Chapter 04: Setting Up Testing Laboratories and Clinics and Building Research
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Description
In this chapter, Dr. Freedman explains how he came to assume the positions of Director and Chief of Immunology and Molecular Biology Research (’88-‘07). This narrative brings together various details: treatment of rare gynecological cancers, billing practices, regulation of laboratory testing, and research.
Identifier
FreedmanR_02_20120301_C04
Publication Date
3-1-2012
City
Houston, Texas
Interview Session
Topics Covered
The University of Texas MD Anderson Cancer Center - Building the Institution; The Administrator; The Researcher; The Clinician; Definitions, Explanations, Translations; MD Anderson History; MD Anderson and Government; MD Anderson Snapshot; Devices, Drugs, Procedures; Overview
Transcript
Tacey Ann Rosolowski, PhD:
This is Tacey Ann Rosolowski, and today is March 1, 2012. The time is just about 1:30, and I’m speaking with Ralph Freedman at his home in Houston. This is our second session together.
Tacey Ann Rosolowski, PhD:
We had just started talking about the various titles in different departments, and I had noted from your CV that you are chief and director of immunology and molecular biology research, and you were starting to talk about kind of the workings of that in the department.
Ralph Freedman, MD:
So when I came to MD Anderson, it was ’76, 1975. I mentioned to you last time that I was working in Dr. Sinkovics’ lab, and our department itself didn’t have a research lab as such. What they had was a trophoblastic laboratory, and this laboratory actually was one of 7 centers throughout the United States, which was involved in monitoring a very rare type of malignancy in females called gestational trophoblastic disease. That’s where post-conception, instead of the fetus and placenta developing normally, the fetus doesn’t develop, and the placenta develops into a tumor, and most of the time, it has a benign course. It evacuates itself or it gets removed by intervention, but in some cases, it actually developed into a highly malignant condition called choriocarcinoma. And when I came, it was Dr. [Felix] Rutledge, Dr. Julian Smith, who was the next in seniority on staff at the time, and then there was Taylor Wharton, who later became chair. So Julian Smith ran the trophoblastic disease center. What used to happen there was these patients produced human choriogonadotropin hormone, and as the same thing happens in normal pregnancy, they produce that hormone. So in the case of malignancy, because this was specific to pregnancy states, it was actually used to monitor the disease condition, so when you gave these patients chemotherapy, you could monitor their response by the drop in the HGC. In effect, it was the only condition in cancer where you could actually make a diagnosis based on history and the presence of this hormone in the blood and doesn’t require pathology, but for this condition, you wouldn’t require it. And you initiate treatment based on clinical history, clinical findings and elevated HGC, so, in fact, you shouldn’t actually biopsy these, because they were vascular, and they could bleed. So there was a thing between Julian [Smith] and Taylor Wharton. You had two people who aspired to the leadership of that department when Dr. Rutledge eventually stepped down, and both of them basically were, I think, vying for this position. And Julian––which he left and moved on. I was left with his lab that did the monitoring. Now at that time, this lab actually could bill for services, but we didn’t have the certificate from the state, so my job was to get the certificate for the state.
Tacey Ann Rosolowski, PhD:
And to clarify, that certificate allowed you to––
Ralph Freedman, MD:
To actually do the test that could be used to monitor and treat patients, and they could actually bill for those tests. So we were told, look, you don’t have a certificate, so you can’t do it. So I worked with the techs that were there, and we actually produced the information that was required in order to get the state certificate which allowed us to continue the job. The institution, however, rightly decided that all tests that were done for clinical purposes should be done in the same pathology laboratories, and I wanted that to be part of it. So what happened was they did some kind of a deal, and they left us with the lab space. They took over the assay, said was now done in clinical chemistry actually under Dr. [Karen] Fritchie, and then we were left with that and also a state-supported technician. And that was the beginning of my research program.
Tacey Ann Rosolowski, PhD:
Hmm, interesting.
Ralph Freedman, MD:
But fortunately we had something to deal with basically, we demonstrated––well, we got the certificate. If we give this up now––this functioning––we also lose our lab, so the institution came back and allowed us to keep the space and the state-supported position.
