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THE OFF-LABEL USE OF ACEPROMAZINE MALEATE

by

JAMIE LYNN BARTHOLOMEW

CLASS OF 2006

This paper is submitted in satisfaction of the Food and Drug Law course requirement as well as the third year written paper requirement.

HARVARD LAW SCHOOL

Cambridge, Massachusetts

May 2006

To Lydia Highley Willits & Lydia Willits Bartholomew

ii

TABLE OF CONTENTS

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . iv

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . v

CHAPTER ONE: An Introduction to the Off-Label Use of

Acepromazine Maleate . . . . . . . . . . . . . . . . . . . . . 6

CHAPTER TWO: The Food and Drug Administration’s Regulation of Animal Drugs and their Off-Label Uses. . . . . . . . . . . . . 17

CHAPTER THREE: Use or Abuse: The Off-Label Use of

Acepromazine Maleate by Foxhunters . . . . . . . . . . . . 49

CHAPTER FOUR: What, if Anything, should the Food and Drug Administration do about the Off-Label use of Acepromazine

Maleate . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

iii

ACKNOWLEDGEMENTS

I would like to first thank my advisor, Mr. Peter Barton Hutt, for his enthusiasm, guidance, expertise, and patience. I am deeply grateful to him for his advice and support. I would also like to thank my friends, family, and especially my grandmother, who has made everything possible for me.

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ABSTRACT

In this paper, I offer an evaluation of the off-label use of Acepromazine Maleate by foxhunters. In Chapter One, I provide readers with an explanation of the most important elements of the topic, including what Acepromazine Maleate is, the nature of its off-label use, and how the Animal Medicinal Drug Use Clarification Act of 1994 affects the off-label use of the drug. I also offer readers a roadmap of the remainder of the paper, and I conclude Chapter One with a literature review. In Chapter Two, I examine how the Food and Drug Administration regulates animal drugs, as well as how it handles the off-label use of drugs in animals. In Chapter Three, I consider the off-label use of Acepromazine Maleate, analyzing the physiological effects of the drug, its labeled uses, side effects, as well as its off-label uses. In doing so, I take into account the perspectives of both foxhunters and veterinarians. In Chapter Four, I conclude the paper by offering an assessment of the off-label use of Acepromazine Maleate by foxhunters. I argue that although the drug is currently being used by foxhunters with great frequency, it is also being used by foxhunters with great precaution, making it, in the vast majority of cases, both safe and effective. Veterinarians, however, need to do more on their end to comply with Food and Drug Administration regulations and labeling requirements, to ensure that this level of safety does not drop.

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CHAPTER ONE

An Introduction to the Off-Label Use of Acepromazine Maleate

INTRODUCTION

“It takes the buck [1] out of them ...” one woman explained “I would not hunt [2] this horse without at least one-and-a-half CCs [3] .” [4] “Broken backs, cracked ribs, shattered patellae, and concussions are all too common on the hunt field because of the crazy horses some people ride without taking the necessary precautions. Just the other day, in fact, a woman’s horse bucked her off and she landed on her head. She was wearing a derby [5] , which of course offers little to no head protection. She was knocked unconscious for seven minutes and had to be airlifted to the nearest trauma center...” [6] It is “just like a cocktail” another interviewee offered “it makes him relax. Without it, he spends the entire day jigging, [7] and quite frankly, ruins an otherwise lovely day of hunting.” [8] “It is really a matter of safety ...” a third interviewee commented, “for you, your horse, the other riders on the hunt field, their horses ... even the hounds [9] ! I have watched a jittery horse kick a hound directly in the head and knock it dead!” [10]

ACEPROMAZINE MALEATE

What exactly is “it”? What does “it” do? How does “it” work? Why are so many foxhunters offering “it” such a ringing endorsement? “It” is Acepromazine Maleate, commonly referred to in the foxhunting community as simply “Ace.” Acepromazine Maleate is available only by prescription from a veterinarian. [11] Fort Dodge Animal Health, the manufacturer of PromAce Injectable, the most commonly prescribed form of Acepromazine Maleate, summarizes the drug’s labeled uses on the insert accompanying the vial of Acepromazine Maleate: “PromAce Injectable can be used as an aid in controlling fractious animals during examination, treatment, loading, and transportation. Particularly useful when used in conjunction with local anesthesia for firing, castration, neurectomy, removal of skin tumors, ocular surgery, and applying casts.” [12]

Surprisingly - or not so surprisingly upon closer examination of the physiological effects of the drug - no mention is made of the drug’s use for riding purposes. Foxhunters, however, are nonetheless administering the drug to their horses with great frequency, in a capacity not tested and/or approved by the Food and Drug Administration. Are they violating Federal law and possibly subjecting themselves to civil and/or criminal sanctions in their efforts to keep their horses calm while foxhunting them?

THE ANIMAL MEDICINAL DRUG USE CLARIFICATION ACT OF 1994

The Animal Medicinal Drug Use Clarification Act of 1994 amended the Federal Food, Drug, and Cosmetic Act to clarify the Federal Food, Drug, and Cosmetic Act in regards to “other uses” of animal drugs. In particular, a drug can be used in an off-label capacity as long as the different use is prescribed by a veterinarian who has an ongoing relationship with the horse and owner, the use is not in or on animal feed, and it complies with the regulations provided by the Secretary of Health and Human Services. [13] The foxhunters who use Acepromazine Maleate for foxhunting purposes are not violating federal law, therefore, assuming that they comply with the Food and Drug Administration’s above restrictions on off-label animal drug usage.

THE FOOD AND DRUG ADMINISTRATION’S REGULATION OF ANIMAL

DRUGS AND ITS POSITION ON OFF-LABEL DRUG USE

The question then becomes whether the Food and Drug Administration adequately controls the regulation, distribution and/or administration of animal drugs. In general, is the Food and Drug Administration doing enough to regulate the use of drugs in animals, or should it be doing more? Or less? How does the Food and Drug Administration regulate the use of drugs in animals in an extra-label capacity? Are the regulations on off-label use sufficient?

A CLOSER LOOK AT ACEPROMAZINE MALEATE

Narrowing the focus, I will then consider the off-label use of animal drugs in the specific context of Acepromazine Maleate. To do so, I will first look at how much Acepromazine Maleate is actually being administered to horses. Is the use of Acepromazine Maleate for foxhunting purposes relatively rare, or is it commonplace? Based on the (admittedly incomplete) information available, roughly 80% to 90% of foxhunters use Acepromazine Maleate whenever they fox hunt, typically three times per week. [14] Around 10% to 20% of foxhunters give Acepromazine Maleate to their horses every time they ride, on average five to six times per week. [15] Assuming that these figures are accurate, Acepromazine Maleate is, by any measure, being administered by foxhunters with substantial frequency.

I will then consider what exactly Acepromazine Maleate is and how it affects the physiology of a horse. How is it currently prescribed? What are its approved uses? How do the veterinarians prescribing Acepromazine Maleate feel about the nature and high rates of its use? Are foxhunters sufficiently capable of determining the appropriate amount of Acepromazine Maleate to administer to their horses under veterinarian guidance?

CONCLUSIONS

In this research paper, I will explore the above questions and many others. Ultimately, my goal is to offer an assessment of the off-label use of Acepromazine Maleate by foxhunters. Is the current use of Acepromazine Maleate in an off-label capacity acceptable? Safe? Or are further restrictions and regulations in order? I will conclude the paper by offering an assessment of the off-label use of Acepromazine Maleate by foxhunters, always keeping in mind the impact of any proposed changes on the Food and Drug Administration, the Center for Veterinary Medicine, veterinarians, foxhunters, and of course, horses.

As the situation stands, nothing at all has been written about the off-label use of Acepromazine Maleate. Indeed, very little has been written about the off-label use of animal drugs in general. As one academic astutely commented, “the regulation of animal drugs at the FDA always has taken a backseat to the larger regulation of human food, drugs, and medical devices. Even with ‘Center’ status, the Center for Veterinary Medicine (CVM) is not on par with the other four Centers: the Center for Food Safety and Applied Nutrition, the Center for Devices and Radiological Health, the Center for Drug Evaluation and Research, or the Center for Biologics Evaluation and Research.” [16]

Given the relatively high frequency in which foxhunters are using Acepromazine Maleate in an off-label capacity, often with extremely vague guidance from the prescribing veterinarian, this issue deserves attention. Even if one agrees with the Food and Drug Administration’s general prioritization of human health over animal health, human health is on the line here has well. If horses are being drugged to the point that they cannot perform what is being asked of them on the hunt field, both horses and human health are in danger.

My research indicates is that although Acepromazine Maleate is currently being used by foxhunters with great frequency, it is also being used by foxhunters with great precaution, making it, in the vast majority of cases, both safe and effective. Veterinarians, however, need to do more on their end to comply with Food and Drug Administration regulations and labeling requirements, to ensure that this level of safety does not drop.

LITERATURE REVIEW

I will begin this paper by exploring the Food and Drug Administration’s regulation of animal drugs, both in general and in an off-label capacity. Existing literature thoroughly details the current regulation of animal drugs. The Food and Drug Administration’s website, in fact, provides quite extensive details on the approval process for animal drugs.

In analyzing the off-label use of animal drugs, I will also make heavy use of the legislative history [17] behind the Animal Medicinal Drug Use Clarification Act of 1994, whose purpose is: "to amend the Federal Food, Drug, and Cosmetic Act to clarify the application of the Act with respect to alternate uses of new animal drugs and new drugs intended for human use, and for other purposes." [18] What are the reasons behind the passage of the Animal Medicinal Drug Use Clarification Act of 1994? These justifications will enable me to later assess whether the uses I have encountered in the realm of foxhunting are in line with what was intended by Congress in passing the Act. Prior to 1994, the off-label use of prescription drugs was a criminal act – should it still be?

Few other sources, unfortunately, examine the off-label use of drugs in animals. I will therefore draw on several articles exploring the extra-label use of drugs in humans, as many of the same issues arise. The Food and Drug Law Journal offers a plethora of information in this regard, and Food and Drug Law: Cases and Materials provides a good overview of off-label drug use.

I will then explore the capacities in which and exactly how much Acepromazine Maleate is being used by foxhunters in an off-label capacity. To obtain this information, I conducted interviews with subscribers of three hunts in Pennsylvania: Mr. Stewart’s Cheshire Hounds, the Radnor Hunt, and former members of the Brandywine Hunt, which dissolved in 2004. This data presents an admittedly incomplete picture of foxhunters as a whole and the extent to which they use Acepromazine Maleate in an off-label capacity, but due to the relatively small number of foxhunts in the United States as well as the general unwillingness of hunt leadership to provide me with access to membership databases and/or mailing lists, interviews were hard to obtain. As a result, the interviews were exclusively with foxhunters I know personally (fortunately, as a foxhunter myself, I know quite a few). For various reasons, foxhunts are quite protective of their subscribers’ privacy, and they often restrict the use of their email lists to “matters relating to the hunt, to local equestrian events, and land preservation matters,” as one hunt spokesman noted in an email in which he declined to distribute my questionnaire to hunt members. [19]

Many individuals also refused my request to interview them. A Board Member of Cheshire Conservancy, the governing body of Mr. Stewart’s Cheshire Foxhounds, briefly summarized some of the reasons behind people’s hesitation: “Is there a possibility your paper would result in a negative reaction about or criticism of the use of ace [Acepromazine Maleate] as we use it or that it will call for greater regulation of its use? Also, the "antis" will jump on any aspect of hunting that they believe they can use to end hunting, so even a questionnaire that relates to "drugging horses" (which is how they would characterize it) could be exploited by them if they got their hands on it...” [20]

Despite the limitations noted above, these interviews nonetheless provide me with some sense of the nature and frequency of the off-label use of Acepromazine Maleate by foxhunters. No data has even been collected on this subject matter in the past, so although incomplete, the data is indeed the first of its kind.

After assessing the frequency and nature of Acepromazine Maleate use, I then examine the drug itself more closely. The manufacturer of Acepromazine Maleate provides some basic information on the drug, as do various veterinary databases and discussion groups. What exactly does the drug do? How does it affect the physiology of the horse? Is it safe for foxhunters to use the drug to sedate their horses before riding and/or foxhunting them? Are foxhunters overusing the drug? Are foxhunters capable of selecting and/or administering the appropriate dosage of the drug (per guidance from the veterinarian)? The answers to these questions offer useful insight into how the drug is used in an off-label capacity and the general safety doing so.

