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The Military’s Need For “Speed”:

A Case Study On The FDA’s Regulation Of Off-Label Prescriptions

Matthew A. Hoffman

Class of 2003

April 2003

This paper is submitted in satisfaction of both the course requirement and the third-year written work requirement.



This paper is a case study in the legality and ethics of prescribing amphetamines (“go-pills”) to military aviators for fatigue management, a practice that has not been approved by the Food and Drug Administration (FDA). Currently, the FDA has very little authority to regulate this type of “off-label” prescription and would have to adopt its “Proposed Regulation on Prescribing for Uses Unapproved by the FDA” to have any chance of controlling the use of “go-pills” in the military. In the alternative, the agency could only regulate the drug indirectly through total withdrawal or limited distribution. However, many off-label prescriptions improve the practice of medicine and these alternative approaches would deny patients use of the drug for those indications that have been approved by the FDA. Therefore, this paper proposes an FDA “disapproval process” for those off-label prescriptions that are an imminent danger to public health.


On the night of April 17, 2002, fifteen Canadian soldiers were practicing anti-tank attacks on what had once been an al-Qaeda training camp near Kandahar in Afghanistan.[1] Two Illinois Air National Guard F-16 pilots, Maj. Harry Schmidt and Maj. William Umbach, saw flashes on the ground and reported surface-to-air fire to flight controllers.[2] Schmidt rolled in on the target and dropped a bomb that killed four Canadian soldiers and wounded eight others.[3] Initially, the military stated that the two pilots would be charged with involuntary manslaughter, aggravated assault and dereliction of duty, and if Umbach and Schmidt were convicted, they could have faced up to 64 years in prison.[4]

Although the military recently stated that they will not initiate court-martial proceedings, this friendly-fire incident has focused attention on the United States military's long-held but little-known practice of using amphetamines, or “go-pills,” to help its aviators fight fatigue. Schmidt and Umbach were in the sixth hour of a 14-hour mission when the accident occurred and each had taken a dose of Dexedrine, a military-prescribed amphetamine, prior to the flight.[5] While the FDA has approved Dexedrine as a prescription drug, the prescribing of Dexedrine for fatigue management is an “off-label prescription” that varies from the FDA-approved uses indicated on the drug’s label.[6] Defense lawyers for the pilots stated that the men had felt compelled to take the amphetamine or be scrubbed from their mission, and that the drug may have clouded their judgment.[7]

Many in the U.S. military consider amphetamines useful tools that help prevent fatigue-related accidents.[8] Due to the recent cutbacks in the number of military personnel and equipment, the military, particularly the Air Force, must order its pilots to fly longer missions from fewer overseas bases. Additionally, the modern American military likes to fight at night, given its technological superiority in finding targets and avoiding detection in the dark. These realities of modern warfare have only increased concerns about fatigue. Currently, military scientists are researching even more potent pills to fight fatigue, including some that may keep combat forces alert for 40 hours or more.[9]

Whether or not amphetamines actually contributed to the friendly-fire incident in Afghanistan, the prescribing of amphetamines to military personnel raises some significant statutory, regulatory and ethical questions. This paper focuses on the legality and ethics of prescribing amphetamines to military aviators for fatigue management under the Federal Food, Drug & Cosmetic Act (“FDCA”) and the Comprehensive Drug Abuse Prevention and Control Act of 1970 (“Controlled Substances Act” or “CSA”). This paper also critiques the practice of off-label prescriptions, in order to provide an assessment of the present military policy and recommendations for future regulatory initiatives.

Specifically, Part III provides a background on amphetamines and a brief history of their use in the military. Part IV analyzes whether military prescriptions of amphetamines are “valid” prescriptions under the FDCA and Controlled Substances Act, including whether military physicians have a legitimate scope of expertise and a legitimate medical purpose, as well as whether a genuine physician-patient relationship exists. Part V explores the background of off-label prescriptions, the FDA’s authority to regulate off-label prescriptions and the arguments both for and against off-label prescriptions in light of the recent controversy surrounding amphetamine use in the military. Part VI discusses the ethical considerations surrounding the prescription and use of amphetamines in the military. Finally, Part VII presents a proposal for regulating off-label prescriptions, including military prescriptions of amphetamines for fatigue management.


