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How gaps in regulation of compounding pharmacy set the stage for a multistate fungal meningitis outbreak
COMMENTARY
How gaps in regulation of compounding pharmacy set the stage for a multistate fungal meningitis outbreak Besu F. Teshome, Kelly R. Reveles, Grace C. Lee, Laurajo Ryan, and Christopher R. Frei
Received January 16, 2014, and in revised form April 8, 2014. Accepted for publication April 20, 2014.
Abstract Objective: To provide an overview of the regulation issues surrounding compounding pharmacy that allowed the United States fungal meningitis outbreak to occur and the changes in regulation that ensued. Summary: In September 2012, a single case report sparked an investigation into a nationwide outbreak of fungal meningitis due to contaminated injectable drugs. The source of the contamination, New England Compounding Center (NECC), was in violation of several state and federal laws and had a history of such violations. The regulation of compounding pharmacies has historically been left to the states, while manufacturing fell under the jurisdiction of the Food and Drug Administration. However, as more compounders took part in large-scale interstate distribution of drugs, the current state-based regulatory system became less equipped to provide oversight. The lack of a clear definition of “compounding pharmacy” further obscures proper oversight and regulation. Congress and several states have taken steps to build safeguards against large-scale compounding by increasing inspections, adopting stricter licensing requirements, and enacting the Drug Quality and Security Act of 2013. Conclusion: While the current compounding regulation changes are a necessary step forward, it remains to be seen how effective they will be in safeguarding the public.
Besu F. Teshome, PharmD; Kelly R. Reveles, PharmD, BCPS; and Grace C. Lee, PharmD, BCPS, are graduate students. Laurajo Ryan, PharmD, MSc, BCPS, is Clinical Associate Professor. Christopher R. Frei, PharmD, MSc, FCCP, BCPS, is Associate Professor, University of Texas at Austin, Austin, and University of Texas Health Science Center at San Antonio, San Antonio. Correspondence: Christopher R. Frei, PharmD, MSc, FCCP, BCPS, University of Texas Health Science Center at San Antonio, Pharmacotherapy Education and Research Center, 7703 Floyd Curl Dr., MSC6220, San Antonio, TX 78229-3900. E-mail: [email protected] Disclosure: Dr. Frei has received research grants and/or served as a scientific consultant/advisor for the National Institutes of Health, AstraZeneca, Bristol-Myers Squibb, Elan, Forest, Ortho-McNeil-Janssen Pharmaceuticals, and Pfizer. The other authors declare no conflicts of interest or financial interests in any product or service mentioned in this article, including grants, employment, gifts, stock, holdings, or honoraria.
Keywords: Compounding, regulations, laws, patient safety, microbiology, quality assurance. J Am Pharm Assoc. 2014; 54:441–445. doi: 10.1331/JAPhA.2014.14011
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n September 2012, a single case report sparked an investigation that uncovered the most devastating drugrelated tragedy in recent history. An estimated 14,000 people in 23 states were exposed to contaminated, preservative-free methylprednisolone acetate (MPA) for injection, leading to 751 cases and 64 deaths from fungal infections.1,2 The source of this widespread tragedy was not a large multinational drug manufacturer. Instead, the contaminated MPA originated from a single compounding pharmacy in Massachusetts—New England Compounding Center (NECC). Other compounding contaminations have been reported previously, but the magnitude of the NECC case brought this issue into the national spotlight.3–5 The goal of this commentary is to provide a brief overview of the history of compounding regulation, the NECC tragedy, and the regulatory issues that allowed it to occur. We then provide a more comprehensive look at the new compounding law and discuss its potential limitations in preventing another compounding tragedy.
Fungal meningitis outbreak NECC, based in Framingham, MA, was a compounding pharmacy that distributed medications to more than 3,000 facilities in all 50 states.6 In 1998, NECC became licensed to produce compounded pharmaceutical
At a Glance
Synopsis: In this Commentary, the events leading up to and surrounding the multistate outbreak of fungal meningitis in the fall of 2012 are reviewed and subsequent actions analyzed. The New England Compounding Center (NECC), a Massachusetts-based compounding operation, had a decade-long history of citations from the Food and Drug Administration (FDA) and complaints to the Massachusetts State Board Pharmacy when the fungal outbreak began. A total of 751 cases and 64 deaths were associated with the use of NECC’s preservative-free methylprednisolone acetate (MPA) for injection. The federal legislative response was passage of the Drug Quality and Security Act of 2013. It leaves jurisdiction of traditional compounding pharmacies with the states, but gives compounders the option to register as an “outsourcing facility.” Analysis: While the United States Congress acted relatively quickly to pass legislation following the NECC tragedy, it remains to be seen whether the law will be sufficient to prevent similar tragedies in the future. Large-scale compounders are not required to register as “outsourcing facilities,” and without FDA oversight that accompanies registration, past history suggests that the state boards of pharmacy are not adequately trained and staffed to oversee such operations.
