The Ethics of Necessity

MD Anderson Cancer Center
Date: October 2013

 

Jeffrey S. Farroni, PhD, JD: Today’s episode: the ethics of necessity. At its most fundamental level the translation in translational science refers to taking discoveries and findings that emerge from the laboratory bench and driving them toward clinical impact and utility. So this movement of translational science predicates itself on the notions of collaboration, multidicliplinarity, particularly this era of complex research involving teams of scientists. But you, know this idea is not necessarily novel. The idea of a collaborative team-based framework for patient centered research was actually implemented in the 1950’s at the National Cancer Institute’s clinical center.

Emil J. Freireich, MD:   What was important about the clinical center when it was founded is that the brilliant people thought of creating such a place wanted to put doctors and patients in a milieu where they were surrounded by laboratory scientists. They were the first translational people. They wanted to see the result of basic science research converted to the clinic. So you can cure a mouse…so we had the scientific bases for what we were about. We did things that people would laugh at today because it was just stupid to do that kind of work.

Farroni: That was Dr. Emil Freireich who is the Ruth Harriet Hainsworth chair of developmental therapeutics at the University of Texas MD Anderson Cancer Center. Dr. Freireich is a cancer research pioneer in the area of leukemia treatment. What is interesting is his approach to research within this translational like environment and also his confidence and resolve for the research decisions that were made at the time and, most importantly, his dedication to his patients. Now, one general issue that arises in research ethics is distinguishing medical practice and research. The Nuremberg Code mentions that an important aspect of clinical research is that it yields “fruitful results for the good of society.” The code of federal regulations that governs human subject protections, defined research as the “systematic investigation that’s designed to contribute to generalizable knowledge.” The Belmont Report makes a careful distinction between therapeutic practice and the conduct of research, particularity if they’re blended together. Now, most would not argue that physicians have a fiduciary duty to serve the best interest of their patients. But less certainty exists around a researcher’s duty to study participants. Some believe that the researcher has indeed has the same duty that a physician would to his or her patients. While others believe that researchers have more of a protective duty, which means that they would certainly inform a potential participant about such things as the risks involved with a particular protocol, what are alternatives to participating in the research, the right to withdraw from the research project, etc. At the heart of the conflict is how does one balance practice, which aims with reasonable certainty to treat the patent in front of you versus research which serves the generalizable interest of future patients. How do you balance these sometimes opposing aims? But here we will take a look at the context by which Dr. Freireich conducted his groundbreaking research and the context by which informed his ethical approach.

Freireich:   We found ourselves with a group of young guys who had little or no research training. They maybe had done, I had done, one publication or something of that kind. When I was hired by Dr. Zubrod, who was running the Clinical Center, he said, “what do you do,” I said “I am a hematologist.” That’s because I had two years of hematology training in research. So he thought a minute he said, “Hematology…cancer…why don’t you cure leukemia?” And that’s how it all came about, you know.  I had inherited five kids dying of leukemia…and you know…If you…how does it go? If you find yourself in a pile of horseshit, you look around for the horse.  Well you know, there we were, we didn’t know what to do, so you do the best you could do. So went to work

Farroni: Along with the mandate to cure leukemia was the dogma of the day involving cancer treatment.

Freireich:   Is that attempts to treat these children were futile. In general people felt, or the gestalt in the literature was that cancer could never be cured because the cancer cell was identical to the normal person’s cell. So how could you kill, dissolve, the left ear and leave the right ear intact, so to speak. So treating cancer was a matter of just surgery and radiation, local treatment. But once the disease spread outside the local thing, it was hopeless to treat it with systemic therapy made no sense. But since we had nothing else to do, we went ahead and did it. So really our formulation of the ethics of research was the same as the ethics of getting out of a drowning boat, I mean, you just did what you could do…there weren’t any options.

Farroni: The hopelessness of systematic cancer therapy in a way helped guide Dr. Freireich ethical approach of both treatment and clinical research.

Freireich:   Remember when you experiment, your concern is to find the answer to a question. When you investigate, that’s why my department was called Developmental Therapeutics not Experimental Therapeutics, we don’t experiment on people. We only offer people things that could potentially be more beneficial than harmful. We are doctors so we follow the Hippocratic Oath.

