Sounding Board: Controversy Surrounding the FDA Approval of Avastin

ONCNG Oncology, April 2008, Volume 9, Issue 4

The recent FDA approval for Avastin has sparked discussion about the approval of pharmaceuticals that may improve quality of life but do not necessarily extend life.

The recent FDA accelerated approval for Avastin (bevacizumab), in combination with paclitaxel chemotherapy for the treatment of patients who have not received chemotherapy for their metastatic HER2-negative breast cancer, has sparked larger discussion about the approval of pharmaceuticals that may improve quality of life but do not necessarily extend life. Below are the thoughts of three OncNG editorial board members:

Maurie Markman, MD

Unfortunately, the discussion regarding the utility of bevacizumab has failed to differentiate between benefit defined by evidence-based (randomized phase III) clinical trial data and the actual cost of that therapy. While the highly statistically significant improvement in the time to clinical disease progression demonstrated in this trial will certainly not be of relevance to all patients in this setting, it will be to many—and perhaps most—individuals.

Of great importance in this discussion, cost is not defined by “scientific evidence,” but rather by the “marketplace.” As a society, we absolutely must deal with the issue of the staggering costs of oncology drugs. But in this discussion, we should not permit these legitimate concerns about cost to negate the documented benefits to quality of life as revealed in well-conducted, evidence-based clinical trials. It is absolutely acceptable to declare, “We can’t afford this drug at its current cost.” Conversely, it is inappropriate to state, “This drug did not impact a meaningful clinical outcome in women with breast cancer.”

E. Roy Berger, MD, FACP

Lately, disease-free survival, or progression-free survival (PFS), has sometimes worked and other times not worked when it comes to predicting survival. My feeling is that in today’s marketplace, in which drugs and medical oncology are so expensive, it’s very difficult to approve a lot of drugs. My personal preference is that metastatic disease survival should be the endpoint, rather than PFS. The pro to that is that you’ll get drugs that show survival differences. The con is that it’s going to take some drugs a long time to reach that endpoint.

PFS had, in a number of cases, predicted survival differences. Now that we’ve seen a number of drugs in which there were survival diff erences but no PFS, it creates a big question mark. It’s going to be more expensive to reach survival diff erences and thereby possibly drive the prices of those drugs up when they do get approved, but they will also eliminate a lot of drugs that might have been approved based on PFS that don’t reach survival diff erences. Another way to do it would be to approve drugs based on PFS but withdraw the approval if they don’t show survival diff erences. That way, patients can get earlier access to drugs that look like they are going to show a survival difference and also avoid those drugs being on the market long-term if they don’t.

For example, Provenge missed its mark of PFS by 0.07; in two trials, it did show a survival diff erence, and the FDA advisory board advised that the FDA approve it. But then a month later, it was not approved. So, the FDA gave an approvable letter saying that “as soon as you show us a survival difference” in the IMPACT study that they’re doing now, “we’ll approve you.” Many cancer patients were upset that they couldn’t get access to the drug. A lot of people could have benefi ted from it, but they didn’t because it wasn’t approved. Now, you take Avastin, and for one reason or another, that was approved based on PFS, but no survival diff erence was shown in breast cancer.

Should a drug like Avastin that does not show a survival diff erence be approved? My feeling is that it’s too expensive, there are toxic eff ects from it, and I’m not sure it’s the right thing to do. I wouldn’t prescribe it to my patients with metastatic breast cancer. I think that the approval of Avastin sets a precedent. How can you tell one company for whom you approve a very expensive drug based on PFS and not survival diff erence “yes” and tell another company “no”? I think we’re spending way too much on the last three months of life and that we’re going to have to ration healthcare. So, if you have a 25- or 30-year-old woman who could use something like Avastin to improve PFS, we can consider that if we can stop having secondary and tertiary lung cancer patients, let’s say, who are 85 years old getting chemotherapy when we’ve shown that there’s very, very little chance of helping them.

But our health system isn’t set up to ration care yet. We’re going to have to cut back someplace in this economy and this environment, and nobody seems to be able to come up with the answers. I think symptomatic, supportive, and palliative care for comfort is the way to go. But most families in this country aren’t prepared to make the decision for such care, and we’re spending healthcare dollars on such patients and not allowing those dollars to go to younger patients who really need them. We have 47 million uninsured who can’t even aff ord healthcare. We have to begin to set standards and get palliative care to prevent people from getting drugs that won’t help them.

Jeremy R. Geffen, MD, FACP

The standards for FDA approval of a drug are already fairly well defi ned and established. First of all, the drug should be safe, meaning it has a toxicity profile that’s within the range of what we’re willing to accept in medicine and oncology. And, of course, it has to have proven, measurable, clinical activity and benefit. I believe that is why Avastin was approved, even in the absence of improvement in survival. I personally believe that if a drug has demonstrable clinical activity, even if it doesn’t prolong overall survival, the benefi ts may nonetheless be valuable to many patients. I think it’s important that, as a profession, we look beyond the standard five-year overall survival marker as the primary determinant of whether a drug or treatment is meaningful and valuable to patients and their family members.

Anyone who has gone through cancer—personally or with a loved one—understands this immediately; survival is not the only issue that matters. I believe that part of our job as oncologists is not only to add more years to our patients’ lives, but more life to their years. And based on the data that we presently have for Avastin, it appears that it may in fact do just that. I can assure you that, for many patients, it matters greatly to them to have CT scans that show no disease progression—even for a period of six months. For some, those six months may be the most important of their lives, and the relief of knowing that their disease is stable, even temporarily, can be immensely meaningful.

A large part of the controversy around Avastin, of course, is its high cost. It points a very sharp spotlight, frankly, on many of the complex, and at times even agonizing, issues that oncologists, patients, and family members face and struggle with every single day. Th e economic realities of medicine in this country often force heartbreaking choices and decisions regarding the distribution of resources and care. As a society, we have to ask, “Is it appropriate to administer Avastin at $7,700 per month to a woman with breast cancer who happens to be insured, even though we know we’re not going to extend her survival … and to struggle to provide the most basic, minimum care to another woman with breast cancer, sitting in the very next room, who doesn’t have insurance?” I think that the degree to which we can openly and respectfully talk about these issues will benefi t not only oncologists, but also our patients and their families, and ultimately society as a whole. Unfortunately, there aren’t easy answers or solutions, because these issues can be argued very strongly and legitimately from different perspectives.

It seems that the approval of Avastin will open the door for approval of other anticancer drugs that don’t necessarily extend life but do have some positive eff ects. I personally think that’s a good thing—with the caveats mentioned above. We’re in an era in which Pandora’s box has been swung wide open because of the extraordinary costs of these drugs and the complex issues involved in their use. It raises very profound questions about what we are doing as a profession and as a culture—such as spending $92,000 per year on a single patient for a drug that doesn’t extend survival while there are 47 million people in America who are uninsured and struggling to get just the most basic healthcare services. There is overwhelming data about the compelling needs of underinsured people in this country, and the widening gap in life expectancy based on income. Th is raises agonizing questions—medical, social, economic, and ethical—for which there are no easy answers. My hope is that this preliminary approval of Avastin might actually accelerate a deeper and more open discussion of what our goals and objectives are in oncology and how we’re going to handle the exploding costs of medical care in this country.

The discussions raised in this controversy—which highlight issues regarding the value of quality versus quantity of life, and how we evaluate and make decisions about them—is decades long overdue, and I welcome the process. I believe that everyone will be served if we, as a profession and a society, would consciously embrace the notion that quality of life is indeed an important and worthy marker of the value of what we’re doing, and in many cases, is as important as survival. I think it would be a great step forward.