Because these resources, although helpful, are somewhat incomplete, I also draw on the interviews I conducted with veterinarians at New Bolton Center, the site of the University of Pennsylvania’s School of Veterinary Medicine's teaching hospital for large animals. [21] What is their perspective on the off-label use of Acepromazine Maleate?

I conclude the paper by returning to the original questions posed at the beginning of the paper. Is the current practice of using Acepromazine Maleate in an off-label capacity safe? What more, if anything, should the Food and Drug Administration be doing to step in and regulate? How can the Food and Drug Administration curtail abuse while permitting legitimate off-label use of the drug? Most of the information for this portion of the paper I extract from the foxhunters and veterinarians I interviewed, as well as my own thoughts and impressions.

CHAPTER TWO

The Food and Drug Administration’s Regulation of Animal Drugs and their Off-Label Uses

INTRODUCTION

The Food and Drug Administration (FDA) is the United States government agency in charge of regulating food (human and animal), dietary supplements, drugs (human and animal), medical devices (human and animal), cosmetics, biologics, and blood products in the United States. [22] The Food and Drug Administration is one branch of the Department of Health and Human Services (HHS), which itself is one of the fifteen Cabinet-level Departments of the United States Government. [23] The Food and Drug Administraton is divided into five Centers: the Center for Biologics Evaluation and Research (CBER), the Center for Devices and Radiological Health (CDRH), the Center for Drug Evaluation and Research (CDER), the Center for Food Safety and Applied Nutrition (CFSAN) and lastly, the Center for Veterinary Medicine (CVM). [24]

The primary responsibility of the Food and Drug Administration is to regulate the broad array of medicinal products in a manner that protects the American public’s safety and ensures marketed drugs’ effectiveness. [25] The Food and Drug Administration's budget for approving, monitoring, and labeling drugs is roughly $290 million per year. [26] "Review teams" staff approximately 1,300 employees to decide whether or not to approve new drugs. [27] The Food and Drug Administration "Safety team" staffs seventy-two employees to determine whether new drugs present risks undisclosed in the labeling of the product or are generally unsafe. [28] The safety team currently monitors the effects of over three-thousand prescription drugs on two-hundred million people, with an operating budget of about fifteen million dollars per year. [29]

The Center for Veterinary Medicine (CVM), one of the five primary centers of the Food and Drug Administration, regulates the manufacture and distribution of drugs and food additives administered to animals. [30] These animals can include animals from which human foods are derived (cows, chicken, etc.), as either pets or companion animals. [31] The Center for Vetrinary Medicine is responsible for regulating drugs, devices, and food additives given to, or used on, over one-hundred million companion animals, plus millions of “poultry, cattle, swine, and minor animal species. [32] [33]

THE FOOD AND DRUG ADMINISTRATION’S REGULATION OF ANIMAL DRUGS

As required by the Federal Food, Drug and Cosmetic Act, a new animal drug may not be “sold in interstate commerce” unless it is the subject of a New Animal Drug Application (NADA). [34]

What does New Animal Drug Application approval require? First, the methods, facilities and controls used for the manufacturing, processing and packaging of the drug must be adequate to preserve its identity, strength, quality and purity. [35] Second, the product must be “safe” and “effective” for its intended use. [36]

In effect, NADA offers a systematic approach to document evidence that drug products are safe and effective. The Center for Veterinary Medicine describes the documented evidence in a Freedom of Information Summary, an Environmental Assessment, and in drug labeling. All of this information is available to the public. A New Animal Drug Application-Approved drug product consists of the drug, the packaging and the labeling.

How exactly does the Food and Drug Administration determine whether an animal drug is “safe” and/or “effective”? An animal drug is considered “safe” if “adequate tests by all methods reasonably applicable must show that the drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling.” [37] “Safe” may be broken down into four categories: human food safety, target animal safety, environmental safety, and user safety. In regards to human food safety, the Food and Drug Administration is primarily concerned with whether the drug has left any residue in the meat, milk, and eggs of the animal, which may harm human health either directly (acute toxic response or chronic exposure toxicity) or indirectly (antimicrobial resistance). [38] To make such an assessment, the Food and Drug Administration frequently employs (1) mutagenicity studies, (2) two 90-day feeding studies, (3) reproductive studies, (4) teratology studies, (5) other special studies as needed, (6) Salmonella shedding studies, (7) resistance studies, (8) studies of total metabolism in target animals as well as comparative metabolism in rodents, and/or (9) Tissue residue depletion studies. [39]

To assess target animal safety, the Food and Drug Administration monitors the cumulative effect of the drug on animals to ensure that the drug does not adversely affect the treated animal’s health. [40] To do so, it conducts (1) tolerance studies, (2) reproductive safety studies, (3) animal class safety studies (e.g., young, geriatric), and/or (4) special case studies (specific breeds).

To create environmental safety, the Food and Drug Administration aims to ensure that the use, manufacture and disposal of the drug do not pose a significant environmental impact as per the National Environmental Policy Act [41] and Clean Water Act [42] . [43] In fact, New Animal Drug Application approval must include either a Categorical Exclusion or an Environmental Assessment accompanied by a Finding of “No Significant Impact ? [44] or an “Environmental Impact Statement” [45] . [46] To assess the environmental impact of the drug, researchers often use (1) environmental introduction and fate studies, (2) environmental effects studies, and (3) environmental assessment. [47]

Finally, in regards to user safety, the Food and Drug Administration aims to assess the dangers associated with manufacturing the drug, either direct (occupational exposure at the site) or indirect (manufacturing emissions) as well as the hazards associated with administering the drug to animals and the hazards associated with the use of air, water and solid wastes contaminated via use and disposal of the drug. [48]

An animal drug is considered “effective” based on substantial evidence consisting of one or more adequate and well-controlled investigations, such as: (1) a study in a target species, (2) a study in laboratory animals, (3) any field investigation, (4) a bioequivalence study, and (5) an in vitro study. [49] These investigations must be performed by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which “it could fairly and reasonably be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended or suggested in the labeling or proposed labeling thereof.” [50]

THE MARGINALIZATION OF THE CENTER FOR VETERINARY MEDICINE

Despite the seemingly extensive procedures described above, some critics argue that organizationally, the regulation of animal drugs at the Food and Drug Administration “has always taken a backseat to the larger regulation of human food, drugs, and medical devices.” [51] Even with "Center" status, some say that the Center for Veterinary Medicine (CVM) is “not on par” with the other four Centers: the Center for Food Safety and Applied Nutrition, the Center for Devices and Radiological Health, the Center for Drug Evaluation and Research, or the Center for Biologics Evaluation and Research. [52]

The Food and Drug Administration, or more specifically, the Center for Veterinary Medicine, has particularly marginalized companion animal [53] drugs, which for many years remained stagnant and limited almost exclusively to drugs for which there was no real human market, such as wormers. [54] As owners have grown more concerned with extending the life and maximizing the comfort of their pets, however, many of the issues that humans face in regards to aging have become issues for companion animals as well. [55] Pet owners have shown increasing interest in the development of drugs that have been proven “effective and safe in the target companion animal species.” [56] Specifically, nonsteroidal anti-inflammatory drugs have taken off, and other "aging population" drugs are likely to follow. [57] Because consumers are now demanding the same safety and effectiveness of drugs for their companion animals as already exist for humans, the Food and Drug Administration will not be able to avoid devoting significant resources to the arena of animal drugs for much longer. [58] The Food and Drug Administration will probably have to address "alternative care [59] " for companion animals as well, including not only medical but also dietary supplement issues. [60] Others questions will also likely arise: does the Dietary Supplement Health and Education Act of 1994 [61] apply, for example, or should it?

ANIMAL MEDICINAL DRUG USE CLARIFICATION ACT OF 1994

1. INTRODUCTION

The Animal Medicinal Drug Use Clarification Act of 1994 modified veterinarians’ ability to prescribe both approved human and animal drugs in an off-label capacity. In doing so, it broadened the variety of drugs available to treat companion animals and addressed a concern with the Center for Veterinary Medicine stated above, namely that not enough drugs are on the market to treat the various ailments suffered by animals. The Animal Medicinal Drug Use Clarification Act of 1994 states that if a New Animal Drug Application (NADA) is approved and in effect with respect to a particular use or intended use of a new animal drug, the drug “shall not be deemed unsafe” and “shall be exempt from the requirements ... with respect to a different use or intended use of the drug, other than a use in or on animal feed,” if such use or intended use: (i) is by or on the lawful written or oral order of a licensed veterinarian within the context of a veterinarian-client-patient relationship and (ii) is in compliance with regulations promulgated by the Secretary that establish the conditions for such different use or intended use.” [62]

2. OFF-LABEL DRUG USE DEFINED

Technically, "off-label" prescribing occurs when a physician prescribes a drug either “for a use, or in a manner” not indicated on its FDA-approved label. [63] Terms such as "unlabeled use" or "unapproved use of approved drugs" are synonymous with "off-label." [64]

Variations from the "package insert," or manufacturer’s label for the product, can take many forms. Prescribing an approved drug to treat a disease that is not indicated on its label as a method of treatment, for example, but is closely related to an indicated disease, [65] treating diseases that are both unrelated and not indicated (although treating diseases unrelated to approved uses may constitute dangerous experimentation [66] ), and treating the disease indicated in the labeling but varying from the regimen, dosage, or patient population indicated may all also constitute off-label use. [67]

3. SMOOTH SAILING FROM BILL TO LAW

Senator Howell Heflin of Alabama introduced the Animal Medicinal Drug Use Clarification Act of 1994 (before its passage, “a bill to amend the Federal Food, Drug, and Cosmetic Act to clarify the application of the Act with respect to alternate uses of new animal drugs and new drugs intended for human use, and for other purposes”) to the United States Senate on February 4, 1993. [68] The measure was read twice and referred to the Senate Committee of Labor and Human Resources. [69] On October 4, 1993, the Committee on Labor and Human Resources discharged the bill by Unanimous Consent, and on the same day, the measure was laid before the Senate. [70] Senator Ford, for Senator Heflin, proposed an amendment, Amendment SP 2612, which the Senate agreed to by Voice Vote. [71] This Amendment primarily altered the title of the bill and added some exceptions to permit more extensive off-label drug use in some situations. [72] On October 5, 1994, the Message on Senate action was sent to the House, and on October 7, 1994, the bill was Passed without objection and cleared for the White House. [73] On October 17, 1994, the bill was presented to the President, who signed it on October 22, 1994. [74] On the same day, the Animal Medicinal Drug Use Clarification Act of 1994 became public law. [75]

4. THE NEED FOR OFF-LABEL DRUG USE IN ANIMALS

As one can observe above, the Animal Medicinal Drug Use Clarification Act of 1994 created little controversy, disagreement, or protest in either the United States House of Representatives or the United States Senate. What were the arguments put forth by the bill’s sponsors to enable it to sail so smoothly through Congress?

