FDA Concerned About Avastin Repackaging
Compounding Pharmacies Argue That Agency Oversteps its Authority.
BY JERRY HELZNER, SENIOR EDITOR
The FDA is expressing concern over some of the practices of compounding pharmacies. The federal agency has recently sent at least 9 warning letters to compounding pharmacies primarily focusing on safety issues. Though the specific content of the letters varies, one of the issues cited by the FDA is the repackaging of Genentech’s colorectal cancer drug Avastin for use as an injectable treatment for wet AMD.
Numerous retina specialists have been using repackaged Avastin as an off-label, low-cost alternative to Lucentis, Genentech’s FDA-approved treatment for wet AMD. The widespread interest in Avastin for wet AMD has led the National Institutes of Health to mandate a head-to-head trial to compare the efficacy and safety of the 2 drugs.
The flurry of warning letters has led the International Association of Compounding Pharmacies (IACP), which represents the industry, to lash back at the FDA. The IACP has accused the FDA of “aggressively overstepping its authority,” citing an August ruling by a U.S. District Court in Midland, Texas, that restricts the FDA’s jurisdiction over compounding pharmacies.
In what the IACP is calling “a landmark ruling,” Judge Robert Junell ruled that compounded drugs produced pursuant to prescriptions are not new drugs under the federal Food, Drug and Cosmetic act. The FDA had argued that compounded medications are “new drugs” subject to FDA jurisdiction.
In addition, the IACP contends that the FDA’s actions have negative implications for the rights of physicians to prescribe medications that they deem most appropriate for patients and for the future use of offlabel drugs in general. At this writing, the FDA has taken no further action beyond the warning letters, though actions such as product seizure and injunctions are available to the agency as remedies for continued noncompliance.
Though FDA personnel will not be directly quoted in this article, Retinal Physician has been able to interview reliable sources close to the FDA who explained in some detail the agency’s concerns about the activities of compounding pharmacies.
FDA: REPACKAGING IS NOT COMPOUNDING
Generally, the FDA is concerned that some compounding pharmacies have gone beyond their traditional role, which the FDA describes as preparing drugs that are not commercially available, such as a unique medicine for a patient who is allergic to an ingredient in an FDA-approved drug. This kind of compounding follows a physician’s decision that his or her patient has a special medical need that cannot be met by an FDA-approved drug.
The FDA has concerns when compounders take a single-use, preservative- free sterile vial of an approved drug, such as Avastin, and then repackage it in small amounts for ocular use.
Though this process may be performed in so-called “clean rooms,” the FDA believes that repackaging is not compounding and that this practice comes with a risk of compromising sterility. The FDA is specifically vigilant in the case of Avastin repackaging because it is injected into the eye.
Though the FDA is currently abiding by the Midland ruling in the geographic area under the jurisdiction of the federal district court that handed down the decision, the agency believes that the ruling is only applicable to that district and the plaintiffs in that case. It does not consider the ruling binding on its national enforcement program. Thus, the FDA has continued to send out warning letters to compounding pharmacies.
In addition, the FDA has noted 2 recent deaths of women who used topical anesthetic creams that were compounded. These risks were cited in 5 of the warning letters.
It is not yet clear whether the FDA will take additional, stronger steps to halt or limit the repackaging of Avastin. The agency deals with compliance issues on a case-by-case basis. No matter what happens in the future, the FDA has made a clear statement that it intends to keep a close watch on the business practices of compounding pharmacies.
Genaera Ends Evizon Program
AMD Treatment Deemed Not Competitive.
Genaera Corporation is terminating the Evizon (squalamine lactate) clinical development program in wet AMD and will focus company resources on the development of trodusqemine for the treatment of obesity. Despite a devoted and vocal following of stock investors who endlessly touted the potential of Evizon, the antiangiogenic drug never caused a ripple in the retina community. In trials, it had a good safety profile but could not come close to matching the efficacy of Genentech’s Lucentis and Avastin.
As a result of this strategic decision, Genaera will reduce its workforce by approximately 30%. The company has also engaged Banc of America Securities LLC as its financial adviser to assist the company in its review of strategic alternatives. Genaera common stock, which traded as high as $6 a share in 2003, was recently trading at 38 cents a share.