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products in accordance with Massachusetts state law. The law required them to have an individual patient prescription for each compounded product and follow the U.S. Pharmacopeia (USP) <797> standards for compounding sterile products.7 USP <797> establishes provisions that include proper garbing, training of personnel, environmental control, quality assurance, preparation, handling, and storage of compounded products to maintain sterility. A complete description of USP <797> requirements can be found on its website.8 NECC was found to be in violation of both aspects of the law during a joint inspection by the Food and Drug Administration (FDA) and the Massachusetts State Board of Pharmacy on October 1, 2012. This was not the first time NECC had been in the spotlight; the company had been the target of several state and federal investigations between 1999 and 2011. Health professionals and state boards of pharmacy from at least seven other states had issued complaints to the Massachusetts State Board of Pharmacy regarding NECC’s practices. The allegations included illegal solicitation, production of non-FDA approved drugs, and distribution of compounded products without a prescription.9 The most recent complaint was filed in April 2011, when a routine Colorado State Board of Pharmacy inspection identified NECC products without patient-specific prescriptions in a Colorado facility. This violated both Massachusetts and Colorado laws and resulted in the Colorado Board issuing a cease-and-desist order stating NECC was no longer allowed to ship products into Colorado.9,10 However, as with previous complaints filed against NECC, the Massachusetts State Board of Pharmacy did not take formal disciplinary action against NECC, and a year after the cease-and-desist order was filed, more nonpatient-specific drugs were found in Colorado facilities during inspections.9 FDA investigated NECC on three separate occasions between 2002 and 2006, including twice for reports of adverse events linked to epidural steroid injections produced by NECC.9 The inspectors found violations of sterility procedures, but their investigation was impeded when NECC challenged FDA’s jurisdiction over the pharmacy and refused to cooperate. FDA issued written warnings to NECC on three separate occasions, but again, jurisdictional issues and the lack of proper oversight by the state officials allowed NECC to continue to operate.9
Compounding versus manufacturing The regulation of compounding pharmacy has historically been left to individual states, while manufacturing falls under the jurisdiction of FDA. A major regulatory distinction is that manufacturers must adhere to a more stringent set of procedures and requirements, such as good manufacturing practices, national reporting of adJournal of the American Pharmacists Association
REGULATORY GAPS IN COMPOUNDING PHARMACY COMMENTARY
verse events, and New Drug Applications (NDA) for all new drugs. However, as more compounders take part in large-scale interstate distribution of drugs, the statebased regulatory system has become inadequate to provide proper oversight. The lack of a clear definition for when compounding becomes manufacturing further complicates the regulation of compounding pharmacies such as NECC, which operate in a similar manner to manufacturers. A precise definition of compounding has been difficult to determine, but in essence it is the mixing or altering of ingredients by a pharmacist to meet the individual needs of a patient after receipt of a valid prescription.10 Many definitions also include the preparation of drugs in anticipation of receiving prescriptions based on an established practitioner–patient–pharmacist relationship.10 Unlike manufacturers, compounding pharmacies have the added benefit of not having to recoup costs spent on research and development, which allows them to offer the drug at a fraction of the cost. Until the 1950s, 80% of prescribed drugs were compounded; by the 1960s, manufacturers of ready-to-dispense dosage forms began to dominate the market. However, compounding re-emerged in the 1980s and has been growing ever since.11 The factors that led the shift to increased use of compounded sterile products are multifactorial and complex. In recent years, the increased need for compounded products in health care facilities due to national drug shortages has added to substantially increased production by compounding pharmacies.12 This development has led to some compounding pharmacies operating on a national scale; however, the regulation of those pharmacies remains at the state level. This lack of national oversight of large-scale compounders poses a potential threat to the public.27
Federal regulation of compounding pharmacy FDA regulation of compounding pharmacies is not a new concept. In the 1990s, the agency became concerned that some compounding pharmacies were functioning and operating like manufacturers without the same level of oversight. In an attempt to clarify the point at which compounding becomes manufacturing, FDA issued a Compliance Policy Guide (CPG) in 1992.13 Among other policies, the CPG stated that FDA viewed compounded drugs as new drugs, thereby necessitating full NDA requirements; however, as a matter of policy, FDA would exercise “discretionary enforcement” and only prosecute those pharmacies perceived to be “behaving like manufacturers.” The concept of “discretionary enforcement” garnered criticism from compounders and led Congress to enact the Food and Drug Administration Modernization Act (FDAMA) of 1997 in an effort to delineate Journal of the American Pharmacists Association
the conditions that exempt a compounder from FDA oversight.14 The FDAMA added section 503A to the Food, Drug, and Cosmetic Act; it gave compounded products safe harbor from FDA regulation, provided three provisions were met. These provisions included a valid prescription for each compounded medication, limited anticipatory compounding, and no advertising of compounded drugs. Just days before that law was to take effect, seven pharmacies challenged the advertising provision in court. In 2001, the Ninth Circuit Court determined that the advertising provision violated commercial free speech and deemed the provision “unconstitutional.” In addition, the court ruled that the other provisions of 503A could not be separated from the advertising section; therefore, the entirety of 503A was considered invalid. Despite an FDA appeal, the Supreme Court reaffirmed the Ninth Circuit’s ruling in 2002, proclaiming that the advertising provision violated the compounder’s first amendment rights. This left the other provisions of 503A open to continued litigation in states covered by other circuit courts. In response to the rulings, FDA issued another CPG in 2002 that stated that 503A is invalid and listed factors that differentiated manufacturing from compounding. This CPG included many of the nonadvertising provisions of the FDAMA and additional rule violations (e.g., use of commercial-scale manufacturing equipment and not conforming to state pharmacy laws).15 It is important