that their design is less than rigorous.
“Unfortunately, many patients who are well intentioned are in trials that really don’t advance the field very much,” said Dr. Richard Schilsky, an oncologist at the University of Chicago and immediate past president of the American Society of Clinical Oncology.
Others studies, by companies, are designed to persuade doctors to use their drugs.
Still others are testing questions like whether it makes a difference to give a drug every nine days or every two weeks. “These are practical real-world questions,” Dr. Schilsky said. “But they don’t do a great deal to advance the research field. They are not going to provide the next breakthrough.”
Though it's about cancer, I believe it applies to MS. This, and the design of some of the MS studies make them difficult to enroll. For instance, I was begging to get into the Campath trial. No center near me was doing the CARE MS I trial; and you have to be near the trial site because of the frequent visits and possible side effects. Now, I could eventually be eligible for the CARE MS II trial, but it is so narrowly designed, my MS center got dropped as a site because they didn't enroll anyone.
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