Chapter 07: Service on the National Cancer Advisory Board and Other National Bodies

Chapter 07: Service on the National Cancer Advisory Board and Other National Bodies

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Description

In this chapter, Dr. Freedman discusses his role as a presidential appointee to National Cancer Advisory Board (President Bill Clinton, ’00 – ’06). He begins with a brief sketch of the birth of the NCAB (and the National Cancer Institute) in the National Cancer Act, then covers NCAB review processes and grant procedures and compares the different styles of the Directors of the National Cancer Institute, who work with the NCAB. He shares his view that all the institutes need to reconsider the kinds of clinical research they are supporting. This discussion leads naturally to his post-retirement role on the Oncologic Drug Advisory Board (since ’09), “one of the most productive Boards at the FDA,” in Dr. Freedman’s words. He notes that he had to divest himself of certain stocks and remove himself from committees to satisfy the Board’s conflict of guidelines. He also talks about the Board’s procedures for questioning drug companies, offering several examples (including a drug company’s challenge to a rejection). He concludes that “They [the FDA] do a terrific job of protecting the public.”

Identifier

FreedmanR_02_20120301_C07

Publication Date

3-1-2012

City

Houston, Texas

Topics Covered

The Interview Subject's Story - Professional Service beyond MD Anderson; Contributions; Beyond the Institution; Understanding Cancer, the History of Science, Cancer Research; The History of Health Care, Patient Care; Business of Research; Fiscal Realities in Healthcare; MD Anderson and Government; Professional Practice; The Professional at Work; Critical Perspectives; Faith, Values, Beliefs; Ethics; Post Retirement Activities

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 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 like to speak now about your role on the National Cancer Advisory Board?

Ralph Freedman, MD Yeah.

Tacey Ann Rosolowski, PhD You were appointed to that in 2000, served between 2000 and 2006 and––

Ralph Freedman, MD Yeah, that was very––

Tacey Ann Rosolowski, PhD Kind of amazing.

Ralph Freedman, MD Well, that was very interesting. I was nominated to the board. I don’t know the process, but my office got a call telling me that I’ve been nominated for that and to supply information. The members of the board are presidential appointees—actually, I still have the certificate here; it’s back in my study––and so it was done under Clinton’s presidency, and I didn’t give any money at that time. I did give Hilary [Clinton] some money later on, but she disappointed me. But that was years later after I was off the board. It was 2008, of course.

Tacey Ann Rosolowski, PhD I notice that you’re careful to dot those conflict-of-interest I’s and cross those T’s.

