HER2 Support Group Forums - View Single Post - Changing End Points in Breast-Cancer Drug Approval

gdpawel · 07-09-2011, 10:44 AM

[Dr. Robert A. Nagourney is medical director at Rational Therapeutics and instructor in Pharmacology at the University of California, Irvine School of Medicine. He posted on his blog about the issue surrounding Avastin.]

We previously wrote about bevacizumab (Avastin) and its approval for breast cancer. The early clinical trials revealed evidence of improved time to disease progression. This surrogate measure for survival benefit had, over recent years, gained popularity, as time to disease progression is a measure of the impact of a given treatment upon the patient’s response durability. It was hoped and believed that time to progression would be an early measure of survival.

Unfortunately, the survival advantage for the Avastin-based therapies in breast cancer has not met statistical significance. As such, careful review by the oncology drug committee of the FDA lead to a unanimous decision to remove Avastin’s indication in breast cancer. Avastin has not been removed from the market, but instead, cannot be promoted or advertised, nor do insurers necessarily reimburse it. This decision, however, will have a very big impact on Medicare patients and many others who are in managed care programs (HMOs).

There are no villains here. Instead, dedicated physicians empowered to scrutinize the best data could not prove beyond any doubt that the drug improved survival. The time to progression data was favorable and the survival data also trended in a favorable direction. But, the final arbiter of clinical approval — statistically significant survival — was not met.

The physicians who want to provide this for the patients, the company that produces the drug and the patients who believe it offers benefit all have legitimate positions. As Jerome Groopman, MD, once said, in a similar situation with regard to the FDA approval of interleukin 2 (a biological agent with profound activity in a small minority of melanoma and renal cell cancer patients), “I am confronted with a dilemma of biblical proportions, how to help the few at the expense of the many.”

The Avastin saga is but one example of what will occur repeatedly. The one-size-fits-all paradigm is crumbling as individual patients with unique biological features confront the results of the blunt instrument of randomized clinical trials. Our laboratory has been deeply involved in these stories for 20 years. When we first observed synergy for purine analogs (2CDA and fludarabine) with cytoxan, and then recommended and used this doublet in advanced hematologic malignancies (highly successfully, we might add) we were a lone voice in the woods. Eventually, clinical trials conducted at M.D. Anderson and other centers confirmed the activity establishing these treatments as the standards of care for CLL and low-grade lymphoma.

The exact same experience occurred in our solid tumor work when we combined cisplatin plus gemcitabine in pancreatic, ovarian, breast, bladder, lung and other cancers. While our first patient (presumably the first patient in the world) received cisplatin plus gemcitabine for drug-resistant recurrent ovarian cancer in 1995 — providing her an additional five years of life — it wasn’t until 2006 that the FDA approved the closely related carboplatin plus gemcitabine for this indication.

We now confront an even greater hurdle. With our discoveries, using novel combinations of targeted agents, we are years (perhaps decades) ahead of the clinical trial process. We know that patients evaluated in our laboratory with favorable profiles can respond to some of the newest drugs, many of which have already completed Phase I of clinical trials. It is our fervent belief that we could accelerate the drug development process if we could join with the pharmaceutical companies and the FDA to put these hypotheses to a formal test.

Again, there are no villains here. Patients want, and should, receive active drugs. Doctors should be allowed to give them. The drug companies want to sell their agents and the FDA wants to see good therapies go forward.

The rancor that surrounds these emotionally charged issues will best be resolved when we introduce techniques that match patients to active therapies. We believe that the primary culture platform used in our laboratory, and a small number of dedicated investigators like us, may be the answer to this dilemma.

We will redouble our efforts to apply these methods for our patients and encourage our patients to lobby their health care insurers and representatives to sponsor these approaches. To date, we have been unsuccessful in convincing any cooperative group to test the predictive ability of these selection methodologies. In response, I reiterate that I will gladly participate and, to the best of my ability, support at least the laboratory component of any fair test of our primary culture methodologies.

We stand at the ready for the challenge.