As Senator Heflin, the sponsor of the bill, described it: “Extra-label drug use is an important issue for farmers and ranchers, veterinarians, pet owners, and consumers. For many years, [the Food and Drug Administration] has recognized that the current Food, Drug and Cosmetic Act places veterinarians in an untenable position. On the one hand, the Veterinarian's Oath pledges the veterinarian to use scientific knowledge and skills for the benefit of society through the protection of animal health, the relief of animal suffering, the conservation of livestock resources, the promotion of public health, and the advancement of medical knowledge. On the other hand, the use of many effective drugs is illegal because they are not specifically labeled for the use intended by the veterinary medical practitioners.” [76]

Representative Waxman of California, in his statement to the United States House of Representatives, describes the situation prior to the passage of the Animal Medicinal Drug Use Clarification Act of 1994 in similar terms: “a problem that has plagued veterinarians for many years: namely, the divergence between the law and veterinary practice with respect to the prescribing of animal drugs.” [77] “It is common medical practice for animal doctors to use drugs that have been approved by the [Food and Drug Administration] for unapproved uses” Waxman states. [78] He provides an example for clarification: “A drug that has been approved for sheep is often used in cows. Since there may be no drug approved for cows for a particular disease, the veterinarian has little choice but to break the law.” [79] In fact, as a matter of “enforcement discretion” (a.k.a. not prosecuting veterinarians even though they are technically breaking the law), the Food and Drug Administration implicitly permits animal doctors to prescribe drugs for unapproved uses. [80]

Waxman notes that in recent years, veterinarians have grown “increasingly concerned” with the fact that on a regular basis, they are breaking the law. [81] In his statement to the United States House of Representatives, therefore, Waxman urges the House to take in account the “realities of medical practice” and make this type of off-label usage legal. [82]

He offers a caveat worthy noting: “The Food and Drug Administration must know what animal drugs are being used in food-producing animals for unapproved uses, so that it can determine the tools that it needs to monitor drug residue in animals.” [83] In this a way, the Food and Drug Administration can strike a balance between the needs of veterinarians in treating sick animals and the needs of the Food and Drug Administration in monitoring the food supply. [84] In summary, “veterinarians should be allowed to prescribe drugs for unapproved uses, while giving the Food and Drug Administration the power to regulate the drug uses and to create requirements to protect human health where needed.” [85]

What creates the need for veterinarians to prescribe drugs in an off-label capacity in the first place? A modification of the law, according to Senator Heflin, is necessary rectify “a serious problem facing America's veterinarians and the animals they treat. . .” [86] “If the FDA were to strictly enforce the Federal Food, Drug, and Cosmetic Act as it is written today” Heflin comments in his introduction of the bill, “the act would prevent the relief of pain and the prevention of suffering in a host of animal species from cattle to pet birds, for which there are no FDA approved drugs for these purposes.” [87] Basically, there is a huge shortage of drugs available to treat animals. A new animal drug application review process must be completed, as required by the law, within six months. The reality, however, is that the review process at the Food and Drug Administration now takes, on average, four years. [88]

Furthermore, Senator Heflin describes how the Food and Drug Administration has approved only a very small number animal drugs, and only for the most common of domestic species. Few, if any, new animal drugs are approved for species of animals which are used extensively in most of the Nation's research facilities, such as “mice, rats, hamsters, gerbils, guinea pigs, and rabbits.” [89]

Given the shortage of Food and Drug Administration-approved drugs therefore, proper veterinary care effectively requires extra-label drug use. The Food and Drug Administration has simply not approved enough therapies to treat the conditions that veterinarians routinely come across in practice. Examples of necessary off-label uses in companion animals include “insulin to treat diabetes, cardiac and chemotherapeutic drugs that bear a human drug label; anesthetic, analgesic and sedative agents for food animals; and effective antibiotics for food and companion animals to name just a few.” [90]

Representative Moorhead confirms the need for the passage of the Animal Medicinal Drug Use Clarification Act of 1994 in his statement to the United States House of Representatives:

The primary purpose of this legislation is to permit veterinarians to prescribe approved animal or human drugs to species of animals for which the drugs are not currently approved. The legislation is necessary because there are an insufficient number of drugs approved for all the various disease problems in all the animal species. Generally, an animal drug is approved on a species-by-species basis. For example, if a drug is approved for use in cows, the company must also go through the approval process to get that same drug approved for use in sheep. This process can be prohibitively expensive and, therefore, many animal drugs are not approved for use in multiple animals, especially for so-called minor species. [91]

As Representative Waxman realizes himself, it is just not cost-effective for a pharmaceutical company to seek an approved label for all of the species for which a drug is both beneficial and safe.

The Animal Medicinal Drug Use Clarification Act of 1994, however, provides a solution to this problem, “enabl[ing] veterinarians to prevent pain, suffering, and death in animals.” [92] Drugs such as insulin, which was tested in dogs prior to its use in humans, can be an effective treatment for dogs with diabetes, even though the drug has never been formally approved for use in dogs. [93] Other medications, including anesthetics and analgesics, may not be approved in cattle or goats, but are nonetheless invaluable in relieving pain in animals and making surgery more bearable. [94] “Can you imagine that in the United Kingdom it is illegal to dehorn a goat without an anesthetic - and that in the United States it is currently illegal to use one?” Senator Heflin asks. [95] By authorizing judicious extra-label use, Animal Medicinal Drug Use Clarification Act of 1994 rectifies the situation. [96]

5. THE CONSEQUENCES OF NOT LEGALIZING THE OFF-LABEL USE OF DRUGS

IN ANIMALS

According to Senator Heflin, “veterinarians use drugs in an extra-label manner to save animal lives, prevent suffering, and to protect human health.” [97] What are the beneficial effects of making off-label drug use in animals legal, or conversely, the drawbacks of keeping such extra-label usage illegal? Permitting veterinarians to treat sick food-producing animals with drugs in an off-label capacity would likely result in increased food safety, because sick animals would not be shipped to market as frequently. Under the current state of the law, if legal therapies are unavailable to veterinarians, producers “may ship sick animals to market, rather than watch them suffer and perhaps die, or take a chance that they may infect the remainder of the herd.” [98]

Public health may also be at stake if veterinarians cannot prescribe drugs off-label for animals. Chlamydiosis, for example, a disease which is transmitted from birds to man, is most effectively treated in birds with an antibiotic known as doxycycline. [99] This drug is presently only approved for use in humans. The only Food and Drug Association approved animal drug for the treatment of chlamydiosis in birds is no longer marketed. [100] Without the ability to use a human drug on a non-food producing animal, however, an increased risk presents itself that the disease will transmit between birds and humans. [101]

Another upside of making extra-label use of drugs in animals legal is that pharmaceutical companies may develop more new animal drugs. Before the passage of the Animal Medicinal Drug Use Clarification Act of 1994, Federal law prohibited the use of any animal drug in a species for which that drug had not been approved. [102] As a result, the drug manufacturer's incentive for developing and bringing to market separate drugs for each species of animal was almost nonexistent. If veterinarians could legally prescribe a single drug for more than once species, more profit potential would exists and pharmaceutical companies would have greater incentive to develop new animal drugs. Pre-Animal Medicinal Drug Use Clarification Act of 1994, however, there were very few species-specific animal drugs on the market, and little incentive existed to develop more. [103]

6. THE ULTIMATE TAKEAWAY

According to the sponsor of the bill, “Simple codification of current policy is absolutely necessary to decriminalize extra-label drug use and to facilitate new animal drug research. Without such a codification, “we will perpetuate a silly and unnecessary situation within the practice of animal medicine.” [104] The Animal Medicinal Drug Use Clarification Act of 1994, which permits extra-label drug use in animals, transforms this section of the Food, Drug, and Cosmetics Act from a “non-enforceable, confusing law” into a “clear and easily enforceable statute.” [105]

Furthermore, it codifies current Food and Drug Administration policy and authorizes extra-label drug use by veterinarians only, under carefully controlled supervision. [106] It does not, therefore, result in increased harmful drug residues in food products and it does not increase or alter overall patterns of drug usage by veterinarians.” [107]

THE OFF-LABEL USE OF DRUGS: A CLOSER LOOK

1. INTRODUCTION

What are the possible upsides and downsides of permitting the off-label use of drugs, both in humans and in animals? In the section above, the United States Senators and Representatives supporting the bill described many of the upsides of off-label drug use in animals. Because there was no opposition to the bill, however, none of the downsides of off-label drug use are brought to light. The question remains, therefore, whether the off-label use of prescription drugs, subject to some reasonable constraints, is a really good thing. In this section, I will examine the question more closely.

2. THE ART OF MEDICINE

“The practice of medicine is often described not as a science, but as an art . . . consistent with this simile, physicians attack some attempts to regulate medicine with the vigor of an artist resisting censorship.” [108] The medical community largely believes that “overregulation chills innovation and reduces medicine to ‘cookbook’ therapy.” [109] An editor of the Journal of the American Medical Society recently expressed the suspicion with which physicians view the Food and Drug Administration, saying: "I would rather have the [Food and Drug Administration] withdraw a drug from the market for adverse effects [than regulate prescribing practices]. Otherwise, the Food and Drug Administration would be involved in actually regulating the in-office practice of medicine by the individual physician. And, frankly, I don't trust the government to do that." [110]

Certain types of regulation, however, are clearly necessary to ensure the safety and effectiveness health care. [111] In balancing competing interests, the Food and Drug Administration must distinguish between necessary regulations, which ensure patient safety, and unnecessary interference, which curbs the expansion of medical knowledge and may limit treatment to outdated procedures. The regulation of drugs becomes even more difficult when the patients themselves condemn the regulators as bureaucratic roadblocks to necessary treatment . [112]

3. OFF-LABEL PRESCRIBING

Finding the appropriate level of regulation is a problem that was brought to the Food and Drug Administration’s attention by the practice of off-label prescribing. [113] Once the Food and Drug Administration approves a drug, physicians can prescribe the drug to (human) patients “as they see fit”. [114]

As we have seen in the section prior to this one, the Food and Drug Administration is more conservative in its regulation of the off-label use of drugs in animals. Although the Animal Medicinal Drug Use Clarification Act of 1994 gave veterinarians more leeway in their ability to prescribe drugs to animals in an off-label capacity, veterinarians, unlike doctors, are not free to prescribe drugs to animals “as they see fit.” The benefits and drawbacks of off-label prescribing, however, are largely the similar. Thus, as there is little existing literature examining the off-label use of drugs in animals, I will mainly discuss articles and examples assessing the off-label use of drugs in humans.

4. THE FREQUENCY OF OFF-LABEL PRESCRIBING

In a study conducted by the United States Government Accounting Office (GAO), the Office found off-label prescribing more the rule than the exception in the context of cancer therapy. [115] One-third of all prescriptions in cancer chemotherapy were off-label. [116] Furthermore, off-label use was not limited to certain patients [117] , a few popular drugs [118] , or some specific forms of cancer [119] , rather the practice was found to be prevalent in every realm. [120]

5. THE POTENTIAL DANGERS OF OFF-LABEL PRESCRIBING

In treating cancer, off-label chemotherapy is beneficial to patients “in most circumstances,” and data indicates that off-label use frequently leads to unforeseen drug discovery. [121] The benefits of off-label drug use, either to the patient or to society, may be less certain when one factors cost into the analysis. [122] Probably not surprisingly, the use of off-label therapies is higher in cases of incurable cancer in the advanced stages, as well as when standard chemotherapy proves ineffective. [123] This desperate search for a cure is expensive, though. One physician at the Mayo Clinic reports reviewing an insurance claim for nearly $750,000 for off-label drugs given to a single, dying patient. [124] Such "treatments of last resort" raise ethical questions about “costs and benefits to the individual and society, patient autonomy, and the decision-making process on the appropriateness of the therapy.” [125]

Costs aside, regulators and physicians must also acknowledge that health risks from off-label use are alive and real. The antibiotic chloramphenicol, for example, was widely prescribed off-label during the 1970s despite its association with fatal aplastic anemia. [126] Similarly, physicians often prescribed “DES” off-label. [127] DES” is a synthetic estrogen that was heavily prescribed between 1940 and 1970; known as diethylstilbestrol, DES was used to prevent miscarriages. An estimated ten million children that were exposed to the DES during pregnancy and are now suffering side effects because of it. Some DES problems that have occurred include physical, psychological, and reproductive system abnormalities and disorders. DES exposure has been found to affect even third-generation children from DES-exposed women. [128]

Even if not physically dangerous, in many cases an off-label use of a drug may not be desirable either politically or ethically . The controversial progesterone antagonist RU-486, for example, is a potential treatment for breast and uterine tumors, Cushing's syndrome, glaucoma, and other medical problems. [129] Anti-abortionists in this country oppose importation of the drug for a study, however, fearing that Food and Drug Administration approval for any use would lead to widespread off- label use.

Thomas Murray provides another example: “years ago, at an FDA hearing, I speculated that once hGH [human growth hormone] was approved, people would want to use it for all sorts of non-therapeutic purposes. One member of the FDA committee told me that several parents had already asked her if they could get the drug for their kids, who weren't hGH-deficient. All, she recalled, were physicians. Why...? Quite simply, because it's advantageous to be tall....” [130]

6. NO CLEAR ANSWERS

The term “off-label use” includes a wide range of treatments, from "clearly experimental use to standard therapy and even to state of the art treatment." [131] The multiple meanings of “off-label use,” however, make any efforts to define the practice as either useful or harmful, to determine if regulation is necessary, or to decide if the Food and Drug Administration, the courts, or the marketplace should regulate, somewhat futile. [132]

CHAPTER THREE

Use or Abuse: The Off-Label Use of Acepromazine Maleate

INTRODUCTION

In this chapter I will consider a specific example of the off-label use of drugs in animals, namely, the extra-label use of Acepromazine Maleate for foxhunting purposes. I will begin by exploring the question of how often and in what capacities the drug is used in an off-label manner. Next, I will look at the physiology of the drug – how exactly does it affect a horse? What are the drug’s side effects? What are its labeled uses? What are its off-label uses? Is the way in which foxhunters are using Acepromazine Maleate in an off-label manner safe? Effective? How do veterinarians feel about the current off-label uses of the drug? Under veterinarian supervision, are horse owners capable of determining the appropriate quantities of the drug to administer their horses? In this chapter, I will explore these questions and more in order to flesh out a specific example of just how the off-label use of drugs in animals operates in practice, as well as the positives and negatives of the status quo.