Ralph Freedman, MD So anyway, the National Cancer Advisory Board was created as a result of the Cancer Act in 19––I think it was 1970. I might be wrong on the date, 1970, ’71. Basically what the Cancer Act did was––this was [Richard] Nixon’s effort to eliminate cancer, and of course, we hear that many times now––and what it did for––R. Lee Clark was involved––and I think that’s also nicely dealt with Jim’s book. But what it did, it created a separate budget line for the National Cancer Institute. I think they were hoping to get, initially, a separate institute from the NIH entirely that was totally independent. But the American College of Professors and others around the country, I think there was a lot of competitiveness or antagonism from people out of the cancer field as to why should cancer be so prominent. I mean, you can imagine the cardiologists thinking, Well, why not us? We need a separate institute. So NCI is one of the twenty-eight to twenty-nine institutes but they have a separate budget line. So the director of the institute submits a budget which goes to the White House. The NIH director submits a budget on behalf of all the institutes separately, and so that’s a potential advantage, and it’s probably served in the interest. That’s why they have–– I don’t know exactly today what the budget is, but I think it’s about five billion dollars a year, theNCI, and I think that the NIH budget must be around thirty billion dollars, so that’s a sizeable proportion considering how many institutes there actually are. So it’s been beneficial. I learned a lot of interesting things there. First of all, at the NCAB there’s a board of the President’s Advisory Board, and Margaret Kripke was on that committee. There are three members, and they go around the country. Then there’s the NCAB, and then you also have a Board of Scientific Counselors. And what the NCAB actually does is the second level of review of grants. So the grants go through the review process, they get triaged, and they go to their study sections and they get scored. Then the NCAB, in collaboration with the administrators, determine what the cutoff level is going to be how much money they’ve got, because a lot of money has to be set aside for continuing renewals. For example, you get a grant this year, and it takes––it’s for three years or four years—they have to have money next year and the year after to fund them, so really, a very small proportion of the money actually goes towards new grants. Ten percent gets taken off automatically to go to the intramural program. That’s what goes on at those buildings, and they do a certain amount of research up there. They don’t have to compete for grants. They actually are competitors today with the institutions around the country, the fifty or so cancer centers around the country. We’ve got these institutions where they do clinical trials. They have their own one at NIH. They have a clinical research center, and patients can get their––they get free treatments there, and I’m not sure if they also get their transport paid, but at least they––I think they get their accommodation covered. So in a way, they’re competitors. But they have the ten percent of the budget, and that’s been a bone of contention for a while—and also, because dynamics have changed. In the early days, when Dr. [Emil J] Freireich was at NIH and people like Roth and Grimm were with the NIH, you had a large number of prominent researchers working at NIH and NCI. And basically, the main discoveries were being made there. Taxol—Horwitz discovered Taxol—it came out of there. And the cytokines have been developed there, and therapeutic approaches in leukemia, so there was a time when they had a critical mass of scientists. Now those scientists are getting older––like all of us, getting older––and they’re getting close to retirement, and the question is what are they going to do? What’s the future going to be for NIH? So NCAB would get reports at its regular meetings as to what was going on.

The meetings would occur every quarter, and they also went along the grant cycle because they had to do the second level of review and approval of those grants and determine what I think they qualify for. That was all done behind closed doors. The first part of the session was a public session in which innovative research from around the country was being presented. Sometimes they’d bring investigators up to present, and that was fascinating. That was exciting and interesting. We had different–– During my tenure there, we had two directors. Andy von Eschenbach was the last one, and before that was Dr. [Richard] Klausner, and he was actually very excellent. They had different styles. The directors had different styles. These are political appointments, also, so the director of The National Cancer Institute is an appointee of that administration as are the members of the NCAB. So you listen to all this stuff, and you hear reports from the preventive group and from the biology group or areas of importance. I attended something called colorectal screening in which they reviewed all the approaches towards early detection of colon cancer. And it was very informative because on that day that the specialty that I come from––OB/GYN––was actually doing the worst job in screening patients because they would do a single digital exam and do an occult test in the rooms, which is totally inadequate. His patient had that sigmoidoscopy every five years and colonoscopy every ten years if nothing was–– So all of that data was presented at a special meeting, and then the guidelines came out of that. HPV vaccines were discovered while I was there, so we heard all of these interesting and fascinating things, but in terms of actually making policy, the board doesn’t really do that. The director has a lot of––he has his own boards inside that determine a lot about what they do at NIH. There have been some interesting books written about theNCI. There’s a fellow, Epstein, who wrote about the politics of cancer—actually wrote two books—and he was an epidemiologist. Of course he felt that more of the funds should go towards prevention and early detection in epidemiology research, which may not be the wrong thing considering now that most of the drug innovation is actually done by pharmaceutical companies who develop the drugs today and it costs so much to conduct clinical trials. It’s a question whether government-supported trials can actually have enough resources in order to conduct large trials effectively, and some of these issues have come up. And some of the observations that I’ve made where some of the studies were done by some of the groups that are supported by the NIH––oncology groups—they’ve now consolidated them in the last year because of budgetary reasons. Well, it takes a lot of money and resources to conduct a big study, and certainly I think industry has got an advantage there because they can rely on the R & D funds and the profits that they get out of marketing their other products, unless it’s a single product in an early company. So I think it’s time that theNCIdoes look at their whole portfolio, looks at their whole structure, and in Britain, for example, you have the MRC. I’ve participated in reviews for them, and you have ten pages. You answer questions about the conduct and the study that’s being proposed for funding, and they give you a very succinct list of questions. You send your review in, and then it’s looked at it in England by the MRC group. Here, you’ve got to invite people up to study sanctions. There’s always the question of how the study sections are constituted and how fair are they. You can have very prominent researchers that can suddenly lose their funding, and it’s not always––or else they may get a score that they don’t get funding this time. Then they’ve got to wait another year before––eventually they do get funding. In the meantime, the process is slowed down. It doesn’t seem to be a very efficient system for today, but the basic question is what type of research should the institutes be supporting now? Can they still do a good job in supporting clinical trials? They get their drugs from industry through what they call a Crada mechanism. It’s a cooperative research agreement, so a company provides NRH with a group of drugs, and then they have the investigators at different institutions apply or send in a––by the way, the name of the previous director was Klausner, Richard Klausner.