to note, however, that CPGs are not laws, but rather guidance. As a result, compounding pharmacies, such as NECC, challenged FDA enforcement of these CPGs in court. To further add to the ambiguity of federal oversight, in 2008, the Fifth Circuit Court disagreed with the Ninth Circuit Court’s ruling. These judges ruled that it was possible to separate 503A from the advertising portion, making the nonadvertising provisions valid in the Fifth Circuit.13 The fungal-contamination tragedy catapulted the public safety ramifications of this regulatory gray area into the national spotlight. Large-scale compounders, including NECC, have been operating out of the jurisdictional reach of FDA. The confusion over which regulatory agency is best equipped to safeguard the public from these entities has hampered the degree to which the public can hold regulators accountable for lapses in oversight. The lack of transparency by FDA in determining which pharmacies merit “discretionary enforcement” has further added to the already complicated landscape of compounding pharmacy regulation. The United States Congress took strides toward resolution of this issue on November 27, 2013, with passage of the Drug Quality and Security Act of 2013.16 The law addresses the ambiguity regarding 503A by removing the advertising and soliciting provisions. The reaffirmation of 503A led to FDA’s withdrawal of the CPG and the exercise of “discretionary enforcement.”17 The law j apha.org
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also includes a clause stating that if any one provision is found to be unconstitutional in the future, it can be removed without affecting the other provisions of the Act. This Act leaves jurisdiction of traditional compounding pharmacies with the states, but gives compounders the option to register as an “outsourcing facility.” An outsourcing facility that is overseen by a pharmacist will be able to qualify for exemptions to compound with a bulk drug substance, as long as that substance is on FDA’s drug shortage list or can be found on an FDA-issued list for which there is a clinical need. These facilities must pay a minimum $15,000 annual fee to register with FDA and will be subject to federal oversight.16 Once registered, outsourcing facilities will not have limits in the amount they can compound from the FDA-approved list and, unlike compounding pharmacies, these facilities are not required to have a prescription or to be a registered pharmacy.16 FDA is currently updating the list of acceptable drugs that can be compounded under 503A and 503B.18 Furthermore, this Act mandates increased levels of communication between the state and federal regulators regarding any concerns or actions taken for a compounding pharmacy.16 This law is supported by a number of professional organizations, including the American Pharmacists Association and the American Society of Health-System Pharmacists.19 The Act fails to address the issue of compounded products for “office use” in advance of a prescription, which is illegal according to federal law but has been allowed in some states. This omission has garnered opposition of the Act from the International Academy of Compounding Pharmacists.19 This Act is a necessary step toward defining jurisdiction, which hindered federal oversight of compounders like NECC. In addition, the Act provides for outsourcing facilities to meet needs in the case of drug shortages, particularly in the hospital setting. The Act may be limited by its reliance on compounders to voluntarily register as outsourcing facilities. The Act is also dependent on individual states to initially recognize violators of 503A but does not provide additional funding for this purpose. This means that pharmacies can still operate if the state in which they operate is not properly equipped to promptly identify and report violations to FDA.
State regulation of compounding pharmacy The lack of uniformity among states regarding compounding regulation increases the risk for similar lapses of oversight in the future. Differences include the number of inspections required, their stance on anticipatory compounding, and even the incorporation of USP <797> into their laws.20,21 A survey of pharmacy law conducted in 2013 found that only 23 states required full compliance with USP <797>.21 This poses a tremendous challenge to regulating entities that distribute products over 444 JAPhA | 5 4:4 | JUL /AUG 2 0 1 4
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state lines. Most state pharmacy boards do not have the resources to inspect out-of-state pharmacies that distribute to their state; instead, state regulators have historically relied on the home state of that particular pharmacy to provide the necessary oversight.22 Following the fungal meningitis outbreak, Massachusetts closed NECC and recalled all of the company’s products. In addition to having their licenses revoked and filing for bankruptcy due to the hundreds of lawsuits, NECC owners are facing a federal grand jury investigation that could result in criminal charges.23–25 The incident also prompted regulatory changes including reporting of adverse events, disciplinary actions, and total number of prescriptions dispensed out of state, as well as increased unannounced inspections.26,27 Several other states have followed suit and implemented similar regulations. Yet, considerable differences remain among the states.21
Conclusion The fungal meningitis outbreak is one of the most devastating manmade health-related tragedies in recent history. Its consequences have brought to light the gaps in the regulation of large-scale compounders. Federal and state regulators have acted quickly to close some of the regulatory gaps that have allowed some large-scale compounders to function with minimal oversight. However, it remains to be seen if the new law is sufficient to safeguard the public. References 1. Smith RM, Schaefer MK, Kainer MA, et al. Fungal infections associated with contaminated methylprednisolone injections. N Engl J Med. 2013;369:1598–1609. 2. Centers for Disease Control and Prevention. Multistate meningitis outbreak—current case count. www.cdc.gov/hai/outbreaks/ meningitis‐map‐large.html. Accessed July 5, 2014. 3. Centers for Disease Control and Prevention. Multistate outbreak of fungal infection associated with injection of methylprednisolone acetate solution from a single compounding pharmacy—United States, 2012. MMWR Morb Mortal Wkly Rep. 2012;61(41):839–842. 4. Gershman MD, Kennedy DJ, Noble-Wang J, et al. Multistate outbreak of Pseudomonas fluorescens bloodstream infection after exposure to contaminated heparinized saline flush prepared by a compounding pharmacy. Clin Infect Dis. 2008;47:1372–1379. 5. Centers for Disease Control and Prevention. Notes from the field: multistate outbreak of postprocedural fungal endophthalmitis associated with a single compounding pharmacy—United States, March–April 2012. MMWR Morb Mortal Wkly Rep. 2012;61(17):310–311. 6. New England Compounding Center customer list as of May 21, 2012. www.fda.gov/downloads/Drugs/DrugSafety/ FungalMeningitis/UCM325467.pdf. Accessed May 1, 2013.