THE FREQUENCY AND NATURE OF OFF-LABEL ACEPROMAZINE MALEATE USE

Although not a violation of Federal law, should the off-label use of Acepromazine Maleate be a cause for concern? To answer this question, one must consider just how much Acepromazine Maleate is actually being administered to horses. First, is the use of Acepromazine Maleate for foxhunting purposes relatively rare, or is it commonplace? Based on the (admittedly incomplete) information available, roughly 80% to 90% of foxhunters use Acepromazine Maleate whenever they foxhunt, typically three times per week. [133] Around 10% to 20% of foxhunters give Acepromazine Maleate to their horses every time they ride, on average five to six times per week. [134] Assuming that these statistics are accurate, Acepromazine Maleate is, by any measure, being administered to horses by foxhunters with substantial frequency.

ACEPROMAZINE MALEATE: AN OVERVIEW OF THE DRUG

1. BASIC INFORMATION

Acepromazine Maleate is a very effective tranquilizer that depresses the central nervous system, causing sedation, relaxation, and a reduction in involuntary movements. It is a phenothiazine [135] derivative, used by veterinarians as a neuroleptic [136] agent, primarily in dogs, cats and horses. [137] Phenothiazines decrease dopamine levels and depress some portions of the reticular activating system. [138] Acepromazine Maleate is metabolized by the liver and excreted in the urine. [139]

In addition to tranquilization, Acepromazine Maleate has multiple other important systemic effects including anti-cholinergic [140] , anti-emetic [141] , antispasmodic [142] , antihistaminic, and alpha-adrenergic [143] blocking properties. Acepromazine causes hypotension due to decreased vasomotor [144] tone. It may change heart and respiratory rate, and thermoregulatory ability, allowing for either hypo- or hyperthermia. [145]

Acepromazine Maleate may be given intramuscularly, intravenously or orally. It provides no analgesia and the tranquilizing effect of the drug can be overcome unexpectedly, particularly by sensory stimulation. [146] Acepromazine Maleate is usually less effective if given after the animal is excited.

Noteworthy is the fact that there is a great deal of individual variability in the response to Acepromazine Maleate. Despite being a very commonly used medication, there are important species and even breed differences in response to Acepromazine Maleate that need to be taken into consideration. [147] Draft horses, for example, are particularly sensitive to Acepromazine Maleate’s effects. Pony breeds, however, do not appear to differ from horses in their response to Acepromazine Maleate. [148]

2. SIDE EFFECTS OF ACEPROMAZINE MALEATE

Common side effects of Acepromazine Maleate include hypotension, decreased respiratory rate and bradycardia [149] . Sudden collapse, decreased or absent pulse and breathing, pale gums, and unconsciousness may occur in some animals. [150] Acepromazine Maleate will cause a dose dependent decrease in hematocrit [151] in both dogs and horses. This effect occurs within thirty minutes of administration and may last for twelve hours or more. [152] The hematocrit in horses may decrease by as much as 50%. [153] Penile paralysis is a rare but recognized adverse side effect of Acepromazine Maleate use in the horse. [154] Thus, the drug should be avoided in breeding stallions.

Acepromazine Maleate overdose will cause excessive sedation, slow respiratory and heart rate, pale gums, unsteady gait, poor coordination, and inability to stand. [155] It may also cause sudden collapse, unconsciousness, seizures and even death. [156]

3. ACEPROMAZINE MALEATE DOSAGES

Intravenous and intramuscular administration is recommended at a dosage of 2-4 mg per 100 pounds of body weight. [157] This dose generally results in marked sedation, suitable for carrying out minor surgical procedures with the use of a local anesthetic. [158] When tranquilizing horses for minor procedures, such as clipping, braiding, or for shipping, doses of 0.5-1 mg per 100 pounds of body weight will usually prove adequate and leave the horse with enough muscular coordination so that tailing is not a serious problem. [159]

When given intravenously, full effect is reached in approximately fifteen minutes. [160] With intramuscular use, a full thirty to forty-five minutes should be allowed (occasionally longer). [161] For best effect, horses should be left undisturbed following administration of the drug. [162] Peak activity lasts from one to four hours after administration. [163] This may be prolonged in sensitive animals. [164] Residual mild tranquilization is commonly observed for twelve hours or even longer after administration. [165]

A warning in regards to the dosage of Acepromazine Maleate is worth noting: “THE DOSAGE OF ACEPROMAZINE MALEATE MUST BE INDIVIDUALIZED. WHILE SOME HORSES TOLERATE A FULL DOSE WELL OTHERS WILL BECOME MARKEDLY ATAXIC [166] AT LOWER DOSES.” [167]

4. THE LABELED USES OF ACEPROMAZINE MALEATE

Like all prescription drugs, federal law restricts Acepromazine Maleate to use by or on the order of a licensed veterinarian. Acepromazine Maleate is labeled for use as “an aid in controlling intractable animals during examination, treatment, x-ray and minor surgical procedures.” [168]

5. THE OFF-LABEL USE OF ACEPROMAZINE MALEATE

In an off-label capacity, Acepromazine Maleate serves a different function. For years, riders have used Acepromazine Maleate to keep their horses calm while foxhunting them. Until the passage of the Animal Medicinal Drug Use Clarification Act of 1994, which made off-label use of the drug legal, foxhunters were largely secretive about their use of Acepromazine Maleate. “A dangling penis [169] here and there was the only sign that the drug was being used” one foxhunter comments. [170] “Twenty years ago, people were as hush hush about Ace as you could imagine” another interviewee confirms. [171] Most got the drug from their veterinarians but were told not to discuss their use of the drug with others, as it was technically illegal.

Since that time, however, the widespread use of the drug has been brought out into the open to a much greater extent. Foxhunters today are much more frank about their use of Acepromazine Maleate, at least with each other. As one foxhunter describes, “almost a day doesn’t pass now where you don’t hear one rider or another chuckling about the fact that they should have given their horse an extra CC of Ace.” [172]

6. WHY THE NEED FOR OFF-LABEL USE OF ACEPROMAZINE MALEATE?

Why should foxhunters need Acepromazine Maleate to keep their horses calm? Shouldn’t training alone be sufficient? Generally, horses that are athletic enough to be able to jump over five foot fences and gallop through field after field for hours on end (what is often entailed in the sport of foxhunting) are very athletic and have huge amounts of energy. Unfortunately, many of these horses are too energetic for their riders to be able to control them, and they misbehave in various ways. Their antics, including bucking and rearing up, often sends their riders flying off their backs. Indeed, “at least a person or two falls off during every foxhunt, most often resulting in a trip to the emergency room in the back of an ambulance, if not a trip to the nearest trauma center in the back of a helicopter.” [173]

To avoid this potentially dangerous situation, foxhunters give their horses Acepromazine Maleate to “take the buck” out of them. [174] Foxhunters do not administer enough of the drug to their horses to fully sedate, as they still want to run and jump them. Rather, they aim to give their horses just enough to keep them from misbehaving.

7. FOXHUNTERS’ ASSESSMENT OF THE DRUG

How do foxhunters feel about Acepromazine Maleate? The vast majority seem to think that Acepromazine Maleate is fantastic: “I would not be foxhunting today if it were not for Ace! My horse is wonderful on his own, but put him with a group of a hundred other horses and hounds, and he goes crazy ... Ace is the only thing that keeps his head on straight!” [175] The numbers actually speak for themselves, though: with roughly 80% - 90% of foxhunters using Acepromazine Maleate every time they foxhunt, typically three times per week, the drug must be doing something right. [176]

A couple of interviewees, however, are more skeptical of the drug. One interviewee noted the following: “I am all too aware of the rampant use of Acepromazine Maleate by my contemporaries. I have never used the drug myself. Think about it . . . you are giving a horse something that significantly slows down its brain processing capacity. Then, you are asking it to perform at its peak, running over, under, through, and around obstacles that most horses could never touch. Is this really fair?” [177]

Another interviewee analogizes Acepromazine Maleate to alcohol: “Imagine getting drunk. Now you try to jump over a three-rail fence!” [178] Yet another discusses some of the adverse effects of the drug: “I have had couple of dozen experiences using this product in training, when riding, or training for other trainers, in my younger days (small doses, usually only one CC). My experiences produced following observations: in racehorses I have noticed "heavier" breathing and excessive perspiration, while the product had no effect in reducing the horse’s nervousness for which the product was used. The horses also seemed to tire quicker when on this drug. When riding and training, this drug noticeably dulled the horse’s responses and the animal was in less cooperative mood. It was also obvious that the learning speed was noticeably reduced; as the horses were very often barely aware of what was going on, and their attention/interest to the work was greatly reduced as well.” [179] This interviewee concludes by noting: “There are alternate ‘calmers’ (tranquilizers) that can be used in training without in any way abusing the animal.” [180]

The overwhelming majority of foxhunters fully endorse the off-label use of Acepromazine Maleate, however, and have little to no reserve in using it on a regular basis. Several interviewees note, however, the potential dangers of using the drug if its effects have not been thoroughly tested on the horse before taking it foxhunting. “As Acepromazine Maleate affects different horses differently, and you can never tell just how sensitive a horse will be to the drug, you must test test test it before using it on the hunt field! Follow this rule of thumb, and you’re golden!” As another interviewee put it: “Each horse requires a specific dosage of Acepromazine Maleate. It can take several trial and errors to know for sure exactly what that dosage is ...” [181]

Most foxhunters have spent years and years around horses and are certain that they, as well as their fellow foxhunters, are fully able to determine the appropriate dosage of Acepromazine Maleate for each horse they ride: “We’re horse people. We know horses and we know how to take care of them.” [182] Another interviewee notes: “We are aware enough of the dangers of using Acepromazine Maleate recklessly NOT to use the drug recklessly.” “Many of the horses we ride cost upwards of $50,000” a third interviewee commented ... our pocketbooks alone keep us precautious!” [183] Statistically, this statement could be true. Out of the fifty foxhunters interviewed, not a single one reported an accident with their horse in any way related to their use of Acepromazine Maleate. [184]

8. A VETERINARIAN’S PERSPECTIVE

How do veterinarians feel about the off-label use of Acepromazine Maleate? They must be pretty confident in its safety, or they wouldn’t be prescribing it as frequently as they do. In some interviews with veterinarians at University of Pennsylvania’s New Bolton Center, I explore the question in further depth.

Dr. Ray Sweeney, VMD, my first interviewee, is an Assistant Professor of Medicine at University of Pennsylvania’s New Bolton Center, the School of Veterinary Medicine’s Large Animal Teaching Hospital. [185] When asked how the Animal Medicinal Drug Use Clarification Act of 1994 affected veterinarian prescribing practices, Dr. Sweeney responded:

It affected veterinarians primarily in the areas of cattle and food-producing animals. It did not affect actual prescribing, but rather it legalized what we were doing. Before, it was illegal to use prescription drugs off-label. This law was not enforced by the Food and Drug Administration’s Center of Veterinary Medicine. They did not step in unless the extra-label use led to adultered food products. Veterinarians lobbied to legalize what was already taking place in practice, and finally, in 1994, the bill was passed and the necessary provisions were codified. [186]

My second veterinarian interviewee, Dr. Mark Donaldson, a former Assistant Professor of Medicine at University of Pennsylvania’s New Bolton Center and current solo practitioner, was far less knowledgeable about the Animal Medicinal Drug Use Clarification Act of 1994. In fact when asked about the Act, Dr. Donaldson admitted to having no knowledge of it at all. [187]

What could account for this disparity of knowledge? First, Dr. Donaldson has only been practicing for ten years, so the off-label use of animal drugs has been legal as long as he has been a practicing veterinarian. Dr. Sweeney, in contrast, has been working at New Bolton Center since he graduated from the school himself twenty-five years ago. He was therefore a practicing veterinarian for many years prior to the passage Animal Medicinal Drug Use Clarification Act of 1994’s passage, whereas Dr. Donaldson never practiced during the era in which the off-label uses drugs in animals was illegal.

Second, Dr. Sweeney asked detailed questions about the content of the interview prior to the interview. I suspect based on the notes he was examining during the interview that he did some research on the Animal Medicinal Drug Use Clarification Act of 1994 as well as on Acepromazine Maleate prior to the interview. Dr. Donaldson, in contrast, did not ask any questions about the content of the interview prior to the interview, so he had no chance to research information.