Tacey Ann Rosolowski, PhD Thank you.

Ralph Freedman, MD It came back to me, K-L-A-U-S-N-E-R. He had to leave. He was actually a phenomenal guy, brilliant, very brilliant. I remember he gave one talk once on Lewis and Clark, and he related basic science to the Lewis and Clark expedition, though it’s fact-finding, not clearly hypothesis-driven, and it was absolutely a brilliant presentation that he gave.

Tacey Ann Rosolowski, PhD You mentioned Lewis and Clark in our last session.

[Redacted]

Tacey Ann Rosolowski, PhD Oh, the cooperative research appointments.

Ralph Freedman, MD

Right, right, so that’s the company’s––NCIwould have arrangements with industry to allow their drugs to be used in clinical trials, and they have a review process atNCI, which they would do, and the company, I think, would have some kind of final decision on where the drug goes. Now I think if you think about it logically––and certainly, not everything is logical––or intuitively, you have a company that has a drug that they think is very important. Are they going to release that drug to be done by investigators that they have little choice over because theNCIpicks the investigators to test the drug? And with the chance that the study may––the way it’s designed and the way it’s constructed or other variables may apply––may lead to a false negative outcome for that drug? So I’m a little suspicious of this mechanism. I think that the companies, if they have a really good drug, are going to keep that drug close to their chests, and they’re going to wait until the drug is approved and then maybe release it to theNCIor other people to work with it, say, for other indications. I suspect that that’s what happens. I don’t know this for a fact, but they are the creators—makers—so the thing is that people have to write a notice of intent, LOI––letter of intent––that they want to study the drug, and they put down a few things there—how they want to study—and it gets reviewed by theNCIcommittee. And then again, it’s done on a competitive basis, and then they give the drug out for the study to be done. Well, then you have to have money to do that study. Can theNCIprovide enough monetary support to do these studies? Why did they have to consolidate the cooperative groups? Often there’s a limit to grants. There’s a ceiling on which you can actually get, so you––and I’ve had experience because I’ve done––I’ve had grants through the different mechanisms or ROI or R21 and so forth, and one of the difficulties is that the institutions take big overheads from these grants––sometimes up to ninety percent from some institutions.

Tacey Ann Rosolowski, PhD Wow.

