American Journal of Law & Medicine

Compounding Problems and Compounding Confusion: Federal Regulation of Compounded Drug Products and the FDAMA Circuit Split

I. INTRODUCTION

Drug compounding is the long-standing pharmacy practice of mixing, combining, or altering ingredients to create drugs tailored to individual patient needs. Compounding is as old as the practice of pharmacy and close to the heart of the modern profession. Indeed, the mortar and pestle--an iconic emblem of compounding--have long been the prevailing symbol of pharmacy. Prior to the emergence of commercially available drug products, the practice of compounding was the practice of pharmacy--to create medicines, early pharmacists inevitably needed to extract and compound natural vegetable, animal, and mineral substances. (1) In one impressive example of successful early compounding, God commanded Moses to "compoundeth" a holy anointing oil of myrrh, cinnamon, cassia, olive oil, and sweet calamus. (2) Not generally one to shrink from a challenge, Moses followed God's recipe and used his compounded oil to anoint the vessels of the Tabernacle and High Priest. (3)

For most of our history, the federal government virtually ignored the practice of compounding, leaving the matter to the individual State Boards of Pharmacy in their general regulatory oversight of the profession. In the early 1990s, however, a confluence of events--including a resurgence in the practice's popularity and an increased awareness of the practice's risks--led the United States Food and Drug Administration ("FDA") to assert regulatory jurisdiction over compounding for the first time. The FDA's assertion of regulatory authority triggered a fierce backlash from organized pharmacy and a protracted legislative battle. This battle eventually culminated in the passage of the Food and Drug Administration Modernization Act of 1997 ("FDAMA") which, in pertinent part, clarified the status of pharmacy compounding under federal law. (4)

In 2002, the Supreme Court declared certain compounding-related provisions of the FDAMA unconstitutional on First Amendment grounds in Thompson v. Western States Medical Center. (5) In the wake of Western States Medical Center, a circuit split has emerged on the severability of the unconstitutional provisions from the remainder of the compounding-related provisions of the FDAMA. (6) The Ninth Circuit has held the unconstitutional provisions to be unseverable and thus declared the compounding-related provisions of the FDAMA entirely invalid. (7) The Fifth Circuit has held the unconstitutional provisions to be severable and thus found the compounding provisions of the FDAMA to be continuing in effect. (8) This Note examines this significant circuit split and the related questions of why the split happened, why it matters, and which circuit got it right.

Part II of this Note presents an introduction to the practice of compounding, explaining both its history and continuing importance in our modern health care system. Part III documents the serious and often severe risks that inhere in the practice of compounding. In particular, Part III reviews five general types of compounding risks--subpotency, superpotency, contamination, overmedication, and medication-replacement. Part IV introduces compounding's 'pirate manufacturing problem.' For decades, rogue pharmacies have engaged in large-scale manufacturing under the guise of compounding. This problem is both widespread and dangerous and it has, by most indications, been the primary impetus for the FDA's renewed interest in the area. Part V explains the unsettled federal regulatory framework that provides the backdrop for a consideration of the FDAMA circuit split. Part VI then turns to the circuit split and examines its two principal cases--the Ninth Circuit and Supreme Court decisions in Thompson v. Western States Medical Center and the Fifth Circuit decision in Medical Center Pharmacy v. Mukasey. Part VII, finally, offers a closer look at the issue and implications of severability. It argues that while the Ninth Circuit position has merit, the Fifth Circuit's analysis is both more defensible and more faithful to Supreme Court precedent. Part VII concludes by analyzing the difficulties with the FDA's assertion of regulatory authority under a non-FDAMA regime. In light of those difficulties, Part VII argues that both the FDA and organized pharmacy should prefer the Fifth Circuit's modified FDAMA to the Ninth Circuit's regulatory vacuum.

II. THE PRACTICE OF COMPOUNDING

As late as the 1920s, compounding was employed in upwards of 80% of all prescriptions. (9) Indeed, up until the dawn of modern pharmaceutical manufacturing in the 1950s, the majority of prescriptions were still compounded. (10) The number of compounded prescriptions dropped precipitously in the 1950s and 1960s, as mass pharmaceutical production supplanted labor-intensive compounding. (11) In the 1970s, pharmacy colleges began to deemphasize compounding-related training as the proportion of prescriptions compounded dropped to a reported all-time low of less than 1%. (12)

A modern compounding revival emerged in the 1990s as savvy pharmacists, with eyes on the country's growing wellness movement, took to the internet to promote and sell compounded products branded as low-risk, all-natural, or more effective alternatives to commercially available drugs. (13) Between 1992 and 2000, the International Academy of Compounding Pharmacists grew from only 352 members to more than 1,500. (14) Today, at least thirty million prescriptions are compounded each year, amounting to a roughly $5 billion business. (15) Compounding is now arguably "the fastest growing branch of the profession." (16) Estimates of the proportion of prescriptions that are compounded range from 1% to 10% of all prescriptions. (17) While virtually every pharmacy compounds, a much smaller number--somewhere between 3,000 and 5,000 of the 200,000 total pharmacies in this country--makes compounding its specialty. (18) A 2001 study by the FDA found that a mere 650 specialty pharmacies fill more than 13 million of the total prescriptions for compounded products each year. (19)

When a pharmacist engages in compounding, she mixes and modifies drugs by customizing their dose, delivery vehicle, binding agents, or flavor. (20) Some of the most commonly compounded products include creams, gels, suppositories, and oral suspensions. (21) A customary use of compounding is for a pharmacist to prepare a child's medication by removing the contents of an adult-sized tablet and reformulating them into a lower dose in liquid form. (22) A one-time president of the American Pharmacists Association estimates that over 40% of the doses delivered in a pediatric hospital are compounded. (23) During the flu epidemic in fall 2009, the standard commercial version of children's Tamiflu fell into short supply, prompting many pharmacists to compound their own children's version by mixing the contents of adult Tamiflu capsules with flavored syrups. (24)