This disparity of knowledge between Dr. Sweeney and Dr. Donaldson also arose in regards to the labeled uses of Acepromazine Maleate. Dr. Sweeney readily listed all of the labeled uses, whereas Dr. Donaldson summarized the labeled uses as: “Acepromazine Maleate is a tranquilizer/sedative for horses ... I [think] it is for restraint purposes?” [188]

Neither veterinarian seems to have a problem with the off-label use of Acepromazine Maleate for foxhunting purposes. Dr. Sweeney is confident that what is taking place is entirely acceptable, with one important caveat: “It is essential that it [Acepromazine Maleate] is used only at the discretion of a veterinarian, who guides dosage administration and timing.” [189] He also notes that “the veterinarian must have a client-patient relationship, know the animal, and know the condition in which the drug is being used so that he/she can make the judgment whether or not the animal can be used safely with the drug in its system.” [190]

Dr. Sweeney believes that Acepromazine Maleate is generally prescribed and used at completely appropriate levels. He knows that many barns and ferriers [191] keep Acepromazine Maleate around, though, and use it without a prescription. This practice, he condemns as “both wrong and illegal.” [192]

In regards to how safe it is to ride a horse after having given it Acepromazine Maleate, Dr. Sweeney responds: “Safety is always a concern whenever you tranquilize an animal. You worry about danger to the rider, if the horse stumbles or falls. Of all the tranquilizers available, [Acepromazine Maleate] is the mildest on the gate of a horse; [horses] don’t become uncoordinated as with other tranquilizers. In this regard, it is the safest. But it requires dose titration with every animal, as there is variability as far as how each horse is affected by the drug. Also, if the horse is already excited, the drug is not effective. Buy it is safe and legal for laypersons to use the drug as long as they follow the directions given to them by their veterinarian.” [193]

Dr. Donaldson reflects similar sentiments: “There is a huge range of knowledge of horse owners, so I am selective in whether I prescribe Ace or not. I base it on an assessment of the knowledge of the person I am dispensing it to.” [194] In regards to whether the drug is being overused, he agrees with Dr. Sweeney that “overall, I believe the current levels of Acepromazine Maleate use are appropriate. And it is used frequently – it is a pretty widespread thing.” [195]

9. VETERINARIAN PERSCRIBING PRACTICES:

In addition to considering the appropriateness of the off-label uses of the drug, it is important to examine whether the prescribing veterinarians are following FDA labeling guidelines. All of the interviewees with whom I spoke said that the veterinarians from whom they received the Acepromazine Maleate prescription were their regular veterinarians with whom they have had an ongoing relationship.

Are the veterinarians meeting the labeling requirements, however? The drug’s container, according to Food and Drug Administration regulations, must bear the veterinarian's name, address, name of the drug (active ingredient), identification of the animal(s) to be treated, adequate directions for proper use, and cautions/precautions. [196] This information may be on the label applied by the manufacturer, or on a label attached to the product by the veterinarian. If there is inadequate space on the label for any of the other required information, the veterinarian must provide the additional information on a separate sheet that accompanies the drug dispensed or prescribed.

In order to examine compliance with labeling requirements more closely, anonymous Interviewee #4 provided two Acepromazine Maleate packages given to her by separate veterinarians. The first prescription said “1ml I.M. 1/2 hour before excise (sic).” [197] What exactly is excise? Exercise? For what horse(s) does this prescription pertain? Clearly, this prescription does not comply with labeling requirements.

The second prescription reads: “For Windfield - give 1 to 1.5mls in the muscle as needed. Dr. Puchalski.” [198] In this instance, the horse’s name is actually Winfield, not Windfield. How often is “as needed”? This prescription also fails to comply with Animal Medicinal Drug Use Clarification Act of 1994 requirements.

If out of the two prescriptions I examined, neither meet Animal Medicinal Drug Use Clarification Act of 1994 requirements, it appears that there is at least somewhat of a compliance problem here. Without closer Food and Drug Administration regulation, however, nothing will change.

CHAPTER FOUR

What, if Anything, should the Food and Drug Administration do about the Off-Label Use of Acepromazine Maleate?

In Chapter One, I provided readers with a brief description of the most important elements of this paper: what Acepromazine Maleate is, how foxhunters use Acepromazine Maleate in an off-label capacity, and how the Animal Medicinal Drug Use Clarification Act of 1994 affects the off-label use of the drug. Next, I provided readers with a roadmap of the paper. I concluded the chapter with a literature review, exploring how each of the various sources contributed to an understanding of the issues at hand.

In Chapter Two, I examined how the Food and Drug Administration regulates animal drugs. In doing so, I looked extensively at the Center for Veterinary Medicine’s approval process for animal drugs. I then considered the off-label use of animal drugs. In this portion of the paper, I drew heavily on the legislative history behind the Animal Medicinal Drug Use Clarification Act of 1994, whose purpose was: "to amend the Federal Food, Drug, and Cosmetic Act to clarify the application of the Act with respect to alternate uses of new animal drugs and new drugs intended for human use, and for other purposes." [199] I paid particularly close attention in this portion of the paper to the reasons behind the passage of the Act.

In Chapter Three, I explored the capacities in which and exactly how much Acepromazine Maleate fox hunters use in an off-label capacity, noting the limitations of these figures. No data, however, has even been collected on this subject matter in the past, so although incomplete this information is nonetheless the first of its kind.

I then considered the off-label use of Acepromazine Maleate by foxhunters more closely. First, I explored the physiology of the drug itself: how it affects the animal’s body, its labeled uses, its side effects, and the dangers of using the drug while foxhunting. I made extensive use of the interviews I conducted with foxhunters in this portion of the paper, and scrutinized how they feel about the off-label use of the drug.

Finally, I explored the opinions of veterinarians at New Bolton Center, the site of the University of Pennsylvania’s School of Veterinary Medicine's teaching hospital for large animals. I also wanted their opinion on Acepromazine Maleate and the acceptability of its off-label use by foxhunters.

From the information gathered in above chapters, I would now like to revisit the various questions posed at the beginning of the paper.

In this paper, I aimed to assess whether foxhunters are safe using Acepromazine Maleate in an off-label capacity. From my research, it appears that the answer to this question is, for the most part, yes. The foxhunters themselves overwhelmingly believe that the off-label use of Acepromazine Maleate is safe, as long as the necessary precautions are taken. And because most foxhunters have spent years and years around horses, they have the judgment to meet, if not exceed, this safety bar.

Veterinarians themselves are also quite confident in the safety of off-label Acepromazine Maleate use by foxhunters. They too believe that if the proper precautions are taken, there is no problem with its frequent use.

In regards to whether foxhunters are capable of selecting and/or administering the appropriate dosage of Acepromazine Maleate (per guidance from the veterinarian), the answer again appears to be yes. In not a single one of the fifty interviews I conducted did a foxhunter report having had a riding accident related to their use of Acepromazine Maleate. Not a single interviewee even reported having heard of such an occurrence. My interviews with veterinarians painted a similar picture. None of the veterinarians I interviewed had ever even heard of an accident in any way related to the off-label use of Acepromazine Maleate. If anything, the drug may have prevented accidents. By helping to calm otherwise antsy horses, the drug may (and likely) improves safety on the hunt field.

What does deserve additional attention, however, is veterinarian compliance with the Food and Drug Administration’s labeling requirements. Veterinarians are now permitted to prescribe drugs such as Acepromazine Maleate off-label, but they must be absolutely certain to provide horse owners with appropriate guidance in administering the drug. Particularly with a drug like Acepromazine Maleate, which is extremely sensitive to both timing and dosage, the drug can affect a horse radically differently depending on when the drug is administered as well as how much is given. Also, the line between giving a horse just enough Acepromazine Maleate to calm it down, and giving it a little bit too much, such that the horse’s athletic ability is hindered, is an extremely fine one. Foxhunters do not want to discover that they gave their horse one too many CCs of Ace while jumping over a five foot fence. This mistake could be dangerous and potentially life-threatening to both the rider and the horse. Given the inadequate labeling I encountered in my research, veterinarians need to be much more meticulous in their prescribing practices. They must be absolutely sure that the horse owner is competent and fully aware of the dangers of the drug.

In this regard, the Food and Drug Administration needs to be doing more. Even before the passage of the Animal Medicinal Drug Use Clarification Act of 1994’s passage, veterinarians were prescribing Acepromazine Maleate off-label on a regular basis because the Center of Veterinary Medicine was not enforcing the law. Now that Congress has passed a more reasonable statute, the current law needs proper enforcement to actually affect veterinarian behavior. Ultimately, this change will enhance the safety of both horses and humans.


[1] To “buck” is for a horse to leap upward arching the back. http://www.thefreedictionary.com/buck (March 14, 2005).

[2] A “hunt” entails mounted hunters follow hounds in pursuit of a

fox. http://www.thefreedictionary.com/foxhunt (March 14, 2005).

[3] A CC is a metric unit of volume equal to one thousandth of a

liter. http://www.thefreedictionary.com/CC (March 14, 2005).

[4] Anonymous Interview #33. Interview on file with author. Conducted on January 29, 2005 in Unionville, PA.

5 A derby is a stiff felt hat with a round crown and a narrow, curved brim. Also known as the Bowler, this Derby hat popular for the past century and a half, has been worn by personalities ranging from Charlie Chaplin to Dion Sanders.

6 Anonymous Interview #12. Interview on file with author. Conducted on January 29, 2005 in Unionville, PA.

[7] To “jig” is to move or bob up and down jerkily and rapidly. http://www.thefreedictionary.com/Jig (March 14, 2006).

8 Anonymous Interview #14. Interview on file with author. Conducted on January 30, 2005 in Unionville, PA.

9 A “hound” or “foxhound” is a medium-sized glossy-coated hounds developed for hunting foxes. http://www.thefreedictionary.com/hound (March 14, 2005).

10 Anonymous Interview #11. Interview on file with author. Conducted on February 1, 2005 in Unionville, PA.

11 PromAce Injectable (Acepromazine Maleate Injection, USP) Label, Ford Dodge Animal Health, Fort Dodge Iowa 50501 USA, Rev. Apr. 2002.

[12] PromAce Injectable (Acepromazine Maleate Injection, USP) Label, Ford Dodge Animal Health, Fort Dodge Iowa 50501 USA, Rev. Apr. 2002.

13 “The New Extra-Label Use Law: An Overview,” by Jeannie Perron, Esq. Texas A&M ‘97

14 Information is based on anonymous interviews with subscribers to Mr. Stewart’s Cheshire Foxhounds (Unionville, PA), the Radnor Hunt (Malvern, PA), and former members of the Brandywine Hunt (West Chester, PA), which dissolved in 2004.

15 Information is based on anonymous interviews with subscribers to Mr. Stewart’s Cheshire Foxhounds (Unionville, PA), the Radnor Hunt (Malvern, PA), and former members of the Brandywine Hunt (West Chester, PA), which dissolved in 2004.

[16] Lambert, Eugene. “Animal Drugs: Future Stepchild or Pioneer?” 55 Food & Drug L.J. 33. (2000).

17 94 CIS PL 103396; 103 CIS Legis. Hist. P.L. 396.

[18] 140 Congressional Record, 103rd Congress, 2nd Session – December 1994. CIS-NO: 94-PL103-396.

[19] Email from an anonymous Board Member of Cheshire Conservancy, dated February 10, 2006.

[20] Id.

[21] In 1964 the large-animal clinic opened at New Bolton Center, a farm in Chester County that the University acquired in 1952. The Widener Hospital at New Bolton Center has more than 70 buildings and 141 stalls for patients. Each year the George D. Widener Hospital for Large Animals sees more than 6,000 patient visits, and the Field Service sees more than 19,000 animals. Penn boasts one of the largest equine surgical faculties in the world. Many members of Penn's surgical faculty are known internationally in their fields. Because of these credentials, New Bolton Center enjoys a large and varied caseload. Because of its location, it treats valuable horses that engage in all kinds of athletic activities. http://www.vet.upenn.edu/nbc/ (March 14, 2005)

[22] Wikipedia Contributors, Wikopedia, the Free Encyclopedia, Page Version ID: 50195723 http://en.wikipedia.org/wiki/Food_and_Drug_Administration , April 24, 2005.

[23] Wikipedia Contributors, Wikopedia, the Free Encyclopedia, Page Version ID: 50195723 http://en.wikipedia.org/wiki/Food_and_Drug_Administration , April 24, 2005.

[24] Wikipedia Contributors, Wikopedia, the Free Encyclopedia, Page Version ID: 50195723 http://en.wikipedia.org/wiki/Food_and_Drug

_Administration , April 24, 2006.

[25] Wikipedia Contributors, Wikopedia, the Free Encyclopedia, Page Version ID: 50195723 http://en.wikipedia.org/wiki/Food_and_Drug

_Administration , April 24, 2006.