Ralph Freedman, MD And the decisions on the overheads is not made by theNCI or NIH. It’s made––it’s another government level. So an institution can apply and say we want seventy percent overhead, and whoever this body is that grants it––because I know I asked this question in the committee in my naivety, and they get it mainly atNCI, when it awards the funds, has to comply with this. In other words, they give their direct funds, and they have whatever the percentage is allowed by indirect. That indirect goes to the institution for whatever purposes, but very little of that goes back to the researcher. So you’ve got this system in place, and now we’re dealing with a success rate for grants of under ten percent of average, maybe much under that. That’s a one in ten chance of getting your study funded, so by the time your study may get funded in another year or so, maybe their drug is irrelevant; there are two or three better ones. So is this the system that we want to support such a system? And it’s worth going back and looking at some of Epstein’s comments, especially in his first book. The second book was not––he was quite critical of the processes and the politics, and I think there is a lot to that. It’s hard for us to––you can’t separate politics from all this. It’s there inbetween. You get actions that are taken in Congress, for example, to award certain areas of funding. Somehow theNCI had come up with supporting a certain area of research. It’s decided not by scientists, but by officials, and they’ve got the same pot of money to do it. They don’t actually get more money to do it, so it means they’re going to take from somewhere else to. So maybe a congressman from a certain district—say it’s a number of patients with a certain type of cancer, and they think not enough is being done for this. What they did do, which was useful, was to actually provide the amount of support for different disease entities, and we saw that when I was there. And then they did provide programs to cover those areas that they felt had been sort of underrepresented.

Tacey Ann Rosolowski, PhD So this was like a national averaging of what money that was being––

Ralph Freedman, MD Yes, and how much money was actually assigned, say, to pancreatic cancer. And you’ve still got to go through their review process, and that’s the problem. You don’t necessarily have all the experts of that disease. I think they try to create some disease site by these––through these groups.

Tacey Ann Rosolowski, PhD Do you happen to recall what the breakdown was? I mean, what struck you at the time about the breakdown of how funds were being directed to different cancers?

Ralph Freedman, MD Yeah, for different cancers. I don’t have the information. I remember looking at that in gynecologic cancer. At the time, there was relatively little support for uterine cancer, and now some of our researchers have been able to exploit that and to get more grants to cover uterine cancer, and of course, gynecologic cancer; if you take out breast cancer—because most gynecological oncologists treat breast cancer, except for some parts of the country—it’s a relatively small part of the whole spectrum of cancer, so therefore, relatively less can go there, but I think whenever you can show results––of course, results mean support for further work in that area.

Tacey Ann Rosolowski, PhD Right. Did you have something else you wanted to add about the National Cancer Advisory Board?

Ralph Freedman, MD Well, we had some very interesting people, and they had Susan Love, I remember. Do you know Susan Love at all?

Tacey Ann Rosolowski, PhD I remember the name.

Ralph Freedman, MD She wrote a lot––she treated breast cancer. She was a surgeon from UCLA.

Tacey Ann Rosolowski, PhD Okay. Yes.

Ralph Freedman, MD ––that is it may––and she actually made a very good contribution for women. And she was very eloquent, the things that she said, and that was actually great things. We shared books. She sent me a copy of her book, and after that, I haven’t spoken to her for a long time, so it was nice having her on board. And then there were––I can’t think of––oh, it was Larry Norton who was from Memorial Sloan-Kettering, quite an intensive knowledge on cancer. I think it was simply a privilege to be there. I don’t know how much difference it made whenever they have––because we––second level of review may be the most important part of the work, but seldom were decisions made that had wide impact there and that were not already made somewhere else. When Andy von Eschenbach came out with cure cancer by 2015, he had made that decision already when he came and announced it to the board. The board is a public meeting. You’ve got people from the newspaper, from Cancer Letter, Goldberg—I think his name is—the editor from the––who sat in the audience and listened to it, so once the directors made this announcement, I just––people, I think, were just frozen to their seats, and you can’t really go back on it. It’s done, and I think the––I don’t know where––who persuaded him to do that, but obviously it’s ridiculous. The year 2015 is three years away, and we’ve got as much cancer now as we had––maybe a little bit less.

Tacey Ann Rosolowski, PhD You’re serving now on the Oncologic Drug Advisory Board and carries with the––

Ralph Freedman, MD That’s the Food and Drug Administration.

Tacey Ann Rosolowski, PhD And I’m just curious about the comparison of those experiences and also, of course, what your activities are on that.

