SANDRA ZOOK FISCHLER, Patient Representative to the Oncologic Drug Advisory Committee: “And in general, doxorubicin has been considered to be the standard. We have often said it conveys a six month survival benefit. We’ve heard this morning it could really be anywhere from two to six, depending on the literature.
I see some benefits, but I don’t see significant ones, and I hear you saying no survival benefit, and I just wonder why the time, money, and energy is being invested in drugs that don’t provide the patient with any really significant long-term benefits of survival. I mean I see it’s comparable to doxorubicin, and I see in some instances they do show some benefit, but when we talk about a two month survival rate, it goes back to what we were discussing this morning. It doesn’t answer the needs of the patients.
So it’s just a very general question as to why.
CHAIRPERSON DUTCHER: Anybody have a comment for her? What is the niche for this drug? Dr. Miller, do you have any comment?(Laughter.)
DR. MILLER: Yeah. Well, I just want to make sure to emphasize again there is a survival benefit with this drug, and the survival benefit is clearly documented in the adjuvant setting in two studies, major studies. And I think what we’re saying here in essence is the drug provides tumor control and tumor shrinkage that in the early setting can result — in the adjuvant setting can result in survival advantage and disease control and in the advanced setting can result in disease control, and that the two, in essence, go together, very symmetrical designs of studies which document, I think, the same basic principles for this drug in both early and advanced breast cancer.
MS. ZOOK-FISCHLER: I guess my concern has to do with the cardiac toxicity, which for me, you know, it’s a risk that I’m not sure for me offsets the benefits. I guess I’m just posing — I’m just expounding some of my concerns. I’m not sure there are concrete answers, but as a patient and as an advocate, I would love to see those drugs that offer substantial survival benefit, and if they can’t offer substantial survival benefit, then significantly less toxic effects, one or the other.
But in this case I see it has some survival benefit, but with significant toxic effects. So when you propose it to the average patient, I’m not quite sure how excited about it she can be, and statistically it may be very exciting.
CHAIRPERSON DUTCHER: Well, I think one of the comments made by one of the speakers at the open public hearing was that it might provide some economic competition. Dr. Levine, did you want to make a comment?
DR. LEVINE: If I may. I’m very sympathetic to the comments that were just made, but nonetheless if you look at the survival benefits demonstrated in adjuvant chemotherapy, if we look at the PETO overview, the meta analyses, which is what’s quoted to most patients by physicians, the magnitude of the survival benefit from chemotherapy in general in the adjuvant setting is small or modest, at best, and many of those trials that went into that overview were with CMF.
The benefit that you’re seeing with this epirubicin containing regimen or regimens is almost of the same magnitude improvement over and above that with CMF. So that when Kathy and I use this in Canada and we explain it very carefully to patients, the risks and the benefits, some people do choose to take the medication or the regimen because the magnitude of the benefit is over and above that which is commonly accepted. So it is an improvement.
…DR. TEMPLE: Do I understand that even though everyone would like to see studies against adriamycin, there are no data showing that an adriamycin regimen is better than CMF, and there are data showing that this epirubicin regimen is better than CMF? So that there’s a survival advantage over an active survival increasing regimen. That’s what you’re contending is the benefit here.
DR. LEVINE: Yes, sir. There --
DR. TEMPLE: That’s why someone might choose this you’re saying?
DR. LEVINE: Yes, that CAF has not been compared to CEF, and the trials of CMF versus CAF have been negative
DR. SIMON: I would just like to say I think censoring patients who die or go off study because of toxicity is a very questionable thing to do. I would actually favor the time to treatment failure endpoint because censoring the others, that their subsequent prognosis would be no different than had they not — that they would be sort of representative patients, I think, is very questionable.
DR. MILLER: But I would want to emphasize that we did analyze TTF for that very reason in these studies and did show significant benefits in that endpoint.
DR. SIMON: Well, with time to treatment failure, the difference was between — the median was five months to 6.2 months.
