Chapter 04: Challenges of Clinical Trials: Informed Consent

Chapter 04: Challenges of Clinical Trials: Informed Consent

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Description

Dr. Cox explains that, while in his residency at Penrose, he became interested in the issues involved when obtaining the collaboration of patients in a study. He then discusses informed consent at length, describing the issues involved and making reference to the Tuskegee syphilis case as a summary of the ethical issues at play. To demonstrate his ideas about informed consent, Dr. Cox describes a trial on cancer of the esophagus. While patients treated with radiation or surgery had some results, pairing chemotherapy with radiation therapy has such profound results that they “couldn’t ethically continue the trial.”

Dr. Cox explains that the Data Safety Monitoring Committee makes recommendations to stop any trial that is not ethically sound. Dr. Cox talks about several cases in which trials were conducted without any informed consent, and talks about the ethical and philosophical issues involved. He notes that informed consent was not a prominent issue until the 1970s, though now Institutional Review Boards are “out of hand.”

Identifier

CoxJ_01_20130103_C04

Publication Date

1-3-2013

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The Researcher; Institutional Processes; Institutional Mission and Values; Ethics; Ethics; Professional Values, Ethics, Purpose; The Professional at Work; The Administrator; The Administrator; Understanding Cancer, the History of Science, Cancer Research; The History of Health Care, Patient Care

Transcript

Tacey Ann Rosolowski, PhD:

I was actually thinking about earlier—how your research started before you even came here.

James D. Cox, MD:

Well it was also influenced by people in the field that I got to know—del Regado being one of them. I mean—when I was a resident at Penrose we were involved in what subsequently, I think, came to be known as the BO4 trial of the NSABPN—the National Surgical Adjuvant Breast—later Breast and Bowel Project—which was run by a surgeon, Bernie Fisher.[Dr. Bernard] We were injecting patients who had just had a mastectomy—I guess—with drugs in the perioperative period trying to prevent metastasis. That was part of the work that was done. And then there were trials of their getting postoperative radiation to the breast. Then I became interested in the process of how you used the clinical information to pose questions and how you involve the collaboration of patients in the answer of those questions because patients became collaborators too.

Tacey Ann Rosolowski, PhD:

How so?

James D. Cox, MD:

Well because you were asking them to participate in a laboratory—in a clinical investigation, and then there is the whole big area of the ethics of clinical trials, which I also became very interested in and involved with to some degree. Although it was not a part of informed consent in those early years, it subsequently became clear that in the informed consent was the commitment that you would—that the patients would be able to know the results of what happened to them as a group, and if the results were profound and striking it might even—you know—it might even change what would be done for them, but that is pretty rare. And then by chance when I was—there are many digressions, and I do not want to get too involved in them, but when I was active with the American College of Radiology at first as a member of the steering committee and then later as a chancellor, one of the people that I got to know was a guy named Paul Gebhard who is lawyer—who was the lawyer for the College of Radiology at the time, and then an amicus brief, and I do not remember the exact case, but he was the first person to put in print the words informed consent.

Tacey Ann Rosolowski, PhD:

In what year was that?

James D. Cox, MD:

Well I think it was in the late ‘50s. I have got a brief reference to it somewhere in something that I wrote because we did a—when I was with the RTOG one of the sort of—I don’t know how we got the Red Journal involved with it. I guess maybe I was—was I already editor in chief of the Red Journal? I guess in the late ‘90s on the anniversary of—on one of the anniversaries of the infamous trial on syphilis in the African-American men from Tuskegee, we actually held a meeting in Tuskegee and had part of—had several—I think three or four papers contributed to the Red Journal—you may be familiar with it. This is the journal I am talking about. It’s over there next to you too.

Tacey Ann Rosolowski, PhD:

Radiation Oncology? James Cox. MD Yeah. It’s this. International Journal of Radiation Oncology. One of the issues had the sculpture of Booker T. Washington outside—see that Tuskegee anniversary on the cover, and in that I wrote about the history—it was an editorial, so it was not long. So it was sort of taking the old history from the syphilis trials and how things had changed since that time. And in that editorial I referenced the work of Paul Gebhard and his use of the term informed consent for the first time in the legal arena.

Tacey Ann Rosolowski, PhD:

So this was—this idea of informed consent—it seems like it was evolving and actually becoming kind of a theoretical piece of how you were seeing the design of experiments with seeing patients as collaborators?