Ralph Freedman, MD Yeah, this is different. I was asked to––if I wanted to participate in this—and I had to go up to FDA and make a presentation, and I think I was one of—I don’t know how many people there were, but I was chosen, and it’s a fourteen-or-so-member board. It’s the Oncology Drug Advisory Board, which is part of CDER––Center for Drug Evaluation and Research––and it relates to the oncology drugs, primarily. It’s primarily because some of the products that we’ve approved have not been actually oncology drugs––they’ve been others––and it’s advisory, so whatever decision is made is purely advisory. And typically what happens is the FDA advisory group will review a new drug application, employee license to market them in a different application, and then they may have some questions about it. So they’ll have some cases which are clear-cut, and they will give it approval. There are others where they’re not sure about the study. It may be that the balance between the toxicity and the benefit is a little uncertain, so they’ll bring those to the board before each meeting, and we may have––I think we had up to 6 meetings last year. It’s actually one of the most productive boards at the FDA, the oncology section. So the company presents its data. The FDA does its own analysis of the raw data, so what you basically get is you get a review from the FDA; you get a review from the drug company––two separate amounts of data, which are quite extensive—and the FDA basically will ask the board members certain questions––do you think that the level of effect is justified by the risks, something like that, so the questions are always different. There’s a very tight company intra-screening. I don’t keep any drug stocks. When I started, I had one, I think—or two. I just divested them. I had to take myself off the Data Safety Monitoring Board here at Anderson because I was on that just because––they didn’t tell me that I had to, but there were so many questions being asked about what drugs that I had reviewed in the past year, and we had so many protocols involving so many drugs, it was just easier to do that. And then they decide if you can participate or not, so the people that go there are their regular board members, and then they bring the experts in––ad hoc members––who have been screened and maybe experts in a particular disease––prostate cancer, kidney cancer. The presentation is made, first of all, by the company, and then it’s made by the FDA people, and the way they set up the meeting is kind of interesting. It’s in a public forum, and the public are separated from the board members. The FDA people sit at the table. You have the ad hoc members sit at the table. There’s supposed to be no communication. We’re not supposed to communicate about the product with each other while the session is ongoing and also with others. So if you go out for a break or something, you can’t communicate, and of course, once you’ve got the information they sent you to review, you cannot communicate that to anyone, either. Ayou can understand there are obvious reasons why they don’t want that to happen. You’ve also got insider rules, which could apply if you did divulge anything.

Tacey Ann Rosolowski, PhD I’m curious of what the logic is of not having the committee members talk among themselves, however.

Ralph Freedman, MD You can discuss it in the meeting.

Tacey Ann Rosolowski, PhD Oh, okay.

Ralph Freedman, MD Like for example, not privately.

Tacey Ann Rosolowski, PhD Oh, okay.

Ralph Freedman, MD Not privately, but when the case is being presented, there may be questions from one board member to another, but it’s all over the microphone.

Tacey Ann Rosolowski, PhD So everything’s transparent, public mention.

Ralph Freedman, MD Right. Everything is transparent. It’s a very––I didn’t know about this process––most people don’t––but to be open and transparent process. So the FDA do their thing, the sponsors do their thing—and of course, their conclusions may be a little different—and then they present questions to the board. The board discusses. They also have public members. A person who happened to be a patient, perhaps, or represents a group of patients—say, Lymphoma Society or whatever––could make a statement in open forum. They have to indicate that they want to speak, and they are treated respectfully. They’re allowed to make their comments over a certain period of time, and then they––there’s no questioning of those public members, but they’re allowed to make a statement. Then this process can take a full morning or full afternoon––usually, I would say one half day per drug in most cases. Sometimes it goes over, and then you vote, and the vote is public. You press a button, screen comes up, and it’s got your name there that you voted yes or no or abstain. Then they go around the table and you have to say why you voted yes or no, and it’s over, and that’s the recommendation. The committee votes to approve this indication, the committee votes not to approve it, and then after that, the FDA can do––yeah, the FDA, in most cases, will take the decision that’s made by the committee. I’ve seen it happen at the––for various reasons––

Tacey Ann Rosolowski, PhD They overturned it?