CHAIRPERSON DUTCHER: Thank you. We’re going to have one more comment for open public hearing, very briefly. Ms. Fonfa.
MS. FONFA: Thank you very much for allowing me to speak.
This is not at all to be taken as specifically against this drug. I want to say a sort of global thing.
CHAIRPERSON DUTCHER: Name and --
MS. FONFA: I’m Ann Fonfa, representing the Annie Appleseed Project, New York City. My perspective is, and I think it was brought out by the word “significant,” I don’t see significant change in survival, and I don’t see significant change in time to disease progression or any other thing, and as a cancer patient, I want to reiterate long term survival is what we care about.
Advances in quality of life, and if it has to be time to disease progression, we want a lot of time, and I don’t see that here, and I don’t see it on anything that we have. And I want to say that if we don’t hold drug companies to very high standards, we get drugs that are only an eentsy-teensy (phonetic) bit, and this is the measurement I use, better than what we have.
It’s no good. We have to get you folks to look a little higher. You’re spending millions of dollars, and you’re not getting anything that matters to cancer patients, and now it’s 30 years later. For me it’s personally six and a half years later. I’m very unhappy, and I represent thousands, hundreds of thousands of people who feel the same way.
Please, please, aim higher. I beg you.
CHAIRPERSON DUTCHER: Thank you. Thank you very much.
So we have some issues.
Ann’s NOTE: Advocate Sandra Zook Fischler, a personal friend of mine, died of breast cancer in 2001. She will be missed.
And at a separate time:
DR. TEMPLETON-SOMERS (FDA Hearing 1990’s): Next we have a letter from Ann Fonfa, founder of the Annie Appleseed Project which educates and informs cancer patients, health care providers and others on issues of interest, especially complementary alternative therapies.
This is an extremely difficult question to address but I want to share with you some of my thoughts on the issue of compassionate use of unapproved therapies. As a woman who has had neither chemotherapy nor radiation, I am not eligible for most trials. While I understand why there are study entry criteria, I wonder if they are directed to ease the approval of a particular drug and not so much toward the benefits of the trial participants or the patient population in general.
For patients who have been heavily pretreated, and there are so many of these with metastatic breast cancer, I wonder if the entry criteria have to be set up they way they often are. If someone like myself, and I am not alone in this category, wanted to enter a trial we could not. We would have to have compassionate use approval. So, with those most needing a new therapy-women who have tried just about everything else first-in order to benefit these women a drug may actually have to work in that patient population. Therefore testing it on them may be a good idea. I recently read an article that stated drug companies can increase the likelihood of a drug success by using exclusion criteria, as one investigator told the Inspector General’s office, “to enrich trials with patients who are most likely to benefit”. Yet, having attended two meetings devoting to discussing how to promote clinical trials, I understand that we need completed studies to better aid us in discovering good treatment. Should performance status be a standard for entry?
On the other hand, when I look at the actual survival of most approved therapies I often fail to understand their benefit to patients. At another ODAC meeting I referred to continued approval of drugs with so little better benefits to patients than existing drugs by comparing the process to crawling on our hands and knees through a field of broken glass.
Patients want to leap forward, yet we are continually presented with tiny steps. Yes, they add up to moderate gains, as has been stated at various medical conferences I attend, but must we continue to crawl inch by inch or is that simply an artifact of the current system?
So, part of my problem is continuing to doubt whether we are using the best possible methods of finding, testing and approving drugs at all. As a cancer patient myself, I cannot imagine denying women with advanced disease the opportunity to try one more conventional therapy even when the end results will be two more months of survival laden with the negative effects of the therapy.
I will end by urging everyone in this room to consider the benefits of complementary natural therapies. Studies in animals and cell cultures indicate benefits may include better tolerance to cytotoxic regimens, support to the host — that is us, human beings — and possibly enhancement of therapy.
