Chapter 11: A Successful Phase III Trial and European Approval, But No FDA Approval for MEPACT
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Description
In this chapter, Dr. Kleinerman brings the MEPACT story to a close.
She first describes how the Pediatric Oncology Groups of the NCI first had a very negative reaction to the results of the Phase II trial, then explains why this turned around. Dr. Kleinerman worked with collaborators to design a Phase III trial. She describes practical and political complexities that resulted in the FDA not approving MEPACT, despite its efficacy.
Dr. Kleinerman next explains the process that won approval for MEPACT from the European Medical Association, where her work defined has become standard of care in the United Kingdom.
Dr. Kleinerman discusses FDA approval processes.
In the final moments of this Chapter, Dr. Kleinerman talks about the impact that clinical trials can have on faculty careers, when it takes years to achieve results.
Identifier
KleinermanES_02_20140529_C11
Publication Date
5-29-2014
City
Houston, Texas
Interview Session
Eugenie Kleinerman, MD, Oral History Interview, May 29, 2014
Topics Covered
The Interview Subject's Story - The ResearcherProfessional Practice The Professional at Work Collaborations On Pharmaceutical Companies and Industry Ethics Beyond the Institution MD Anderson and Government Global Issues –Cancer, Health, Medicine
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
Disciplines
History of Science, Technology, and Medicine | Oncology | Oral History
Transcript
Tacey Ann Rosolowski, PhD:
Would you mind if we just kind of close out your story with this particular drug?
Eugenie Kleinerman, MD:
Sure.
Tacey Ann Rosolowski, PhD:
Because you’re talking about the results that you received. So what’s been the fate of this therapy?
Eugenie Kleinerman, MD:
Okay. So I went to the Pediatric Oncology Branch, and they said, “No, no, we’re going to do Ifosfamide,” and that’s when I came back very dejected and talked to Dr. Fidler. He says, “You know, this is absurd.” If you—you met him, so you know him.
Tacey Ann Rosolowski, PhD:
Yeah.
Eugenie Kleinerman, MD:
“This is ridiculous.” And so he talked to Dr. Krakoff, and Dr. Krakoff says, “Look, I’m going to invite all of the experts of osteosarcoma that I know—Jerry Rosen, Joe Simone from St. Jude’s, Rich O’Reilly from Memorial Sloan Kettering—and I want you to show them your pathology lesions, because that is the thing that has convinced me that this drug is effective.” So he paid for everybody to come here. We had a meeting in his office. It turns out that Dr. Rich O’Reilly, who was chief of pediatrics at Memorial Sloan Kettering, couldn’t come, so he sent Dr. Paul Meyers, who was the clinician that took care of osteosarcoma patients, who was head of the Bone Tumor Strategy Group in the Children’s Cancer Study Group, the opposite one. He took a look. He came down, grudgingly, “Oh, you know, Rich told me I have to come down. All right, I have to spend a day.” He flew in in the morning, he was going to fly back. And he said to me, “Genie, this if fantastic. This is absolutely fantastic. I’m the head of the Bone Tumor Strategy Group. We’re having a meeting.” So this was probably about a year later, nine months to a year later. “We’re just getting ready to design a new protocol. I want you to come to present this.” And I thought, “Oh, god, I can’t take this again. I mean, you know. I just really don’t want to be pounded like I was before.” And I went and talked to my husband. He says, “You’ve got to go, Genie. You’ve just got to. Do you believe this or not?” Okay. So I went, I presented the data. It was like I was in another world. Excitement, “Yes, we’ve got to do this.” It was like, is this the same data? (laughter) Why is the reaction so different? I have no idea. So then Paul designed the Phase 3 trial, randomizing patients to receive chemotherapy alone or chemotherapy plus MTP. You know, there a lot of things I don’t know that you need in designing the trial because there still was an Ifosfamide group, and at that time then the NCI said both of the two pediatric groups have to merge. And so the Children’s Cancer Study Group won in terms of which protocol, and so to appease them, Paul built in an Ifosfamide arm, and so it ended up being a four-arm trial, which created problems down the road.
Tacey Ann Rosolowski, PhD:
What problems did that create?
