FDA to Seniors: Food or Blindness?

In his famous novel Catch-22, Joseph Heller (spoiler alert) concocted a rule that appeared to allow combat pilots of questionable sanity to be grounded. However, because the rule also required pilots to ask for that reprieve, they in reality couldn't escape their duties, because making such a request would suggest presence of mind.

Apparently borrowing a page from Heller's book, the Food and Drug Administration has issued proposed rules that continue to allow the "repackaging" of pharmaceuticals, yet make it nearly impossible to use key repackaged drugs. Put simply, FDA's proposed "beyond use dates" (time from preparation to expiration) are unworkable for some important medications.

"Repackaging" is dividing a drug into smaller doses under sterile conditions — which are vitally important for, say, something injected into an eye, because eyes can be lost if contamination exists. Of particular interest here, the drug Avastin, originally approved to treat cancer, comes in large doses and requires repackaging to be used in treating the blinding disease wet macular degeneration (typically in seniors) as an alternative to more expensive drugs called Lucentis and Eylea.

We are not talking a trivial price difference. Avastin runs $50 a dose and Lucentis and Eyelea around $2,000. So under Medicare, a patient's 20 percent out-of-pocket expense is $10 or $400 respectively. Furthermore, such amounts represent just one of a series of 6 to 12 doses given monthly or every other month. Ignoring the huge potential fiscal impact on the Medicare program itself (which pays the remaining 80 percent), that difference could mean making a choice between buying food or going blind for those with limited incomes.

The FDA's rules would make it much more difficult to use Avastin. In the best case scenario (that is not even guaranteed under the wording), the proposed "beyond use date" is five days, and this starts when the compounding pharmacy (called an "outsourcing facility") opens the manufacturer's vial. Preparation is not instantaneous. Shipping, particularly to more rural areas, eats even more of this time. Long story short, this just won't result in a usable supply of the drug.

The rules stem from the 2013 "Drug Quality and Security Act," a response to a 2012 tragedy where a Massachusetts-based compounding pharmacy allegedly distributed contaminated medications that resulted in numerous cases of fungal meningitis and many deaths. As I wrote just before it passed, others and I feared the law did not sufficiently protect repackaged drugs — a fear that has apparently come to pass.

Key to the 2013 law is a provision requiring that drug compounding comply with the standards of the United States Pharmacopoeia (USP). For those who don't follow the esoterica of compounding, the pertinent chapter is affectionately known as "USP 797" in pharmacy circles. I link to it so you know it exists (access requires payment), but in general, it says "don't do stupid things" and explains what those might be.

It is fairly well accepted that contaminations are almost always traceable to breaches of USP 797 (see, for example, a case from 2011 involving Avastin). So it isn't rocket science to conclude that following its standards is likely our best hope to prevent future disasters, rather than layering on additional rules, and the FDA's proposal seems to ignore a vast body of existing experience with Avastin regarding safety and efficacy.

First off, contamination events have been extraordinarily rare even without the proposed regulations' "beyond use dates." According to the 2012 Medicare data I wrote about earlier, and using the reasonable assumption that 50 percent of eye injections were Avastin, approximately 1.3 million such doses were given under that program, the vast majority of which were compounded. A chart from the Pew Charitable Trust, meanwhile, shows a range of 5-45 eye complications traceable to compounding in most years from 2009-2013 (one episode had an unknown number). Yes, the number should be zero, and it may be higher than the chart suggests because of underreporting — but the fact it would require going to at least the fifth decimal place to record the percentage seems strong evidence of how uncommon problems have been. Furthermore, we might expect the numbers to be even lower in the future, since the FDA has limited repackaging to special "outsourcing facilites" created by the new law that will be subject to direct FDA regulation.

In addition, some have argued longer storage times are correlated with drug degradation. However, clinicians have found adequate clinical responses with Avastin under existing protocols, undermining that concern.

Lastly, no ophthalmologist would intentionally use a drug he or she thought would harm a patient. Working with an outsourcing facility that one trusts based on reputation and other factors is an ethical imperative.

So why might the FDA go this route? Consider that it works far more with drug manufacturers than with consumers and has a vested interest in the perceived value of one of its major functions: approving uses of drugs.

Unique here is the somewhat inside-baseball fact that the makers of Avastin once considered using it for eye treatment, but concluded it was too large a molecule. So they successfully put a small part of that molecule (its "active" fragment) through the (very complex and expensive) FDA approval process, creating Lucentis — only to have it discovered after the fact that Avastin worked essentially as well "off label" (meaning it has no formal FDA indication) at a vastly lower cost. But to achieve that lower cost requires dividing the contents of a manufacturer's vial into many small doses through repackaging.

So making repackaged Avastin unavailable via overly complex use standards has the effect of making Lucentis the only option and restoring the value of FDA approval of substitutable drugs. Draw your own conclusions, but FDA's appointments to its recently created Pharmacy Compounding Advisory Committee — which has an ophthalmic pharmaceutical company representative (who happens to work for the maker of Eylea) but not an ophthalmologist with actual experience using compounded drugs — seems to support that analysis.

Whatever its motivation, the FDA — which is taking comments on the rules through May 20 — should not create unwarranted roadblocks to the use of an important therapeutic option. I bet Heller would have backed me up when I say we need to restore some sanity to this process.

Craig H. Kliger is an ophthalmologist and executive vice president of the California Academy of Eye Physicians and Surgeons.