[26] Wikipedia Contributors, Wikopedia, the Free Encyclopedia, Page Version ID: 50195723 http://en.wikipedia.org/wiki/Food_and_Drug

_Administration , April 24, 2006.

[27] Wikipedia Contributors, Wikopedia, the Free Encyclopedia, Page Version ID: 50195723 http://en.wikipedia.org/wiki/Food_and_Drug

_Administration , April 24, 2006.

28 Wikipedia Contributors, Wikopedia, the Free Encyclopedia, Page Version ID: 50195723 http://en.wikipedia.org/wiki/Food_and_Drug

_Administration , April 24, 2006.

[29] Wikipedia Contributors, Wikipedia, the Free Encyclopedia, Page Version ID: 50195723 http://en.wikipedia.org/wiki/Food_and_Drug

_Administration , April 24, 2006.

[30] Wikipedia Contributors, Wikipedia, the Free Encyclopedia, Page Version ID: 48489674 http://en.wikipedia.org/wiki/Center_for_

Veterinary Medicine , April 24, 2006.

31 Wikipedia Contributors, Wikipedia, the Free Encyclopedia, Page Version ID: 48489674 http://en.wikipedia.org/wiki/Center_for_

Veterinary Medicine , April 24, 2006.

32 Minor animal species include animals other than cattle, swine, chickens, turkeys, horses, dogs, and cats.

33 Wikipedia Contributors, Wikipedia, the Free Encyclopedia, Page Version ID: 48489674 http://en.wikipedia.org/wiki/Center_for_

Veterinary Medicine , April 24, 2006.

34 Vaughn, Steven D., D.V.M. “Overview of the Animal Drug Approval Process” United States Food an Drug Administration, Center for Veterinary Medicine, Office of New Animal Drug Evaluation.

[35] Vaughn, Steven D., D.V.M. “Overview of the Animal Drug Approval Process” United States Food an Drug Administration, Center for Veterinary Medicine, Office of New Animal Drug Evaluation.

[36] Vaughn, Steven D., D.V.M. “Overview of the Animal Drug Approval Process” United States Food an Drug Administration, Center for Veterinary Medicine, Office of New Animal Drug Evaluation.

[37] Vaughn, Steven D., D.V.M. “Overview of the Animal Drug Approval Process” United States Food an Drug Administration, Center for Veterinary Medicine, Office of New Animal Drug Evaluation.

[38] Vaughn, Steven D., D.V.M. “Overview of the Animal Drug Approval Process” United States Food an Drug Administration, Center for Veterinary Medicine, Office of New Animal Drug Evaluation.

[39] Vaughn, Steven D., D.V.M. “Overview of the Animal Drug Approval Process” United States Food an Drug Administration, Center for Veterinary Medicine, Office of New Animal Drug Evaluation.

[40] Vaughn, Steven D., D.V.M. “Overview of the Animal Drug Approval Process” United States Food an Drug Administration, Center for Veterinary Medicine, Office of New Animal Drug Evaluation.

[41] The National Environmental Policy Act (NEPA) requires federal agencies to integrate environmental values into their decision making processes by considering the environmental impacts of their proposed actions and reasonable alternatives to those actions. To meet this requirement, federal agencies prepare a detailed statement known as an Environmental Impact Statement (EIS). EPA reviews and comments on EISs prepared by other federal agencies, maintains a national filing system for all EISs, and assures that its own actions comply with NEPA. http://www.epa.gov/compliance/nepa/index.html . April 24, 2006.

[42] Growing public awareness and concern for controlling water pollution led to enactment of the Federal Water Pollution Control Act Amendments of 1972. As amended in 1977, this law became commonly known as the Clean Water Act. The Act established the basic structure for regulating discharges of pollutants into the waters of the United States. It gave EPA the authority to implement pollution control programs such as setting wastewater standards for industry. The Clean Water Act also continued requirements to set water quality standards for all contaminants in surface waters. The Act made it unlawful for any person to discharge any pollutant from a point source into navigable waters, unless a permit was obtained under its provisions. It also funded the construction of sewage treatment plants under the construction grants program and recognized the need for planning to address the critical problems posed by non-point source pollution. Subsequent enactments modified some of the earlier Clean Water Act provisions. http://www.epa.gov/r5water/cwa.htm . April 24, 2006.

[43] Vaughn, Steven D., D.V.M. “Overview of the Animal Drug Approval Process” United States Food an Drug Administration, Center for Veterinary Medicine, Office of New Animal Drug Evaluation.

[ ] 44 “Finding of No Significant Impact.” The purpose of this Notice is to make available to the public the Finding of No Significant Impact pursuant to an Environmental Assessment. www.epa.gov

[45] “Environmental Impact Statement.” www.epa.gov

[46] Vaughn, Steven D., D.V.M. “Overview of the Animal Drug Approval Process” United States Food an Drug Administration, Center for Veterinary Medicine, Office of New Animal Drug Evaluation.

[47] Vaughn, Steven D., D.V.M. “Overview of the Animal Drug Approval Process” United States Food an Drug Administration, Center for Veterinary Medicine, Office of New Animal Drug Evaluation.

[48] Vaughn, Steven D., D.V.M. “Overview of the Animal Drug Approval Process” United States Food an Drug Administration, Center for Veterinary Medicine, Office of New Animal Drug Evaluation.

[49] Vaughn, Steven D., D.V.M. “Overview of the Animal Drug Approval Process” United States Food an Drug Administration, Center for Veterinary Medicine, Office of New Animal Drug Evaluation.

[50] Vaughn, Steven D., D.V.M. “Overview of the Animal Drug Approval Process” United States Food an Drug Administration, Center for Veterinary Medicine, Office of New Animal Drug Evaluation.

[51] Lambert, Eugene I. “Animal Drugs: Future Stepchild or Pioneer?” 55 Food & Drug L.J. 33. Food and Drug Law Institute (2000).

[52] Lambert, Eugene I. “Animal Drugs: Future Stepchild or Pioneer?” 55 Food & Drug L.J. 33. Food and Drug Law Institute (2000).

[53] A pet or companion animal is an animal that is kept by humans for companionship and enjoyment, rather than for economic reasons. "Companion animal" or "pet" means any dog or cat, and shall also mean any other domesticated animal normally maintained in or near the household of the owner or person who cares for such other domesticated animal. "Pet" or "companion animal" shall not include a "farm animal."

54 Lambert, Eugene I. “Animal Drugs: Future Stepchild or Pioneer?” 55 Food & Drug L.J. 33. Food and Drug Law Institute (2000).

55 Lambert, Eugene I. “Animal Drugs: Future Stepchild or Pioneer?” 55 Food & Drug L.J. 33. Food and Drug Law Institute (2000).

56 Lambert, Eugene I. “Animal Drugs: Future Stepchild or Pioneer?” 55 Food & Drug L.J. 33. Food and Drug Law Institute (2000).

57 Lambert, Eugene I. “Animal Drugs: Future Stepchild or Pioneer?” 55 Food & Drug L.J. 33. Food and Drug Law Institute (2000).

[58] Lambert, Eugene I. “Animal Drugs: Future Stepchild or Pioneer?” 55 Food & Drug L.J. 33. Food and Drug Law Institute (2000).

59 Chiropractic, high-dose vitamins and herbal therapies such as St. John's Wort and Ginkgo are among the myriad of "alternative treatments" currently enticing and perplexing patients and physicians alike. Approximately $13 billion a year are spent in the United States on these therapies, which some patients opt to use over conventional medicines. Alternative therapies, as they have become known, can range from innocuous family remedies to unproven but potentially promising remedies to harmful and ineffective treatments. Many physicians take issue with the term "alternative," feeling it gives a degree of legitimacy to therapies that may or may not be effective. For example, in conventional medicine, alternative usually refers to options within generally accepted medical practices, such as medical vs. surgical therapy for coronary artery disease. One common definition of alternative medicine refers to therapies not widely taught in medical schools, not generally used in hospitals and not typically reimbursed by medical insurance companies. More than 50 medical schools in the United States now offer courses in alternative medicine.

[60] Lambert, Eugene I. “Animal Drugs: Future Stepchild or Pioneer?” 55 Food & Drug L.J. 33. Food and Drug Law Institute (2000).

[61] The Dietary Supplement Health and Education Act of 1994 (DSHEA) acknowledges that millions of consumers believe dietary supplements may help to augment daily diets and provide health benefits. Congress's intent in enacting the DSHEA was to meet the concerns of consumers and manufacturers to help ensure that safe and appropriately labeled products remain available to those who want to use them. In the findings associated with the DSHEA, Congress stated that there may be a positive relationship between sound dietary practice and good health, and that, although further scientific research is needed, there may be a connection between dietary supplement use, reduced health-care expenses, and disease prevention. The provisions of DSHEA define dietary supplements and dietary ingredients; establish a new framework for assuring safety; outline guidelines for literature displayed where supplements are sold; provide for use of claims and nutritional support statements; require ingredient and nutrition labeling; and grant FDA the authority to establish good manufacturing practice (GMP) regulations. The law also requires formation of an executive level Commission on Dietary Supplement Labels and an Office of Dietary Supplements within the National Institutes of Health.

[62] Pub. L. No. 103-396 , 108 Stat. 4153 (codified at 21 U.S.C. § 360b(a) (1994) ).

[63] Lambert, Eugene I. “Animal Drugs: Future Stepchild or Pioneer?” 55 Food & Drug Law Journal 33, Food and Drug Law Institute, 2000.

[64] “For an overview of the medical and legal issues of off-label drug use, see David A. Kessler, Regulating the Prescribing of Human Drugs for Nonapproved Uses Under the Food, Drug, and Cosmetic Act, 15 HARV.J. ON LEGIS. 693 (1978); Sidney A. Shapiro, Limiting Physician Freedom to Prescribe a Drug for Any Purpose: The Need for FDA Regulation, 73 NW.U.L.REV. 801 (1978).” In William L. Christopher’s “Off-Label Drug Prescription: Filling the Regulatory Vacuum,” 48 Food & Drug Law Journal 247, Food and Drug Law Institute (1993).

[65] “UNITED STATES GOV. ACCT. OFF., OFF-LABEL DRUGS: REIMBURSEMENT POLICIES CONSTRAIN PHYSICIANS IN THEIR CHOICE OF CANCER THERAPIES, GAO/PEMD-91- 14 at 11 (1991) (off-label use of breast cancer drug to treat colon cancer)” in William L. Christopher’s “Off-Label Drug Prescription: Filling the Regulatory Vacuum,” 48 Food & Drug Law Journal 247, Food and Drug Law Institute (1993).

66 “The drug DES was once the subject of widespread, informal experimentation despite limited FDA approval; one physician prescribed the drug as a "growth retardant" for adolescents. See DIANA B. DUTTON, WORSE THAN THE DISEASE 46 (1988)” in William L. Christopher’s “Off-Label Drug Prescription: Filling the Regulatory Vacuum,” 48 Food & Drug Law Journal 247, Food and Drug Law Institute (1993).

67 Christopher, William L. “Off-Label Drug Prescription: Filling the Regulatory Vacuum,” 48 Food & Drug Law Journal 247, Food and Drug Law Institute (1993).

