Chapter 20: The Controversy over Randomized Trials

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Chapter 20: The Controversy over Randomized Trials

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Dr. Benjamin begins this chapter by commenting on how today's research approval processes would hinder studies of anthracylines in patients with abnormal liver function. He states the research philosophy at MD Anderson: treat everyone, regardless of how sick they are and determine why they are ill. Dr. Benjamin then talks about the belief held in the Department of Developmental Therapeutics that randomized trials were unethical.

Identifier

BenjaminR_02_20150116_C20

Publication Date

1-16-2015

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The Researcher; The Researcher; Controversy; Understanding Cancer, the History of Science, Cancer Research; The History of Health Care, Patient Care; Patients, Treatment, Survivors; Ethics; On Research and Researchers; Professional Values, Ethics, Purpose; Critical Perspectives

Transcript

Tacey Ann Rosolowski, PhD:

So this may be a loaded question, but would that study—what would be different about doing that study now, you know, in terms of getting approval? (laughs)

Robert Benjamin, MD:

Okay. So, first of all, we would not have learned that in the initial study, because the initial study would have excluded all patients with significant abnormalities of liver and kidney function, because everybody protocol today that’s written says, you know, everything has to be within certain parameters, even if they’re irrelevant. But the basic boilerplate for every protocol has that information in it, so we always copy it. We always do it that way.We could have written a specific separate protocol to see what happens to people who have abnormal liver function, and there have been some protocols like that written where pharmacology of drugs in people with abnormal end organ function has been studied, and the ones that I can think of were actually written by a physician who became sort of probably the preeminent clinical pharmacologist of antineoplastic drugs, who was a student working in the laboratory where I was doing the Adriamycin studies.

Tacey Ann Rosolowski, PhD:

His name?

Robert Benjamin, MD:

Merrill Egorin.

Tacey Ann Rosolowski, PhD:

Marilee Gorin [phonetic]?

Robert Benjamin, MD:

Merrill.

Tacey Ann Rosolowski, PhD:

Oh, Merrill. And then—

Robert Benjamin, MD:

$$Egorin, E-g-o-r-i-n. He, unfortunately, died a couple of years ago of myeloma. But he’s done some very interesting studies of the effects of abnormal organ function on the pharmacology of drugs, where the pharmacology had already been known in patients with normal organ function. When we did it, it was just treated everybody, and we treated people that we probably shouldn’t have, because they got very sick. But because we were measuring the blood levels, we knew exactly why they were getting sick, and we were then able to compensate for that pretty quickly. So that’s in my original clinical pharmacology paper on Adriamycin.

Tacey Ann Rosolowski, PhD:

And I’m kind of seeing by some of the work done in Developmental Therapeutics was controversial, because this whole—I mean, these drugs are incredibly powerful, and you administered them.

Robert Benjamin, MD:

Oh, yeah.

Tacey Ann Rosolowski, PhD:

People get sick. Ostensibly they’re making the patient worse. So I can see where this was a large subject for discussion in the institution at the time.

Robert Benjamin, MD:

Yeah. We sometimes made sick people sicker.

Tacey Ann Rosolowski, PhD:

How did you respond to any comments or those arguments against what the kind of philosophy of Developmental Therapeutics?

Robert Benjamin, MD:

So, I mean, it’s what’s the alternative? Does a patient really care whether he dies of drug toxicity when you’re trying to make him better versus whether he dies of cancer because you tell him there’s nothing you can do? Most patients, if they’re not too sick to begin with and just ready to die, will tell you, “Well, isn’t there something you can try for me?” As I say, patients don’t want to die. They don’t not want to die of drug toxicity; they don’t want to die, period. If there’s any chance that you can make them better, they want to take that chance. We see that all the time with people who come here.The problem now is now we’re much better at treating cancer than we were when I started doing it, but at the same time, we’re also much more limited. The only way you got treated when we started off was to be on some sort of a study, because there was no established treatment. And in Developmental Therapeutics we argued that in most cases, having a control group was unethical because we knew how bad those results were, and it wasn’t a question of was the new treatment worse than control. That didn’t matter. It had to be better than control. You had to have something that offered the patient some chance of doing better than on the minimally effective therapies that were there at the time.But we got criticized for that because we would make a leap of faith that says if end results of the treatment are better than we expected, that that was due to the treatment, and people would always say, “Well, how do you know it wasn’t just due to the selection that you used and the criteria and whatever?” And that’s very hard to deal with. I mean, the argument is scientifically sound. It’s just there’s sort of an absolute minimum acceptable status for each patient, and if the patient is about to die and you don’t do anything to show that they’re going to die, that’s not something that any of us would want to be put into the position of having, and sometimes you run out of things to do. Now we don’t have all of those studies that we can put patients on because the studies are much more restrictive. Then what do you do? Do you do something you know doesn’t work just because the patient says, “I want treatment”? I think the answer is no, you can’t do that. But that’s—

Tacey Ann Rosolowski, PhD:

Interesting.

Robert Benjamin, MD:

There are times that even I give up, but not often.

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Chapter 20: The Controversy over Randomized Trials

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