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7. Smith L. Testimony of Dr. Lauren Smith, Interim Commissioner Massachusetts Department of Public Health to the United States Senate Committee on Health, Education, Labor, and Pensions. November 15, 2012. www.help.senate.gov/hearings/hearing/?id=5f5def0d‐5056‐a032‐5297‐eab57634d209. Accessed July 5, 2014. 8. United States Pharmacopeia. USP on compounding: a guide for the compounding practitioner. www.usp.org/store/products‐ services/usp‐compounding. Accessed April 1, 2014. 9. U.S. House of Representatives, Energy & Commerce Committee. The fungal meningitis outbreak: could it have been prevented? November 14, 2012. energycommerce.house.gov/ hearing/fungal‐meningitis‐outbreak‐could‐it‐have‐been‐prevented. Accessed May 1, 2013. 10. Mullarkey T. Pharmacy compounding of high-risk level products and patient safety. Am J Health-Syst Pharm. 2009;66(17 Suppl 5):S4–S13. 11. Shaughnessy AF. Meningitis outbreak shines light on compounding pharmacies. BMJ. 2012;345:e7432. 12. Guharoy R, Noviasky J, Haydar Z, et al. Compounding pharmacy conundrum: “we cannot live without them but we cannot live with them” according to the present paradigm. Chest. 2013;143(4):896–900. 13. Williams KG. Regulation of compounding by the Food and Drug Administration: a tale of 2 circuits. J Pharm Pract. 2010;23(5):502–506. 14. Food and Drug Administration Modernization Act of 1997. www. fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ PharmacyCompounding/ucm155666.htm. Accessed July 5, 2014. 15. Food and Drug Administration. Compliance Policy Guide Section 460.200 Pharmacy Compounding (Reissued 05/29/2002). www.fda.gov/ohrms/dockets/98fr/02d‐0242_gdl0001.pdf. Accessed July 5, 2014. 16. Drug Quality and Security Act of 2013. H.R. 3204. beta.congress.gov/bill/113th‐congress/house‐bill/3204. 17. U.S. Food and Drug Administration. FDA implementation of the Compounding Act. www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm375804. htm. Accessed December 2, 2013.
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18. U.S. Federal Register. Drug products that present demonstrable difficulties for compounding under sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act; request for nominations. December 4, 2013. federalregister.gov/a/2013‐28980. Accessed April 1, 2014. 19. Traynor K. President signs compounding law. Am J Health-Syst Pharm. 2014;71(1):7. 20. Traynor K. FDA, states discuss pharmacy compounding regulatory framework. Am J Health-Syst Pharm. 2013;70:180–182. 21. Anonymous. State boards and NABP take action to clarify regulation and bolster state regulatory systems specific to compounding pharmacies. National Association of Boards of Pharmacy Newsletter. 2013(Feb);42(2):25–30. 22. Food and Drug Administration. Framework for pharmacy compounding: state and federal roles. Public Meeting. December 19, 2012. Silver Spring, MD. www.fda.gov/downloads/NewsEvents/MeetingsConferencesWorkshops/UCM335791.pdf. Accessed May 1, 2013. 23. Petroni S. Judge tells NECC don’t destroy, tamper with anything, consolidates lawsuits. Framingham Patch. December 1, 2012. framingham.patch.com/articles/judge‐tells‐necc‐don‐t‐destroy‐ tamper‐with‐anything‐consolidates‐lawsuits. Accessed May 1, 2013. 24. Wilemon T. Meningitis outbreak: NECC files for bankruptcy. The Tennessean. December 21, 2012. www.tennessean.com/ article/20121221/NEWS07/312210128/Meningitis‐outbreak‐ NECC‐files‐bankruptcy. Accessed May 1, 2013. 25. Wallack T. Grand jury sets sights on compounding pharmacy. The Boston Globe. December 1, 2012. www.bostonglobe.com/ business/2012/12/01/federal‐grand‐jury‐investigating‐new‐ england‐compounding‐meningitis‐outbreak/IlRHC3wOchnaS188UB7EyN/story.html. Accessed May 1, 2013. 26. Massachusetts Department of Public Health. Pharmacy board draft emergency regulations. Nov 2012. www.mass.gov/eohhs/ docs/dph/quality/boards/necc/121101‐pharmacy‐board‐draft‐ emergency‐regs.pdf. Accessed May 1, 2013. 27. Massachusetts cracks down on compounding pharmacies. February 5, 2013. www.cnn.com/2013/02/05/health/massachusetts-compounding-pharmacies. Accessed May 1, 2013.
