The FDA and the pharmaceutical industry: is regulation contributing to drug shortages?

• Author: Roman, Aubrey

1. Introduction

   Rebecca Robinson was a thirty six-year-old historical interpreter when she was diagnosed with Angiosarcoma, a rare blood-based soft tissue cancer, in February of 2010. (1) Over the next year and a half, after receiving five Doxil (2) chemotherapy treatments at the Dana Farber Cancer Center in Boston, Rebecca's cancer had weakened and her prognosis was positive. (3) But, in July of 2011, Rebecca's condition took an abrupt and unexpected turn for the worse because she could not receive her sixth life-saving Doxil chemotherapy treatment. (4) As her doctors explained, "there was no more Doxil available." (5) Similarly, at the young age of nine, Alyssa Divers was diagnosed with Osteosarcoma, a rare and aggressive cancer. (6) After many sessions of chemotherapy to fight this vicious disease, Alyssa found out that her next chemotherapy appointment might be delayed because the hospital had a shortage of methotrexate--the "cornerstone of therapy" for Osteosarcoma. (7) Alyssa knew that her tumors would double every thirty four days without methotrexate treatments, but in the case of a shortage there was nothing she or her doctors could do to get her the medication that she needed to stop the proliferation of her cancer. (8)

   Over the last decade, these stories have become increasingly common in the United States because we are experiencing an unprecedented drug shortage pandemic. (9) Recently, the term "drug shortage" has become prolific; the term appears in newspaper headlines, hospital forms, and pharmaceutical paperwork informing practitioners and patients alike that the drugs needed to keep patients alive are indefinitely unavailable. (10) The facts are glaring. The number of drugs in short supply has quadrupled from 2005 to 2011, jumping from sixty one drugs to a staggering 251. (11) Ominously, in 2010 and 2011, almost seventy five percent of the drugs in short supply were sterile injectable agents, which are the foundation of life-saving cancer treatments, antibiotics, and emergency room medications. (12)

   These startling figures, along with stories like those of Rebecca and Alyssa, seem to implore the inquiry: why are so many of these critical drugs suddenly and simultaneously unavailable? The reason for the shortage of sterile injectable drugs is an exceedingly complex issue and there is no prevailing consensus with regard to why these drugs are in short supply. (13) The origins of this pandemic can be traced to a variety of factors, including: industry consolidation, production delays due to quality and manufacturing challenges, discontinuations, small profit margins, shortages of the necessary raw materials, changes to inventory practices, unanticipated increase in demand, a public shift in policy within the Food and Drug Administration (FDA) regarding its compliance mechanisms, and an increase in the prosecution of high-level corporate managers for statutory violations. (14) Despite disagreement among commentators as to the cause of the crisis, it is indisputable that the drug shortage is having devastating effects on both patient care and our health care system as a whole, and the problem must be remedied. (15)

   The next Part of this article sets out the current drug shortage problem by analyzing data compiled by the FDA and the American Society of Health-System Pharmacists (ASHP). Within this part, we focus on the submarket that accounts for most of the current drugs on shortage, sterile injectable drugs. Part III discusses the FDA's current policy initiatives concerning regulatory compliance in the pharmaceutical industry. Part IV discusses one device that the FDA is using with extraordinary frequency to carry out its compliance policy--the issuance of warning letters that mandate that companies correct all violations within fifteen days or face forced closure. Next, Part V explores the resurrection of the Park doctrine, a legal device used by the FDA and the Department of Justice (DOJ) to criminally prosecute corporate executives whose companies are not in strict compliance with FDA regulations or the Food, Drug, and Cosmetic Act. In conclusion, Part VI suggests that the FDA's movement to overhaul the pharmaceutical industry has had an unintentional and dramatic effect on the supply of critical life-saving drugs because many manufacturers are "voluntarily" closing their plants, or shutting down production lines in order to avoid the very real possibility of forced plant closures and/or the criminal prosecution of their corporate executives.