Eugenie Kleinerman, MD:
Okay. So at the time of the design of the trial, the way one did it—because what patients were, it was a double randomization. You either got randomized to receive three drugs or four drugs, and then the second randomization was did you receive MTP or not receive MTP. At the time, when there was a double randomization, it was done upfront. So that means a patient comes in, “Yes, I’ll be on the trial.” Okay, the computer is going to say are you assigned to three drugs or four drugs, and then randomize you again; are you going to get MTP or not MTP. The problem with that is the way we look at prognostic signs in osteosarcoma is we give preoperative chemotherapy, then we resect the lesion and we look at it under the microscope. If there is less than 95 percent necrosis, those patients have a poor prognosis. They’re more likely to relapse. So you can see if in one group you have a higher percentage of poor prognostic people, that can throw your data off. We did not include in the trial what we call stratification, to make sure that the arms were balanced for poor prognostic. And in retrospect, there was a higher percentage of poor responders in the group of patients that got three drugs plus MTP, so that threw off the analysis when you compare three drugs to three drugs plus MTP. Now, four drugs and four drugs plus MTP, they were balanced for some reason, and there was a clear advantage to both disease-free survival and survival in the patients that got MTP. In the three drugs, there was only advantage in survival, not disease-free survive. So the NCI says, “We don’t understand. How can you not have an effect on disease-free survival?” Well, to me, it’s easy, because disease-free survival depends on when you look, right? But survival, you can determine whether a patient is alive or dead, correct? You don’t need an MD degree.
Tacey Ann Rosolowski, PhD:
(laughs) Yes.
Eugenie Kleinerman, MD:
But what you call relapse, if the patient, “I can’t come in this week. I can come in next week,” they come in next week or they come in earlier or—you know, what’s on the x-ray, maybe it’s a lesion but maybe it’s the lesion like I did that if I didn’t look.
Tacey Ann Rosolowski, PhD:
[unclear], yeah.
Eugenie Kleinerman, MD:
And people don’t have the resources to do the analysis that I had to do. But the FDA couldn’t grasp that, so they said even though there was 700-plus patients randomized at the trial, it was the largest osteosarcoma trial ever done in the United States, they wouldn’t give approval. They said, “You have to do another trial.” Well, the company said—now, I should also tell you, in the middle of the trial, the Phase 3 trial, Ciba-Geigy decided, “We’re not interested in this drug anymore. It’s not going to be a moneymaker.” And they stopped making it. So here we were in the middle of the trial, and no drug. I had opened a melanoma trial, because that’s what I promised Josh I would do, because he was—and so I had to make a decision, do I continue the melanoma trial or do I close that and transfer all the drugs? So I did that. So I closed the melanoma trial.
Tacey Ann Rosolowski, PhD:
Okay. And used the drug that was available.
Eugenie Kleinerman, MD:
And used the drug.
Tacey Ann Rosolowski, PhD:
Gotcha.
Eugenie Kleinerman, MD:
So we had a temporary hold on the trial. Then a small biotech company picked the drug up, and they started manufacturing it so we could complete the trial. The trial was completed. That company went out of business, so we had a completed trial, but nobody to take it to the FDA.
Tacey Ann Rosolowski, PhD:
Gosh. And you had a successful trial. (laughs)
Eugenie Kleinerman, MD:
Several years later, a company, I guess, had bought the rights or whatever, the properties of this company that went bankrupt, and one of the PhD people who were looking at it went through the data and said, “Oh, my god. Here’s a Phase 3 trial that was completed, that showed increased in survival, improvement in survival, and nothing ever happened.” They had bought the company for something else, another drug, and she was just assessing what are the assets. So she came to me and came to Dr. Meyers and said, “We’d like to move forward with this.” “Really? Okay.” So they’re the ones that took it forward to the FDA.
Tacey Ann Rosolowski, PhD:
And what is that company or group?
Eugenie Kleinerman, MD:
That company was called IDM. It was a French company. That company is no more either. (laughs)
Tacey Ann Rosolowski, PhD:
Interesting.
Eugenie Kleinerman, MD:
So anyway, so we went to the FDA, and they said, “We don’t understand how you can not have an impact on disease-free and have an improvement in survival. You’ll have to do another trial.” Well, IDM said, “You know, we can’t afford to do another trial. This is an expensive drug in an orphan disease. It’s going to take another four or five years. We’re not interested.” So they had a fairly—so the guy who was the CEO at that time, of course, lost his job, and so the person who took over, the guy who took over, was very aggressive. He says, “Okay, we’re going to take it to the EMA.”
Tacey Ann Rosolowski, PhD:
What’s the EMA?