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How gaps in regulation of compounding pharmacy set the stage for a multistate fungal meningitis outbreak Besu F. Teshome, Kelly R. Reveles, Grace C. Lee, Laurajo Ryan, and Christopher R. Frei
Received January 16, 2014, and in revised form April 8, 2014. Accepted for publication April 20, 2014.
Abstract Objective: To provide an overview of the regulation issues surrounding compounding pharmacy that allowed the United States fungal meningitis outbreak to occur and the changes in regulation that ensued. Summary: In September 2012, a single case report sparked an investigation into a nationwide outbreak of fungal meningitis due to contaminated injectable drugs. The source of the contamination, New England Compounding Center (NECC), was in violation of several state and federal laws and had a history of such violations. The regulation of compounding pharmacies has historically been left to the states, while manufacturing fell under the jurisdiction of the Food and Drug Administration. However, as more compounders took part in large-scale interstate distribution of drugs, the current state-based regulatory system became less equipped to provide oversight. The lack of a clear definition of “compounding pharmacy” further obscures proper oversight and regulation. Congress and several states have taken steps to build safeguards against large-scale compounding by increasing inspections, adopting stricter licensing requirements, and enacting the Drug Quality and Security Act of 2013. Conclusion: While the current compounding regulation changes are a necessary step forward, it remains to be seen how effective they will be in safeguarding the public.
Besu F. Teshome, PharmD; Kelly R. Reveles, PharmD, BCPS; and Grace C. Lee, PharmD, BCPS, are graduate students. Laurajo Ryan, PharmD, MSc, BCPS, is Clinical Associate Professor. Christopher R. Frei, PharmD, MSc, FCCP, BCPS, is Associate Professor, University of Texas at Austin, Austin, and University of Texas Health Science Center at San Antonio, San Antonio. Correspondence: Christopher R. Frei, PharmD, MSc, FCCP, BCPS, University of Texas Health Science Center at San Antonio, Pharmacotherapy Education and Research Center, 7703 Floyd Curl Dr., MSC6220, San Antonio, TX 78229-3900. E-mail: [email protected] Disclosure: Dr. Frei has received research grants and/or served as a scientific consultant/advisor for the National Institutes of Health, AstraZeneca, Bristol-Myers Squibb, Elan, Forest, Ortho-McNeil-Janssen Pharmaceuticals, and Pfizer. The other authors declare no conflicts of interest or financial interests in any product or service mentioned in this article, including grants, employment, gifts, stock, holdings, or honoraria.
Keywords: Compounding, regulations, laws, patient safety, microbiology, quality assurance. J Am Pharm Assoc. 2014; 54:441–445. doi: 10.1331/JAPhA.2014.14011
Journal of the American Pharmacists Association
j apha.org
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n September 2012, a single case report sparked an investigation that uncovered the most devastating drugrelated tragedy in recent history. An estimated 14,000 people in 23 states were exposed to contaminated, preservative-free methylprednisolone acetate (MPA) for injection, leading to 751 cases and 64 deaths from fungal infections.1,2 The source of this widespread tragedy was not a large multinational drug manufacturer. Instead, the contaminated MPA originated from a single compounding pharmacy in Massachusetts—New England Compounding Center (NECC). Other compounding contaminations have been reported previously, but the magnitude of the NECC case brought this issue into the national spotlight.3–5 The goal of this commentary is to provide a brief overview of the history of compounding regulation, the NECC tragedy, and the regulatory issues that allowed it to occur. We then provide a more comprehensive look at the new compounding law and discuss its potential limitations in preventing another compounding tragedy.
Fungal meningitis outbreak NECC, based in Framingham, MA, was a compounding pharmacy that distributed medications to more than 3,000 facilities in all 50 states.6 In 1998, NECC became licensed to produce compounded pharmaceutical
At a Glance
Synopsis: In this Commentary, the events leading up to and surrounding the multistate outbreak of fungal meningitis in the fall of 2012 are reviewed and subsequent actions analyzed. The New England Compounding Center (NECC), a Massachusetts-based compounding operation, had a decade-long history of citations from the Food and Drug Administration (FDA) and complaints to the Massachusetts State Board Pharmacy when the fungal outbreak began. A total of 751 cases and 64 deaths were associated with the use of NECC’s preservative-free methylprednisolone acetate (MPA) for injection. The federal legislative response was passage of the Drug Quality and Security Act of 2013. It leaves jurisdiction of traditional compounding pharmacies with the states, but gives compounders the option to register as an “outsourcing facility.” Analysis: While the United States Congress acted relatively quickly to pass legislation following the NECC tragedy, it remains to be seen whether the law will be sufficient to prevent similar tragedies in the future. Large-scale compounders are not required to register as “outsourcing facilities,” and without FDA oversight that accompanies registration, past history suggests that the state boards of pharmacy are not adequately trained and staffed to oversee such operations.