Ralph Freedman, MD Overturned it. Well, it’s not like they’re overturning it because it is advisory.

Tacey Ann Rosolowski, PhD Advisory?

Ralph Freedman, MD And I think a lot of people don’t also realize that the FDA have really––they have regulations under which they operate in approving drugs, and this goes back a century. Their regs started developing even before the human subject research regulations were published in the register in the ‘70s, and they started off when they were vaudeville snake-oil salesmen and went around. So I think things which were pretty dangerous–– So the first type of rules that they had were safety rules. In other words, they just had––in the 1930’s, they had to show that a drug was safe. They didn’t have to show that it was effective. A company had to show that it was safe. And then in the ‘60s, they had to show efficacy, and then later on they defined what efficacy meant, and that’s an ongoing process. So when you look at efficacy end points, we’re looking at primary and secondary end points. The primary is the main thing that determines whether a drug––if it’s successful. If they can show that this is a clinical impact of––a difference between the control––these are usually at randomized controlled studies. That is the difference in survival, for example. That is absolute––people live longer from the treatment. You can’t argue too much with that, and then often is the secondary––but sometimes even if a primary end point––they will have what they call progression-free survival. That’s the time that it takes for a tumor to actually progress, so it may not be an effect on survival, and it’s considered to be a surrogate because it’s expected that in some cases, if you have an improvement in time to progression, this might translate into some improvement in survival, but it doesn’t always happen. It frequently doesn’t happen because you get small increments in time to progression, and therefore, either because it’s crossover from one arm to the other or because the difference is so small––maybe two or three months, which is what happened with Avastin and breast cancer––that there really cannot realistically be a difference in survival. So then the question is how significant is that to the patients, and that’s where the––they have to be able to show that the patients are actually getting a defined clinical benefit. And defining clinical benefit is sometimes the most difficult thing in cancer because the patients are getting side effects from the disease, they get side effects from the treatment, and then it’s a balance. And that’s where people are asked to make a decision, and what’s the risk benefit of this? Can you see a clear clinical benefit from this? And––

Tacey Ann Rosolowski, PhD That’s kind of going back to those quality of life–– You were talking about the need for some kind of systematic way of defining how a patient’s quality of life had been improved.

Ralph Freedman, MD Oh, well, the quality-of-life instruments are very complex, and a lot of academic institutions do those studies. But they’re not relevant to the approval process because what is approved is the indication, and that indication goes onto the label for that drug. The labeled information basically reflects largely what is presented as part of the new drug application, so how well the drug did in the trial, what was the toxicity profile, what is a whole range of serious toxicities, percentages— all that has to be given to physicians and to patients. And the one thing they are not allowed to look at is the cost effectiveness, because that’s not been––Congress has never given that authority, and––

Tacey Ann Rosolowski, PhD Why is that?

Ralph Freedman, MD Well, I think a lot of it is political issues. It’s a sensitive area.

Tacey Ann Rosolowski, PhD Should I turn off the recorder?

Ralph Freedman, MD Yeah, just in case I may say something.

Tacey Ann Rosolowski, PhD I’ve turned the recorder back on after a brief pause.

Ralph Freedman, MD They do a great job, I think, in protecting the public. It’s a public health issue when you have a drug that’s released to thousands and thousands of patients, which may have a significant toxic effect. Like one drug that was disapproved was an antibody, denosumab, which is actually used––this was already in the public arena, and it was at our last session. It was for prostate cancer patients, and the idea was it would reduce osteal occurrences. But they couldn’t show that it actually reduced symptoms from developing, so a lot of patients who have prostate cancer may have sub-clinical metastases to bond and don’t even realize that when does it become clinically important is when they start to develop fractures or when they get pain from their metastasis. So that wasn’t part of the evaluation, or if it was, it didn’t show up, and there was no difference in survival, and the difference––the time to developing these osteal metastases was short. It was two months or three months––maybe about three months, perhaps, and there are a lot of questions, right? So the recommendation was against it.