Please consider starting trials immediately that will look at chemotherapy with the use of antioxidants. Thank you for your attention. As you may imagine, no pharmaceutical company has ever sponsored the Annie Appleseed project.
[Laughter]
I see some benefits, but I don’t see significant ones, and I hear you saying no survival benefit, and I just wonder why the time, money, and energy is being invested in drugs that don’t provide the patient with any really significant long-term benefits of survival. I mean I see it’s comparable to doxorubicin, and I see in some instances they do show some benefit, but when we talk about a two month survival rate, it goes back to what we were discussing this morning. It doesn’t answer the needs of the patients.
So it’s just a very general question as to why.
CHAIRPERSON DUTCHER: Anybody have a comment for her? What is the niche for this drug? Dr. Miller, do you have any comment?(Laughter.)
DR. MILLER: Yeah. Well, I just want to make sure to emphasize again there is a survival benefit with this drug, and the survival benefit is clearly documented in the adjuvant setting in two studies, major studies. And I think what we’re saying here in essence is the drug provides tumor control and tumor shrinkage that in the early setting can result — in the adjuvant setting can result in survival advantage and disease control and in the advanced setting can result in disease control, and that the two, in essence, go together, very symmetrical designs of studies which document, I think, the same basic principles for this drug in both early and advanced breast cancer.
MS. ZOOK-FISCHLER: I guess my concern has to do with the cardiac toxicity, which for me, you know, it’s a risk that I’m not sure for me offsets the benefits. I guess I’m just posing — I’m just expounding some of my concerns. I’m not sure there are concrete answers, but as a patient and as an advocate, I would love to see those drugs that offer substantial survival benefit, and if they can’t offer substantial survival benefit, then significantly less toxic effects, one or the other.
But in this case I see it has some survival benefit, but with significant toxic effects. So when you propose it to the average patient, I’m not quite sure how excited about it she can be, and statistically it may be very exciting.
CHAIRPERSON DUTCHER: Well, I think one of the comments made by one of the speakers at the open public hearing was that it might provide some economic competition. Dr. Levine, did you want to make a comment?
DR. LEVINE: If I may. I’m very sympathetic to the comments that were just made, but nonetheless if you look at the survival benefits demonstrated in adjuvant chemotherapy, if we look at the PETO overview, the meta analyses, which is what’s quoted to most patients by physicians, the magnitude of the survival benefit from chemotherapy in general in the adjuvant setting is small or modest, at best, and many of those trials that went into that overview were with CMF.
The benefit that you’re seeing with this epirubicin containing regimen or regimens is almost of the same magnitude improvement over and above that with CMF. So that when Kathy and I use this in Canada and we explain it very carefully to patients, the risks and the benefits, some people do choose to take the medication or the regimen because the magnitude of the benefit is over and above that which is commonly accepted. So it is an improvement.
…DR. TEMPLE: Do I understand that even though everyone would like to see studies against adriamycin, there are no data showing that an adriamycin regimen is better than CMF, and there are data showing that this epirubicin regimen is better than CMF? So that there’s a survival advantage over an active survival increasing regimen. That’s what you’re contending is the benefit here.
DR. LEVINE: Yes, sir. There --
DR. TEMPLE: That’s why someone might choose this you’re saying?
DR. LEVINE: Yes, that CAF has not been compared to CEF, and the trials of CMF versus CAF have been negative
DR. SIMON: I would just like to say I think censoring patients who die or go off study because of toxicity is a very questionable thing to do. I would actually favor the time to treatment failure endpoint because censoring the others, that their subsequent prognosis would be no different than had they not — that they would be sort of representative patients, I think, is very questionable.
DR. MILLER: But I would want to emphasize that we did analyze TTF for that very reason in these studies and did show significant benefits in that endpoint.
DR. SIMON: Well, with time to treatment failure, the difference was between — the median was five months to 6.2 months.
CHAIRPERSON DUTCHER: Thank you. We’re going to have one more comment for open public hearing, very briefly. Ms. Fonfa.