Along similar lines, a pharmacist might make a liquid or suppository dosage form for an elderly patient who has difficulty swallowing. (25) Compounding is especially prominent in hospice settings where patients commonly require alternative delivery mechanisms and pain medications of higher strengths than those available in commercially manufactured products. (26) Many medications, particularly radioactive chemotherapy drugs, must be compounded because they would otherwise not possess sufficient "shelf life" to support large-scale manufacture and distribution. (27) Frequently, compounding is used to simulate a discontinued drug or customize drugs for individuals with severe allergies, particularly allergies to the common inactive fillers or binding agents found in drugs. (28) In the hospital setting, compounding is constantly used to prepare intravenous mixtures "ranging from simple fluid replacement to the delivery of complicated, individualized chemotherapy regiments." (29) As a result, "nearly every person who has ever been admitted to a hospital ... has received a compounded medication." (30)

These examples reflect the heart of compounding practice--the design of individualized drugs where a patient's unique needs rule out the use of commercial products--and illustrate the necessity of compounding in a modern health care system. (31) Pharmaceutical manufacturers simply cannot profitably produce multitudinous customized varieties of their products, and compounding pharmacists fill this important gap in the market. (32) As one patient with a severe allergy to corn (an inactive filler in almost all drugs) recently told a reporter: "I'd be dead without compounded drugs." (33) Echoing that sentiment, the American Pharmacists Association maintains that "[w]ithout compounding, pharmacists and physicians would be limited to a 'one size fits all' strategy, which would have a direct, immediate, negative impact on the ability of health care providers to provide care to patients." (34) Some states consider compounding to be so vital as to require licensed pharmacies to offer compounding services. (35) The FDA has called compounding "an integral part of our modern health care system," (36) and the Supreme Court has recognized an important governmental interest "in permitting the continuation of the practice of compounding so that patients with particular needs may obtain medications suited to those needs." (37)

III. THE RISKS OF COMPOUNDING

While drug compounding is an indispensable component of health care delivery, the practice does in fact entail a series of serious and often severe risks. Unlike drug manufacturers, who are required to demonstrate the safety, efficacy, strength, quality, and purity of their proposed products via the FDA's New Drug Application, drug compounders design and distribute their products easily and unrestrictedly, outside of the federal regulatory framework and without pre- or post-market testing. As one former pharmacist and critic of drug compounding cuttingly observes: "[I]f a physician can imagine it, a compounding pharmacist can make it--without prior approval for safety or efficacy, without adherence to current Good Manufacturing Practices and without adhering to labeling, marketing or advertising requirements." (38)

Problems associated with drug compounding surface with alarming frequency. Between 1990 and 2003, there were at least 200 adverse events involving 71 compounded products. (39) Compounded drugs carry five general types of risk--subpotency, superpotency, contamination, overmedication, and medication-replacement. (40) Subpotency is likely the most common infirmity associated with compounded drugs. A 2002 FDA survey of twelve pharmacies and twenty-nine compounded drug samples, selected based on their common use and potential health risk if improperly compounded, found that 34% of the samples fell below the acceptable potency ranges prescribed by the United States Pharmacopeia ("USP"). (41) Of the samples that failed to meet USP ranges, more than half had a potency of less than 70% of the labeled value. (42)

While subpotency typically follows from negligent pharmacist errors, it can be caused by reckless or even purposeful pharmacist conduct as well. In an enormous 2001 scandal that eventually led the Missouri Board of Pharmacy to revamp its regulations governing compounding, Robert Courtney, the owner and president of Research Medical Tower Pharmacy, intentionally diluted chemotherapy drugs and misrepresented their potency to physicians. (43) Courtney admitted to investigators that he diluted at least 4,000 prescriptions over a ten-year period. (44) Courtney explained that he was trying to save money so that he could make more donations to his church. (45) Courtney was ultimately sentenced to thirty years in prison and ordered to pay $10.4 million in restitution. (46)

Superpotency is a less common but far more deadly risk associated with compounding. A 2006 FDA study of compounded drugs found active ingredients ranging up to an astonishing 268.4% of labeled potency. (47) In a 2001 instance of compounding-related overdose, a Massachusetts man was hospitalized after ingesting a capsule with 1000% of the labeled dose of 4-Aminopyridine, a drug sometimes used to treat symptoms of multiple sclerosis and spinal cord injury. (48) After a twenty-five day hospitalization and forty-three day rehabilitation stay, the man was discharged with permanent short-term memory loss caused by the overdose. (49) In another well-publicized compounding error in 2007, ApotheCure, a Texas pharmacy that widely touts its compounded drugs, distributed mismeasured vials of compounded colchicine, a drug occasionally prescribed off-label for back pain by alternative medicine providers. (50) An error at the pharmacy resulted in the preparation of vials containing eight times the intended dose of colchicine. (51) Three patients in Oregon and Washington died after injecting themselves with the mismeasured colchicine, and ApotheCure recalled at least 3,500 vials distributed nationwide. (52)

Contamination is another comparatively uncommon but highly deadly risk of compounding. More than one million doses of compounded drugs have been recalled for bacterial or fungal contamination. (53) Compounded drugs are susceptible to two major types of contamination: source ingredient contamination and preparation contamination. A former pharmacist concisely explains the problem of source ingredient contamination as follows:

   The quality of raw bulk chemicals used in compounding is suspect. … 

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