Clinical trial process "plays God"

[REWahoo]

Here is another interesting example of how modern science and big pharma have created moral and ethical nightmares. I'm hoping this story is an exaggeration of how clinical trials are conducted.

Two cousins are diagnosed with skin cancer....

And when, last year, each learned that a lethal skin cancer called melanoma was spreading rapidly through his body, the young men found themselves with the shared chance of benefiting from a recent medical breakthrough.

Only months before, a new drug had shown that it could safely slow the cancer’s progress in certain patients. Both cousins had the type of tumor almost sure to respond to it. And major cancer centers, including the University of California, Los Angeles, were enrolling patients for the last, crucial test that regulators required to consider approving it for sale.

“Dude, you have to get on these superpills,” Thomas McLaughlin, then 24, whose melanoma was diagnosed first, urged his cousin, Brandon Ryan. Mr. McLaughlin’s tumors had stopped growing after two months of taking the pills.

But when Mr. Ryan, 22, was admitted to the trial in May, he was assigned by a computer lottery to what is known as the control arm. Instead of the pills, he was to get infusions of the chemotherapy drug that has been the notoriously ineffective recourse in treating melanoma for 30 years.

Even if it became clear that the chemotherapy could not hold back the tumors advancing into his lungs, liver and, most painfully, his spine, he would not be allowed to switch, lest it muddy the trial’s results.

http://www.nytimes.com/2010/09/19/health/research/19trial.html?_r=1

A question for all you docs on the forum - is this story over-dramatized or is this really how the clinical trial process works in the US?

 

[Rich_by_the_Bay]

A question for all you docs on the forum - is this story over-dramatized or is this really how the clinical trial process works in the US?

Pretty much. Though not always with quite that much emotion and complexity.

Theoretically there are oversight committees that follow such studies in progress and the members are aware of which patients are getting which treatment, and these committees are sworn to confidentiality.

If midway through the study it becomes apparent that one group is doing much better than the other (in a statistically compelling way, ideally determined before the study begins) they have the right to call off the study prematurely. Same goes for serious side-effects emerging.

To the extent that patients are allowed to switch over mid-trial to the other drug, or that patients drop out, etc. the study results become scientifically less valid. The trick is balancing ethics with scientific rigor.

As this case shows, the real-world decisions are much more complex and personal than even the best clinical trial can address in advance.

 

[Meadbh]

What Rich said.

The problem, scientifically, is that if patients are allowed to trial the intervention without a control group, or if allocation to the groups is not randomized, or if the study is not "blinded", bias creeps in. The results may be misleading, and it may take years to discover that the apparently wildly successful treatment was actually useless, or worse, that it caused some serious side effect.

In my own field (neonatology), the most striking example of this problem was the failure to properly study the effects of high concentrations of oxygen in preterm babies in the 1940s/50s. This led to an epidemic of blindness (not a trivial side effect) in preterm babies. Stevie Wonder was one of them. You can read about it here:

A Cautionary Tale About Supplemental Oxygen: The Albatross of Neonatal Medicine -- Silverman 113 (2): 394 -- Pediatrics

Neonatologists are strong proponents of properly conducted randomized controlled trials (RCTs), and almost every major change is subjected to this level of scrutiny before being introduced on a wide scale. To ensure that we have an answer in a timely way that will benefit most patients, RCTs are now usually conducted across multiple sites with thousands of patients, with numbers calculated to answer the question of whether the intervention improves the primary outcome.

I would also like to address the fact that you mentioned "big pharma" as the cause of your cousin's inability to access the study medication. That's not the case. The study would have been reviewed by a Research Ethics Board at the hospital and without randomization, it probably would not have been approved.

 

[ERD50]

Trouble is, if you look at it from the other angle, how would we ever find out what is effective and what isn't if we didn't do side-by-side comparisons? In the long run, many more people would die/suffer since we couldn't find out what works best.

Wouldn't that 'ethical and moral nightmare' be worse?