Eugenie Kleinerman, MD:
The European Medicine Association, so the FDA equivalent in Europe. So, okay. So it was, I believe—I don’t [unclear] the first time. Okay. So the first time, so I flew to London to present the data with Dr. Meyers, and we presented it. And the EMA, the experience in the EMA is totally different than the FDA. In the FDA, there’s an advisory panel made up, like, of twelve people, and there’s the twelve people and the FDA picks them and whatever, and the FDA presents their data, their interpretation of the data, and the company presents their interpretation of the data, then the people vote. The EMA, you walk in and it looks like the United Nations. You have circles of each country has two representatives, and in front of them is a computer. So they are reviewing the primary data that you’re talking about, each individual person. The FDA, you don’t get any data here. You just see what the FDA presents and you see what the company presents. Here, they’re looking at the data.
Tacey Ann Rosolowski, PhD:
Wow.
Eugenie Kleinerman, MD:
So they had a very favorable response, and they said, “But we want to come and we want to validate the primary data in Los Angeles,” because that’s where the headquarters of COG was. So they sent—
Tacey Ann Rosolowski, PhD:
COG? I’m sorry, that’s—
Eugenie Kleinerman, MD:
Children’s Oncology Group.
Tacey Ann Rosolowski, PhD:
Oh, okay.
Eugenie Kleinerman, MD:
That was the merged group. So they sent their representatives to Los Angeles and went through the primary patient data, the charts. They looked at everything. They had their statisticians do everything. And what they said was, “You know, we noticed here that you have a higher percentage of poor-prognosis patients in the three arms. Why don’t you see if you can come up with a way—were these patients in any specific particular type—did they have any characteristics that are consistent?” So we looked and we found that there was a higher percentage of poor-prognosis patients in the group that was above sixteen that got three drugs. That doesn’t mean it doesn’t—it’s just patients who were above the age, more of them got randomized to the three drugs plus MTP. So they said, “Okay, why don’t you analyze. Look at the patient distribution for all the patients that were under the age of sixteen.” So we looked, and the arms were perfectly balanced. They said, “Okay. Do the disease-free in the long-term survival in that group.” And when we did it in that group, it showed an improvement in disease-free survival and survival in the patients that received MTP.
Tacey Ann Rosolowski, PhD:
So the, quote, “repeat” of the study was very focused, is that—
Eugenie Kleinerman, MD:
It wasn’t—it was a reanalysis, a reanalysis of the data. So we did a subgroup analysis. And the FDA says, “We don’t accept any data from the subgroup analysis. If you didn’t put that in your aims, it’s not valid.” You know, this is where I say, “Come on.”
Tacey Ann Rosolowski, PhD:
Right. Interesting. Well, I had—because the European Union approved this drug in 2009.
Eugenie Kleinerman, MD:
Correct.
Tacey Ann Rosolowski, PhD:
And the FDA has never approved it.
Eugenie Kleinerman, MD:
Correct. So the election was November 2008 that I had to fly—because they wanted us to come back and present to the whole body of EMA, because they wanted us to re-present and they wanted to reexamine all the data. So it was November 2008, and the reason I know that is because I had to vote absentee ballot for President Obama because I was going to be on a plane to London November whatever Election Day was, first Tuesday in November. So I flew to London, and I had to be back. So I flew to London. I got there in the morning. I went to the legal offices that were supporting the company, because you have to hire a legal firm that has dealings with the EMA, so they can tell you what things you have to do. Flew. We rehearsed the presentation. We went to the EMA. We presented all the data. Then you’re ushered back to a room, and within fifteen, thirty minutes, they called us back, and I thought, “Oh, god, it’s bad.” And during the presentation, I could see people were just not interested. Because there was this one representative from the Netherlands who kept badgering about the data, who kept being negative, the same things that we heard at the FDA. And Dr. Meyers and I were looking at each other, saying, ‘Oh, this is not going well. This is not going well. This is not going well.” Nobody else was saying anything. They were writing. So we went back and then they called us in and they said, “We’ve approved it.” So in retrospect, my conclusion was the reason nobody was saying anything is because they’d already made up their mind, and they weren’t going to argue with this guy, because what’s the point? They had already made up their mind. And they looked at the data on the computer and they saw everything. They said, “Okay, I’m going to approve it.” So it was a very—I don’t remember what the vote is, but it was very heavily in favor. I think there were only a few—
Tacey Ann Rosolowski, PhD:
And so this treatment is available, then, in Europe, and is it standard of care or—
Eugenie Kleinerman, MD:
It is standard of care in the UK. So the data—in the UK, you know, they have nationalized health insurance, and so something can be approved, but the British government doesn’t necessarily have to pay for it, so it has to go through a second approval process by NICE, National Institute of Clinical Excellence. So they review all the data, and only if they approve it will the government pay for it. Well, it was re-reviewed by NICE, and they pay for it, so it was part of standard of care.