A. Background on Amphetamines and Their Effects

Amphetamines are members of a family of synthetic drugs that are similar in chemical structure to adrenalin.[10]  Amphetamines enhance the release of naturally occurring neurotransmitters that affect central nervous system neurons, such as the brain, and neurotransmitters that are involved with peripheral neurotransmission, such as nervous control of muscular contractions.[11] Amphetamines were first synthesized in 1887 and became commercially available in America for clinical use in 1937 and since then have become widely prescribed.[12] Amphetamines were first introduced into clinical medicine as inhalants to reduce nasal congestion and to treat narcolepsy.[13] They were subsequently used as an antidote to fatigue, and rapidly found favor as a treatment for a number of other conditions, including obesity and depression.[14] Amphetamine usage also occasionally reduces hyperactivity in children and improves some types of Parkinson’s disease.[15] Some studies conducted over the last forty years suggest that low doses of amphetamines do not affect alertness, reaction time or decision-making ability in well-rested people.[16] However, the drugs have been shown to improve the mental performance of people who are fatigued.[17]

The major disadvantage in the use of amphetamines lies in their addictive property, which was first reported in 1938[18] and provides a high potential for abuse. Though such a risk would suggest limited usage, amphetamines are still widely prescribed by physicians, often without adequate diagnoses, proper testing, or appropriate precautionary measures.[19] These drugs can also cause a variety of side effects, such as anxiety, paranoia, dizziness and heart problems.[20] Large doses of amphetamines create mood-altering effects, which may explain why amphetamines became a drug of choice to abuse in the 1960s and 1970s.[21] Amphetamines have been extensively abused and can create an extreme psychological dependence.[22] These undesirable traits have led to the strict government control of amphetamines as controlled substances.[23]

B. History of Military-Use of Amphetamines

The use of amphetamines to maintain performance in soldiers and aviators is not a new idea. The first reported military use of amphetamines was by German, Japanese and British soldiers during World War II to combat fatigue and boredom.[24] Although American troops reportedly did not have access to amphetamines during World War II, scientists began studies in the late 1940s and 1950s to determine the military significance of the drug.[25]  In numerous studies using normal, nonfatigued human volunteers, including some military personnel, amphetamines improved performance by about 5 percent on most mental tasks.[26]  Reaction time and hand-eye coordination were significantly improved and amphetamine administration restored the mental performance of sleep-deprived subjects to nondeprived levels.[27] Additionally, studies found amphetamines improved physical strength and endurance.[28]

The U.S. military gave amphetamines to pilots on trans-ocean missions in the 1950s and 1960s[29] and possibly made them available during the Korean conflict.[30] In 1960, the U.S. Air Force officially sanctioned the use of amphetamines as Strategic Air Command (SAC) approved limited use of the drug.[31] Tactical Air Command (TAC) followed in 1962.[32] During the Korean War era, the earliest intravenous use of amphetamines by United States military personnel was reported.[33] During the Vietnam War, the U.S. military made amphetamines available to aviators to fight fatigue and their use was widespread.[34] Air Force and Army pilots who used amphetamines during Vietnam noted an increased alertness during flight operations, but described side effects including feelings of nervousness, loss of appetite, and inability to sleep.[35]  A Cobra gunship pilot in Vietnam reported that “uppers” were available like candy, with essentially no control over the dose or frequency of use.[36]  

From Vietnam through Desert Storm, the Air Force has intermittently used amphetamines in selected aircraft for specific missions.[37] TAC authorized the use of amphetamines to single-seat pilots during deployments overseas and during extended combat air patrols to counter the effects of boredom and fatigue.[38] While the Navy did not use amphetamines to fight fatigue, dextroamphetamine (Dexedrine) was administered frequently in combination with scopolamine during this period to combat motion sickness during primary Navy flight training.[39]