[68] ALTERNATE USES OF NEW ANIMAL DRUGS, STATEMENTS ON INTRODUCED BILLS AND JOINT RESOLUTIONS (Senate - February 04, 1993) http://thomas.loc.gov/cgi-bin/query/F?r103:1:./temp/~r103QRnTQL:e586177 :

[69] ALL ACTIONS, Floor Actions/Congressional Record Page References

http://thomas.loc.gov/cgi-bin/bdquery/z?d103:SN00340:@@@S

70 ALL ACTIONS, Floor Actions/Congressional Record Page References

http://thomas.loc.gov/cgi-bin/bdquery/z?d103:SN00340:@@@S

71 ALL ACTIONS, Floor Actions/Congressional Record Page References

http://thomas.loc.gov/cgi-bin/bdquery/z?d103:SN00340:@@@S

72 ALL ACTIONS, Floor Actions/Congressional Record Page References

http://thomas.loc.gov/cgi-bin/bdquery/z?d103:SN00340:@@@S

73 ALL ACTIONS, Floor Actions/Congressional Record Page References

http://thomas.loc.gov/cgi-bin/bdquery/z?d103:SN00340:@@@S

74 ALL ACTIONS, Floor Actions/Congressional Record Page References

http://thomas.loc.gov/cgi-bin/bdquery/z?d103:SN00340:@@@S

75 ALL ACTIONS, Floor Actions/Congressional Record Page References

http://thomas.loc.gov/cgi-bin/bdquery/z?d103:SN00340:@@@S

[76] THE FEDERAL FOOD, DRUG, AND COSMETIC ACT AMENDMENTS (Senate - October 04, 1994) http://thomas.loc.gov/cgi-bin/query/F?r103:2:./temp/~r1039lNPvy:e0 :

[77] ANIMAL MEDICINAL DRUG USE CLARIFICATION ACT OF 1994 (House of Representatives - October 06, 1994) http://thomas.loc.gov/cgi-bin/query/F?r103:3:./temp/~r103KcX1jL:e47 :

78 ANIMAL MEDICINAL DRUG USE CLARIFICATION ACT OF 1994 (House of Representatives - October 06, 1994) http://thomas.loc.gov/cgi-bin/query/F?r103:3:./temp/~r103KcX1jL:e47 :

79 ANIMAL MEDICINAL DRUG USE CLARIFICATION ACT OF 1994 (House of Representatives - October 06, 1994) http://thomas.loc.gov/cgi-bin/query/F?r103:3:./temp/~r103KcX1jL:e47 :

[80] ANIMAL MEDICINAL DRUG USE CLARIFICATION ACT OF 1994 (House of Representatives - October 06, 1994) http://thomas.loc.gov/cgi-bin/query/F?r103:3:./temp/~r103KcX1jL:e47 :

81 ANIMAL MEDICINAL DRUG USE CLARIFICATION ACT OF 1994 (House of Representatives - October 06, 1994) http://thomas.loc.gov/cgi-bin/query/F?r103:3:./temp/~r103KcX1jL:e47 :

82 ANIMAL MEDICINAL DRUG USE CLARIFICATION ACT OF 1994 (House of Representatives - October 06, 1994) http://thomas.loc.gov/cgi-bin/query/F?r103:3:./temp/~r103KcX1jL:e47 :

83 ANIMAL MEDICINAL DRUG USE CLARIFICATION ACT OF 1994 (House of Representatives - October 06, 1994) http://thomas.loc.gov/cgi-bin/query/F?r103:3:./temp/~r103KcX1jL:e47 :

[84] ANIMAL MEDICINAL DRUG USE CLARIFICATION ACT OF 1994 (House of Representatives - October 06, 1994) http://thomas.loc.gov/cgi-bin/query/F?r103:3:./temp/~r103KcX1jL:e47 :

85 ANIMAL MEDICINAL DRUG USE CLARIFICATION ACT OF 1994 (House of Representatives - October 06, 1994) http://thomas.loc.gov/cgi-bin/query/F?r103:3:./temp/~r103KcX1jL:e47 :

86 ALTERNATE USES OF NEW ANIMAL DRUGS, STATEMENTS ON INTRODUCED BILLS AND JOINT RESOLUTIONS (Senate - February 04, 1993) http://thomas.loc.gov/cgi-bin/query/F?r103:1:./temp/~r103QRnTQL:e586177 :
[87] ALTERNATE USES OF NEW ANIMAL DRUGS, STATEMENTS ON INTRODUCED BILLS AND JOINT RESOLUTIONS (Senate - February 04, 1993) http://thomas.loc.gov/cgi-bin/query/F?r103:1:./temp/~r103QRnTQL:e586177 :

[88] ANIMAL MEDICINAL DRUG USE CLARIFICATION ACT OF 1994 (House of Representatives - October 06, 1994) http://thomas.loc.gov/cgi-bin/query/F?r103:3:./temp/~r103Dy6ypy:e0 :

89 ALTERNATE USES OF NEW ANIMAL DRUGS, STATEMENTS ON INTRODUCED BILLS AND JOINT RESOLUTIONS (Senate - February 04, 1993) http://thomas.loc.gov/cgibin/query/F?r103:1:./temp/~r103QRnTQL:e586177 :

[90] STATEMENTS ON INTRODUCED BILLS AND JOINT RESOLUTIONS (Senate - February 04, 1993) http://thomas.loc.gov/cgi-bin/query/F?r103:1:./temp/~r103sVc74R:e586177 :

[91] ANIMAL MEDICINAL DRUG USE CLARIFICATION ACT OF 1994 (House of Representatives - October 06, 1994) http://thomas.loc.gov/cgi-bin/query/F?r103:3:./temp/~r103RV7XqP:e609 :

[92] THE FEDERAL FOOD, DRUG, AND COSMETIC ACT AMENDMENTS (Senate - October 04, 1994) http://thomas.loc.gov/cgi-bin/query/F?r103:2:./temp/~r103btaZup:e0 :

93 THE FEDERAL FOOD, DRUG, AND COSMETIC ACT AMENDMENTS (Senate - October 04, 1994) http://thomas.loc.gov/cgi-bin/query/F?r103:2:./temp/~r103btaZup:e0 :

[94] THE FEDERAL FOOD, DRUG, AND COSMETIC ACT AMENDMENTS (Senate - October 04, 1994) http://thomas.loc.gov/cgi-bin/query/F?r103:2:./temp/~r103btaZup:e0 :

95 THE FEDERAL FOOD, DRUG, AND COSMETIC ACT AMENDMENTS (Senate - October 04, 1994) http://thomas.loc.gov/cgi-bin/query/F?r103:2:./temp/~r103btaZup:e0 :

96 THE FEDERAL FOOD, DRUG, AND COSMETIC ACT AMENDMENTS (Senate - October 04, 1994) http://thomas.loc.gov/cgi-bin/query/F?r103:2:./temp/~r103btaZup:e0 :

[97] THE FEDERAL FOOD, DRUG, AND COSMETIC ACT AMENDMENTS (Senate - October 04, 1994) http://thomas.loc.gov/cgi-bin/query/F?r103:2:./temp/~r103btaZup:e0 :

[98] STATEMENTS ON INTRODUCED BILLS AND JOINT RESOLUTIONS (Senate - February 04, 1993) http://thomas.loc.gov/cgi-bin/query/F?r103:1:./temp/~r103sVc74R:e586177 :

99 STATEMENTS ON INTRODUCED BILLS AND JOINT RESOLUTIONS (Senate - February 04, 1993) http://thomas.loc.gov/cgi-bin/query/F?r103:1:./temp/~r103sVc74R:e586177 :

[100] STATEMENTS ON INTRODUCED BILLS AND JOINT RESOLUTIONS (Senate - February 04, 1993) http://thomas.loc.gov/cgi-bin/query/F?r103:1:./temp/~r103sVc74R:e586177 :

[101] STATEMENTS ON INTRODUCED BILLS AND JOINT RESOLUTIONS (Senate - February 04, 1993) http://thomas.loc.gov/cgi-bin/query/F?r103:1:./temp/~r103sVc74R:e586177 :

[102] STATEMENTS ON INTRODUCED BILLS AND JOINT RESOLUTIONS (Senate - February 04, 1993) http://thomas.loc.gov/cgi-bin/query/F?r103:1:./temp/~r103sVc74R:e586177 :

103 STATEMENTS ON INTRODUCED BILLS AND JOINT RESOLUTIONS (Senate - February 04, 1993) http://thomas.loc.gov/cgi-bin/query/F?r103:1:./temp/~r103sVc74R:e586177 :

104 STATEMENTS ON INTRODUCED BILLS AND JOINT RESOLUTIONS (Senate - February 04, 1993) http://thomas.loc.gov/cgi-bin/query/F?r103:1:./temp/~r103xOZI9Q:e586177 :

105 STATEMENTS ON INTRODUCED BILLS AND JOINT RESOLUTIONS (Senate - February 04, 1993) http://thomas.loc.gov/cgi-bin/query/F?r103:1:./temp/~r103xOZI9Q:e586177 :

106 STATEMENTS ON INTRODUCED BILLS AND JOINT RESOLUTIONS (Senate - February 04, 1993) http://thomas.loc.gov/cgi-bin/query/F?r103:1:./temp/~r103xOZI9Q:e586177 :

107 STATEMENTS ON INTRODUCED BILLS AND JOINT RESOLUTIONS (Senate - February 04, 1993) http://thomas.loc.gov/cgi-bin/query/F?r103:1:./temp/~r103xOZI9Q:e586177 :

108 “Legislation generally has overridden the physician lobby against drug regulation only in times of medical disaster. See, e.g., Nancy M.P. King & Gail Henderson, Treatments of Last Resort: Informed Consent and the Diffusion of New Technology, 42 MERCER L.REV. 1007, 1015-19 (1991) .” in William L. Christopher’s “Off-Label Drug Prescription: Filling the Regulatory Vacuum,” 48 Food & Drug Law Journal 247, Food and Drug Law Institute (1993).

[109] “See, e.g., Mary McCabe & Michael A. Friedman, Impact of Third-Party Reimbursement on Cancer Clinical Investigation: A Consensus Statement Coordinated by the National Cancer Institute, 81 J.NAT'L CANCER INST. 1585, 1585-86 (1989) (The American Medical Association and the National Cancer Institute, among others, arguing that efficacy should primarily determine appropriate drug therapy; other criteria "may prevent patients from receiving the best available therapy").” in William L. Christopher’s “Off-Label Drug Prescription: Filling the Regulatory Vacuum,” 48 Food & Drug Law Journal 247, Food and Drug Law Institute (1993).

[110] “Henig, Robin Marantz, FDA Assails "Off-Label" Uses of Cosmetic Drugs; Painful Medical Problems Continue for Years, Patients Allege, WASH. POST, June 18, 1991, at Z7.” In William L. Christopher’s “Off-Label Drug Prescription: Filling the Regulatory Vacuum,” 48 Food & Drug Law Journal 247, Food and Drug Law Institute (1993).

[111] Christopher, William L. “Off-Label Drug Prescription: Filling the Regulatory Vacuum,” 48 Food & Drug Law Journal 247, Food and Drug Law Institute (1993).

[112] Christopher, William L. “Off-Label Drug Prescription: Filling the Regulatory Vacuum,” 48 Food & Drug Law Journal 247, Food and Drug Law Institute (1993).

113 Christopher, William L. “Off-Label Drug Prescription: Filling the Regulatory Vacuum,” 48 Food & Drug Law Journal 247, Food and Drug Law Institute (1993).

114 Lambert, Eugene I. “Animal Drugs: Future Stepchild or Pioneer?” 55 Food & Drug Law Journal 33, Food and Drug Law Institute, 2000.

115 “GAO REPORT, supra note 7, at 3. The GAO Report was summarized and editorialized recently in the Journal of the American Medical Association. See Thomas Laetz & George Silverman, Reimbursement Policies Constrain the Practice of Oncology, 266 JAMA 2996 (1991); Charles G. Moertel, Off-Label Drug Use for Cancer Therapy and National Health Care Priorities, 266 JAMA 3031 (1991).” William L. Christopher’s “Off-Label Drug Prescription: Filling the Regulatory Vacuum,” 48 Food & Drug Law Journal 247, Food and Drug Law Institute (1993).

116 The study covered 2018 patients suffering from 15 forms of cancer, who were prescribed a total of 5239 administrations of 46 anticancer drugs. Id. at 18-19.

[117] Fifty-six percent of the patients received at least one off-label drug. Id. at 21.

118 Forty-four of the 46 approved anticancer drugs were prescribed off-label at least once. Id. at 20. Off-label use of three drugs, ifosfamide, interferon, and mitoxantrone, constituted 85% of their total prescriptions. Id. at 22.

119 All of the fifteen cancers were treated with at least one off-label drug; in the case of society's most prevalent cancer, lung cancer, nearly all the studied patients received at least one off-label drug. Id. at 25.

120 Christopher, William L. “Off-Label Drug Prescription: Filling the Regulatory Vacuum,” 48 Food & Drug Law Journal 247, Food and Drug Law Institute (1993).

121 Christopher, William L. “Off-Label Drug Prescription: Filling the Regulatory Vacuum,” 48 Food & Drug Law Journal 247, Food and Drug Law Institute (1993).

[122] Christopher, William L. “Off-Label Drug Prescription: Filling the Regulatory Vacuum,” 48 Food & Drug Law Journal 247, Food and Drug Law Institute (1993).

123 GAO REPORT, at 27.

124 Charles G. Moertel, Off-Label Drug Use for Cancer Therapy and National Health Care Priorities, 266 JAMA 3031 (1991) at 3031.

125 Christopher, William L. “Off-Label Drug Prescription: Filling the Regulatory Vacuum,” 48 Food & Drug Law Journal 247, Food and Drug Law Institute (1993).