And just because it appeared to work for his cousin, that does not mean that it would have a better chance of working for someone else than the old drug. We don't know that until we conduct the studies.

edit/add - I didn't read the whole article, but this came early on (bold mine):

And major cancer centers, including the University of California, Los Angeles, were enrolling patients for the last, crucial test that regulators required to consider approving it for sale.

I can't help but think that if they gave everyone the drug without this required test, and if the subjects had adverse effects, the 'journalists' would be demon-izing 'big pharma' for shirking their responsibilities.

I'm not a doctor, don't even try to play on on the Internet, I'm just applying logic to the situation.


-ERD50

 

[REWahoo]

I would also like to address the fact that you mentioned "big pharma" as the cause of your cousin's inability to access the study medication.

Although I am an admitted redneck, I am not related to the individuals in the article...

 

[REWahoo]

As this case shows, the real-world decisions are much more complex and personal than even the best clinical trial can address in advance.

I think this is a key point. It is much easier to tout following the scientific process in these studies when the individuals involved aren't you or one of your loved ones.

 

[Meadbh]

Although I am an admitted redneck, I am not related to the individuals in the article...

Sorry REW, I just read your quotes, not the article. I assumed they were "your" cousins. I'm glad nobody in your family is facing this dilemma!

 

[Nords]

I think this is a key point. It is much easier to tout following the scientific process in these studies when the individuals involved aren't you or one of your loved ones.

It pretty much describes the entire healthcare system and its expenses...

A devil's advocate to the article would be the first cousin suffering worse side effects, despite his "cure", than the cousin in the control group. One reason that the article serves to inflame opinion is because the trial treatment appears to be working, and intellectually we know that's rarely the straightforward answer.

I'm also not so sure about the draconian "Even if it became clear..." sentence. It certainly makes a dramatic impact, but IIRC study guidelines allow for intervention where it becomes clear that switching sides would possibly save lives.

 

[DblDoc]

RiT and Meadbh have summed it up well. Unfortunately much of what we do currently was never subjected to such rigorous study and at best is not harming patients, at worst it is and we don't know it (yet).

DD

 

[DblDoc]

I'm also not so sure about the draconian "Even if it became clear..." sentence. It certainly makes a dramatic impact, but IIRC study guidelines allow for intervention where it becomes clear that switching sides would possibly save lives.

You are correct. The data is analyzed as the trial proceeds. If the new therapy arm demonstrates a significant benefit or detriment the study is "unblinded" and the participants switched to the appropriate therapy.

DD

 

[BigNick]

This whole story is so full of bad science, I hardly know where to begin.

lethal skin cancer

As opposed to "cuddly" skin cancer? Score one for emotion. Score zero for facts.

benefiting from a recent medical breakthrough.

No. A "claimed" medical "advance", perhaps. Breakthroughs are rare (and journalese). To even be an "advance", it has to pass the trials. And the whole point of the article is that "the trials are killing people", or something. But without the trials, it's just snake oil.

safely slow the cancer’s progress in certain patients.

A-ha. "Slow the cancer's action". Note that, despite the overall innuendo in the article, it turns out nobody is claiming that this drug make the cancer disappear, poof. It "slows its action" in "certain patients". And in other patients? Does it kill them in a week? That's what the trials are for...

Both cousins had the type of tumor almost sure to respond to it.

"Almost", eh? Care to put some numbers on that?

last, crucial test that regulators required to consider approving it for sale.

Darn those evil regulators! Get them out of here! I want whatever the pharmaceutical industry wants to sell me. How could they ever be wrong?

superpills

Oh puh-leeze.

computer lottery

Nothing worse than a lottery, except a computer lottery. It's Obama's Death Panels By Computer! Boo, hiss. Question for the journalist: how else would you like people to be assigned to the control group? By how hot you think they are?

to what is known as the control arm

Hold on a second. How did the guy know he was in the control arm? What kind of randomised, double-blind study is this?

lest it muddy the trial’s results

Yes, and the results are already irrelevant, because we already know, because an NYT journalist told us, that these are *superpills* !!!