Tacey Ann Rosolowski, PhD:
And just for the record, because this treatment has several names, it’s called MTP-PE?
Eugenie Kleinerman, MD:
Right.
Tacey Ann Rosolowski, PhD:
Yeah, in the European Union.
Eugenie Kleinerman, MD:
Actually, it’s Mifamurtide or MEPACT. That’s the trade name. MEPACT, M-E-P-A-C-T. That’s the trade name.
Tacey Ann Rosolowski, PhD:
All right. Wow. And so the fate in the U.S. of this is it’s not going to go anywhere because nobody’s going to have the money to do another trial?
Eugenie Kleinerman, MD:
No. So Takeda is the company that bought IDM. So after it was approved, Takeda acquired IDM because they wanted to get into the oncology market, so they bought IDM, and they had no company in the United States that did oncology, so they bought Millenium, which is in Boston. So Paul and I had been up to Millenium, and Millenium has tried to go back to the FDA, from what I understand, and the response is, “No, you have to do another trial.” Millennium’s decision, which I totally understand, is to do everything that the FDA wants us to do. They want more safety data, even though, as I told you, this drug was given to normal people when they were in accidents and actually, subsequently, normal volunteers. So the safety profile, we have twenty-five years of safety data, but they want more safety data, they want another trial, and it would cost the company close to $160 million, from what the company tells me, and they can’t, they just can’t—
Tacey Ann Rosolowski, PhD:
[unclear] do it.
Eugenie Kleinerman, MD:
How can they, for an orphan disease and the drug is now off patent. Not that anybody’s going to make it, because it’s very complicated because of this phosphatidylserine business, but nobody’s—you know, which I understand. I can’t fault the company for that.
Tacey Ann Rosolowski, PhD:
Right. Sure.
Eugenie Kleinerman, MD:
And they have asked can the FDA re-review the data, now that we have more survival data and the subset analysis, and the answer I’ve been told is, “No.”
Tacey Ann Rosolowski, PhD:
What’s going on there?
Eugenie Kleinerman, MD:
Again, this is my opinion. I have absolutely no data to support it. I think the woman who initially—Patricia Keegan is her name—who initially was the person responsible for the analysis of the data, analysis of the drug, and, you know, I’ve had contact with her. I actually was on an FDA panel for her section of the FDA. So it’s her group. They get a drug, it’s her responsibility then to shepherd the approval request through the procedural. I think she’s never liked it. I did at one point push her, on the phone, so I think probably some of it is against me, because I was very pushy. She didn’t want to have it, “No, you can’t review it. You and Dr. Meyers never consulted the FDA in terms of the design of the trial. We don’t like the design of the trial.” And she’s right. Dr. Meyers and I were stupid in terms of that. We designed an academic trial. We never thought, knew that when you want to take a drug for approval, you need to get the blessing of the FDA before you design the trial, and they need to help you in setting up what the analysis—
Tacey Ann Rosolowski, PhD:
[unclear] getting them what they need.
Eugenie Kleinerman, MD:
Right, right. So they’re absolutely right, absolutely correct. We didn’t design it with their permission, with their okay. But what I say is this is a rare disease in kids where there’s no alternative treatment. Can’t you bend the rules a little bit? And they’re going to say no. So this is where I disagree with them. Not that they’re wrong and I’m right, or I’m wrong and they’re right. I think it’s just a difference of opinion. And I do think that with approval of the EMA and with NICE and now it being widely used in Europe and Mexico and Israel, you know, I think that sometimes one has to say the rules can be bent a little bit. But they’re saying, “We’re the FDA and we can’t. If we do it for you, we do it for other people,” which is true, but so what? So at one point, I pushed her and said, “Fine. Then we just won’t. This drug’ll never get approved.” This was on a phone call. And so she said, “Fine, fine. Go ahead, put it forth.” So I think I read into that she said, “Go ahead, put it forth for approval, and I’m going to do everything I can to make sure it doesn’t.” Now, I may be wrong, but that’s my perception.