Many U.S. Air Force pilots used Dexedrine frequently during Operation Desert Storm. While the effect of amphetamine use on safety is uncertain because of a lack of applicable data, aeromedical after-action reports of Desert Storm attempted to quantify amphetamine use.[40] Data from an anonymous survey of fighter pilots found that, of the 464 pilots who responded, 65 percent of them used Dexedrine during the deployment to the Gulf region, and 57 percent used it at some time during the air war (17 percent routinely, 58 percent occasionally, 25 percent only once).[41] Within individual squadrons, usage of the drug varied from 3 percent to 96 percent, with higher usage in squadrons tasked for sustained combat air patrol (CAP) missions.[42] No one reported adverse side effects in the aeromedical after-action reports and pilots reported that 5 mgs of Dexedrine helped maintain their vigilance without causing other changes in mood or perception.[43] However, there were some reports during Desert Storm of American pilots using more medication than the flight surgeons thought were needed,[44] with some pilots becoming psychologically addicted to amphetamines.[45] Of the major accidents occurring during Desert Shield/Desert Storm, several were partially attributed to pilot fatigue, but no pilots were reported as using amphetamines at the time of any accident.[46]

In March 1991, following successful completion of Desert Storm, the Air Force Chief of Staff, Gen. Merrill A. McPeak, terminated the policy of prescribing amphetamines to pilots.[47] McPeak said his decision to ban go-pills was prompted by personal experience, and not based on any formal research.[48] The current Air Force Chief of Staff, Gen. John Jumper, reauthorized the prescriptions of amphetamines in 1996, when he was head of the Air Force operations in the Pentagon.[49] According to Air Force officials, amphetamines have never been shown to cause a flight mishap.[50] Current policy allows a flight surgeon to dispense amphetamines on sorties over 8 hours in a single-pilot fighter or 12 hours in a two-pilot bomber.[51]


Before considering whether the prescription of amphetamines for fatigue management is a legitimate practice, it is important to consider whether the actual act of distributing amphetamines to military pilots meets the various legal definitions of “prescription.” Both the FDCA and Controlled Substances Act require more than just a doctor’s signature on a piece of paper for a prescription to be valid.

A. FDCA “Prescriptions”

According to section 353(b)(1) of the FDCA:

A drug intended for use by man which . . . [b]ecause of its toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use, is not safe for use except under the supervision of a practitioner licensed by law to administer such a drug; . . . shall be dispensed only (i) upon a written prescription of a practitioner licensed by law to administer such drug, or (ii) upon an oral prescription of such practitioner which is reduced promptly to writing and filed by the pharmacist, or (iii) by refilling any such written or oral prescription if such refilling is authorized by the prescriber either in the original prescription or by oral order which is reduced promptly to writing and filed by the pharmacist.[52]

The statute basically provides that amphetamines such as Dexedrine can only be dispensed with a written prescription by a licensed physician and the legality of the distribution depends upon whether the activity meets the definition of “prescription.” While the FDCA itself is fairly silent on what this definition entails, various courts have relied on standard medical definitions to determine what “prescription” means under the FDCA. As quoted in a Fifth Circuit case, a pharmacology textbook from around the time when FDCA section 353(b)(1) was enacted provides the following definition of prescription:

A prescription, by strict definition, is a physician’s written order to a pharmacist for medicinal substances for a patient. It includes directions to the pharmacist regarding the preparation and to the patient regarding the use of the medicine. In reality, however, a prescription is infinitively more than can be simply defined. It is a summary of the physician’s diagnosis, prognosis, and treatment of the patient’s illness. It brings to a focus on one slip of paper the diagnostic acumen and therapeutic proficiency of the physician. The prescription is an important practical phase in the application of pharmacology to clinical medicine, and combines the knowledge of the absorption, fate, excretion, action, toxicology, and dosage of drugs with the requirements for restoration of the patient’s health.[53]

Another court stated that the word prescription in section 353(b)(1) means “directions for the preparation and administration of a medicine, remedy, or drug for a real patient who actually needs it after some sort of examination or consultation by a licensed doctor.”[54]

These court definitions of “prescription” capture two important requirements in order to satisfy the provisions of the FDCA. First, a prescription must fall within the legitimate scope of the prescriber’s expertise and area of practice.[55] Second, a genuine physician-patient relationship needs to exist for a prescription to be valid.[56] These requirements will now be examined in turn.