Tacey Ann Rosolowski, PhD Interesting.

Ralph Freedman, MD ––felt–– So I don’t think the FDA have come out with their final decision on this drug. It’s an antibody, and it’s marketed–– And another name called Prolia––in order to strengthen bones in post-menopausal women, but in this case, it was used at a higher dose. What it actually did, it caused a high frequency of bone necrosis of the jaw, and that’s one of the complications of these drugs. And it was weighing up this three months’ time interval versus the other. And we didn’t know how long treatment would––these patients would be exposed to treatment, because if they were exposed for three years or four years or whatever it is, the incidence of the bone necrosis may continue to go up accumulatively. So it is a public health issue because there are a lot of prostate—a lot of patients eligible for the treatment. Once it’s released up there, then you got to think about how many people are going to be exposed to the drug that could get a significant side effect from that which can sometimes require major surgery. So those are the kind of decisions, but there are backed by legislation. When we had the Avastin––which is a very interesting situation because it’s the first time, I think, that they’ve actually had a public meeting––after the ODA Committee had reviewed this drug twice—

Tacey Ann Rosolowski, PhD What’s the name of the drug again?

Ralph Freedman, MD It’s bevacizumab. It’s owned by Genentech Roche, and they submitted it for study in patients with advanced breast cancer. The FDA had given them what they call accelerated approval. In other words, the first study that they basically approved showed a five-month difference in progression-free survival, but under the accelerated approval rules, they have to come back with definitive studies. They can market the drug for that purpose, but if the studies that they do are not strong enough as the first one, the FDA has the authority to withdraw the approval. So when they came back, they had several studies. They were done with different drugs––some was the same drug, some with a different drug, and there were about three or four trials––but the magnitude of difference, instead of being five months now, is one to two months, and there was increased toxicity for some of them. And as I said, this is a population of patients. They could survive twenty-four months with current available chemotherapy, so the right of the committee was to disapprove. This represented an amount of––pretty sure it represented quite a large amount of money to the company, so they challenged it, and they asked for a public meeting, which they had––according to their rules, they had the option to have. And this public meeting had a very interesting format. You’re going to have the two groups there––the company and the FDA—each representing their side. And interestingly, the lawyers were the ones that were pushing the main issues. In the–– Oh, the other thing was that the usual FDA people that sit around the table couldn’t be there. The officer running the meeting had to be from another part of the FDA––nothing to do with oncology drugs––so they had to divide up all this responsibility. And then the ODA––there were several of us that were there––were part of the process but not sitting at any main table. So the lawyers from each side, their main push was why––whether there were inconsistencies in the way the FDA applied the ruling here, with other drugs got it, and these at least didn’t. And the FDA came back and said, well, each drug is different and each disease is different. You can’t apply necessarily the same rule to each, but basically, we were looking at the same data again, and the conclusions were the same. I did try to see whether I could find something that I could get my hands around, and I did ask some questions, which apparently were thought of as indicating, that maybe I was changing my mind. But all I was doing was trying to see if there were other applications––advantages that had been––perhaps strengthened the support for it. So it was open public meeting, so we had a lot of demonstrators there. We had, oh, a group of women from an advocacy. They sued FDA once before because they wanted access to experimental drugs that hadn’t been approved. It’s named after a patient, too. He had end-stage disease, basically. And there was a lot of vocal criticism. You had to endure this and just sit and listen passively. There were people outside with placards, and it was really an active demonstration. They were allowed inside as long as they didn’t make a noise. Once they started to interfere with the meeting proceedings, then they were escorted out. They had Homeland Security people there who escorted them out.

Tacey Ann Rosolowski, PhD What did you take away from that whole experience?

