Compound Interest: What Do You Know About Off-Label Avastin Preparation?

A spate of endophthalmitis cases prompts a re-evaluation of compounding pharmacies.

Frank Celia, Contributing Editor

When investigators traced to a single pharmacy in Hollywood, FL, all the Avastin injections that caused a dozen cases of endophthalmitis, the FDA naturally suspected a mistake in the repackaging process had contaminated the shots. In August, the agency warned that “repackaging sterile drugs without proper aseptic techniques can compromise product sterility,” and urging physicians to be certain their supplies were “obtained from appropriate, reliable sources.”

Then, just days after the FDA warning, several additional cases of Avastin-related endophthalmitis being treated at two VA hospitals, one in Los Angeles and one in Tennessee, came to light. The outbreaks received coverage from the New York Times, and a number of other media outlets picked up the story. Malpractice lawsuits were filed in conjunction with the Florida and Tennessee injections. By late September, the De partment of Veterans Affairs had announced that, pending an internal investigation, it would discontinue treating wet AMD with bevacizumab. Sensing a potential windfall, plaintiff attorneys' Web sites began trawling for off-label Avastin patients with health problems.

Clinically, the timing and disparate geography of the out breaks seem peculiar. According to a spokesperson, the FDA's ongoing investigation has not ruled out the possibility that the contamination occurred at the manufacturing stage. It is also possible that the three clusters represent little more than a highly regrettable statistical anomaly or perhaps two opposite poles of outcome reporting bias; ie, similar outbreaks under-reported in the past are now being overemphasized due to heightened media and legal awareness.

What is certain is that the infections have shaken and chagrined the retinal world. In their wake, surgeons who prescribe Avastin off-label are taking a second look at their compounding pharmacies' quality assurance safeguards. This article highlights what to look for and attempts to shed light on the legal and regulatory framework within which compounding pharmacies do business.

GRAY AREA

All pharmacists learn how to compound drugs as part of their training. The process of mixing, combining or altering in gredients to create customized medications for specific patients constitutes an integral branch of health care. For example, if a two-year-old transplant patient needs an antirejection medication that is only available in tablet form, a pharmacist would be called upon to reformulate it into an oral liquid. Compounded agents might also be tailor-made for patients allergic to an in gredient in a manufactured drug. Compounding pharmacies often play a role in serving small patient populations whose therapies are not mass produced or have been discontinued by manufacturers — so-called orphan drugs.

Though all pharmacists receive compounding training, in practice a cottage industry of specialty shops invariably handles these services. Sterile compounding, the kind needed to create products like intravitreal Avastin, requires considerable financial overhead, space and periodic personnel training and testing, and thus lies well beyond the scope of conventional pharmacies. Yet like conventional pharmacies, sterile compounding facilities are regulated by state pharmacy practice acts, which in turn are enforced by state pharmacy boards.

At the close of the last century, as pharmacological therapies grew more prevalent and complex, some began to question whether the patchwork of state laws and regulations was up to the task. In 1997, inspired in part by lurid press reports, several compounding cases that resulted in injuries and death, and the potential for such pharmacies to serve as fronts for counterfeit drug operations, Congress attempted to include the industry within its FDA Modernization Act. Objecting to provisions in the law that would limit advertising to consumers, pharmacists mounted a legal challenge to the increased FDA oversight. The result was a 2002 Supreme Court ruling that nullified the entire drug compounding provision of the act.

As it stands now, according to a General Accounting Office report on the subject, “FDA maintains that drug compounding activities are generally subject to FDA oversight, including its authority to oversee the safety and quality of news drugs. In practice, however, the agency generally relies on states to regulate the limited compounding of drugs as part of the traditional practice of pharmacy.”¹. Unless the compounding approaches a scale similar to manufacturing — that is, an apparent effort to circumvent new drug approval requirements — the FDA has little interest in day-to-day regulation, the GAO concluded.

Thus the compounding drug industry exists in a kind of regulatory gray area. Unlike drug manufacturers, compounding pharmacies are not required to report adverse events associated with the drugs they produce, nor are they subject to rigorous FDA oversight. Furthermore, the state pharmacy boards often lack the manpower and expertise to supervise and safeguard compounding fundamentals such as clean-room technology, in which aseptic standards essentially match those of a hospital operating room.

“The lack of regulation was amazing to us,” says Pravin Dugel, MD, a Phoenix-based retinal surgeon. Several years ago, when off-label Avastin use became widespread, he and other officers of the ASRS conducted an investigation into the compounding industry following Ge nentech's announced plans to curtail Avastin's availability to pharmacies. The company professed to be motivated by safety concerns, but the ASRS concluded profitability was more at issue.

“The bottom line is there are some outstanding compounding pharmacies that regulate themselves very well, that do everything that's expected of them,” says Dr. Dugel. “But there are also some compounding pharmacies that are not quite like that.” The challenge, of course, lies in differentiating the two. It's worth remembering that the Avastin used in the CATT trial was prepared under pristine conditions with much oversight and shipped to study sites in glass vials — conditions simply not possible in “real-world” practice. So it falls to physicians to source their inventory carefully and be mindful of the methods used by the vendor.

