Latest developments in the Avastin/Lucentis saga raise new questions

As posted earlier, Genentech has announced its intention to stop selling Avastin to compounding pharmacies, which turned the product into $40 doses of eye drug Lucentis (the same drug as Avastin), undercutting the usual $2000 pricing. Genentech has taken a good deal of flak for this move. In particular, physicians and patients worry that off-label ocular uses of the drug will become harder to arrange.There are some interesting new communications out this week, but they don't answer all my questions. Genentech is trying to place the onus for the changes on the FDA, but it's not completely clear to me whether that's fair. In addition, ophthalmologists and retinal specialists who met with Genentech seem to have taken slightly different understandings from their meetings.Genentech posted an open letter explaining the rationale for its actions and announcing some changes.By way of explanation, Genentech offers the following:

• "We understood that some would disagree with our decision to stop supplying Avastin to compounding pharmacies and would accuse Genentech of making profit, not patients, its priority. Genentech's decision was not motivated by a desire for increased profits."
• "A series of FDA actions contributed to our decision," including:
• A warning letter to a compounding pharmacy
• "...FDA... concerns related to the ongoing ocular use of Avastin, because it is not manufactured for that use. In order to resolve the concerns raised by the FDA, we destroyed four batches of Avastin deemed unsuitable for use in the eye due to a higher visual inspection standard. (These lots would have been entirely suitable for its approved use as an intravenous cancer medication.) The action resulted in the loss of more than 350,000 vials of Avastin with a market value of more than $200 million."

Genentech has decided to make a few changes:

• Delaying implementation from November 30 to Jan 1 to give doctors time to make the transition
• Agreed to "reinstate its supply of Avastin to compounding pharmacies if the FDA gave the company legal and regulatory authorization to do so."
• Step up support for reimbursement for Lucentis so doctors and patients are less likely to be left on the hook
• Streamline access to free Lucentis for wet AMD patients (that's the approved indication) but also for "other ocular diseases that can lead to blindness," i.e., off-label use

A letter from the American Academy of Ophthalmology largely echoes Genentech's announcement, but includes a couple of other points not mentioned by Genentech. According to the letter, Genentech has agreed to:

• "Not impede physicians or other legal agents (e.g., group purchasing agents) from ordering Avastin or using compounding pharmacies after the embargo is in place"
• "Seek advance comment from the Academy and ASRS on any direct-to-patient or -physician communications on Avastin versus Lucentis"

First, let's examine Genentech's rationale.

• It's a bit rich for Genentech to feign offense at being accused of "making profits, not patients, its priority." Of course the company wants to make profits. It's a commercial enterprise and if it's not seeking profits it's not fulfilling its charter or satisfying its investors. That doesn't mean the company is heartless or that it doesn't balance patients' needs with financial goals.
• The warning letter to the compounding pharmacy isn't quite as clear cut as it sounds. I found the warning letter Genentech is probably referring to on the FDA website. The letter, dated December 4, 2006 is addressed to New England Compounding Center (just down the road from me in Framingham, MA) and refers to an inspection conducted on September 23, 2004. The five-page letter covers a lot of ground. It is not primarily about Avastin. FDA's basic beef is that the pharmacy is manufacturing drugs rather than performing typical compounding services, such as making a drug "for a patient who is allergic to an ingredient in a mass-produced product, or diluted doses for children." The letter's first complaint concerns trypan blue ophthalmic products. The pharmacy says this is a device, FDA says its a drug. The second complaint is that the pharmacy is making a 20% ALA solution, which is a commercially available product. The third complaint is that the company is marketing an "Extra Strength Triple Anesthetic cream," providing samples, and otherwise acting as a manufacturer. FDA also thinks this product is dangerous, as its ingredients have been linked to serious adverse events.Finally, on page 4 of the letter, FDA addresses the issue of Avastin repackaging with some pretty strong words. "...[W]e are in receipt of a complaint that you are repackaging the approved injectable drug, Avastin, into syringes for subsequent promotion and sale to health professionals." FDA states that, "[t]he moment a sterile container is opened and manipulated, a quality standard (sterility) is destroyed and previous studies supporting the standard are compromised and are no longer valid. We are especially concerned with the potential microbial contamination of Avastin --a single-use, preservative-free, vial-- into multiple doses. When used intravitrealiy, microbes could cause endophthalmitis, which has a high probability for significant vision loss. The absence of control over storage, and delays before use after repackaging, only exacerbate these concerns."I have two questions about this letter. 1) Who initiated the complaint? (Could it have been Genentech?) 2) If the inspection occurred in 2004 and the warning letter was issued a year ago, why is Genentech changing the policy now?
• The sentences about the FDA inspection of Genentech's plant are curious. Apparently FDA held Avastin to a "higher visual inspection standard" since they assumed the product was going to be used in the eye. Visual inspection refers to things you can see, like crimping of the package or particulates floating around. But since the product is in a vial and anyway is intended for injection, what did they see that was different? I doubt the inspectors could have seen anything floating around. As for the $200 million of product that had to be destroyed, if you divide by 100 you won't be far off from the actual manufacturing cost.

Finally, what did the doctors hear from Genentech about compounding pharmacies. If I understand their letter, it seems that hospitals and physicians will be allowed to buy Avastin and supply it to compounding pharmacies, presumably for repackaging as before. Did Genentech really agree to this? If so, what have they gained by this announcement?