Now, if I were the patient, I'd probably be trying to get hold of both types of medication, the new one and the "control" one. But that's just because I'm just this guy who doesn't want to die, and who thinks that medicine is, generally, a good thing. Of course, it turns out that it's all waaaaay more complicated than that. Having seen the medical profession screw up royally in the past week over something a simple as a slightly bruised ankle, I'm not inclined to believe in miracles.

 

[Texas Proud]

As some of the docs have chimed in on some of the things I do not know about..... I will chime in on my thinking of the gist of this thread without reading the article...

One of the problems I see with medical advances is the cost/benefit problem... and from this small thread I can not see if there is anything in the article that talks about it...


Say that the medicine works 100% of the time (not likely), but costs $100,000 to give... but does not cure anything... but slows it down where the person lives maybe 1 month longer... to me (and I am going to DUCK right now).... that is an abuse of the medical system that should be stopped... medicine already costs all of us a LOT of money.. it might not be all out of our pockets if your company pays your health insurance, but it is out of your pocket somehow... and a lot of the costs provide very little benefits to our health..

An example... I had someone who worked for me who found out she had terminal cancer... she was stage 4 and had less than 6 months to live according to the docs (she lived only 4).... but a month later she was having some eating problems and they (docs and family) decided to perform an operation on her stomach to fix this problem (something to do with acid reflux)... knowing that it cost over $10K for them to work on my wife's foot... I can only guess that this cost in the $20K to $40K range... it did not extend her life one bit... IMO it did not help her out as she spent a month recovering from that operation... and when you only have 3 months to live that is a LOT of your life...


SOOO, I feel for the guy who might die from his cancer.... but he was going to die anyhow... without a trial to determine IF this drug even works AND to know how much better it is than what they do now.... how are we to know what to do I do not see big pharma as the problem... in fact, IF the drug works then they were able to help half of the people during this trial phase.... that would not have been helped if they had not developed the drug... IOW, more people would have died than not... sorry that the one that did has a cousin that did not... (at least as far as we know)....

 

[Meadbh]

Exactly, TP!

The public hysteria about CCSVI surgery for MS right now (I want it NOW, whether it works or not) is another example of the conflict between good science and the frustrations of individual patients. I have heard Dr. Zamboni being interviewed and he himself says that more research is needed before this treatment is adopted as standard.

 

[Emeritus]

You are correct. The data is analyzed as the trial proceeds. If the new therapy arm demonstrates a significant benefit or detriment the study is "unblinded" and the participants switched to the appropriate therapy.

DD

I served for 3 years as an ethics adviser to a Data Safety and Monitoring Board on two large clinical trials. I assure you the Board took its obligations to the patients very very seriously and constantly asked the statistical analysts to determine if there was if there was any evidence whatever that would cause a reasonable person to stop the trial.

 

[Emeritus]

This whole story is so full of bad science, I hardly know where to begin.....

As opposed to "cuddly" skin cancer? Score one for emotion. Score zero for facts.

.

Melanoma is a very different problem from Basal cell carcinoma
Both are skin cancers.

 

[Texas Proud]

Exactly, TP!

The public hysteria about CCSVI surgery for MS right now (I want it NOW, whether it works or not) is another example of the conflict between good science and the frustrations of individual patients. I have heard Dr. Zamboni being interviewed and he himself says that more research is needed before this treatment is adopted as standard.

Yes... I remember someone saying that the chance of you being drafted and going to Vietnam was slim.... but if you were there it was 100%....

Therein lies the problem... if you are the one that is going to die... you WANT something done right now... even if it does not work... because you will be dead if nothing happens...

 

[kumquat]

Exactly, TP!

The public hysteria about CCSVI surgery for MS right now (I want it NOW, whether it works or not) is another example of the conflict between good science and the frustrations of individual patients. I have heard Dr. Zamboni being interviewed and he himself says that more research is needed before this treatment is adopted as standard.

Not to hijack the thread, but is this a good example? As a friend and relative of several MS patients (some of whom have had the procedure), I remain a sceptic. However their complaints tend not to be that the treatment isn't generally available but that those who fund the research are not in favour of the trials. See this article.