Farroni: In 1976 after already two decades in clinical cancer research, Dr. Freireich was honored by the American Society for Clinical Oncologists with the David A. Karnofsky Memorial Award and Lecturer. Now this is an award that recognizes an oncologist who has made outstanding contributions to cancer research, diagnosis and/or treatment. Now it was during this lecture that Dr. Freireich took the opportunity to reflect on his guiding principles of clinical research and it was where he formulated what has been called as Freireich Seven Laws. This lecture served as a springboard to stimulate dialogue regarding particular barriers or obstacles in the conduct of clinical research. And these laws touched on a number of issues from research regulation, healthcare delivery, statistics even, setting priorities, academic environments, and ethics. And it’s this ethical commitment to the patient that Dr. Freireich felt was most important, in fact it comprises Freireich’s Law Number 1.

Freireich:   You know Freireich Law Number 1? The primary beneficiary of clinical research is the patient who’s participating in that research.

Farroni: Dr. Freireich calls this the clinical investigators creed and was quite controversial at the time. So let’s examine what lead to this formulation of research ethics, by providing the context by which Dr. Freireich was faced in the clinical center back in the 1950’s.

Farroni : What did a leukemia diagnosis mean?

Freireich: Well at that time leukemia diagnosis were death certificates. Median lifespan was about 6-8 weeks and 100% of them were dead in 8 months.

Farroni: So there was an imperative to do something?

Freireich: Well. It’s a death sentence. But it’s not, as I have said many times, its one thing to die. You get hit by a car or you get shot…tragic. But leukemia is horrible. These children literally bled to death. They drown in their own blood. Now they’re 4-10 years old, they don’t know what the hell is going on. But they’re bleeding from the nose, their eyes are all covered with blood, blood coming out of their mouth, they have bloody urine, they have black stools, they can’t breathe….it’s really horrible. So you can imagine a young guy like me, facing this kind of horribleness….we didn’t know what to do.

The engine behind it was the parents. There is no doubt that we face the opposite of an ethical problem. It was the parents who drove the investigation. “You have got to do something for my son.“  When you are treating children, the main business is treating the parents. Children are wonderful, particularly, under the age of 10. They have no anticipation, they don’t think about dying, or being sick, or being poor, or being rich, or being successful, you know. They are just happy kids; they just do the best they can. So they’re sick, but the parents are overwhelmed with horror. The human being’s most horrible experience is probably having your child sick and dying.

So the big discovery came because of a parent. I had a patient whose name was Scotty Dinsmore and I still remember it like it was today. And Scotty’s father was a minister and he was their only child. He was totally developed he was 5 years old. Scotty was lying in bed bleeding to death and his father came in and said, “Dr Freireich you have got to do something, not so much that he is bleeding, but he’s miserable…torture, I can’t stand it.” I said “well I’ll tell you, I do have an idea, all my laboratory studies indicate, that these children are bleeding because they do not have enough platelets and Dr. Brecher has shown in dogs that they have an anticoagulant in their blood. So the obvious thing for me is to do is to replace the platelets and the plasma. I said “can you get me 20 volunteers to come to my lab and allow me to exchange transfuse, the way you do it in newborn children with erythroblastosis. When you are doing an exchange, you are exchanging the good and the bad, you really have to exchange about two blood volumes to get a 50% increase. So we had to exchange two blood volumes, and then his platelet count was normal. But that wasn’t the important thing, the important thing was during the procedure, all the bleeding stopped, right before our eyes. And we got blood from parents, freshly drawn in plastic bags and gave it to these children….night and day. It didn’t take 10 children to prove that when we got the platelets up and beyond the bleeding threshold, the bleeding stops immediately…problem solved.

Farroni: Not quite, even after it was determined that the anticoagulation was due to the platelets the debate arose as to whether fresh blood or banked blood would be the most effective.

Freireich:   Dr. Brecher and Dr. Schmidt decided to have a high level conference in our big conference room in the top floor of the Clinical Center where all the clinical directors and all the scientific directors, and all the big guns came and we presented this issue. I presented our data and they presented their data and when it was done Dr. Brecher, who was 30 years senior to me and 50 publications and I have none, says “Ok. Problem solved, we will not issue fresh blood from the blood bank.” Of course I was crushed, my whole career was ruined. Although I wasn’t fired, but Dr. Zubrod who was a hero of a scientist, he was a devout Catholic who went to mass every morning. This was the highest quality human, when you talk about ethics, this was a high quality man, he looked at it objectively not emotionally. And he stood up, hundred people in the room, and he said, “Dr. Schmidt, when the doctors in my institute order fresh blood, you have to deliver it.” In public! Everybody took a deep breath and we walked out of the room. No one could believe he could do a thing like that in public.