James D. Cox, MD:

Yeah. It was. I mean—I think—certainly my whole view of informed consent changed, but that was part and parcel of the evolving interest in clinical research and philosophical and mechanical and the administrative and the scientific and the results. And then when we got the results of probably the earliest trial I recall, it was a trial in cancer of the esophagus, which was at that time a disease that killed almost everybody that was afflicted. And we treated them with radiation therapy or they were treated surgically, and the results were terrible with both. And there were various ways of trying to combine radiation therapy and surgery, and they by and large did not work. And putting chemotherapy together with radiation therapy had really quite a profound effect. I mean—there were people who were cured of the disease. And so a clinical trial was done that compared chemotherapy and radiation therapy versus radiation therapy alone, and the results were so strikingly different that they had to stop the trial. They could not ethically continue it anymore and—

Tacey Ann Rosolowski, PhD:

And what year was this about?

James D. Cox, MD:

I think the first publication was probably about somewhere around—somewhere between 1990 and 1992 and probably the more definitive publication was in JAMA in about ’99.

Tacey Ann Rosolowski, PhD:

And you were involved with this trial?

James D. Cox, MD:

I was heading the RTOG when the results of that trial came out. It was started in the ‘80s. I was involved in the RTOG in the ‘80s, but I was not directly involved with the start of the trial. But when it came out and we had the results that required us to stop the trial, I was involved with that.

Tacey Ann Rosolowski, PhD:

So how did that work? The results came out, and did—were they sent to a committee?

James D. Cox, MD:

Uh-hunh (affirmative).

Tacey Ann Rosolowski, PhD:

Did you convene a committee?

James D. Cox, MD:

This was where we—very early times when we had the Data Safety Monitoring committees. And the Data Monitoring—we had to present the results to the Data Monitoring committee, which were all independent people. They were not RTOG members. They were absolutely independent, and you presented the studies to them, and they indicated whether—their recommendation—I mean—they could not say do this or do that, but their recommendation was either to stop the trial or to continue it on. If the results were sufficiently similar, they would say continue it. And if the results were strikingly different, they would say, “You have got to stop because you cannot enroll people in a study where you know the results of the other arm are much better.” So there are some interesting philosophical and ethical issues related to clinical trials. There was a time when nobody paid attention to those at all. I mean—some of the most famous people in the United States accomplished terrific things by doing things with patients where the patients had no say in it whatsoever, and there wasn’t any idea of informed consent. I think of the trials of treating burns in patients—the trials that were done in Boston in—I think in the ‘50s—by Francis Moore and others in terms of how to manage serious burns. They did things with those patients that were not—well—there was no consent involved. They just did them. And sometimes they were successful, and sometimes they were totally unsuccessful. But the patients were going to die anyhow, and so they figured we got to do something. That drove a lot of the decision-making before the idea of informed consent came about. And the informed consent really—I believe—was not prominent—it did not begin to become prominent until the early ‘70s. It was at the early ‘70s when there was the discovery of what had been done in Tuskegee and the just awful thought that people had—men had not been treated for syphilis when they knew that there was a medication that could cure them. And then the whole idea of informed consent developed and institution review boards developed, and then maybe institution review boards got out of hand as they have here. But that is a whole interesting story all on its own. I remember there is a wonderful article written by Atul Gawande—you know him?

Tacey Ann Rosolowski, PhD:

Uh-hunh (negative).

James D. Cox, MD:

It was—it is actually a biography of Francis Moore. And Gawande covers the history of what Moore and his colleagues did in treating burn patients in Boston and how they did things by trial and error. And when the trials were successful, they profoundly changed the practice of medicine. And Francis Moore was kind of a wild man—I mean—he did things that I think people thought were pretty crazy, but they cured some people and changed medicine. And later on Francis Moore became one of the people who were most strict about not wanting to see that done in the future.

Tacey Ann Rosolowski, PhD:

Interesting.

James D. Cox, MD:

He was one who was most strict about informed consent and not doing things on patients for which there was no approval by anybody. In his later life he went—anyhow Gawande does a wonderful job. It was published in The New Yorker, and it is a great piece.

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Chapter 04: Challenges of Clinical Trials: Informed Consent

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