Monday, September 20, 2010

Clinical trials on trial

So, how do pharmaceutical companies figure out whether a new drug is effective or not?  Or whether it saves lives?  The Sunday New York Times has a front page story about a drug trial of a new treatment for melanoma (skin cancer) and answers these questions, while also asking about the morality of drug testing as it's currently carried out.

Generally, drugs are tested in double-blind case-control studies.  Some subjects receive the treatment being tested and others, the controls, are given either the existing therapy or a placebo, and in a double-bline study neither the subjects nor the physicians know which group a patient is enrolled in.

Two young cousins had the extreme misfortune of being diagnosed with melanoma at about the same time.  Both were enrolled in a drug trial, but one was given the new therapy and the other the comparison state-of-the-art therapy.  The question being asked is apparently not whether the new drug 'cures' melanoma, but whether it lengthens the lives of those who are treated with it.  It was already known that the new drug improves quality of life, but the apparently the tumors of those treated with this drug in an early study returned.

As it turned out, the tumors of the cousin on the new drug shrank immediately and dramatically, while  those of the cousin in the control group did not.  In fact, he has now died from his cancer, while the first cousin has survived past the average longevity for people diagnosed with the advanced melanoma with which both he and his cousin were diagnosed, that is, 8 months.  He's now been alive for 9 months.

One man was 24 and the other 22 when diagnosed, one had children and the other, the one in the control group, did not.  When it was clear that the cousin on the new therapy was in much better shape than the one in the control group, his mother begged the researchers to switch him from the old therapy to the new.  They refused, saying that would make their test results uninterpretable.  Indeed, subjects in their control group need to die at a higher rate than those given the new therapy if the new treatment is to be deemed effective.

Two things are troubling about this story, if it's an accurate portrayal of this drug trial.  One, it seems that it was already known that the new drug for melanoma produces dramatically better results than any previous therapy -- at least in the short term.
The standard chemotherapy used in melanoma, dacarbazine, slowed tumor growth in 15 percent of patients for an average of two months. By contrast, PLX4032 had halted tumor growth in 81 percent of patients for an average of eight.
That is, quality of life is greatly improved for those whose tumors are genetically disposed to respond (apparently 80% of people with melanoma) on this drug.  The thing that isn't yet known is whether the new drug allows patients to live longer.

Even so, it's ethically troubling to many, including many oncologists, that answering this question requires allowing patients -- the control group -- to suffer unnecessarily.  Should longevity remain the only outcome of interest, when it's clear that a new medication can reduce suffering -- even if it doesn't improve longevity, which it may?  We think not, and there is plenty of precedent for halting clinical trials when it's clear that the drug being tested is either significantly more harmful or more beneficial than the state-of-the-art treatment.  If the NYTimes story is accurately portraying this trial, it should be halted now.

Second and more troubling, according to the story it's already known that patients diagnosed at the stage at which these two young men were diagnosed survive, on average, for eight more months.  Why isn't that a good enough comparison statistic for this new drug?  Why subject more people to the pain and suffering the state-of-the-art therapy entails in order to confirm this statistic?

The stainless steel answer is that without a 'gold standard' double-blind clinical trial, one cannot accurately assess if, or to what extent, a new therapy improves on the existing approach.  This is a gold standard that often falls short for various reasons, and one of the general standards, we thought, was that as soon as you have good reason to think one approach (new drug) or the other (current treatment)  is clearly better, you stop the trial and put everyone on the better treatment.  Why this is not routine, or applied in this case isn't clear (to us).  Granted, the results may be premature, and as the story itself reports,

One of the melanoma field’s senior clinicians, Dr. Chapman had lived through trial after trial of drugs that failed to live up to early promise. Almost every oncologist knew, too, of a case nearly 20 years earlier when bone marrow transplants appeared so effective thatbreast cancer patients demanded their immediate approval, only to learn through a controlled trial that the transplants were less effective than chemotherapy and in some cases caused death.

So perhaps there is reason to be cautious.  But if 'all' the patients get out of this is improved quality of the last months of their lives, isn't that something?

Of course, all the usual questions about evidence arise here, but so do societal questions.  Clinical trials are very expensive, and results often show no effect after many years and much expense.  How easily could we be convinced that some new treatment really works better, if vested interests learn that with any sort of evidence the costly clinical trial can be abandoned?  In other words, if the standard is relaxed, will it be abused?  Yet, if not, are patients being abused who suffer or die because, so to speak, some professor wants to finish and publish a trial, or some government agency wants to fill out a 'satisfactory' grade on some form?

To cause or not to cause, that is the question.  The answer isn't clear.


James Goetz said...

I have mixed feelings about this. I would never participate in double-blind trials. And I would never encourage a seriously ill person to participate in double-blind trials. However, I know that most any medicine ever prescribed to me was subject to double blind trials while I typically read the synopsis of those trial results to learn about the medicine that I'm ingesting.

I suppose that I would favor using what we already know about the average course of an illness with a placebo or no intervention and compare that with a "sighted" trial. But I understand that those results would lack the credibility of using "human guinea pigs" in double-blind trials. (I'll clarify that I've an overall respect for medical trials despite my mixed feelings.)

Anne Buchanan said...

I agree that it's a tricky call. Formal protocols and statistics are the only way we know of to reliably evaluate new drugs and therapies. Given the economic pressures and potential rewards to pharmaceutical and instrument companies for new regimes, it's clearly important that these be followed, and with strict oversight.

However, it seems a little less tricky in this case, if the NYT story is correct. If it's true that average longevity is well-known following the current treatment for advanced-stage melanoma, then it's not at all clear to me why this had to be confirmed again. Given that the only way to confirm it is for patients to die, and in extreme pain.

Bethany Usher said...

It's interesting - I've been thinking a lot about this article, too. And deciding what route I would take to get the PLX4032 if it was me or someone I loved who had that form of melanoma.

What wasn't clear to me in the article was how shrinking the tumors didn't automatically lead to a longer life, even if the tumors eventually return. If the early results show that the tumors shrink, and quality of life is enhanced, then how could this not lead to a longer life expectancy, if the tumors are what kill people? This does seem like the kind of study that should be halted because early results show such significant promise.

The only question I had was to what degree the reporter had the results correct. I worry about the outcry about a news article if the other studies haven't been published yet. But a search on PubMed showed a recent article from the New England Journal of Medicine about the Phase 1 study that showed, "The estimated median progression-free survival among all patients was more than 7 months" (Flaherty et al 2010). In fact, the mutation targeted is in frequent in other cancers, and thus the drug may be useful for other patients, also (Bollag et al 2010). Once it's released, I wouldn't be surprised to see off-label trials for other cancers with the same mutation.

Anne Buchanan said...

Thanks, Bethany. Very interesting to see the papers you cite.

I wondered the same thing about shrinking tumors and life extension. It's possible that no one is yet willing to go on record saying that shrinking tumors extends life, because no trials have yet formally established that for this drug?

Ken Weiss said...

If the main tumor is smaller then it might take longer to grow to dangerous size, or else perhaps continuing on the drug would keep shrinking it.

But the drug may not reach all metastatic sites, so that the main tumor being smaller may not relate to life extension. However, you'd generally expect it to, on the simple principle that size matters!

James Goetz said...

I suppose medical science needs statistical results from double-blind trials to verify that size matters.

Ken Weiss said...

To me it is issues like these that show the dilemmas facing science. When you mix in the vested interests, difficulty of obtaining cogent data, the complex nature of causation, and the poignant nature of people suffering life-threatening diseases and yearning for relief, you have a science and society dilemma.

Anne Buchanan said...

Hear, hear.