1. Legitimate Scope of Expertise

A prescription is not valid unless the physician has sufficient expertise and the prescription is related to his or her area of practice. Under this test, it is likely that military flight doctors are well within their expertise and area of practice to prescribe amphetamines for fatigue. Flight doctors are experts on the physiology of aviators and how long missions affect the minds and bodies of military aviators. Flight doctors prescribing amphetamines is not akin to, for example, a dentist prescribing contraceptives.[57] While it can be argued that fatigue is not an “illness,” and thus prescribing drugs to combat fatigue is not a legitimate medical practice, the fact that amphetamines have been used to treat fatigue since they were first introduced into clinical medicine provides evidence to the contrary.[58] Prescribing amphetamines to manage fatigue is assuredly an “off-label” prescription (discussed further in Section V), but does not seem to violate the condition that a prescription must fall within the legitimate scope of the prescriber’s expertise and area of practice.

2. Physician-Patient Relationship

Even if a physician prescribes a drug that is within his or her legitimate scope of expertise, if that physician writes a prescription for a person for whom no physician-patient relationship exists, then the prescription is not valid and the physician has issued misbranded articles within the meaning of the FDCA.[59] The physician can be criminally prosecuted for such a violation of the Act and there are numerous examples where the FDA has had the U.S. Justice Department prosecute such a doctor.[60] In one such case, Brown v. United States , a practicing physician in Texas sold three separate lots of dextroamphetamine hydrochloride tablets, which had been shipped in interstate commerce, to two federal agents, whom he thought to be truck drivers.[61] The Fifth Circuit Court of Appeals found that the physician had violated the provisions of the FDCA that prohibits the dispensing of certain potentially harmful drugs, transported in interstate commerce without a prescription.[62] In reaching this conclusion, the court stressed not only that the doctor had not prepared or given the agents a piece of paper indicating a prescription, but had not physically examined either of them and had not attempted to familiarize himself with either the physical condition or needs of either man.[63] The court stated that “[t]he inquiry whether there was a bona fide relationship of patient and doctor bears on the question whether there had ever been a ‘prescription’ for the agents.”[64]

In DeFreese v. United States , a licensed physician and his wife owned and operated a restaurant on a route well traveled by truck drivers.[65] The couple distributed large amounts of amphetamines to a food and drug inspector posing as a truck driver.[66] Again, the Fifth Circuit Court of Appeals stated that a doctor who prescribes, dispenses or administers drugs without a valid physician-patient relationship violates the FDCA.[67] Since the doctor never made any attempt to examine the inspector, determine his complaints, or ask him any questions about his medical history, no physician-patient relationship existed and the doctor was convicted of violating the FDCA.[68]

The genuine physician-patient relationship requirement may also require some sort of good faith supervision. In construing the language of FDCA section 353(b)(1), the federal district court in United States v. Nazir held that the statute required a prescription because certain drugs are not safe for use except under the supervision of a licensed physician and that “[s]upervision entails some sort of active (and good-faith) participation by a physician in his professional capacity.”[69] In this case, the doctor was convicted for unlawfully delivering prescription drugs to individuals without the benefit of medical consultations or examinations.[70]

Applying these cases to the prescription of Dexedrine to military pilots, the preponderance of the evidence seems to indicate that a genuine physician-patient relationship probably exists between the flight doctors who dispense go-pills and the pilots who take them. Unlike Brown and DeFreese , where the drugs were dispensed to total strangers, flight doctors have initial medical screenings of pilots in their command and have some knowledge of their medical history. Additionally, the doctors in Brown and DeFreese distributed vast quantities of amphetamines in order to make a profit,[71] whereas flight doctors dispense small amounts of Dexedrine under the specific guidance of their commanding officers. According to a spokeswoman for the Air Force surgeon general, pilots are also tested for their reaction to go-pills before they are permitted to take them on a flight mission.[72] Likewise, the Navy pretests aviators with Dexedrine prior to operational use to allow the aviators to familiarize themselves with the medication and to discover any problematic side effects.[73]

However, there is some uncertainty as to how much “supervision” accompanies the actual distribution and use of Dexedrine tablets. Instead of flight doctors periodically examining the pilots and providing specific directions for the use of the pills, pilots can simply sign up on a clipboard for six go-pills at a time and are told to use them as needed.[74] Additionally, the comments of a commanding officer of an F-15 squadron that used Dexedrine during Desert Storm indicate that flight doctors may not have adequate control of the drug. The officer’s comments on supervision of the aircrew included the statement that “you must give them guidelines and then let them self-regulate. If you can’t trust them with the medication then you can’t trust them with a 50 million dollar airplane to try and go kill someone.” [75]

