Following weeks of uncertainty, executives from Genentech Inc. (South San Francisco) met with members of the American Academy of Ophthalmology (AAO) to address the organization's "deep concern" over the company's decision to discontinue distribution of its drug Avastin (bevacizumab) to compounding pharmacies.

The meeting came on the heels of a letter that Genentech sent to members of the retinal community in October, stating that it would limit distribution of Avastin—an agent used by some ophthalmologists for the off-label treatment of age-related macular degeneration (AMD) and other ocular conditions. Avastin is US Food and Drug Administration (FDA) approved for the treatment of certain types of cancers, but it has been widely used among ophthalmologists despite the widespread availability of a similar agent from the company. Lucentis (ranibizumab) is FDA approved for the treatment of neovascular AMD.

Currently, Avastin is distributed directly to physicians and hospital pharmacies through authorized wholesale distributors. The company has also allowed compounding pharmacies to purchase the agent from wholesalers. In the letter to physicians, Genentech said that it would discontinue allowing compounding pharmacies to purchasing Avastin beginning November 30, 2007.

More recently, however, Genentech announced it would delay the sales embargo from the original date to January 1, 2008. The time extension was seen as an "encouragement" to the AAO and its members because it allows them to "find work-around solutions," said AAO President Charles "Pat" Wilkinson, MD, in a news release.

Genentech also agreed to "not impede physicians or other legal agents (eg, group purchasing agents) from ordering Avastin or using compounding pharmacies after the embargo is in place," according to the AAO.

Dr. Wilkinson said the AAO was "encouraged by the meeting results and hopes that our optimism will be justified by future [company] actions." In the meantime, Genentech also agreed to seek advance comment from the AAO and the American Society of Retinal Surgeons on any direct-to-patient or physician communications on Avastin versus Lucentis.

SERIES OF EVENTS
Genentech's decision to begin the sales embargo was based on several factors including "the FDA approval and broad availability of Lucentis for patients with [neovascular] AMD," according to the company-issued letter.

"Subsequent to the approval of Lucentis, the FDA raised concerns related to the sterility and repackaging of Avastin for ocular use in a warning letter to a compounding pharmacy and, separately, during a routine FDA inspection of our South San Francisco manufacturing facility. Concerns were raised by inspectors related to the ongoing ocular use of Avastin because it is not designed, manufactured, or approved for this use. In addition, we note that Avastin has not undergone any formal, randomized, controlled clinical trials for ocular use," the company letter said.

Some in the ophthalmic community, however, continue to view the move as being financially motivated and not a patient-care decision.

Avastin, which is chemically similar to Lucentis, has been referred to as a "low-cost substitute" for the FDA-approved agent, and one with which surgeons have reported good results. A once-monthly dose of Avastin costs approximately $40 versus a once-monthly dose of Lucentis, which costs about $2,000. US sales of Avastin for the first 6 months of 2007 were $1.1 billion, according to a report in the Wall Street Journal, and $420 million for Lucentis.

Genentech, however, defended its decision, stating that "we understood some would disagree with our decision to stop supplying Avastin to compounding pharmacies and would accuse Genentech of making profit, not patients, its priority. We do not expect the change in policy to lead to a sales increase in Lucentis because Avastin will continue to be available and prescribed by doctors for ocular indications."

Further, Genentech pointed to an incident in which more than 350,000 vials of Avastin had to be destroyed (market value in excess of $200 million) after the FDA raised concerns of their suitability for ophthalmic use. "The implication of this event was that future supplies of Avastin would likewise be at risk of having to be destroyed," the company stated in a letter available on its Web site. "In our judgment, these FDA actions—and the potential for future similar actions—necessitated a change in our policy toward compounding pharmacies."

The company also assured members of the AAO that they will work with appropriate parties to make anti-VEGF therapy available for eligible low-income or underinsured patients. "The Genentech Access to Care Foundation (GATCF) provides Lucentis at no cost to not only qualified patients with wet AMD but also qualified patients with other ocular diseases that can lead to blindness. Genentech is working in conjunction with the GATCF to make the process more efficient and to speed patient access to treatment," it added.

Robert L. Avery, MD, told Retina Today in an e-mail interview, however, that "the GATCF program in its current state is cumbersome, and even when refined does not cover all patients who may need anti-VEGF for non-AMD causes." Dr. Avery is the founder of California Retina Consultants and Research Foundation in Santa Barbara, Calif., and will be Associate Chief Medical Editor of Retina Today, effective January 2008.

ADDRESSING PHYSICIAN CONCERNS
Genentech spokeswoman Dawn Kalmar said the company continues to actively listen to physicians' concerns and will try to address them in a productive fashion. In a telephone interview with Retina Today, Ms. Kalmar said, "our first and foremost concern is for patients, and we want to make sure that patients have access to the therapy they need. We have an extensive access program in place for Lucentis, and we are confident that we can assist patients who need the therapy and are eligible to receive it."

Ms. Kalmar also said that Genentech will not interfere with physicians' practice of medicine. "Avastin will remain available to physicians who determine that it is the best treatment for their patients, albeit off-label. We are not standing in the way of a physician's prescribing choice; this change in distribution simply means that they will have to order it through a different mechanism," she said.

Physicians who purchase Avastin for ocular use from hospital pharmacies will be unaffected by the decision, she added. Additionally, physicians can still order the agent directly from the distributor.

AAO SEEKING A SOLUTION
"The primary concern of ophthalmologists is preserving the sight of our patients. Because Avastin has also been used off-label to treat diabetic retinopathy, macular edema, and various other sight-threatening disorders, Genentech's decision to restrict availability of the drug has much wider implications than just for AMD patients," said H. Dunbar Hoskins Jr, MD, Executive Vice President of the AAO.

Dr. Hoskins' sentiments were echoed by Philip J. Rosenfeld, MD, PhD, Professor of Ophthalmology at the Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine. One of the first retinal surgeons to use Avastin, he told the Wall Street Journal that the need for Avastin does not just go away with providing Lucentis for neovascular AMD, as the agent is being used for conditions in which neither drug is FDA approved. Dr. Rosenfeld is a member of the Retina Today editorial board.

Some surgeons also expressed concern that ophthalmologists will attempt to repackage Avastin themselves. In the Wall Street Journal report, Anne E. Fung, MD, said Genen-tech's decision has taken Avastin out of a regulated environment and put it into an unregulated environment, possibly increasing the risk of contamination and infections. Dr. Fung is in practice with Pacific Eye Associates, a private multispecialty ophthalmology group in San Francisco.

Working to address ophthalmologists' concerns, Genentech told AAO members that it would strive to "ensure that an anti-VEGF (Avastin or Lucentis) will be made rapidly available for patients with time-critical needs, in a legally appropriate manner that minimizes the financial risk to the physician."

Dr. Wilkinson urged the company to follow through on their promises and for the ophthalmic community to show patience during this process. "While it is hard to overlook Genentech's initial decision, we cannot ignore the fact that the company has given ophthalmologists and patients a breakthrough treatment for [AMD] and other eye diseases," he said. "We trust and will continue to seek verification that Genentech is committed to addressing our concerns in a reasonable and timely manner."