MS. FONFA: Thank you very much for allowing me to speak.
This is not at all to be taken as specifically against this drug. I want to say a sort of global thing.
CHAIRPERSON DUTCHER: Name and --
MS. FONFA: I’m Ann Fonfa, representing the Annie Appleseed Project, New York City. My perspective is, and I think it was brought out by the word “significant,” I don’t see significant change in survival, and I don’t see significant change in time to disease progression or any other thing, and as a cancer patient, I want to reiterate long term survival is what we care about.
Advances in quality of life, and if it has to be time to disease progression, we want a lot of time, and I don’t see that here, and I don’t see it on anything that we have. And I want to say that if we don’t hold drug companies to very high standards, we get drugs that are only an eentsy-teensy (phonetic) bit, and this is the measurement I use, better than what we have.
It’s no good. We have to get you folks to look a little higher. You’re spending millions of dollars, and you’re not getting anything that matters to cancer patients, and now it’s 30 years later. For me it’s personally six and a half years later. I’m very unhappy, and I represent thousands, hundreds of thousands of people who feel the same way.
Please, please, aim higher. I beg you.
CHAIRPERSON DUTCHER: Thank you. Thank you very much.
So we have some issues.
Ann’s NOTE: Advocate Sandra Zook Fischler, a personal friend of mine, died of breast cancer in 2001. She will be missed.
And at a separate time:
DR. TEMPLETON-SOMERS (FDA Hearing 1990’s): Next we have a letter from Ann Fonfa, founder of the Annie Appleseed Project which educates and informs cancer patients, health care providers and others on issues of interest, especially complementary alternative therapies.
This is an extremely difficult question to address but I want to share with you some of my thoughts on the issue of compassionate use of unapproved therapies. As a woman who has had neither chemotherapy nor radiation, I am not eligible for most trials. While I understand why there are study entry criteria, I wonder if they are directed to ease the approval of a particular drug and not so much toward the benefits of the trial participants or the patient population in general.
For patients who have been heavily pretreated, and there are so many of these with metastatic breast cancer, I wonder if the entry criteria have to be set up they way they often are. If someone like myself, and I am not alone in this category, wanted to enter a trial we could not. We would have to have compassionate use approval. So, with those most needing a new therapy-women who have tried just about everything else first-in order to benefit these women a drug may actually have to work in that patient population. Therefore testing it on them may be a good idea. I recently read an article that stated drug companies can increase the likelihood of a drug success by using exclusion criteria, as one investigator told the Inspector General’s office, “to enrich trials with patients who are most likely to benefit”. Yet, having attended two meetings devoting to discussing how to promote clinical trials, I understand that we need completed studies to better aid us in discovering good treatment. Should performance status be a standard for entry?
On the other hand, when I look at the actual survival of most approved therapies I often fail to understand their benefit to patients. At another ODAC meeting I referred to continued approval of drugs with so little better benefits to patients than existing drugs by comparing the process to crawling on our hands and knees through a field of broken glass.
Patients want to leap forward, yet we are continually presented with tiny steps. Yes, they add up to moderate gains, as has been stated at various medical conferences I attend, but must we continue to crawl inch by inch or is that simply an artifact of the current system?
So, part of my problem is continuing to doubt whether we are using the best possible methods of finding, testing and approving drugs at all. As a cancer patient myself, I cannot imagine denying women with advanced disease the opportunity to try one more conventional therapy even when the end results will be two more months of survival laden with the negative effects of the therapy.
I will end by urging everyone in this room to consider the benefits of complementary natural therapies. Studies in animals and cell cultures indicate benefits may include better tolerance to cytotoxic regimens, support to the host — that is us, human beings — and possibly enhancement of therapy.
Please consider starting trials immediately that will look at chemotherapy with the use of antioxidants. Thank you for your attention. As you may imagine, no pharmaceutical company has ever sponsored the Annie Appleseed project.
[Laughter]
