Monday, September 20, 2010

Are Trials Necessary?

Today's New York Times ran a heartbreaking story by Amy Harmon about two cousins who developed melanoma. One was entered into a cancer clinical trial and received the investigational drug PLX4032. The other was ineligible for the trial, and therefore unable to access the experimental drug. Guess which cousin died?

The article is one in a series of Harmon articles that seems to raise questions about whether rules governing drug testing and research are depriving desperately ill patients timely access to curative therapy. In this article, the narrative takes aim at two practices: 1- the practice of including control groups within trials, and randomly determining that some patients will receive standard care that is widely regarded as inadequate; 2- excluding patient access to drugs that have not yet demonstrated unequivocal therapeutic advantage.

As with many of my blog entries, I preface this one by saying that I am not a cancer doc, and therefore not in a position to evaluate whether PLX4032 is the wonder drug this story makes it out to be. I also preface my comment on this article by acknowledging the incredible pain and anxiety that patients suffer when denied access to a trial, or when denied access to a preferred drug within a trial. These disclaimers aside, I found the tenor of this article very problematic.

First, the reason investigators randomly determine treatment choice in trials is because, at the outside of a well designed trial, there is genuine uncertainty about whether the new drug is better, the same, or worse than the (inadequate) standard treatment. Many doctors participate in trials because they fervently believe the new regimen is better than the standard one. But the evidence shows, again and again, that on average, new drugs outperform old ones in a small portion of instances (maybe around 15-20%). It is just as likely that new drugs will underperform standard treatments- making patients sicker perhaps, or failing to deliver as much punch. So one concern about the article is the premise that doctor's personal beliefs about which cancer drug will perform better in a randomized controlled trial carries some moral weight. The evidence shows doctors in the aggregate haven't a clue- which is why functional healthcare systems run trials.

A second troubling premise here is that there is no harm to allowing public consumption of drugs that are not yet validated in rigorous clinical trials. CEOs of many pharmaceutical companies perhaps may share this view. But the historical record shows otherwise: in fact, many patients are severely harmed when drugs are introduced into clinical use before they have been established as safe and effective. Perhaps a few readers out there may be familiar with thalidomide? Or autologous bone marrow transplantation for breast cancer? Ever considered the price tag on these new cancer drugs, and do you want your government or insurance company purchasing a potentially useless drug?

Still, article zeros in on an ethical tension that is very difficult to eradicate from clinical research. Patients want- and are entitled- to be treated as individuals. Physicians also prefer to treat patients as individuals. Clinical trials, however require that patients be treated as tokens of larger populations- that they be treated, in a sense, as "stand ins" for future patients. Randomization has not been shown to deprive patients of access to life preserving drugs. However, it does rob patients of fulfilling their desire to be treated as individuals and to exercise personal choice. And this is one of the reasons why the field of research ethics is endlessly fascinating, important, and nettlesome. (photo credit: travelingMango 2008).

6 comments:

Anonymous said...

The issue of randomization between something new and promising, and an old non-effective treatment is a very tough one in cancer treatments when placing oneself as patient, doctor, researcher… However, the alternative of changing the treatment arm at a given (reasonable) time depending on physicians’ decision is a solution that may comply with the requirements of all the decision makers involved, and give physicians and patients the more individualized treatment they need. Why isn’t this option common practice in situations like this one?

Anonymous said...

Thanks for your post. The points you find problematic are actually typical concerns of people who haven't fully researched how our system works. Why do you believe that a randomized controlled trial (RCT) is the only way to know whether progress has been made? Is it because you have heard that RCTs are the “gold standard” so many times from so many people wearing white coats, that you just take it for granted? Most people actually do base their beliefs about medicine and clinical research on precisely that level of evidence, and they are wrong.

The controversy surrounding this drug, which includes a fairly significant and unprecedented rebellion among many clinical research oncologists, which consists of a great many very knowledgable people bluntly questioning the ethics, and the scientific and medical necessity, of the trial the FDA is causing Roche to run – in which patients are and will continue to die prematurely for no good reason other than to generate something called a p-value for a narrow-minded regulator at the FDA (Dr. Richard Pazdur, Director of the Office of Oncology Drug Products) has been building for years. The startling safety, clinical benefit and scientific promise of PLX4032 has finally caused something of breakthrough in thinking among oncologists, which could force real, very much needed change in the way FDA regulates clinical research being conducted to support approval of new cancer drugs. The FDA will and is resisting, as will some dinosaurs in the clinical research community, but the winds of change, finally after 60 years of stagnation fiercely defended by the FDA, is coming.

The randomized trial for PLX4032 really is grossly unethical and scientifically and medically meaningless. Note that some very experienced and knowledgable docs are quotes in the Harmon stories as saying quite bluntly, we have a problem here. It is certain that PLX4032 will be approved, and it is certain that thousands of patients will benefit with longer, better lives when it is finally approved. This delay is being caused by rigid enforcement of a policy made unilaterally by Dr. Pazdur in 2003. That's it. That's the reason this trial is being run.

