By Kevin E. Noonan --
Earlier this year, Patent Docs had several posts relating to the use of an anticancer drug, Avastin® (bevacizumab, a monoclonal antibody), for treating neovascular or "wet" age-related macular degeneration (AMD), a condition that if untreated leads inexorably to blindness (see links below). This is an off-label use; another drug, Lucentis® (ranibizumab injection), has been approved for AMD treatment. This was not good news for the manufacturer of both drugs, Genentech, because the cost of Avastin® treatment is between 1% and 3% of the cost of Lucentis® treatment ($20-60 per dose versus $2,000/dose). In addition, the drug is not a cure for AMD but merely stablizes the wet form, and in many patients prevents the condition from worsening. This means that the drug must be administered like insulin or other maintenance drugs, at a cost of $2,000/dose and a once-a-month dosing schedule. Avastin® is so much cheaper because it is priced at $600/vial for intravenous use, but is injected into the eye at such small doses (0.1cc) that each vial can deliver 30 doses ($20/dose). Not surprisingly, Genentech has opposed the off-label use of Avastin®.
Spurred by complaints from ophthalmologists, the National Eye Institute (NEI) planned a comparative study of the two drugs to determine whether there were any advantages of using the drug approved for AMD treatment, Lucentis®, instead of Avastin®. This study has suffered, however, from a lack of cooperation from Genentech.
On Friday, Genentech raised the stakes. The way the two drugs are sold (their formulations and concentrations of the API) require Avastin® to be prepared by compounding pharmacies that are capable of reformulating the drug to the more dilute concentrations supplied in Lucentis®. In a letter from Susan Desmond-Hellmann, President, Product Development that was sent to members of the retinal community, Genentech stated that it "will no longer allow compounding pharmacies to purchase Avastin® directly from drug wholesalers" as of November 30, 2007. The purported reasons for the ban include the availability of Lucentis®, FDA concerns over sterility and packaging of the reformulated Avastin®, and concerns that Avastin® had not been "designed, manufactured or approved" for the off-label use.
The retinal community has responded, negatively. The American Society of Retinal Specialists (ASRS) sent their members a letter concerning the ban. In the letter, the group states that they have contacted Genentech to protest the decision and to voice their opposition to the ban. They state that they are:
actively investigating the legality, cost, and ramifications of options open to its membership to keep Avastin® available to our patients. This includes efforts in conjunction with the American Association of Ophthalmologists and other groups. Physicians are reminded that, for now, Avastin® remains available, and will remain available from hospital pharmacies even after the ban is put into place. In addition, the NEI study will not be affected by the ban.
Dr. Edward Chaum (at left), Plough Foundation Professor of Ophthalmology, University of Tennessee, informs Patent Docs that the ASRS is actively engaged in the issue, addressing Genentech directly, as well as the FDA and Congress. Specifically, in a letter to their members the Society asserted that it had contacted "the AAO [American Association of Ophthalmologists], the FDA, Genentech, congressional representatives, the compounding pharmacy industry, and legal counsel." The Society provides the following response from the FDA on the purported regulatory basis for the ban (emphasis in original):
Subject: FDA statement on Avastin
Unlike Lucentis (ranibizumab for injection), Avastin (bevacizumab) is not approved for ophthalmic use. However, the Food and Drug Administration (FDA) did not ask Genentech to stop distributing Avastin to compounding pharmacies and FDA has not taken action to limit the off-label use of Avastin. FDA has discussed with Genentech developing Avastin for the treatment of macular degeneration and studying its use in ocular indications. Further, FDA continues to monitor adverse reaction reports related to this off-label use. To date, the adverse reactions reported to FDA following use of Avastin for ocular indications have been consistent with the adverse reactions reported for Lucentis. FDA notes that Avastin is a sterile product and that its off-label use for ophthalmic diseases sometimes involves repackaging Avastin into multiple smaller doses for administration. The agency is concerned about the manipulation of sterile products because of the increased risk of product contamination.
Christopher C. Kelly
Office of Public Affairs
Food and Drug Administration
The Society also provided this insight on Genentech's legitimate concerns for its product:
Senior Genentech leadership described for the first time the actual circumstances of the FDA inspection of one of their oncology plants. In this inspection, the inspector reportedly looked at the particulates in the IV Avastin lots and specifically noted that these were too high for ophthalmic use. The contracts with compounding pharmacies were specifically asked for and reviewed, with verbal warnings about promotion of off-label use of the drug. As a consequence of this inspection, Genentech had to destroy four lots of Avastin.
The Society's letter goes on to say that formulating pharmacies have sufficient stockpiles of Avastin® on hand to supply current patient needs through the spring and possibly into next summer, and that various other avenues are being explored (including individual ophthalmologists reformulating Avastin® in their offices). The letter ends with the threat that "[w]e have also started to explore the legalities of numerous possible sanctions of Genentech by our society and its membership in the event of corporate non-response."
Dr. Chaum also provided Patent Docs with the following research results:
Early results show Avastin superior to PDT (photodynamic therapy) for wet AMD
This randomized, prospective controlled case series compared these two treatments in patients with predominantly classic CNV. At 6 months, mean BCVA and greatest linear dimension were significantly better in the Avastin group. CNV was dry in 81.3 percent of Avastin-treated eyes after the first or second injection (mean 1.6 injections). The benefit seemed to last for a mean of 3.2 months. Archives of Ophthalmology, October 2007
Early results show Avastin can reduce diabetic macular edema in some eyes
This randomized, phase II clinical trial finds that 43 percent of Avastin-treated eyes showed an initial positive response (more than 11 percent reduction in central subfield thickness) at three weeks compared with 28 percent of patients treated with focal photocoagulation. The effect appeared to plateau or decrease in most eyes between the 3- and 6-week visits. And the magnitude of response was not large for most subjects. Ophthalmology, October 2007
And on Friday, Senator Herb Kohl (D-WI) (at right), Chairman of the Senate Special Committee on Aging, sent a letter to acting administrator of the Centers for Medicare and Medicaid Services (CMS) for information about the agency's expenditures on Lucentis® and Avastin® in recent years, prompted by Genentech's decision banning sales of Avastin® to formulating pharmacies. The Senator also asked for any information about what CMS has done to try to reduce costs by using alternatives to Lucentis®, i.e., Avastin®.
Genentech's actions have not endeared the company to the retinal community, according to Dr. Chaum. After all, Genentech is hardly a struggling biotech start-up any longer: its third-quarter profit was up almost 21 percent from a year ago, it had a net profit of $685 million, and revenue of $2.91 billion. Avastin® had $597 million in third-quarter sales, and Lucentis® sales for the quarter were $198 million, a 29 percent increase. Although its actions with respect to Avastin® and Lucentis® are both perfectly legal and within the regulatory framework for drug approval, the cost differential puts the poor, sick, and aged at risk for permanent blindness. Whatever the economic justifications proffered by Genentech, they cannot but fall on deaf ears under these circumstances.
For additional information on this topic, please see:
- "Genentech CEO Defends Differential Cost for Avastin®/Lucentis® Treatment of Macular Degeneration," June 6, 2007
- "Retinal Specialist on the Avastin®/Lucentis® Controversy," February 23, 2007
- "Lower Doses of Genentech's Avastin® Effective in Treating Lung Cancer," February 23, 2007