Compromise Resolves Avastin® Dispute

    By Kevin E. Noonan --

Ophthalmologists and Genentech have forged a compromise over the availability of Genentech's anticancer drug, Avastin®, for use in treating neovascular or "wet" age-related macular degeneration (AMD).

The controversy arose when Genentech decided to ban compounding pharmacies from reformulating Avastin® (bevacizumab, a monoclonal antibody) to be used for treating AMD (see "Genentech Acts to Halt Off-label Use of Avastin® for Age-related Macular Degeneration").  This use of Avastin® is an off-label use; Genentech makes a related drug, Lucentis® (ranibizumab injection), that has been approved for AMD treatment.  The choice of the off-label use is related to the cost differential between the drugs:  Avastin® treatment costs from $20-60 per dose, while Lucentis® treatments cost $2,000/dose.  The cost differential is due to both differences in costs of the drugs per se (Avastin® is priced at only $600/vial) and because Avastin® is injected into the eye at such small doses (0.1cc) that each vial can deliver 30 doses ($20/dose).  This cost differential has even greater significance because neither drug is a cure for AMD, a condition that if untreated leads inexorably to blindness, so that patients require maintenance doses substantially for the remainder of their lives.

The decision outraged the ophthalmological community and their patients, who mounted a broad-based campaign against it.  These efforts were led by the American Association of Ophthalmologists (AAO) and the American Society of Retinal Specialists (ASRS), and included protests directed to (and at) Genentech, development of contingency plans for supplying the diluted Avastin® when the ban went into effect, and political efforts.  These efforts had an effect:  although Genentech initially defended their decision (see "Genentech CEO Defends Differential Cost for Avastin®/Lucentis® Treatment of Macular Degeneration"), more recently the company has responded in a more conciliatory way to the outrage, protests, and threats of political and legal action from its customers and their physicians (see "Age-related Macular Degeneration Patients Get a (Limited) Reprieve").  For example, the company expanded its dialog with ophthalmologists, explaining the actions of the Food and Drug Administration that prompted (in part) its decision, as well as rolling back the proposed implementation date of the ban from November 30th until the end of this year.  FDA concerns that were disclosed by Genentech to these professional societies related to sterility and packaging of the reformulated Avastin®, as well as concerns that Avastin® had not been "designed, manufactured or approved" for the off-label use.

Despite this belated attempt to recapture its clients' goodwill, more recently Senator Herb Kohl (D-WI) made it known that the economic consequences of the ban on the federal health care budget (estimated at $1 to 3 billion per year) had gotten his attention.  In a letter to Kerry Weems, Acting Administrator of the Centers for Medicare and Medicaid Services, the Senator stated that saving taxpayer dollars was of the "utmost importance" to him, and implied that he would take further action if he and the Senate's Special Committee of Aging did not receive satisfactory answers (see "Genentech Beset with Avastin® Woes").

Now, Genentech has substantially relented on its threat, and has agreed to a compromise that should permit ophthalmologists to have access to Avastin® for off-label use.  Compounding pharmacies will still not be permitted to purchase Avastin® directly; however, physicians will be permitted to make such purchases and direct the shipments to the compounding pharmacy of their choice for dilution to the concentration used for AMD treatments.  While the ban itself is little changed from what Genentech originally proposed, creation of this "loophole" will maintain access to the drug to AMD patients at the current, substantially-reduced prices over Lucentis®.

This is good news for AMD patients.  It is also good news for Genentech, which has further distanced itself from any negative consequences of off-label use.  Since the company is not itself selling Avastin® to compounding pharmacies, it should receive some measure of insulation from FDA action based on purported deficiencies attendant upon using Avastin® to treat AMD.  The company has also further distanced itself from liability concerns, since it is no longer directly involved in selling the drug to compounding pharmacies (and, indeed, the compromise involves shipments to such pharmacies on a physician's behalf not by Genentech itself but by "authorized distributors").  A further benefit for Genentech is that the AAO and ASRS agreed to increased efforts to "develop additional programs that will more efficiently facilitate and expedite patient access and physician reimbursement for Lucentis®," according to a joint press release on the societies' and company's websites.

The compromise may not be such good news for ophthalmologists themselves.  These doctors have moved more squarely into whatever medical malpractice and product-liability crosshairs may exist relating to off-label use of Avastin® for treating AMD.  In addition, as the press release notes, the compromise may not be able to be implemented in the same way in each state, due to differences in different states' laws.  The burden of determining whether there are any impediments in a state (and the liability for improperly implementing the compromise) will be borne by the physician, not Genentech.  This includes, presumably, the costs in deciding whether any such impediment exists:  the press release "recommend[s] that physicians check with their legal advisors when considering this new option."

Also missing from the announcement is whether Genentech will participate in, support or even provide Avastin® and Lucentis® for the clinical trial underway by the National Eye Institute, aimed at answering the scientific question of whether there is any difference in clinical outcome over use of the two drugs.  Genentech has not been inclined to support this study in the past (see "Lower Doses of Genentech's Avastin® Effective in Treating Lung Cancer").

For additional information on this topic, please see:

• "Genentech Beset with Avastin® Woes," December 6, 2007
• "Age-related Macular Degeneration Patients Get a (Limited) Reprieve," November 7, 2007
• "Genentech Acts to Halt Off-label Use of Avastin® for Age-related Macular Degeneration," October 21, 2007
• "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

Comments

[Cynic]

Kevin, I'm curious - I understand that ranibizumab (Lucentis) is a genetically modified version of the Fab fragment from the bevacizumab (Avastin) antibody that, unlike Avastin, is produced in a non-glycosylating system. However, neither drug appears to be listed in the Orange Book, so I assume Genentech's ability to price the two products differently is due to either (a) the more recent FDA approval of Lucentis and the concomitant 5-year exclusivity per TRIPs Article 39.3 (codified somewhere in the U.S.C. that I don't recall at the moment), (b) the fact that these are biologics and therefore difficult if not impossible under present regulations for generic manufacturers to knock off, or (c) both. Is this correct?

Of course Genentech isn't going to support a study that compares the efficacy of Avastin to Lucentis - they've got nothing to gain and everything to lose. If it's shown that the two are equally efficacious (or even close), then there will again be an uproar about the price difference. If it's shown that Avastin really is better, well, that's been their line all along; what would they then do, increase the price difference?

[Kevin E. Noonan]

Dear Cynic:

I suspect the answer is #2 in your comment, combined with the difficulties in getting regulatory approval and the traditional patent remedies.

As for helping the NEI, you are correct, of course, that it is not in their best interests, but given the black eye the company has received over its mishandling of this issue from the beginning, there is some merit in the idea that they "go along" with the trial with their fingers crossed, since the "Lucentis is better" answer might spur FDA to impose a ban on using the reformulted Avastin, and the company avoids being the bad guy. If there really is no difference, I don't think things will change much; Genentech certainly won't have any incentive to change the regulatory picture by applying for approval for Avastin for treating AMD, and any such result would further immunize them from liability for adverse incidents occurring from use of reformulated Avastin (at least to the extent that any such problems would be more easily blamed on the physician who administered the drug or the pharmacy who reformulated it, if the drug itself was as safe and effective as Lucentis in the NEI study).

Thanks for the comment.