The regulation
`of compounding
`Pharmacies
`
`The recent outbreak of fungal meningitis emphasizes the need for more efficient oversight.
`
`By Callan navitsky, assoCiate editor
`
`Pharmaceutical compounding is a method of pre-
`
`paring customized medications to meet the spe-
`cific needs of physicians and patients. Examples
`of commonly used ophthalmic medications that
`must be created by a compounding pharmacy are forti-
`fied antibiotics, preservative-free formulations, discon-
`tinued medications, and specialty items such as beva-
`cizumab (Avastin; Genentech) for intravitreal injection.
`Compounding pharmacies play an important role in
`ophthalmology by allowing physicians to prescribe indi-
`vidualized regimens. An improved therapeutic outcome
`may be achieved by the use of a compounded ophthal-
`mic treatment, and, as is the case with bevacizumab, the
`compounded agent is often more cost-effective than a
`commercially available alternative.
`Despite the advantages of pharmaceutical compound-
`ing, there are risks associated with this method of drug
`preparation. Poor practices can result in contamination
`or in products that do not possess the required sterility
`and quality. Unfortunately, compounding pharmacies
`are regulated by the states and are therefore not sub-
`ject to the same regulations as large-scale drug manu-
`facturers. Contaminated compounded drugs have been
`linked to outbreaks of infections such as endophthal-
`mitis and, more recently, have caused a fatal outbreak
`of fungal meningitis. The adverse events associated with
`compounded drugs have caused patients, physicians,
`and lawmakers to question the safety of these pharma-
`cies and the potential need for federal regulation of
`their practices.
`
`regulations
`In the United States, compounding pharmacies
`are licensed and regulated by their respective states.
`Most state boards of pharmacy use the United States
`Pharmacopeia’s (USP) Chapter 797 guidelines in the
`
`development of regulations for compounding sterile
`preparations.
`National standards have been created by the
`Pharmacy Compounding Accreditation Board (PCAB),
`which assesses pharmacies and awards the PCAB Seal of
`Accreditation to those that meet or exceed the PCAB
`requirements and comply with the terms of the PCAB
`program.
`“The state boards of pharmacy that license phar-
`macies and pharmacists oversee their day-to-day
`operations,” Sarah Clark-Lynn, of the US Food and Drug
`Administration (FDA) Office of Public Affairs, told Retina
`Today. “FDA also has some authority over drugs made
`by compounding pharmacies. The Agency can initiate
`enforcement action against a compounded drug if it
`is adulterated or misbranded in certain ways (eg, if the
`drug is contaminated or falsely labeled).”
`Ms. Clark-Lynn explained that the law exempts some
`pharmacy compounding from certain requirements
`that are otherwise applicable to drugs manufactured
`for use in the United States. “For example, compound-
`ed drugs are not approved by the FDA and therefore
`do not undergo premarket review for safety and effec-
`tiveness,” she said.
`Unlike commercial drug manufacturers, compounding
`pharmacies are not required to report adverse events
`associated with compounded drugs, and unless a com-
`plaint is filed or a patient is harmed, drugs made by
`compounders are seldom tested. Only 2 states—Texas
`and Missouri—perform random testing of compounded
`drugs. The FDA therefore learns of adverse events only
`through voluntary reporting, the media, and other
`sources.1 In turn, the FDA refers complaints to the states,
`provides support if requested, and cooperates in investi-
`gations and follow-up actions. If the states are unable to
`act, however, the FDA will proceed without them.
`
`november/december 2012 reTInA TodAy 21
`
`Regeneron Exhibit 1187.001
`Regeneron v. Novartis
`IPR2021-00816
`
`business of retina pennsylvania avenue updates
`Section Editor: George A. Williams, MD
`
`

`

`“When the Agency becomes aware of potentially
`contaminated or otherwise adulterated or misbranded
`compounded drug products, FDA investigates and
`works with its state counterparts to take appropriate
`action as quickly as possible,” Ms. Clark-Lynn said.
`
`reCent outBreaks
`In October 2012, the Centers for Disease Control and
`Prevention (CDC) traced an outbreak of fungal menin-
`gitis to fungal contamination in 3 lots of preservative-
`free methylprednisolone acetate used for epidural
`steroid injections. The medication was packaged and
`marketed by the New England Compounding Center
`(NECC), a compounding pharmacy in Framingham,
`MA. Doses from these lots had been distributed to
`75 medical facilities in 23 states. As of November 14,
`19 states had reported cases, in which 461 people were
`diagnosed with meningitis and other infections associ-
`ated with epidural injection, and 32 of these individuals
`had died.