07-09-2011, 10:44 AM	#3
gdpawel Senior Member Join Date: Aug 2006 Location: Pennsylvania Posts: 1,080	The Avastin Saga Continues [Dr. Robert A. Nagourney is medical director at Rational Therapeutics and instructor in Pharmacology at the University of California, Irvine School of Medicine. He posted on his blog about the issue surrounding Avastin.] We previously wrote about bevacizumab (Avastin) and its approval for breast cancer. The early clinical trials revealed evidence of improved time to disease progression. This surrogate measure for survival benefit had, over recent years, gained popularity, as time to disease progression is a measure of the impact of a given treatment upon the patient’s response durability. It was hoped and believed that time to progression would be an early measure of survival. Unfortunately, the survival advantage for the Avastin-based therapies in breast cancer has not met statistical significance. As such, careful review by the oncology drug committee of the FDA lead to a unanimous decision to remove Avastin’s indication in breast cancer. Avastin has not been removed from the market, but instead, cannot be promoted or advertised, nor do insurers necessarily reimburse it. This decision, however, will have a very big impact on Medicare patients and many others who are in managed care programs (HMOs). There are no villains here. Instead, dedicated physicians empowered to scrutinize the best data could not prove beyond any doubt that the drug improved survival. The time to progression data was favorable and the survival data also trended in a favorable direction. But, the final arbiter of clinical approval — statistically significant survival — was not met. The physicians who want to provide this for the patients, the company that produces the drug and the patients who believe it offers benefit all have legitimate positions. As Jerome Groopman, MD, once said, in a similar situation with regard to the FDA approval of interleukin 2 (a biological agent with profound activity in a small minority of melanoma and renal cell cancer patients), “I am confronted with a dilemma of biblical proportions, how to help the few at the expense of the many.” The Avastin saga is but one example of what will occur repeatedly. The one-size-fits-all paradigm is crumbling as individual patients with unique biological features confront the results of the blunt instrument of randomized clinical trials. Our laboratory has been deeply involved in these stories for 20 years. When we first observed synergy for purine analogs (2CDA and fludarabine) with cytoxan, and then recommended and used this doublet in advanced hematologic malignancies (highly successfully, we might add) we were a lone voice in the woods. Eventually, clinical trials conducted at M.D. Anderson and other centers confirmed the activity establishing these treatments as the standards of care for CLL and low-grade lymphoma. The exact same experience occurred in our solid tumor work when we combined cisplatin plus gemcitabine in pancreatic, ovarian, breast, bladder, lung and other cancers. While our first patient (presumably the first patient in the world) received cisplatin plus gemcitabine for drug-resistant recurrent ovarian cancer in 1995 — providing her an additional five years of life — it wasn’t until 2006 that the FDA approved the closely related carboplatin plus gemcitabine for this indication. We now confront an even greater hurdle. With our discoveries, using novel combinations of targeted agents, we are years (perhaps decades) ahead of the clinical trial process. We know that patients evaluated in our laboratory with favorable profiles can respond to some of the newest drugs, many of which have already completed Phase I of clinical trials. It is our fervent belief that we could accelerate the drug development process if we could join with the pharmaceutical companies and the FDA to put these hypotheses to a formal test. Again, there are no villains here. Patients want, and should, receive active drugs. Doctors should be allowed to give them. The drug companies want to sell their agents and the FDA wants to see good therapies go forward. The rancor that surrounds these emotionally charged issues will best be resolved when we introduce techniques that match patients to active therapies. We believe that the primary culture platform used in our laboratory, and a small number of dedicated investigators like us, may be the answer to this dilemma. We will redouble our efforts to apply these methods for our patients and encourage our patients to lobby their health care insurers and representatives to sponsor these approaches. To date, we have been unsuccessful in convincing any cooperative group to test the predictive ability of these selection methodologies. In response, I reiterate that I will gladly participate and, to the best of my ability, support at least the laboratory component of any fair test of our primary culture methodologies. We stand at the ready for the challenge.