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products in accordance with Massachusetts state law. The law required them to have an individual patient prescription for each compounded product and follow the U.S. Pharmacopeia (USP) <797> standards for compounding sterile products.7 USP <797> establishes provisions that include proper garbing, training of personnel, environmental control, quality assurance, preparation, handling, and storage of compounded products to maintain sterility. A complete description of USP <797> requirements can be found on its website.8 NECC was found to be in violation of both aspects of the law during a joint inspection by the Food and Drug Administration (FDA) and the Massachusetts State Board of Pharmacy on October 1, 2012. This was not the first time NECC had been in the spotlight; the company had been the target of several state and federal investigations between 1999 and 2011. Health professionals and state boards of pharmacy from at least seven other states had issued complaints to the Massachusetts State Board of Pharmacy regarding NECC’s practices. The allegations included illegal solicitation, production of non-FDA approved drugs, and distribution of compounded products without a prescription.9 The most recent complaint was filed in April 2011, when a routine Colorado State Board of Pharmacy inspection identified NECC products without patient-specific prescriptions in a Colorado facility. This violated both Massachusetts and Colorado laws and resulted in the Colorado Board issuing a cease-and-desist order stating NECC was no longer allowed to ship products into Colorado.9,10 However, as with previous complaints filed against NECC, the Massachusetts State Board of Pharmacy did not take formal disciplinary action against NECC, and a year after the cease-and-desist order was filed, more nonpatient-specific drugs were found in Colorado facilities during inspections.9 FDA investigated NECC on three separate occasions between 2002 and 2006, including twice for reports of adverse events linked to epidural steroid injections produced by NECC.9 The inspectors found violations of sterility procedures, but their investigation was impeded when NECC challenged FDA’s jurisdiction over the pharmacy and refused to cooperate. FDA issued written warnings to NECC on three separate occasions, but again, jurisdictional issues and the lack of proper oversight by the state officials allowed NECC to continue to operate.9
Compounding versus manufacturing The regulation of compounding pharmacy has historically been left to individual states, while manufacturing falls under the jurisdiction of FDA. A major regulatory distinction is that manufacturers must adhere to a more stringent set of procedures and requirements, such as good manufacturing practices, national reporting of adJournal of the American Pharmacists Association
REGULATORY GAPS IN COMPOUNDING PHARMACY COMMENTARY
verse events, and New Drug Applications (NDA) for all new drugs. However, as more compounders take part in large-scale interstate distribution of drugs, the statebased regulatory system has become inadequate to provide proper oversight. The lack of a clear definition for when compounding becomes manufacturing further complicates the regulation of compounding pharmacies such as NECC, which operate in a similar manner to manufacturers. A precise definition of compounding has been difficult to determine, but in essence it is the mixing or altering of ingredients by a pharmacist to meet the individual needs of a patient after receipt of a valid prescription.10 Many definitions also include the preparation of drugs in anticipation of receiving prescriptions based on an established practitioner–patient–pharmacist relationship.10 Unlike manufacturers, compounding pharmacies have the added benefit of not having to recoup costs spent on research and development, which allows them to offer the drug at a fraction of the cost. Until the 1950s, 80% of prescribed drugs were compounded; by the 1960s, manufacturers of ready-to-dispense dosage forms began to dominate the market. However, compounding re-emerged in the 1980s and has been growing ever since.11 The factors that led the shift to increased use of compounded sterile products are multifactorial and complex. In recent years, the increased need for compounded products in health care facilities due to national drug shortages has added to substantially increased production by compounding pharmacies.12 This development has led to some compounding pharmacies operating on a national scale; however, the regulation of those pharmacies remains at the state level. This lack of national oversight of large-scale compounders poses a potential threat to the public.27
Federal regulation of compounding pharmacy FDA regulation of compounding pharmacies is not a new concept. In the 1990s, the agency became concerned that some compounding pharmacies were functioning and operating like manufacturers without the same level of oversight. In an attempt to clarify the point at which compounding becomes manufacturing, FDA issued a Compliance Policy Guide (CPG) in 1992.13 Among other policies, the CPG stated that FDA viewed compounded drugs as new drugs, thereby necessitating full NDA requirements; however, as a matter of policy, FDA would exercise “discretionary enforcement” and only prosecute those pharmacies perceived to be “behaving like manufacturers.” The concept of “discretionary enforcement” garnered criticism from compounders and led Congress to enact the Food and Drug Administration Modernization Act (FDAMA) of 1997 in an effort to delineate Journal of the American Pharmacists Association
the conditions that exempt a compounder from FDA oversight.14 The FDAMA added section 503A to the Food, Drug, and Cosmetic Act; it gave compounded products safe harbor from FDA regulation, provided three provisions were met. These provisions included a valid prescription for each compounded medication, limited anticipatory compounding, and no advertising of compounded drugs. Just days before that law was to take effect, seven pharmacies challenged the advertising provision in court. In 2001, the Ninth Circuit Court determined that the advertising provision violated commercial free speech and deemed the provision “unconstitutional.” In addition, the court ruled that the other provisions of 503A could not be separated from the advertising section; therefore, the entirety of 503A was considered invalid. Despite an FDA appeal, the Supreme Court reaffirmed the Ninth Circuit’s ruling in 2002, proclaiming that the advertising provision violated the compounder’s first amendment rights. This left the other provisions of 503A open to continued litigation in states covered by other circuit courts. In response to the rulings, FDA issued another CPG in 2002 that stated that 503A is invalid and listed factors that differentiated manufacturing from compounding. This CPG included many of the nonadvertising provisions of the FDAMA and additional rule violations (e.g., use of commercial-scale manufacturing equipment and not conforming to state pharmacy laws).15 It is important