Nonetheless, unlike Nazir where the doctor made no attempt to gather any medical information on the subject, the prescribing of amphetamines in the military to fight fatigue is based on medical research and at the very least, an initial testing of the pilot to gauge reaction to the drug. In contrast to the doctors in Brown , DeFreese and Nazir , it would likely be very hard to prove a lack of “good faith” by flight doctors in their administration of amphetamines. Additionally, courts have consistently shown substantial deference to military decision makers when issues of national security are at stake.[76] Thus, regardless of the actual level of physician-patient relationship that exists between flight doctors and pilots, it is very unlikely that the FDA and Justice Department would prosecute military physicians under an “illegal prescription” theory.

B. Controlled Substances Act

Unlike the FDCA, the Controlled Substances Act (CSA) provides more detailed language describing what constitutes a valid prescription of controlled substances and provides a wider variety of possible remedies for violations of the Act. The CSA[77] is a companion law to the FDCA that also regulates dangerous human drugs and deals with physicians’ authority to purchase, store, research, prescribe, dispense and distribute those drugs that have a high potential for abuse.[78] These “controlled substances” are divided into five schedules based on their safety, accepted medical uses, and potential for abuse.[79] Under the CSA, amphetamines such as Dexedrine are designated as “Schedule II substances,” meaning they have a high potential for abuse, have a currently accepted medical use, and may lead to severe psychological or physical dependence.[80] 21 U.S.C. §841(a) makes it unlawful for any person to knowingly or intentionally manufacture, distribute, or dispense a controlled substance except as authorized by its subchapter.[81] 21 U.S.C. §829(a) & (b) exempts from section 841(a)(1) the dispensing of a drug by a written prescription of a practitioner.[82] Additionally, every person who dispenses any controlled substance must obtain a registration to do so from the Attorney General.[83]

Like the FDCA, the Controlled Substances Act places limits on what constitutes a valid prescription and provides criminal penalties for those that violate the Act. The CSA and its regulations make it unlawful for a physician to distribute a controlled substance if the prescription is not for a legitimate medical reason and not written in the usual course of the physician’s practice.[84] Specifically, 21 C.F.R. §1306.04(a) provides: “A prescription for a controlled substance to be effective must be issued for a legitimate medical purpose by an individual practitioner acting in the usual course of his professional practice . . . .” [85] Thus, a prescription written by a doctor for an illegitimate medical purpose could be criminally prosecuted under §841(a)(1).

1. Legitimate Medical Purpose

A physician who dispensed controlled drugs without the intent of treating a medically diagnosed illness or disorder would be violating the statute.[86] In United States v. Moore , a physician registered under the CSA was convicted of knowing and unlawful distribution of methadone.[87] The Court held that the doctor exceeded the bounds of professional practice because he gave no physical examinations, ignored results of tests he did make, did not give methadone at clinic and took no precautions against its misuse and diversion, and did not regulate dosage at all, prescribing as much and as frequently as patients demanded.[88] Other courts have found a “good faith” requirement in the CSA similar to the one for the FDCA, where a doctor is only exempt from the CSA when he takes actions that he in good faith believes are for legitimate medical purposes.[89]

Short of such extreme conduct as was exhibited in Moore , it is unlikely that the well-intentioned physician who prescribes improperly would ever be prosecuted under the CSA for pursuing an illegitimate medical purpose.[90] Unlike the physicians who have been successfully prosecuted under the CSA, flight doctors seem to be within the bounds of “professional practice” in administering amphetamines for fatigue management. Flight doctors conduct fairly routine physical examinations of pilots and regulate the dosage of Dexedrine given to pilots. The maximum 10 mg dose the Air Force currently permits its pilots to take is well below the 60 mg the Addiction Research Foundation said is at the top end of the “therapeutic range.”[91] Thus, as was the case with the FDCA, military physicians are probably exempt from the criminal provisions of the CSA because they distribute amphetamines in the good faith belief that fatigue management is a legitimate medical purpose.