Tacey Ann Rosolowski, PhD:
Could I ask you, you said earlier that the institution rightly decided that the central pathology lab should do this. Why was that the right decision?
Ralph Freedman, MD:
Well, I think today, first of all, the law states, same as laws—that’s the authority for Medicare decisions on payments––that any test that is done for clinical purposes for decision making needs to be done in a CLIA-approved lab. CLIA is Clinical Laboratory Improvement Amendment. And you may not use those tests, and you may not document them in the charts or put them in the results unless you have CLIA approval, and that’s a law that goes back into, I think, the 1990s––it’s ‘80s or ‘90s. But this happened actually just before that. So the institution’s labs have now come into compliance with it, and actually, currently we’re facing the same problem with Dr. Mendelsohn’s lab, which are doing these mutational analyses on patients. And it’s not in a CLIA approved facility, so we’ve had to come up with a compromise situation in which those results are done, but they’re not put into the patient’s charts. The physician is informed through what they call a research station which is separate from clinic station. Clinic station is part of the medical record, but research station is not, so the physician whose patient it is is informed of that result and does not enter the result in the chart but informs Dr. [Stanley] Hamilton’s lab that is a CLIA approved facility. And they repeat the test, and then that test can be provided to the physician so that they can act on it—they can treat them with some new drug or put them onto a new protocol that uses a drug that targets their particular mutation. You probably know about some of the stuff that they’re doing.
Tacey Ann Rosolowski, PhD:
I’m imagining why the mechanism works the way it does, but if you could just confirm why what I’m imagining––
Ralph Freedman, MD:
It’s for standardization purposes. It’s so that the tests that are used to treat patients––doesn’t mean to say that the test that’s done in a CLIA approved lab is necessarily better or better done. You may have some superb scientist who does all the quality controls and actually has an assay that’s better than another lab that is CLIA approved, but the CLIA––what it does is it provides standardization and accountability. In other words, every test that goes out, whether it be hemoglobin or blood sugar or mutation analysis—it has a signature on it, and that implies that they have followed strict quality controls to do that test.
Tacey Ann Rosolowski, PhD:
Is there also a sense that if a test is part of some kind of scientific study that has a clear goal, that somehow its objectivities might be compromised or there might be some interpretation applied to it? That was just another perspective.
Ralph Freedman, MD:
Well, you’ve got investigators, of course, always enthusiastic about their work, and unfortunately, sometimes the enthusiasm takes control over their objectivity. What CLIA does––CLIA was actually designed for billing purposes. It’s a CMS requirement. CMS provides the authority for Medicare/Medicaid decisions for reimbursement, and they’ll pay just so much for a test, but it has to be done according to certain objectives. Dr. Hamilton can probably enlighten you better on this whole subject. So CLIA––I’m not sure where we are in this discussion, but––
Tacey Ann Rosolowski, PhD:
Oh, I had–– You were talking about the reporting of the various results to research station versus clinical station, just talking about the mechanisms of how a test would be repeated if it were done in a––
Ralph Freedman, MD:
Yes, just because research lab tests can be reported to researchers and to patients in aggregate. It’s permitted, and I’ve actually seen the presentation, but I’ve seen others. They say that it’s okay to report these results in aggregate. In other words, you have ten people, you’ve got one or two mutations, but what they don’t want you to do is they don’t want research labs to go out there and open up because you’d have no control. The government would have no control over these research labs and the quality, so yes, you might have one lab here that’s very, very good and then ten over here out in the countryside that are supposedly doing quality work upon which decisions are being made and the public is trusting. This provides the public with an opportunity to––an indicator of trust that the result that you’re getting has made certain quality assurance requirements, and you’re paying for that. Its effect determining what treatment is done to you, so the results have to be as accurate as possible, and also––and of course, the billing side of it.
Tacey Ann Rosolowski, PhD:
Now, was the process in the very early days when you had––were organizing getting the certificate, so you could perform the test for the––I’m looking at the form of––the trophoblastic––
Ralph Freedman, MD:
Yeah, the trophoblastic lab was called––
Tacey Ann Rosolowski, PhD:
––related disease.