2. CURRENT STATE OF THE DRUG SHORTAGE PROBLEM

   1. Drugs in Short Supply in the Pharmaceutical Market as a Whole

      There are two major organizations that compile drug shortage data--the FDA and the ASHP. (16) Although both of these organizations produce drug shortage data, it is important to recognize that they formulate their data based upon different methodologies. (17) The FDA, through the Center for Drug Evaluation and Research (CDER), (18) defines a drug shortage as "[a] situation in which the total supply of all clinically interchangeable versions of an FDA-regulated drug is inadequate to meet the current or projected demand at the user level." (19) This narrow definition focuses only on medically necessary drugs which are used to "treat or prevent a serious disease or medical condition ... [for which] there is no other available source of that product or alternative drug that is judged by medical staff to be an adequate substitute." (20)

      In contrast, the ASHP defines a drug shortage broadly as "a supply issue ... [that] affects how the pharmacy prepares or dispenses a drug product or influences patient care when prescribers must use an alternative agent." (21) Due to this definitional difference, it is important to recognize that ASHP data will typically produce a higher quantity of drug shortages at any given time than CDER data. (22) For example, the CDER reported 178 drug shortages in 2010 (23) while the ASHP reported 211. (24) Similarly, in 2012, the CDER reported 117 drug shortages (25) while the ASHP reported 204. (26)

      There are two common data measurements referenced when discussing drug shortage figures: "new" drugs on shortage, and "active" drugs on shortage. (27) Both the FDA and the ASHP measure new drugs on shortage on a yearly basis. (28) This figure includes all drugs that go on shortage from January first of any given year through December thirty first of that same year. (29) This figure is commonly referenced in order to determine the current state of the drug shortage crisis. (30) However, this figure cannot be read in isolation. The second measurement, active drug data, depicts the number of existing drugs on shortage over time. (31) The ASHP measures active drug shortages on a quarterly basis for a more accurate depiction of the total number of drugs on shortage at any given time. (32) Therefore, if the number of total new drugs on shortage declines in any given year, but the number of active drugs on shortage either remains constant or increases, the outlook is not as optimistic as the new drug data may suggest, because this indicates that drugs are remaining in short supply for extended periods of time.

      For example, from 2006 through 2011, the number of new drugs increased every year. (33) In 2012 the number of new drugs on shortage decreased by sixty three, falling from 267 new drugs on shortage in 2011 to 204 in 2012. (34) However, this figure should not provoke too much enthusiasm because the number of active drugs on shortage in 2012 increased from 260 in the first quarter to 299 in the fourth quarter. (35) In addition, from the first quarter of 2010 through the fourth quarter of 2012, the number of active drugs on shortage had risen from 152 to 299. (36) This means that even though the number of new drugs reported to be in short supply in 2012 decreased, the number of existing drugs on shortage that actively remained on shortage had steadily increased throughout the year, leaving many hospitals and pharmacies without critical life-saving drugs.

      The drugs on shortage cover a wide variety of drug classes including those used in oncology, antibiotics, and nutritional and hormonal supplements. (37) As of August 2011, the FDA found that the highest percentage of drugs in short supply were those used for cancer treatment, followed next by antibiotics. (38) If the FDA were to categorize drugs by way of administration, an overwhelming number of the current shortages would be drugs administered by sterile injection. (39)

      According to a March 2011 survey of 311 pharmacy experts representing 228 hospitals and other healthcare facilities, "89 percent experienced shortages that may have caused a medication safety issue or error in patient care," (40) and fifty three percent experienced six or more drug shortages that led to "a medication safety issue or error in patient care." (41) Furthermore, "80 percent [of respondents] experienced shortages that resulted in a delay or cancellation of a patient care intervention." (42) The current drug shortage pandemic is far-reaching and continues to cause life-threatening situations in many of our nation's health care facilities.

   2. A Closer Look at the Market for Sterile Injectable Drugs and Why These Drugs Constitute Such a High Percentage of the Drugs on Shortage

      Injectable drugs account for a disproportionately large share of the total drugs in short supply. (43) This is a frightening fact because sterile injectables are often critical life-saving drugs; they are the source of many oncology drugs such as Leucovorin and Doxil, as well as Naloxone, which is commonly used as a rescue drug, and Furosemide, a frequently used diuretic. (44) It is important to point out that sterile injectable drugs on shortage are frequently older drugs, (45) which have been off patent for many years, meaning that the shortages are concentrated in the generic market for sterile injectable drugs. (46)...