`In response to the outbreak, the Massachusetts
`Department of Public Health issued a recall of all NECC
`medications, and NECC announced that it was sus-
`pending all operations and voluntarily surrendering its
`licenses. On October 9, members of the US House of
`Representatives and US Senate requested that federal
`health officials provide them with briefings on the out-
`break as a first step toward possible legislative action to
`strengthen federal drug safety regulation.
`Adverse events caused by contaminated lots of com-
`pounded ophthalmic drugs have been reported as well.
`Last year, patients in at least 3 US states developed
`severe eye infections—some resulting in permanent
`blindness—after receiving bevacizumab injections. The
`FDA issued a statement alerting health care profes-
`sionals that repackaged bevacizumab had caused the
`cluster of Streptococcus endophthalmitis infections that
`were reported by the Florida Department of Health.
`Investigators traced the infections back to a single com-
`pounding pharmacy in Hollywood, FL. This incident
`prompted the US Department of Veterans Affairs to
`temporarily halt its use of the drug and garnered great
`attention from the public and the media.
`
`Congressional Committee
`On November 14, the House Energy and Commerce
`Committee’s investigations subcommittee held the first
`hearing on the outbreak of fungal meningitis tied to
`contaminated steroids from the NECC. At the hearing,
`lawmakers questioned FDA Commissioner Margaret A.
`Hamburg, MD, and accused the agency of failing to pre-
`vent the crisis by moving too slowly against NECC. The
`
`FDA and Massachusetts officials inspected the NECC
`more than 10 years ago after patients were hospital-
`ized with meningitis-like symptoms, and they identified
`contamination of methylprednisolone acetate, the same
`drug at issue in the current outbreak, as the source. The
`Massachusetts Board of Registration in Pharmacy, which
`oversees the NECC, reportedly failed to carry out sanc-
`tions against the compounding pharmacy.2
`In defense, Dr. Hamburg argued that new laws must
`be passed to give the FDA clearer authority to regulate
`compounding pharmacies as it does larger commer-
`cial drug manufacturers. “This isn’t, sadly, an isolated
`incident,” she said.2 “This is the worst and most tragic.
`It should be the last wakeup call for us. We really need
`a strong, clear, and appropriate legislation. We cannot
`have a crazy quilt where different parts of the country
`are subject to different legal frameworks.”
`Dr. Hamburg suggested that traditional pharmacies
`stay largely under state control, with the FDA being able
`to have greater inspection authority. Nontraditional
`pharmacies and those that prepare drugs on a large
`scale in anticipation of prescriptions, rather than
`adhering to the traditional role of responding to indi-
`vidual physician’s orders, should register with the FDA.
`Dr. Hamburg confirmed that the FDA is pursuing a
`criminal investigation into the NECC, and the Justice
`Department is investigating the company as well. The
`FDA plans to hold a meeting on December 19 with state
`officials to determine how best to regulate compound-
`ing pharmacies.3
`
`ConClusion
`While the regulation of compounding pharma-
`cies continues to be debated, there are ways in which
`physicians can better ensure the quality and safety of
`compounded drugs. The type, quality, and quantity of
`the pharmacy’s customers, as well as how many years
`the pharmacy has been in business, can be clues to its
`expertise. Pharmacies that are used largely by health
`maintenance organizations and universities have likely
`undergone extensive audits and selection procedures.4
`Physicians can take an active role in trying to guarantee
`that the drugs they deliver to their patients come from
`reputable sources until a more efficient surveillance sys-
`tem at the state and federal levels is in place. n
`
`1. US Food and Drug Administration. The special risks of pharmacy compounding. www.fda.gov/consumer/
`updates/compounding053107.html. Published May 31, 2007. Accessed September 20, 2011.
`2. Morgan D, Berkrot B. US Congress takes aim at FDA over meningitis outbreak. Reuters. http://www.reuters.com/
`article/2012/11/14/us-usa-health-meningitis-widow-idUSBRE8AD13020121114. November 14, 2012. Accessed
`November 14, 2012.
`3. Edney A. Meningitis deaths prompt FDA to seek pharmacy oversight. Bloomberg. November 14, 2012. http://
`www.businessweek.com/news/2012-11-14/fda-seeks-power-over-specialty-pharmacies-after-meningitis-cases.
`Accessed November 14, 2012.
`4. Leiter CW. The art of compounding ophthalmic medications. Advanced Ocular Care. August 2010.
`
`22 reTInA TodAy november/december 2012
`
`Regeneron Exhibit 1187.002
`Regeneron v. Novartis
`IPR2021-00816
`
`business of retina pennsylvania avenue updates
`
`