Tacey Ann Rosolowski, PhD:
So do you intend to follow up with that? Do you think you will present the drug for another—sort of go through another—
Eugenie Kleinerman, MD:
I mean, I can’t. It’s got to be Millenium, and I think at this point, I think at this point they’ve received very strong signals that, “We don’t want to hear from you again.” And you also have to understand from their perspective they have other drugs that are coming down the pipeline. They don’t want to aggravate the FDA. So I really think that we need patient advocacy and physician advocacy that’s going to go to the FDA. I think the pediatric oncology community needs to band together and say, “Listen, this is a drug that we want to have for our patients.”
Tacey Ann Rosolowski, PhD:
Are patients going to other nations?
Eugenie Kleinerman, MD:
Yes.
Tacey Ann Rosolowski, PhD:
They are going to other nations to get this therapy.
Eugenie Kleinerman, MD:
Yes. Recently I had a patient call me, or email me, and he’s going to go to Mexico to get the drug. And Dr. Meyers has a couple families that he sends to the UK. So, I mean, it’s sad because you have to have money to do that.
Tacey Ann Rosolowski, PhD:
Absolutely.
Eugenie Kleinerman, MD:
I think there are all sorts of creative ways that we could approach this. They could give it a conditional approval for five years. I mean, COG did want to do another trial, but the company would have had to provide the drug free, and the company said, “It’s an expensive drug. We can’t do it.” So to me, from my understanding from what I hear, give a conditional approval so they can charge for the drug, and then let us do another trial. You want another trial? Fine. I don’t think the company’s against doing another trial; they just can’t support it. They can’t give the drug free, and they can’t provide the support for the clinical trial. To me, that’d be, you know, a win-win and a good compromise.
Tacey Ann Rosolowski, PhD:
Mm-hmm. Hmm. Well, this has been really interesting. (laughs) I really thank you for going into this. I mean, we’ve really hit on a lot of themes that are important and very much part of the reality of what it means to do research in this context.
Eugenie Kleinerman, MD:
Exactly. Exactly. The rewards take a long time, so I think we also have to understand that people’s careers, if they’re going to be measured on a positive outcome of a clinical trial, it’s going to take years, and that we’re going to have to figure out some way to reward people and recognize their participation in clinical research, because you need a lot of Indians to get the work done, and it can’t always be the chief that gets the accolades. I couldn’t have done this, nothing, I couldn’t have done this without other physicians sending me the patients, without the support of the clinical research people that taught me how to do everything.
Tacey Ann Rosolowski, PhD:
Yeah. You kept mentioning all these people along the way that helped make important pieces come into place.
Eugenie Kleinerman, MD:
Right, right, right. So when Dr. Meyers and I get the accolades for moving this forward for this novel treatment, we’re the front people. Yeah, it was my idea, but it wouldn’t have been able to happen without this institution, all the supporting people, people who believed in me, the physicians who sent their patients, the COG that had the infrastructure to support the biostatistics. It would have never happened. And so all of those young physicians, old physicians, whatever, that participated, so they’re a middle author on a paper that has twenty authors. People say, “Eh, a twenty-author paper,” but that’s what it—you know, it really does take a village, particularly in pediatric oncology.
Tacey Ann Rosolowski, PhD:
Interesting. Well, I’m aware that we’re a little bit over time, so I know you’re very, very busy, and I thank you for your time this morning.
Eugenie Kleinerman, MD:
My pleasure. I hope you—I mean, we’ve sort of strayed from MD Anderson, but I hope—
Tacey Ann Rosolowski, PhD:
No, no. Well, actually, I don’t think we really have. (laughs) I mean, I think this story has really shown in many ways, I mean, what the institution sort of enabled in important ways, and so it is very much part of the story. I mean, I always say that this project does double duty. It’s about careers, but it’s MD Anderson, but in a sense where do the two separate exactly, because, as you said, it really does take a village, and MD Anderson has been that, certainly, a village with a very particular mission and attitude.
Eugenie Kleinerman, MD:
Yes. Yes, yes, yes. Well, again, you know, I’m so glad you’re doing this.
Tacey Ann Rosolowski, PhD:
Thank you. Thank you. It’s a pleasure. Thank you for giving me the time this morning.
Eugenie Kleinerman, MD:
My pleasure.
Tacey Ann Rosolowski, PhD:
And I’m turning off the recorder at 11:36. (End of Audio Session Two)
Recommended Citation
Kleinerman, Eugenie S. MD and Rosolowski, Tacey A. PhD, "Chapter 11: A Successful Phase III Trial and European Approval, But No FDA Approval for MEPACT" (2014). Interview Chapters. 1407.
https://openworks.mdanderson.org/mchv_interviewchapters/1407
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