Ralph Freedman, MD:
––the trophoblastic––and the center–– There were seven centers around the country doing pretty much the same thing, so it means all the patients with trophoblastic disease used to go to one of these 7 centers.
Tacey Ann Rosolowski, PhD:
That doesn’t sound like an awful lot to me, seven centers in the entire country.
Ralph Freedman, MD:
Except that it’s a rare condition.
Tacey Ann Rosolowski, PhD:
Okay.
Ralph Freedman, MD:
It’s overall–– The benign form is more common than the very malignant form, but the––it presents itself as what they call a hydatidiform mole. That’s the common version of trophoblastic disease, which is easily managed, but these patients have to be followed very closely with weekly measurements of the HGC to make sure that they don’t transition into a malignant version of that disease.
Tacey Ann Rosolowski, PhD:
How did that particular lab come to be established through the––?
Ralph Freedman, MD:
Well, Julian actually established that lab. He got technicians, and at that time, they were doing a radioimmunoassay, which is, of course, no longer done anymore. It’s now all ELISA assays. It’s an antibody targeting an antigen. When those two combine, you get a reaction with a substrate and you get a blue color. You get a color reaction, and that’s measured with a spectrometer. But at the time this was being done, you had to measure regular activity that was released in the sample, and from that, a standard curve had to be generated, and then you would get a value. Well, we tended to use less and less radioactivity in the lab for obvious reasons. The next step was developed––ELISA assays––to conduct these same assays, which in the past have been done with crude antibodies, which were not monoclonal and of course had a lot of background activity and other interactions, so the ELISA processes was a natural development from monoclonal technology. [Georges] Kohler and [Cesar] Milstein got a Nobel Prize in about, I think, ’75 for developing hybridomas, which were the combination of a cell and that can manufacture antibody with another cell that’s been immunized from the spleen of a mouse. Then the hybridoma would generate antibody, and this is the technique that we had used to generate our human antibody early on. So that’s sort of the background to this lab, and then from there, with the different research programs that I mentioned the last time, initially, we started off with vaccines, and then there was the antibody, which developed with funding from the state. And then, later on, I got into––well, we were into the vaccine phase. These vaccines were crude extracts, so they had to be purified, and that’s why we tried to develop antibodies from patients that had been immunized to see if we could go back again, isolate the antigens of importance. But in the meantime, we were moving along into a more specific therapy which is with T cells, and that was the story that I gave you last time about the adoptive therapy approaches and the work that I did with Platsoucas. So, yeah, that lab then was what was called the immunology laboratory. It was the lab that I used—took basically ‘til I retired. It was down on the fourth floor behind the operating room suite, and––
Tacey Ann Rosolowski, PhD:
In which building?
Ralph Freedman, MD:
That was in the Central Core Building, and our lab is right at the back. There are also–– I didn’t mention at the time, Dr. Lovell Jones was recruited. He’s a biochemist. So he came to occupy the original space of the trophoblastic lab and was brought in because of the department’s interest in estrogen receptors, progesterone receptors. As you know, those have been used in order to predict which patients might benefit from hormone therapy, breast cancer, and then we tried it in ovarian cancers. I worked with Jones for a while on trying to do hormone therapy in ovarian cancer, so this was an area that was not immunology, basically, but the treatments were simple. There was–– We used drugs like ethinylestradiol, progesterone in patients that we knew had receptors that could be targets for their treatment, and we did some interesting results in patients with ovarian cancer, but these had to be patients who had high expression of these receptors. The majority of patients, unfortunately, don’t have high expression. They’re undifferentiated tumors, and expression of their receptors is low, but we found that these patients did respond to a number of different hormone therapies––the two that I mentioned. Tamoxifen is another example, and we applied the same principle to treating endometrial cancer, but that was really the extent of the collaboration that I had with Dr. Jones.
Recommended Citation
Freedman, Ralph MD and Rosolowski, Tacey A. PhD, "Chapter 04: Setting Up Testing Laboratories and Clinics and Building Research" (2012). Interview Chapters. 944.
https://openworks.mdanderson.org/mchv_interviewchapters/944
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