QUALITY ASSURANCE

Some form of industry certification ranks as a minimum requirement for a reputable pharmacy, experts say. The Pharmacy Compounding Accreditation Board (PCAB) tends to be accepted as the gold standard in this regard. Other credentialing bodies exist, but one of the advantages of the PCAB is that it lists credentialed pharmacies on a publicly accessible Web site, according to Mark Boesen, PharmD, vice president of regulatory and governmen affairs for the Apothecary Shops, a national specialty pharmacy with expertise compounding services.

In 2004 another organization, United States Pharmacopeia (USP), responded to the increased turn-of-the-century scrutiny of compounding pharmacies by introducing voluntary industry guidelines, of which its Chapter 797 provides standards for preparations such as intravitreal bevacizumab. “PCAB won't accredit a pharmacy that does sterile compounding unless it independently verifies that the pharmacy meets the guidelines in USP Chapter 797,” notes Dr. Boesen.

Surgeons are being encouraged to pay a visit to their compounding pharmacy, to speak directly to staff and to inspect the quality paper trail. “The pharmacy should be open and transparent with its quality assurance activities,” says Dr. Boesen. “If they are not willing to open the books, that's a red flag.”

Another area of concern is how the pharmacy tests the drugs delivered by the manufacturer, as well as the finished, compounded product before it is shipped to the clinician. Notes Dr. Boesen, “How do they do it? Are they testing a representative sample? How do they know? There are a number of established ways to do that.”

With quality standards in place, the potential weakest link then becomes staff compliance, says Dr. Boesen. “For example, one thing we do is fingertip testing. After they've gowned up and gloved up, is there any colony growth from cultured fingertips?” Wearing masks properly and drawing medication properly from vials (not piercing the rubber stopper) is also important, he says.

LEGAL LIABILITY

Should Avastin malpractice suits become the juggernaut that plaintiffs' attorneys hope, retinal specialists can expect a deluge of public rhetoric about alleged dangers of off-label prescribing. Indeed, many detected in the New York Times coverage of the infections a chastising tone. But legal scholars agree this is mostly boilerplate. Medical history abounds with examples of drugs approved for one condition proving more efficacious for another. Over the years, the benefits of off-label prescribing have garnered the practice consistent support from courts, legislative bodies and regulatory agencies, and it is considered a durable medicolegal principle.²

In terms of off-label prescribing of Avastin for wet AMD and other ophthalmologic conditions, retina specialists appear to be on firm legal ground. “The off-label use of Avastin is something that has become well known and well accepted in the ophthalmic community,” says Alan Reider, of Arnold & Porter, a Washington, DC-based law firm. “Medicare pays for it. It's recognized. Presuming proper informed consent, this should not be a potential liability area for physicians.”

Which is not to say practices and clinicians will avoid being sued. “No doubt doctors will be named in suits,” says Mr. Reider. “The question is: will they lose? This is one of those situations, in my view, where it is hard to say the physician has been negligent, although if a case goes to a jury, you never know what can happen.”

HEIGHTENED AWARENESS

In the absence of more adverse events, it's doubtful the infection clusters will significantly impact prescribing patterns, according to physicians. Infection in anti-VEGF therapy, which occurs in the 0.001% to 0.3% range depending on the study,^3-8 has always been a risk, and as a population Avastin patients do not demonstrate significantly higher rates.

“While these were the first clusters to appear in the press, it is possible there have been others in the past that were not publicized, as there is no central agency to report cases of endophthalmitis” says Michael Ober, MD, of Southfield, MI, adding that the recent events have not discouraged his use of bevacizumab, though they have had an effect. “We have become so comfortable with bevacizumab therapy that it's easy to get complacent until the process goes awry and some thing like this happens,” Dr. Ober says. “It's a wake-up call. It makes us look more carefully at our compounding pharmacies and try to better understand an integral step in bevacizumab treatment that is not under our direct supervision or control but is still within the realm of our responsibility to our patients. It may help tighten regulation of compounding pharmacies by government or peer agencies, all of which is a good thing. Heightened awareness to safety is always a good thing.” RP

REFERENCES

1. United States General Accounting Office. Prescription drugs: state and federal oversight of drug compounding by pharmacies. Testimony before Senate Committee on Health, Education, Labor and Pensions. Delivered Oct. 23, 2003.
2. Moyer CA. Off-label use and the medical negligence standard under Minnesota law. William Mitchell Law Rev. 2005;31:927-938.
3. Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR. VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351:2805-2816.
4. Rosenfeld PJ, Brown DM, Heier JS, et al, for the MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431.
5. Brown DM, Kaiser PK, Michels M, et al; for the ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1432-1444.
6. Moshfeghi AA, Flynn HW, Murray TG, et al. Rate of endophthalmitis following intravitreal injections in the anti-VEGF era. Paper resented at: Annual Meeting of the American Society of Retina Specialists; December 1-5, 2007; Palm Springs, CA.
7. Ferrone PJ, Gray S, Saroj N, Singh A. Endophthalmitis rate and utility of post injection telephone contact and clinical examination in detecting endophthal mitis after ranibizumab injection. Paper resented at: Annual Meeting of the Ameri can Society of Retina Specialists; December 1-5, 2007; Palm Springs, CA.
8. Jager RD, Aiello LP, Patel SC, Cunningham ET Jr. Risks of intravitreous injection: a comprehensive review. Retina. 2004;24:676-698.