2. Potential Remedies: Suspension or Revocation of Registration

While it is unlikely that military doctors will ever be prosecuted for prescribing amphetamines to pilots, the Controlled Substances Act provides an additional course of action that the FDCA does not. Under the CSA, it is possible to remove a schedule of drugs from the physician’s purchase, use, prescription and dispensing prerogatives without instituting further punishment.[92] Specifically, 21 U.S.C. §824(a) provides that a physician’s registration to manufacture, distribute, or dispense a controlled substance may be suspended or revoked by the Attorney General if the registrant has committed such acts as would render his registration inconsistent with the public interest.[93] In determining the public interest, section 823(b) of the CSA states that the following factors shall be considered:

(1) maintenance of effective control against diversion of particular controlled substances into other than legitimate medical, scientific, and industrial channels;

(2) compliance with applicable State and local law;

(3) prior conviction record of applicant under Federal or State laws relating to the manufacture, distribution, or dispensing of such substances;

(4) past experience in the distribution of controlled substances; and

(5) such other factors as may be relevant to and consistent with the public health and safety.[94]

Of these five factors, only the first and fifth factors are relevant to the issue of military prescriptions of amphetamines and there is little reliable evidence to indicate that the Dexedrine issued to military pilots has found its way outside of “legitimate medical channels” and into the hands of recreational users. However, other factors that may be relevant to public health and safety include (1) whether amphetamines do in fact impair pilots’ judgment in the air, (2) to what extent amphetamines are used in other areas of the military and (3) whether there is a potential for abuse within the military. If any of these factors have an adverse effect on public health or safety, the Attorney General would have grounds to suspend or revoke the military’s registration to prescribe Dexedrine.

The first factor to consider is the effect amphetamines have on pilots’ judgment and whether this results in a safety risk to the pilot and to third parties. While recent laboratory studies of Dexedrine’s effect on maintaining performance and alertness in fatigued military pilots have demonstrated clear benefits,[95] it is uncertain how amphetamines may affect a pilot’s judgment in real-life stressful situations. In three studies conducted in the 1990's, helicopter pilots were kept awake for 40 hours and asked to perform certain maneuvers – making left or right turns while maintaining a certain altitude, or ascending or descending while maintaining the same speed.[96] Two of the studies were done in flight simulators and the third was done in real flights.[97] In each case, when the pilots were given 10 milligrams of Dexedrine one hour before being tested, they performed better than when they were given a placebo.[98] However, some scientists question whether these controlled studies of amphetamines are enough to show how the drugs affect judgment in real life.[99]

Consequently, there is great uncertainty regarding whether the use of Dexedrine was a factor in the friendly-fire incident in Afghanistan. According to Dr. Jon Morgenstern, director of treatment research at the National Center on Addiction and Substance Abuse at Columbia University, “[t]hese pilots were in an incredibly stressful situation . . . [and] had fatigue and the need to make a split-second decision. I don't think you could rule out that the amphetamines would be a factor. They might have altered the pilots' perception enough to make them feel more threatened than they normally would have felt."[100] Other scientists outside the military who research the use of amphetamines say it is impossible to know whether Dexedrine affected the pilots' judgment without knowing how tired they were, how long they had been taking the drug, and how strongly their bodies responded to it.[101] Even if this information is brought to light in a court-martial proceeding, it may never be determined whether Dexedrine was a proximate cause of the accident.

The second factor to consider is the extent of amphetamine use in the military. Although the Air Force Surgeon General's office has acknowledged that amphetamines are used to combat pilots’ fatigue, it is not publicly known how widespread the practice is outside of the military aviation community. For example, the U.S. Special Operations Command, which oversees the elite special-operations troops that are part of all the military services, has produced a document that outlines "performance enhancements" designed to produce "iron bodied and iron willed personnel.”[102] While it is not known whether special-operations forces on the ground in Afghanistan are taking such drugs, combat veterans and military experts have hypothesized about their use.[103] More recently, concerns have been raised about aggression and violence among soldiers returning from Afghanistan. In three of four cases in which men killed their wives, the accused husbands were in special forces units based at Fort Bragg, North Carolina.[104] While it is purely speculative as whether these soldiers were using amphetamines or any other kind of performance drugs, it would be worth investigating as “this sort of hyper-aggressive behavior is just what one would associate with excessive use of such drugs or from withdrawal from using them.”[105]