The Canadian Institutes of Health Research on Tuesday recommended a wait-and-see approach to the so-called liberation therapy, citing “an overwhelming lack of scientific evidence” that it works, that it is safe, and that the theory behind it is sound.

I think the patients are saying "we want to know if it works, why not do some research" but when the scientific community responds "sorry, we don't think it does and don't want to find out", they are forced to spend their money in Europe on their own trial.

I believe similar attitudes toward the treatment of stomach ulcers using antibiotics delayed its acceptance by some 20 or 30 years.

 

[Rich_by_the_Bay]

Not to hijack the thread, but is this a good example? As a friend and relative of several MS patients (some of whom have had the procedure), I remain a sceptic. However their complaints tend not to be that the treatment isn't generally available but that those who fund the research are not in favour of the trials. See this article.
I think the patients are saying "we want to know if it works, why not do some research" but when the scientific community responds "sorry, we don't think it does and don't want to find out", they are forced to spend their money in Europe on their own trial.

I believe similar attitudes toward the treatment of stomach ulcers using antibiotics delayed its acceptance by some 20 or 30 years.

Thoughtful comments. But the great equalizers are the many treatments recommended for many diseases which were later proven not to work or even to cause harm. Estrogens to prevent heart disease; lidocaine to treat acute heart attack rhythm disturbances; knee surgery for certain types of arthritis; everything under the sun (including grapes) for MS; chelation therapy for coronary disease -- on and on.

The best we have is clearly derived evidence from well-designed clinical trials. They are sometimes wrong, usually very expensive, and too deeply invaded by big pharma in some cases. The public and health care communities are right to be smartly skeptical without being nihilistic. It's all you can do. Oh, and find a good doctor to coach you through the tough ones.

 

[Nords]

Say that the medicine works 100% of the time (not likely), but costs $100,000 to give... but does not cure anything... but slows it down where the person lives maybe 1 month longer... to me (and I am going to DUCK right now).... that is an abuse of the medical system that should be stopped... medicine already costs all of us a LOT of money.. it might not be all out of our pockets if your company pays your health insurance, but it is out of your pocket somehow... and a lot of the costs provide very little benefits to our health..

So... since you're not going to be using them, can I have your doses?

I have heard Dr. Zamboni being interviewed and he himself says that more research is needed before this treatment is adopted as standard.

"Zamboni"?!? Does the medical licensing board really let that sort of thing happen?

 

[kumquat]

"Zamboni"?!? Does the medical licensing board really let that sort of thing happen?

Ya don't get to pick your parents. Ya don't have to change your name. Ya don't have to work in a hockey rink. Ya don't have to .....

 

[SecondCor521]

My mom has a disease which is still not very well understood and also doesn't have developed therapies for cure or treatment. Fortunately in this case it is not as fatal as cancer, but it is still progressive and ultimately terminal. As a result, she has had a keen personal interest in this kind of thing.

In the end, she does what is best for her own survival first, and then if she can help out future "diagnosees" by being in a clinical trial, then she'll consider it. In her case the nearest clinical trials may be in the next state over, and require traveling there every few weeks for the trial. She considers that hassle, plus the likelihood that the drug or therapy will be promising, plus how her current therapies are working, plus the probability of getting assigned to the control group, and then makes up her own mind after consultation with my dad and her doctor. I think the score at the moment is that she's on three different therapies, has been turned down for one clinical trial, and has turned down another. I think she's still looking a little bit, because even with the three therapies she's still going slowly downhill. Oh, and that's another thing -- how much of your remaining life do you want to spend doing research on various clinical trials to see if there's something there for you, as opposed to just living your remaining time out the way you want to?

Tough questions...

2Cor521

 

[Texas Proud]

The other side of this is someone who dies sooner than they would have if they had not taken something...

I have a friend who's wife had scleroderma.... I do not know much about this illness, but I did not think it was fatal.... I was surprised that she died... later I had heard that she had died because of an adverse reaction to some 'experimental drug'.... I have never asked my friend what really happened and do not plan to do so.... but she died suddenly while she was in the hospital... so the news from others can be true....