Farroni: With the go ahead for fresh blood granted the next step was to conduct a perspective randomized study to address the issue of fresh versus banked blood.

Freireich:   Execution hearing. The bad guys, the good guys, the judges, in one room, at the same time.  Statistician knows nothing, the guys who know it doesn’t work, the guys who know it does work, and it is the impartial people: Dr. Zubrod and Dr. ___  all in the same room. We are going to break the blind, in public. Patient #1. “Freireich, did this patient benefit, yes or no?” Patient #2, “Dr. Schmidt, Patient 1, did he get get fresh blood or banked blood?” We had finished something, I can’t tell you the exact number without looking, 10 to 13 children, it was like night or day. The only ones who stopped bleeding were the ones who got fresh blood.

Farroni: What did this mean for patients?

Freireich:   Mortality from hemorrhage…gone!

Farroni: Apart from addressing the hemorrhaging was treating the cancer itself. Now this was a time when some of the first therapeutic agents were being developed. Things like methotrexate, vincristine, and others. And Dr. Freireich had a radical idea at the time. So Dr. Freireich suggested that combining 4 drugs, a regimen of vincristine, methotrexate, 6-MP and prednisone. If you administer a full dose, utilizing or leveraging a different mechanism of action for each of these patients that that would be the most effective way of treating the leukemia. Some of the contemporaries of the time thought that this idea was crazy. That you would be killing these kids. But again, Dr. Freireich, faced with this ethics of necessity said yes we could do something now about the hemorrhaging and these agents by themselves could prolong a child’s life. But that wasn’t good enough. We were going for a cure.

Freireich:   Again, the driver for my discovery was the parents and the children. These are children who we can put into remission 75-80% of the time. We got four drugs, and we can prolong their lives, instead of only six to eight months to a year, maybe a year and a half. So we were making progress, I want to take these children newly diagnose and give them four agents at the same time…pretty crazy. If you were a parent, would you agree?

It’s again the parents that saved these children’s lives. So I used to meet with the parents. Once a week I would sit down in a room, call the parents, sit around and ask me questions. And I meet with any parent personally when we had to find out what was going on, we didn’t have any informed consent bullshit. They just talked to me and I told them I thought it was good and they believed me. They said, “look you can prolong their lives, we can get remissions, if you think the four drugs could approach a cure, we want to do it.”

So with the parents support, we did it. Four drugs at once, we had no idea what combinations or toxins we would see. And it’s important, you know you ask the question, “why didn’t you do it in animals first?” That four-drug combination that we called VAMP to this day has never proved useful in an animal, there is no animal model. You know it’s amazing how people get, like the platelet thing, you get attached to models of human disease. People don’t want to study patients; they want to study animals because they can experiment. Patients you have to treat.

Farroni: Gerald Bodey, who is infectious disease specialist that worked with Dr. Freireich is quoted as saying that he opposed it. He said quote, “giving these kids 4 drugs all at once, as a Christian, I thought it was immoral because if they relapsed, we would have no fallback. I thought Freireich was crazy.” The initial results were astounding. They had 16 patients, 11 were functionally cured. In fact, today, a childhood diagnoses of acute lymphoblastic leukemia has a 95% chance of attaining remission and approximately 80% of patients age 1-18 long term event free survivors. A cure!

In the context of translational research, I think Dr. Freireich sums it up best:

Freireich:   All progress in human disease starts at the bedside. All. It’s bedside to bench and back.

Farroni: You have been listening to the research ethics podcast, which aims to highlight the ethical and  humanistic dimensions of translational research as a way to deepen ones understanding of the complex and challenging issues facing researchers, clinicians, research participants and the  public. I’m Jeff Farroni from the University of Texas MD Anderson Cancer Center; along with my colleague Craig Klugman from the University of Texas Health Sciences Center San Antonio and a special thanks to The Governors from Austin, Texas for the use of their music.