A third factor to consider in determining whether amphetamine use in the military adversely affects the public health is the potential for abuse. According to military doctors, there is no evidence that aviators attempt to abuse amphetamine if the medication is only made available occasionally.[106] These doctors also claim that there is little similarity between the effects of high dosages or chronic amphetamine abuse among addicts and occasional, low-dose administration of the same drug to military pilots involved in extended operations.[107] This claim is based on three observations. First, “military aircrews are a well-screened, intelligent, motivated, and mentally healthy population” and “[a] remarkably low incidence of any sort of addictive behavior or other mental pathology occurs in this population.”[108]  While recreational drug use within the military has been increasing in general,[109] there has indeed been a low incidence of addiction among military aviators.[110] During Desert Storm, many pilots used more Dexedrine than the flight surgeon thought they needed at the time, but when their flight missions subsided, their behavior changed and use of the drug stopped.[111] The second reason military doctors believe there is a low probability of amphetamine abuse among pilots is that “the medication is administered on a case-by-case basis by a flight doctor working closely with the pilots and under the direction of the squadron commander.”[112]   The claim is that flight doctors would likely note unusual personality traits, increased drug-seeking behavior, weight loss, or any other indication of addiction on the part of the pilots.[113] However, flight surgeons will not have evaluated each pilot in terms of behavior during high-stress situations.[114]  In addition, anecdotal evidence from Desert Storm indicates that flight doctors may not exercise an optimal amount of supervision over the administration of Dexedrine.[115] Finally, military doctors say that the chances of amphetamine abuse are low, “because the source of the medication is a physician and military pharmacy [and thus] the pilot is not exposed to the drug counterculture that he or she would encounter by obtaining the drugs illegally.”[116] While this has not been definitively proven, this may help explain why the incidence of drug abuse among military aviators is fairly low.  

Based on the foregoing factors, there is still a lack of concrete evidence that prescribing amphetamines to military aviators is inconsistent with the public interest. Unless future studies demonstrate that Dexedrine negatively affects pilots’ judgment or has a high potential for abuse in the military, there are few grounds for the suspension or revocation of the military’s registration to distribute the drug under the CSA.


Unless the Attorney General revokes the military’s registration to distribute Dexedrine to its pilots, there is currently very little the FDA can do to prevent the practice of prescribing amphetamines for fatigue management once the drug has been FDA-approved for clinical use. The practice of prescribing drugs for indications not listed on the drug’s label, also known as “off-label” prescribing, has been subject to both support and criticism. This section explores the background of off-label prescriptions, the FDA’s authority to regulate off-label prescriptions and the arguments both for and against off-label prescriptions in light of the recent controversy surrounding amphetamine use in the military.

A. Background of Off-Label Prescriptions

To fully investigate the nature of off-label prescribing, it is important to understand the FDA’s drug approval process and how off-label practices fit within this framework. This Subpart will briefly examine the requirements for testing, labeling and advertising new drugs and provide a definition of “off-label” activities.

1. FDA Drug Approval Process

The FDCA provides that a new drug may not be sold in interstate commerce unless the FDA has approved the drug.[117] In order to obtain FDA approval, the sponsor of the drug must establish that the drug is safe and that there is substantial evidence that it is effective for the uses prescribed, recommended, or suggested in the proposed labeling.[118] “Substantial evidence” of effectiveness means evidence consisting of “adequate and well-controlled investigations,” including clinical investigations by experts qualified by scientific training and experience to evaluate the drug involved.[119] The studies must use formal controls to preserve the identity, strength, quality and purity of the observations.[120]

According to 21 C.F.R. §§310-314, FDA-approval requires both animal and human testing.[121] First, the drug’s sponsor must submit to the FDA a Notice of Claimed Investigational Exemption for a New Drug (IND) containing information from which the FDA can determine whether the drug appears reasonably safe and effective for human subjects.[122] This information must include the results of animal studies on the pharmacological and toxic effects of the drug.[123]