Ralph Freedman, MD Well, I think it’s––

Tacey Ann Rosolowski, PhD A bit of wisdom?

Ralph Freedman, MD It’s a democratic process, and it’s giving them another chance. They still have an option. They could go to court if they want to, but I understand even the usage of the drug and the disease has continued to–– See, what happens when a drug is approved, initially there is a lot of enthusiasm for that drug.

Tacey Ann Rosolowski, PhD It’s like there’s a new miracle cure out or something, yeah.

Ralph Freedman, MD There’s a new thing. You got to get it. And then there’s––doctors get more used to it. They suddenly find––say, look, there are other drugs that do the same thing, and they can maybe have not as much side effects or whatever. They decide, so there’s a lot of off-label usage in this country, and the FDA does not really control it. They consider that medical practice if people want to use a drug that’s already no longer in experimental mode––now, insurance companies may not pay for it, but that’s not an FDA concern. The FDA doesn’t actually liaise directly with Medicare—I mean—in determining how drugs are priced the way they might be. There’s no linkage.

Tacey Ann Rosolowski, PhD Well, it sounds like a really amazing experience.

Ralph Freedman, MD I think it was, and so these––you know what? Some of these things actually––these have been highlights from the point of view of being able to participate in something that is important to the community––drug safety, what drugs are out there is a very important thing. I mean, after the Thalidomide disaster years, we avoided that by having a review process that prevented the drug from getting here, and probably that’s happened a number of times, and it’s hard work. They have to do a very detailed analysis on these drugs that’s actually done by the FDA themselves. Sometimes a drug is approved in Europe, and it’s not approved here and visa versa. There are different standards that are applying to drug approval.

Tacey Ann Rosolowski, PhD Why do you think you were asked to part of that advisory board by––?

Ralph Freedman, MD I don’t know because I don’t know who nominated me. I knew Buzdar because he had been at MD Anderson, but we were not personal friends or anything. Actually, when I went for the interview, he wasn’t available for the actual––the people that interviewed me, he wasn’t one of them. You have to go before a––you do a presentation, and then you get interviewed by a group of people who work at the FDA. I mean, I have been involved a lot with clinical trials, and I suspect the clinical experience and maybe people aware of my interests in this area. Perhaps the IRB had some role in it––I don’t know. And the fact that we had to deal with some of the type of questions must benefit. You’re always looking at this balance, but as I say, I don’t know what the actual criteria were. Now, they do choose people who are not involved to any degree with––I can’t say, because some of the members actually are quite involved with clinical trials, but the more companies that you’re involved with, the less likely––the more difficul it is for you to be there.

Tacey Ann Rosolowski, PhD That makes sense.

Ralph Freedman, MD Because either you cannot review any drug that’s made by the company that’s making the submission or even competitors––they go beyond what we do. When we exclude people from review of trials at Anderson, we cannot include––we exclude the ones that have relationships with competitors because they would have nobody there on the committee. They can draw from a wider arena, so––

Tacey Ann Rosolowski, PhD It sounds like a pretty impressive process you have to––

Ralph Freedman, MD I think the process––I was actually impressed. I had no idea, had no knowledge, really, of the process. I just knew that the FDA did the review somehow and then drugs got approved or didn’t get approved, but I didn’t know how tight the rules were. So the general rules are applied that can be applied generally, but at the same time, there are disease differences and other differences that can result in a drug being approved under one situation and not in another.

Tacey Ann Rosolowski, PhD Now, just for the record, how long have you served on that committee?

Ralph Freedman, MD Well, this is my third year, so I will finish in June.

Tacey Ann Rosolowski, PhD Oh, okay. Yeah, would you have an interest in serving again, or is it a one––?

Ralph Freedman, MD You can’t––I think you cannot go back for––there’s a certain amount of time that you cannot go back. You can come back as an ad hoc member, but you cannot come back as a full member.

Conditions Governing Access

Redacted

Chapter 07: Service on the National Cancer Advisory Board and Other National Bodies

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