126 The manufacturer's label warns that "Chloramphenicol must not be used when less potentially dangerous agents will be effective.... It must not be used in the treatment of trivial infections...." PHYSICIANS' DESK REFERENCE 1588 (1990). Essentially the same warning was in place in 1965 when Helen Muldar died from aplastic anemia following chloramphenicol therapy for an ear infection. See Muldar v. Parke, Davis & Co., 288 Minn. 332, 181 N.W.2d 882 (1970) .

127 Christopher, William L. “Off-Label Drug Prescription: Filling the Regulatory Vacuum,” 48 Food & Drug Law Journal 247, Food and Drug Law Institute (1993).

[128] “Defective Drugs” http://www.adrugrecall.com/des/des.html

129 Rudy M. Baum, RU-486: Abortion Controversy in U.S. Clouds Future of Promising Drug, CHEMICAL & ENGINEERING NEWS, Mar. 11, 1991, at 7, 12-13.

130 Thomas Murray, The Growing Danger from Gene-Spliced Hormones, in ETHICAL ISSUES IN MODERN MEDICINE 409, 410 (John D. Arras & Nancy K. Rhoden eds., 3d ed. 1989).

[131] UNITED STATES GOV. ACCT. OFF., OFF-LABEL DRUGS: REIMBURSEMENT POLICIES CONSTRAIN PHYSICIANS IN THEIR CHOICE OF CANCER THERAPIES, GAO/PEMD-91- 14 at 11 (1991)

132 Christopher, William L. “Off-Label Drug Prescription: Filling the Regulatory Vacuum,” 48 Food & Drug Law Journal 247, Food and Drug Law Institute (1993).

133 Information is based on fifty anonymous interviews with subscribers to Mr. Stewart’s Cheshire Foxhounds (Unionville, PA), the Radnor Hunt (Malvern, PA), and former members of the Brandywine Hunt (West Chester, PA), which dissolved in 2004.

134 Information is based on anonymous fifty interviews with subscribers to Mr. Stewart’s Cheshire Foxhounds (Unionville, PA), the Radnor Hunt (Malvern, PA), and former members of the Brandywine Hunt (West Chester, PA), which dissolved in 2004.

[135] Phenothiazine is a pesticide and industrial chemical used in pharmaceutical manufacturing. It was introduced by DuPont as an insecticide in 1935. It is now most commonly used as an intermediate chemical in the manufacture of various psychiatric drugs. The word "phenothiazines" is used to describe the largest of the five main classes of antipsychotic drugs. Although these drugs are generally effective, there are often serious side effects including tardive dyskinesia and sedation (especially in the early stages of treatment). Wikipedia Contributors, Wikopedia, the Free Encyclopedia, Page Version ID: 50195723 http://en.wikipedia.org/wiki/Phenothiazine (April 22, 2006).

[136] Tranquilizer used to treat psychotic conditions when a calming effect is desired. http://www.thefreedictionary.com/neuroleptic (April 22, 2005).

[137] Dr. Barbara Forney, VMD. “Acepromazine Maleate For Veterinary Use” http://www.medi-vet.com/detail.aspx~ID~2152 (April 24, 2005).

[138] Dr. Barbara Forney, VMD. “Acepromazine Maleate For Veterinary Use” http://www.medi-vet.com/detail.aspx~ID~2152 (April 24, 2005).

139 Dr. Barbara Forney, VMD. “Acepromazine Maleate For Veterinary Use” http://www.medi-vet.com/detail.aspx~ID~2152 (April 24, 2005).

[140] Inhibiting or blocking the action of acetylcholine at a receptor site. http://www.thefreedictionary.com/cholinergic (April 22, 2005).

[141] A drug that prevents or alleviates nausea and vomiting. http://www.thefreedictionary.com/antiemetic (April 22, 2005).

142 A drug used to relieve or prevent spasms (especially of the smooth muscles). http://www.thefreedictionary.com/antispasmodic (April 22, 2005).

143 Of, relating to, or being an alpha-receptor. http://www.thefreedictionary.com/alpha-receptor (April 22, 2005).

[144] Relating to the nerves and muscles that cause the blood vessels to constrict or dilate. http://www.thefreedictionary.com/vasomotor (April 22, 2005).

145 Dr. Barbara Forney, VMD. “Acepromazine Maleate For Veterinary Use” http://www.medi-vet.com/detail.aspx~ID~2152 (April 24, 2005).

[146] Dr. Barbara Forney, VMD. “Acepromazine Maleate For Veterinary Use” http://www.medi-vet.com/detail.aspx~ID~2152 (April 24, 2005).

[147] Dr. Barbara Forney, VMD. “Acepromazine Maleate For Veterinary Use” http://www.medi-vet.com/detail.aspx~ID~2152 (April 24, 2005).

[148] Dr. Barbara Forney, VMD. “Acepromazine Maleate For Veterinary Use” http://www.medi-vet.com/detail.aspx~ID~2152 (April 24, 2005).

149 Slowness of the heart rate, usually fewer than 60 beats per minute in an adult human. http://www.thefreedictionary.com/bradycardia (April 24, 2005).

150 Dr. Barbara Forney, VMD. “Acepromazine Maleate For Veterinary Use” http://www.medi-vet.com/detail.aspx~ID~2152 (April 24, 2005).

[151] The percentage by volume of packed red blood cells in a given sample of blood after centrifugation. http://www.thefreedictionary.com/hematocrit (April 24, 2005).

152 Dr. Barbara Forney, VMD. “Acepromazine Maleate For Veterinary Use” http://www.medi-vet.com/detail.aspx~ID~2152 (April 24, 2005).

153 Dr. Barbara Forney, VMD. “Acepromazine Maleate For Veterinary Use” http://www.medi-vet.com/detail.aspx~ID~2152 (April 24, 2005).

154 Dr. Barbara Forney, VMD. “Acepromazine Maleate For Veterinary Use” http://www.medi-vet.com/detail.aspx~ID~2152 (April 24, 2005).

155 Dr. Barbara Forney, VMD. “Acepromazine Maleate For Veterinary Use” http://www.medi-vet.com/detail.aspx~ID~2152 (April 24, 2005).

156 Dr. Barbara Forney, VMD. “Acepromazine Maleate For Veterinary Use” http://www.medi-vet.com/detail.aspx~ID~2152 (April 24, 2005).

[ ]
157Charlotte M. Newell, DVM. “Vet Rap A-E : ACE [Acepromazine Maleate]” http://www.horse-country.com/vet/newell.html#ace

158 Horseproducts.stablemate.com Author. “Acepromazine Maleate” http://horseproducts.stablemade.com/_Articles/ace.htm (December 15, 2005).

159 Horseproducts.stablemate.com Author. “Acepromazine Maleate” http://horseproducts.stablemade.com/_Articles/ace.htm (December 15, 2005).

[160] Horseproducts.stablemate.com Author. “Acepromazine Maleate” http://horseproducts.stablemade.com/_Articles/ace.htm (December 15, 2005).

161 Horseproducts.stablemate.com Author. “Acepromazine Maleate” http://horseproducts.stablemade.com/_Articles/ace.htm (December 15, 2005).

162 Horseproducts.stablemate.com Author. “Acepromazine Maleate” http://horseproducts.stablemade.com/_Articles/ace.htm (December 15, 2005).

[163] Horseproducts.stablemate.com Author. “Acepromazine Maleate” http://horseproducts.stablemade.com/_Articles/ace.htm (December 15, 2005).

[164] Horseproducts.stablemate.com Author. “Acepromazine Maleate” http://horseproducts.stablemade.com/_Articles/ace.htm (December 15, 2005).

165 Horseproducts.stablemate.com Author. “Acepromazine Maleate” http://horseproducts.stablemade.com/_Articles/ace.htm (December 15, 2005).

[166] Loss of the ability to coordinate muscular movement. http://www.thefreedictionary.com/ataxic (December 16, 2005).

[167] Horseproducts.stablemate.com Author. “Acepromazine Maleate” http://horseproducts.stablemade.com/_Articles/ace.htm (December 15, 2005).

[168] Medi-vet.com Author. http://www.medivet.com/detail.aspx~ID~2152 (April 21, 2006).

169 In adult male horses, Acepromazine Maleate normally causes relaxation of the retractor penis muscle. This results in the penis being relaxed and dropped out other sheath. Very occasional cases have been reported where an irreversible paralysis of the retractor penis muscle has occurred, although this is more common with at least one other phenothiazine tranquilizer. This risk should be considered before giving acepromazine to an intact male horse. When used, minimum dosage recommendations should be followed. http://horseproducts.stablemade.com/_Articles/ace.htm (April 29, 2006).

170 Anonymous Interview #28. Interview on file with author. Conducted on February 4, 2005 in Unionville, PA.

171 Anonymous Interview #24. Interview on file with author. Conducted on February 3, 2005 in Unionville, PA.

172 Anonymous Interview #8. Interview on file with author. Conducted on February 6, 2005 in Unionville, PA.

173 Anonymous Interview #10. Interview on file with author. Conducted on February 6, 2005 in Unionville, PA.

[174] Anonymous Interview #33. Interview on file with author. Conducted on January 29, 2005 in Unionville, PA.

175 Anonymous Interview #31. Interview on file with author. Conducted on February 4, 2005 in Unionville, PA.

176 Information is based on anonymous fifty interviews with subscribers to Mr. Stewart’s Cheshire Foxhounds (Unionville, PA), the Radnor Hunt (Malvern, PA), and former members of the Brandywine Hunt (West Chester, PA), which dissolved in 2004.

[177] Anonymous Interview #1. Interview on file with author. Conducted on February 2, 2005 in Unionville, PA.

178 Anonymous Interview #11. Interview on file with author. Conducted on February 2, 2005 in Unionville, PA.

179 Anonymous Interview #47. Interview on file with author. Conducted on February 2, 2005 in Unionville, PA.

180 Anonymous Interview #47. Interview on file with author. Conducted on February 2, 2005 in Unionville, PA.

181 Anonymous Interview #43. Interview on file with author. Conducted on February 5, 2005 in Unionville, PA.

[182] Anonymous Interview #47. Interview on file with author. Conducted on February 2, 2005 in Unionville, PA.

183 Anonymous Interview #36. Interview on file with author. Conducted on February 2, 2005 in Unionville, PA.

[184] Information is based on anonymous fifty interviews with subscribers to Mr. Stewart’s Cheshire Foxhounds (Unionville, PA), the Radnor Hunt (Malvern, PA), and former members of the Brandywine Hunt (West Chester, PA), which dissolved in 2004.

185 In 1964 the large-animal clinic opened at New Bolton Center, a farm in Chester County that the University acquired in 1952. The Widener Hospital at New Bolton Center has more than 70 buildings and 141 stalls for patients. Each year the George D. Widener Hospital for Large Animals sees more than 6,000 patient visits, and the Field Service sees more than 19,000 animals. Penn boasts one of the largest equine surgical faculties in the world. Many members of Penn's surgical faculty are known internationally in their fields. Because of these credentials, New Bolton Center enjoys a large and varied caseload. Because of its location, it treats valuable horses that engage in all kinds of athletic activities. http://www.vet.upenn.edu/nbc/ (March 14, 2005)

[186] Dr. Ray Sweeney, VMD. Interview on File with Author. Conducted on February 2, 2005 in Unionville, PA.

[187] Dr. Mark Donaldson, VMD. Interview on File with Author. Conducted on February 7, 2005 in Unionville, PA.

[188] Dr. Mark Donaldson, VMD. Interview on File with Author. Conducted on February 7, 2005 in Unionville, PA.

189 Dr. Ray Sweeney, VMD. Interview on File with Author. Conducted on February 2, 2005 in Unionville, PA.

190 Dr. Ray Sweeney, VMD. Interview on File with Author. Conducted on February 2, 2005 in Unionville, PA.

191 A ferrier is a person who comes and puts horseshoes on horses (a blacksmith).

[192] Dr. Ray Sweeney, VMD. Interview on File with Author. Conducted on February 2, 2005 in Unionville, PA.

[193] Dr. Ray Sweeney, VMD. Interview on File with Author. Conducted on February 2, 2005 in Unionville, PA.

194 Dr. Mark Donaldson, VMD. Interview on File with Author. Conducted on February 7, 2005 in Unionville, PA.

195 Dr. Mark Donaldson, VMD. Interview on File with Author. Conducted on February 7, 2005 in Unionville, PA.

[196] American Veterinary Medicine Association Webpage. http://www.avma.org/issues/policy/prescription_drugs.asp . May 1, 2006.

197 Prescription on PromAce Box #1.

198 Prescription on PromAce Box #2.

[199] 140 Congressional Record, 103rd Congress, 2nd Session – December 1994. CIS-NO: 94-PL103-396.