What is happening with PLX4032 is starting a process of change, but it won't come fast enough for the patients being used up in the trial control arm, and the thousands more waiting outside trials they can't get into, and dying while they wait?
What of them?

Anonymous said...

Thanks for your post. The points you find problematic are actually typical concerns of people who haven't fully researched how our system works. Why do you believe that a randomized controlled trial (RCT) is the only way to know whether progress has been made? Is it because you have heard that RCTs are the “gold standard” so many times from so many people wearing white coats, that you just take it for granted? Most people actually do base their beliefs about medicine and clinical research on precisely that level of evidence, and they are wrong.

The controversy surrounding this drug, which includes a fairly significant and unprecedented rebellion among many clinical research oncologists, which consists of a great many very knowledgable people bluntly questioning the ethics, and the scientific and medical necessity, of the trial the FDA is causing Roche to run – in which patients are and will continue to die prematurely for no good reason other than to generate something called a p-value for a narrow-minded regulator at the FDA (Dr. Richard Pazdur, Director of the Office of Oncology Drug Products) has been building for years. The startling safety, clinical benefit and scientific promise of PLX4032 has finally caused something of breakthrough in thinking among oncologists, which could force real, very much needed change in the way FDA regulates clinical research being conducted to support approval of new cancer drugs. The FDA will and is resisting, as will some dinosaurs in the clinical research community, but the winds of change, finally after 60 years of stagnation fiercely defended by the FDA, is coming.

The randomized trial for PLX4032 really is grossly unethical and scientifically and medically meaningless. Note that some very experienced and knowledgable docs are quotes in the Harmon stories as saying quite bluntly, we have a problem here. It is certain that PLX4032 will be approved, and it is certain that thousands of patients will benefit with longer, better lives when it is finally approved. This delay is being caused by rigid enforcement of a policy made unilaterally by Dr. Pazdur in 2003. That's it. That's the reason this trial is being run.

What is happening with PLX4032 is starting a process of change, but it won't come fast enough for the patients being used up in the trial control arm, and the thousands more waiting outside trials they can't get into, and dying while they wait?

What of them?

Anonymous said...

Thanks for your post. The points you find problematic are actually typical concerns of people who haven't fully researched how our system works. Why do you believe that a randomized controlled trial (RCT) is the only way to know whether progress has been made? Is it because you have heard that RCTs are the “gold standard” so many times from so many people wearing white coats, that you just take it for granted? Most people actually do base their beliefs about medicine and clinical research on precisely that level of evidence, and they are wrong.

The controversy surrounding this drug, which includes a fairly significant and unprecedented rebellion among many clinical research oncologists, which consists of a great many very knowledgable people bluntly questioning the ethics, and the scientific and medical necessity, of the trial the FDA is causing Roche to run – in which patients are and will continue to die prematurely for no good reason other than to generate something called a p-value for a narrow-minded regulator at the FDA (Dr. Richard Pazdur, Director of the Office of Oncology Drug Products) has been building for years. The startling safety, clinical benefit and scientific promise of PLX4032 has finally caused something of breakthrough in thinking among oncologists, which could force real, very much needed change in the way FDA regulates clinical research being conducted to support approval of new cancer drugs. The FDA will and is resisting, as will some dinosaurs in the clinical research community, but the winds of change, finally after 60 years of stagnation fiercely defended by the FDA, is coming.

The randomized trial for PLX4032 really is grossly unethical and scientifically and medically meaningless. Note that some very experienced and knowledgable docs are quotes in the Harmon stories as saying quite bluntly, we have a problem here. It is certain that PLX4032 will be approved, and it is certain that thousands of patients will benefit with longer, better lives when it is finally approved. This delay is being caused by rigid enforcement of a policy made unilaterally by Dr. Pazdur in 2003. That's it. That's the reason this trial is being run.

What is happening with PLX4032 is starting a process of change, but it won't come fast enough for the patients being used up in the trial control arm, and the thousands more waiting outside trials they can't get into, and dying while they wait?
What of them?

Anonymous said...

My wife has stage IV Melanoma. I won't bore you with the story - but we have pretty much been told to go home and die. This comes after being tested positive for the Braf Gene - yet not qualifying for a ridiculous reason for the PlX4032 trial.

There are over 8,000 patients dying each year from this Beast. This drug has already proven to be better than anything currently available (which is pretty much nothing anyways!). The one thing I have learned over the years is that nothing motivates people more than money - or lack thereof. Why not a class action against the FDA? Money won't solve our problem - but hitting them with less of it may make them think twice before killing thousands of people over old rigid policies long overdue for change. Surely we have enough people out there who would be happy to spend a few bucks to hit them where it really hurts.

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