 

[kumquat]

It's all an interesting conundrum. My story is almost a novel, unbelievable but true.

Latest story:
I have a sibling with PPMS. When Zamboni's treatment became the rage my DS(ister) pressed sibling to get it. While not without resources, he was a bit wary. His symptoms also included a bit of what his DW describes as "brain fog". They were also suffering a bit of a cash flow problem due the disease forcing him to move to a single story house (bought and old one not sold) as well as rent his farm (as opposed to operating it). It didn't seem immediately possible until the rest of us (siblings) gave them a cheque. I contributed since: it wasn't a lot of money, with PPMS you NEVER get better (if the procedure helps, the sooner the better). He had the procedure. I really didn't notice a lot of difference. His DW did. Then, in her eyes, he went down hill to about the starting point. Based on this, I'm a sceptic. However I have heard many anecdotal stories that rival the miracles of Lourdes. I remain sceptical.

Older story:
My DF died many years ago of a neurolical disease that kills about 1 in a million people. For those who die (and their family) it is a life shattering event. For society, it means squat. There will never be any research into causes and cures of this disease since it affects so few people. I fully understand this.

My post upthread does not suggest that clinical trials are wrong, imoral or anything else. I do suggest that any theory that that contradicts current medical thinking (whether that thinking is based on any facts) will get no research, no trials and no chance. After all, like AGW, the science is "settled", before the trials unless "big pharma" or someone else is ready to fund it.

 

[ERD50]

It's all an interesting conundrum. ...

My post upthread does not suggest that clinical trials are wrong, immoral or anything else. I do suggest that any theory that that contradicts current medical thinking (whether that thinking is based on any facts) will get no research, no trials and no chance. .... unless "big pharma" or someone else is ready to fund it.

It is an interesting conundrum. Since the trials do cost a lot of money, it's clear that any business is not going to pursue the research and a trial unless they have a reasonable chance to recoup their investment and go on to make a profit. I don't think they should be demonized for this any more than most of us worked most of our hours at a job the pays a salary over doing mostly pro-bono volunteer work.

So you are correct, the 1 in a million (orphan diseases) are not likely to get attention from business. This is an area where we might want the government to step in a supply/fund the research. But we want our government to be reasonably cost efficient also - does it make sense to spend big bucks on 1 in a million issues, when there are unfunded issues affecting a much larger population?

There is probably some middle ground (and maybe some of this is also in place?). Are trials less restrictive for orphan diseases? Maybe the government could provide some kind of incentive to shift research away from the profitable areas where we have effective medicine, to th less profitable ones that would provide more total 'quality of life' overall?

Although I'm generally a capitalist & free market proponent, one area that I think our government might be able to some good for us: fund research for potentially very low cost medications and processes. Businesses have little interest in discovering non-patentable or very cheap products - they won't get their money back. But the govt does not have this need, and if the overall benefit was positive to citizens, it could be a good use of taxpayer funds. A different kind of 'profit' (reduced spending).

-ERD50

 

[Meadbh]

So you are correct, the 1 in a million (orphan diseases) are not likely to get attention from business. This is an area where we might want the government to step in a supply/fund the research. But we want our government to be reasonably cost efficient also - does it make sense to spend big bucks on 1 in a million issues, when there are unfunded issues affecting a much larger population?

That's why it's so frustrating to the MS community in Canada that CIHR (the Canadian Institutes of Health Research), which is the equivalent of NIH in the US, is not funding the studies. The Federal Minister of Health had an advisory panel of experts look at the issue, and they advised her that there is insufficient scientific justification to do a good study at this time. CIHR rejects about 83% of the grant proposals submitted to it (including some of mine) because it has very high scientific expectations, and many well designed studies don't get funded. Maybe Rich can comment on the NIH.

Interestingly, several ministers of health in Canadian provinces have pledged to support studies, including a follow up study of patients who have had the treatment. They are under a lot of pressure from lobby groups.