to note, however, that CPGs are not laws, but rather guidance. As a result, compounding pharmacies, such as NECC, challenged FDA enforcement of these CPGs in court. To further add to the ambiguity of federal oversight, in 2008, the Fifth Circuit Court disagreed with the Ninth Circuit Court’s ruling. These judges ruled that it was possible to separate 503A from the advertising portion, making the nonadvertising provisions valid in the Fifth Circuit.13 The fungal-contamination tragedy catapulted the public safety ramifications of this regulatory gray area into the national spotlight. Large-scale compounders, including NECC, have been operating out of the jurisdictional reach of FDA. The confusion over which regulatory agency is best equipped to safeguard the public from these entities has hampered the degree to which the public can hold regulators accountable for lapses in oversight. The lack of transparency by FDA in determining which pharmacies merit “discretionary enforcement” has further added to the already complicated landscape of compounding pharmacy regulation. The United States Congress took strides toward resolution of this issue on November 27, 2013, with passage of the Drug Quality and Security Act of 2013.16 The law addresses the ambiguity regarding 503A by removing the advertising and soliciting provisions. The reaffirmation of 503A led to FDA’s withdrawal of the CPG and the exercise of “discretionary enforcement.”17 The law j apha.org
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also includes a clause stating that if any one provision is found to be unconstitutional in the future, it can be removed without affecting the other provisions of the Act. This Act leaves jurisdiction of traditional compounding pharmacies with the states, but gives compounders the option to register as an “outsourcing facility.” An outsourcing facility that is overseen by a pharmacist will be able to qualify for exemptions to compound with a bulk drug substance, as long as that substance is on FDA’s drug shortage list or can be found on an FDA-issued list for which there is a clinical need. These facilities must pay a minimum $15,000 annual fee to register with FDA and will be subject to federal oversight.16 Once registered, outsourcing facilities will not have limits in the amount they can compound from the FDA-approved list and, unlike compounding pharmacies, these facilities are not required to have a prescription or to be a registered pharmacy.16 FDA is currently updating the list of acceptable drugs that can be compounded under 503A and 503B.18 Furthermore, this Act mandates increased levels of communication between the state and federal regulators regarding any concerns or actions taken for a compounding pharmacy.16 This law is supported by a number of professional organizations, including the American Pharmacists Association and the American Society of Health-System Pharmacists.19 The Act fails to address the issue of compounded products for “office use” in advance of a prescription, which is illegal according to federal law but has been allowed in some states. This omission has garnered opposition of the Act from the International Academy of Compounding Pharmacists.19 This Act is a necessary step toward defining jurisdiction, which hindered federal oversight of compounders like NECC. In addition, the Act provides for outsourcing facilities to meet needs in the case of drug shortages, particularly in the hospital setting. The Act may be limited by its reliance on compounders to voluntarily register as outsourcing facilities. The Act is also dependent on individual states to initially recognize violators of 503A but does not provide additional funding for this purpose. This means that pharmacies can still operate if the state in which they operate is not properly equipped to promptly identify and report violations to FDA.
State regulation of compounding pharmacy The lack of uniformity among states regarding compounding regulation increases the risk for similar lapses of oversight in the future. Differences include the number of inspections required, their stance on anticipatory compounding, and even the incorporation of USP <797> into their laws.20,21 A survey of pharmacy law conducted in 2013 found that only 23 states required full compliance with USP <797>.21 This poses a tremendous challenge to regulating entities that distribute products over 444 JAPhA | 5 4:4 | JUL /AUG 2 0 1 4
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state lines. Most state pharmacy boards do not have the resources to inspect out-of-state pharmacies that distribute to their state; instead, state regulators have historically relied on the home state of that particular pharmacy to provide the necessary oversight.22 Following the fungal meningitis outbreak, Massachusetts closed NECC and recalled all of the company’s products. In addition to having their licenses revoked and filing for bankruptcy due to the hundreds of lawsuits, NECC owners are facing a federal grand jury investigation that could result in criminal charges.23–25 The incident also prompted regulatory changes including reporting of adverse events, disciplinary actions, and total number of prescriptions dispensed out of state, as well as increased unannounced inspections.26,27 Several other states have followed suit and implemented similar regulations. Yet, considerable differences remain among the states.21
Conclusion The fungal meningitis outbreak is one of the most devastating manmade health-related tragedies in recent history. Its consequences have brought to light the gaps in the regulation of large-scale compounders. Federal and state regulators have acted quickly to close some of the regulatory gaps that have allowed some large-scale compounders to function with minimal oversight. However, it remains to be seen if the new law is sufficient to safeguard the public. References 1. Smith RM, Schaefer MK, Kainer MA, et al. Fungal infections associated with contaminated methylprednisolone injections. N Engl J Med. 2013;369:1598–1609. 2. Centers for Disease Control and Prevention. Multistate meningitis outbreak—current case count. www.cdc.gov/hai/outbreaks/ meningitis‐map‐large.html. Accessed July 5, 2014. 3. Centers for Disease Control and Prevention. Multistate outbreak of fungal infection associated with injection of methylprednisolone acetate solution from a single compounding pharmacy—United States, 2012. MMWR Morb Mortal Wkly Rep. 2012;61(41):839–842. 4. Gershman MD, Kennedy DJ, Noble-Wang J, et al. Multistate outbreak of Pseudomonas fluorescens bloodstream infection after exposure to contaminated heparinized saline flush prepared by a compounding pharmacy. Clin Infect Dis. 2008;47:1372–1379. 5. Centers for Disease Control and Prevention. Notes from the field: multistate outbreak of postprocedural fungal endophthalmitis associated with a single compounding pharmacy—United States, March–April 2012. MMWR Morb Mortal Wkly Rep. 2012;61(17):310–311. 6. New England Compounding Center customer list as of May 21, 2012. www.fda.gov/downloads/Drugs/DrugSafety/ FungalMeningitis/UCM325467.pdf. Accessed May 1, 2013.
