Q1. Why is FDA proposing that the breast cancer indication for Avastin be removed?
A1. FDA is proposing that the breast cancer indication for Avastin be removed based on results from required clinical studies of the drug, including the AVADO and RIBBON1 studies, which established the following:
- The addition of Avastin to chemotherapy resulted in only a small delay in tumor growth (i.e., progression-free survival, PFS), and the average time it took for tumors to progress seen in these trials was much shorter than had been expected based on the data from an earlier trial that led to accelerated approval.
- The addition of Avastin to chemotherapy did not prolong the lives of women with breast cancer (i.e., overall survival, OS).
The addition of Avastin to various chemotherapies leads to an increase in incidence of serious adverse events from Avastin, as well as the serious side effects related to chemotherapy. Serious adverse events are toxicities that are severe or life-threatening, require medical intervention, hospitalization, or even result in death.
Considering all information from these clinical trials, FDA concluded that the risks of this drug outweigh its benefits in the treatment of patients with metastatic breast cancer.
Q2. How did the FDA reach the decision to propose removing the breast cancer indication for Avastin?
A2. The decision proposing to remove the indication for breast cancer is based on efficacy and safety data available from four clinical studies: E2100, AVADO, and RIBBON-1 for first-line metastatic breast cancer and AVF2119g for second-line treatment of patients with metastatic breast cancer. Data from these studies have shown very little effectiveness, if any, in delay of tumor growth when Avastin was given to patients with breast cancer.
The serious side effects of adding Avastin to chemotherapy were also taken into consideration. Cancer drugs ordinarily have serious side effects that result from their ability to kill or stop the growth of cancer cells. FDA understands that some safety risks with cancer drugs are acceptable to cancer patients so long as they are effective in prolonging life and improving quality of life. In certain instances, FDA has granted accelerated approval of drugs based on the effect of the drug in significantly delaying the growth of tumors (progression-free survival). In the case of Avastin, FDA approved the drug based on one promising study with PFS as the primary endpoint, with a post-approval obligation to confirm clinical benefit of the drug. After reviewing the data from the studies described above, the agency concluded that patients treated with Avastin did not live any longer than patients who did not receive the drug, and yet were at risk of experiencing severe side effects, including side effects that are unique to this drug. None of these studies showed evidence that Avastin extends the duration of survival in patients with metastatic breast cancer or in any way improves symptoms.
The most common side effects of Avastin are nose bleed and high blood pressure; however, serious and potentially fatal side effects of Avastin include:
- Massive bleeding requiring blood transfusions
- Development of perforations (or holes) in the body including the nose (nasal septal perforation) and the stomach and intestines (gastrointestinal perforation and fistulas)
- Severe high blood pressure
- Blood clots (arterial and venous thrombosis)
- Heart attack (myocardial infarction), heart failure and stroke
- Kidney damage
- Wounds that do not heal or scars from surgery that open up (dehiscence)
- Development of reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome characterized by high blood pressure, headaches, confusion, seizures, visual loss, and evidence of swelling of the brain on brain (MRI) scans.
The agency's proposal to remove the breast cancer indication takes into consideration the risk vs. the benefit of adding Avastin to chemotherapy. The agency also carefully considered advice from the Oncologic Drugs Advisory Committee (ODAC), a group of independent oncologists, patients and other experts that provided medical advice to the agency on the original accelerated approval and on the two confirmatory trials. In July 2010, the FDA's Oncologic Drugs Advisory Committee advised removal of the breast cancer indication in a 12:1 vote.
FDA makes decisions based on what is in the best interest of the population of patients with the disease for whom the drug would be used, not what might work best for an individual patient. Treatment decisions for individual patients are made by the patient's physician in consultation with the patient.
Q3. Will today's decision affect the other approved indications for Avastin?
A3. No, this action will not result in any changes to the other approved indications. Avastin will continue to be an approved treatment option for patients with advanced colon, lung, kidney, and brain (glioblastoma) cancers.
Q4. What happens to patients currently being treated with Avastin for their breast cancer? What should they do?
A4. Patients currently receiving Avastin for breast cancer should speak with their oncologists (cancer physicians) about whether to continue their treatment or explore other treatment options.Oncologists should use their medical judgment when deciding whether their patients should continue using Avastin with the drug paclitaxel, take paclitaxel alone, or consider other treatment options.
Q5. Why is FDA not removing the breast cancer indication immediately?
A5. Under the accelerated approval process, the agency must provide the company with the chance to request a hearing by issuing a Notice of Opportunity for a Hearing (NOOH). The agency issued the NOOH today. Genentech will have 15 days to request a hearing in writing. If Genentech does not request a hearing, the indication will be removed from the label. If Genentech requests a hearing, it must, within 30 days of receiving the NOOH, submit to FDA the data and information upon which it intends to rely at a hearing. If a hearing is requested and granted, it will be open to the public.
Q6. Some women have said Avastin works for them. Is it possible that the drug is effective in some patients?
A6. Outside of controlled clinical trials it is often difficult to interpret anecdotal reports of patient benefit from using any drug, including Avastin. For example, it is not possible in many cases to know whether the benefit seen was due to Avastin or due to the other treatments, such as chemotherapy, the patient received. FDA is interested in learning whether there may be a subset of patients with breast cancer in which Avastin may provide clinical benefit. If Genentech wishes to pursue additional studies, FDA will work with Genentech on the design of trials to explore whether such a subset of patients exists and if so, develop ways to identify such patients for whom Avastin treatment is safe and effective.
Q7. If the drug is shown to work in a certain type of breast cancer or in certain patients with breast cancer, would FDA consider including this information in the product label?
A7. If the company conducts further clinical studies that show Avastin's benefits outweigh its risks for a specific group of patients, then FDA would consider adding this information to the product label.
Q8. Did FDA factor the cost of Avastin into its decision?
A8. No. FDA does not factor costs into its drug approvals or safety related decisions.
Q9. What is accelerated approval?
A9. The accelerated approval program provides earlier patient access to promising new drugs for treatment of patients with serious and life-threatening diseases. Such drugs may receive accelerated approval while confirmatory clinical trials are being conducted to verify that the drugs are truly effective.
Under accelerated approval, the company is required to conduct clinical trials to verify and describe the clinical benefit, e.g., confirm that the drug treatment does prolong life or improve how the patient feels or functions (direct clinical benefit). If those trials fail to confirm clinical benefit to patients, or if the company does not pursue the required confirmatory trials with due diligence, the FDA can withdraw the drug or indication from the market using expedited procedures.
Q10. Did Genentech submit the required confirmatory studies?
A10. Yes. Genentech submitted two required clinical studies evaluating Avastin in metastatic breast cancer (AVADO and RIBBON-1) under their obligation to provide efficacy studies confirming clinical benefit. FDA has evaluated the data from these two studies, as well as the results from E2100 and an additional study (AVF2119g), in reaching its determination regarding the safety and efficacy of Avastin for the treatment of metastatic breast cancer.
Q11. Are there any other FDA approved treatments for metastatic breast cancer? What about other first-line drugs for metastatic breast cancer?
A11. Yes. Table 1 shows a list of other drugs approved for the treatment of MBC.
Table 1 – Other Agents Approved by the FDA for use in Metastatic Breast Cancer
|Indication||Agent||Year of Approval|
|2nd and 3rd line MBC||Paclitaxel
Capecitabine + Docetaxel
|1st line MBC||Trastuzumab + Paclitaxel
Gemcitabine + Paclitaxel