“This restructuring is a fundamental shift in direction for Genaera but represents the best match of our development programs to the new realities of the marketplace,” said Zola P. Horovitz, PhD, lead director of the Genaera board. “By refocusing resources from the Evizon development program, Genaera has the opportunity to bring trodusquemine forward and address a significant market opportunity.”
Genaera had been pursuing a multi-center, randomized, open-label phase 2 study (Study 212) of Evizon to determine if higher dose levels would produce greater and more rapid improvement in visual acuity than those seen in prior phase 2 studies, a result considered a necessary prerequisite to phase 3 development, successful registration, and partnership opportunities. The rapid acceptance, both domestically and abroad, of new and off-label products such as Lucentis and Avastin that improve vision in wet AMD significantly curtailed the rate of subject enrollment in Study 212.
“Despite our extensive recruiting efforts, enrollment of Study 212 has remained extremely difficult,” said Jack Armstrong, president and CEO of Genaera. “Additionally, preliminary information from investigators on patients enrolled to date in Study 212 suggests that Evizon is unlikely to produce vision improvement with the speed or frequency necessary to compete with recently introduced treatments. Faced with this discouraging information, as well as evolving FDA guidance on clinical endpoints, we have concluded that there is no attractive or pragmatic option for the registration and commercialization of Evizon for the treatment of wet AMD. As a result, we cannot justify continuing to expend our limited resources on the clinical development of Evizon.”
Lucentis stroke-risk data.
A largescale study undertaken by Genentech has confirmed earlier clinical trial data indicating that patients have an increased chance of experiencing a stroke when they are given the 0.5 mg dose of Lucentis compared to patients given the 0.3 mg dose. Though the overall incidence of stroke was 1.2% with the 0.5 mg dose and 0.3% with the 0.3 mg dose, the incidence was higher in those patients with a previous history of stroke. Stroke risk data was already on the Lucentis label but because it was confirmed in an interim safety analysis of the phase 3b SAILOR study involving a cohort of 2400 patients, Genentech voluntarily sent a letter to providers noting the increased incidence of stroke with the 0.5 mg dose. Genentech will continue to monitor safety data from the SAILOR study but said it does not believe it will be required to make changes to Lucentis labeling.
Macugen losses continue.
OSI Pharmaceuticals has written off another $212 million of its investment in the wet AMD treatment Macugen. The most recent writeoff, which encompasses unsold inventory and a reduction in potential future Macugen-related revenue, follows a $320 million writeoff taken in 2006. Macugen sales continued to plummet in the fourth quarter of 2006, with US sales totaling $7 million for the 3-month period. In the first quarter of 2006, prior to the approval of the competing wet AMD treatment Lucentis, OSI recorded $50.5 million in Macugen sales. OSI has announced its intention to exit the eyecare business. Pfizer is OSI’s marketing partner for Macugen.
Radiation treatment for AMD.
NeoVista, Inc., of Fremont, Calif, has recently released data demonstrating a potential benefit of treating wet AMD with radiation using the company’s Epi-Rad 90 Ophthalmic System.
Clinical data was presented from 2 separate feasibility studies that utilized the NeoVista product. The first study, involving a total of 24 patients, comprised 2 different doses of radiation (15 Gy and 24 Gy) delivered to the eye. The second study, which involved 20 patients, utilized a concomitant approach of 24 Gy radiation plus Avastin where an injection of the drug was administered at the time of radiation treatment and an additional injection was administered 30 days later. This is the approach the company plans to follow when it begins its pivotal 450-patient CABERNET trial this year. The company will utilize Lucentis instead of Avastin in this trial.
Eugene de Juan, Jr., MD, the Jean Kelly Stock professor of ophthalmology at the University of California San Francisco and the inventor of the NeoVista treatment approach, commented, “Although the follow-up period (3 months) is relatively short, the results observed from the concomitant trial are extremely encouraging. The percentage of patients who improved in visual acuity by greater than 3 lines was reported at 50%, which is far above the 34% that was reported in the Lucentis MARINA Study. Granted, the NeoVista sample size is much smaller than that garnered from MARINA, but the evidence does support a closer investigation of this concomitant approach.”
EU approves Lucentis.
Swiss-based pharmaceutical giant Novartis, which owns the international marketing rights to Lucentis, said that the wet AMD treatment has been approved by the European Union (EU). Lucentis, developed by Genentech, was previously approved in the United States and Switzerland.