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REGULATORY GAPS IN COMPOUNDING PHARMACY COMMENTARY
7. Smith L. Testimony of Dr. Lauren Smith, Interim Commissioner Massachusetts Department of Public Health to the United States Senate Committee on Health, Education, Labor, and Pensions. November 15, 2012. www.help.senate.gov/hearings/hearing/?id=5f5def0d‐5056‐a032‐5297‐eab57634d209. Accessed July 5, 2014. 8. United States Pharmacopeia. USP on compounding: a guide for the compounding practitioner. www.usp.org/store/products‐ services/usp‐compounding. Accessed April 1, 2014. 9. U.S. House of Representatives, Energy & Commerce Committee. The fungal meningitis outbreak: could it have been prevented? November 14, 2012. energycommerce.house.gov/ hearing/fungal‐meningitis‐outbreak‐could‐it‐have‐been‐prevented. Accessed May 1, 2013. 10. Mullarkey T. Pharmacy compounding of high-risk level products and patient safety. Am J Health-Syst Pharm. 2009;66(17 Suppl 5):S4–S13. 11. Shaughnessy AF. Meningitis outbreak shines light on compounding pharmacies. BMJ. 2012;345:e7432. 12. Guharoy R, Noviasky J, Haydar Z, et al. Compounding pharmacy conundrum: “we cannot live without them but we cannot live with them” according to the present paradigm. Chest. 2013;143(4):896–900. 13. Williams KG. Regulation of compounding by the Food and Drug Administration: a tale of 2 circuits. J Pharm Pract. 2010;23(5):502–506. 14. Food and Drug Administration Modernization Act of 1997. www. fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ PharmacyCompounding/ucm155666.htm. Accessed July 5, 2014. 15. Food and Drug Administration. Compliance Policy Guide Section 460.200 Pharmacy Compounding (Reissued 05/29/2002). www.fda.gov/ohrms/dockets/98fr/02d‐0242_gdl0001.pdf. Accessed July 5, 2014. 16. Drug Quality and Security Act of 2013. H.R. 3204. beta.congress.gov/bill/113th‐congress/house‐bill/3204. 17. U.S. Food and Drug Administration. FDA implementation of the Compounding Act. www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm375804. htm. Accessed December 2, 2013.
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18. U.S. Federal Register. Drug products that present demonstrable difficulties for compounding under sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act; request for nominations. December 4, 2013. federalregister.gov/a/2013‐28980. Accessed April 1, 2014. 19. Traynor K. President signs compounding law. Am J Health-Syst Pharm. 2014;71(1):7. 20. Traynor K. FDA, states discuss pharmacy compounding regulatory framework. Am J Health-Syst Pharm. 2013;70:180–182. 21. Anonymous. State boards and NABP take action to clarify regulation and bolster state regulatory systems specific to compounding pharmacies. National Association of Boards of Pharmacy Newsletter. 2013(Feb);42(2):25–30. 22. Food and Drug Administration. Framework for pharmacy compounding: state and federal roles. Public Meeting. December 19, 2012. Silver Spring, MD. www.fda.gov/downloads/NewsEvents/MeetingsConferencesWorkshops/UCM335791.pdf. Accessed May 1, 2013. 23. Petroni S. Judge tells NECC don’t destroy, tamper with anything, consolidates lawsuits. Framingham Patch. December 1, 2012. framingham.patch.com/articles/judge‐tells‐necc‐don‐t‐destroy‐ tamper‐with‐anything‐consolidates‐lawsuits. Accessed May 1, 2013. 24. Wilemon T. Meningitis outbreak: NECC files for bankruptcy. The Tennessean. December 21, 2012. www.tennessean.com/ article/20121221/NEWS07/312210128/Meningitis‐outbreak‐ NECC‐files‐bankruptcy. Accessed May 1, 2013. 25. Wallack T. Grand jury sets sights on compounding pharmacy. The Boston Globe. December 1, 2012. www.bostonglobe.com/ business/2012/12/01/federal‐grand‐jury‐investigating‐new‐ england‐compounding‐meningitis‐outbreak/IlRHC3wOchnaS188UB7EyN/story.html. Accessed May 1, 2013. 26. Massachusetts Department of Public Health. Pharmacy board draft emergency regulations. Nov 2012. www.mass.gov/eohhs/ docs/dph/quality/boards/necc/121101‐pharmacy‐board‐draft‐ emergency‐regs.pdf. Accessed May 1, 2013. 27. Massachusetts cracks down on compounding pharmacies. February 5, 2013. www.cnn.com/2013/02/05/health/massachusetts-compounding-pharmacies. Accessed May 1, 2013.
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