If human testing is then allowed, it is conducted in three phases. Phase one includes the initial introduction of an investigational new drug into humans to determine the drug’s safety and chemical effects.[124] These tests usually are conducted on 20-80 healthy volunteers. [125] During phase one, sufficient information about the drug's pharmacological effect should be obtained to permit the design of well-controlled, scientifically valid, phase two studies.[126] Phase two of human testing is directed at treatment or prevention of a specific disease and involves tests on about 200 patients with the specific disease.[127] During this phase, patients are closely monitored to learn more about the drug's safety and effectiveness, while animal testing is continued to obtain additional data on safety.[128] If the tests indicate that the drug may be useful in treating a specific disease and appears safe, then the sponsor may proceed to the third phase.[129] Phase three involves the most extensive testing, as the drug is tested on large numbers of ill humans to assess the safety, effectiveness, and most desirable dosage of the drug.[130] Typically, several hundred to several thousand patients with the specific disease are tested in this phase.[131]

All of the data from animal and human testing, including any information about health dangers posed by the drug, is submitted to the FDA in the form of a New Drug Application (NDA).[132] If the NDA is approved, the sponsor may then market the drug. However, the FDA will not approve the NDA unless the sponsor includes certain information in the label or package insert that is to accompany the drug.[133] The information required includes the uses for which the manufacturer provided data to establish the safety and efficacy of the drug, as well as possible health hazards associated with the drug.[134] The FDA will not approve an NDA if the labeling includes uses other than those for which the drug has been shown to be safe and effective in testing. [135] In order to approve new uses for a prescription drug, the manufacturer must submit a Supplemental New Drug Application to the FDA.[136] The manufacturer can only add a new use to the drug’s labeling if this supplemental application is approved . [137] Finally, if a label or package insert containing certain required information does not accompany the drug when it is shipped to a pharmacist or physician for dispensing, the drug will be considered “misbranded” and subject to withdrawal from the market.[138]

In summary, when the FDA determines a drug to be safe during its approval process, it makes a relative decision that the therapeutic benefit of the drug outweighs the risk that one of the adverse side effects may occur.[139] The risk/benefit decision for a drug is particularly complex because, among other reasons, the question of the drug’s benefit always depends on the intended use or uses of the drug.[140] Thus, if the FDA concludes that the drug is, on the whole, beneficial, the drug is considered “safe” only for the intended use or uses that are listed on the drug’s label.[141]

2. Defining “Off-Label” Activities

The term “off-label” comes by inference from the statutes and FDA regulations concerning drug approval and labeling.[142] These statutes and regulations are intended to ensure that prescription drugs and their promotional literature contain accurate and complete information regarding approved uses.[143] Today, prescription drug labels are primarily aimed at doctors, who serve as "learned intermediaries" between manufacturers and users of prescription drugs.[144 ] The final FDA-approved labeling not only forms the package insert that accompanies the drug, but also appears in the Physician’s Desk Reference.[145]

As previously discussed, the FDA approves a new drug for specific medical uses associated with the human and animal testing that supported the drug's application. Since the number of possible unapproved uses is infinite, it would be virtually impossible for the FDA to promulgate labeling requirements for all uses beyond those for which the drug was approved.[146] Accordingly, drug manufacturers are required to convey, in the drug's formal labeling, information regarding only those uses for which the drug was approved.[147] All other uses of a drug have come to be designated as "off-label" uses.[148] More specifically, an off-label prescription of a drug occurs when a doctor prescribes a drug in any manner that varies from the drug’s labeling specifications. [149] For example, prescribing an approved drug to treat a disease that is not indicated on its label, but is closely related to an indicated disease, or treating unrelated, unindicated diseases, are both considered off-label prescriptions.[150] Among the prescriptions that fail to conform to the drug’s labeling are prescriptions of drugs without regard to the special precautions listed on the label.[151]

B. FDA’s Authority to Regulate Off-Label Prescriptions

Currently, the FDA has very little authority to regulate a physician's drug-prescribing practices. Once a drug is marketed pursuant to the FDA license, the physician may not only prescribe the drug for the indications or uses for which it was approved, but may also prescribe the drug for any other use the physician deems fit.[152] When an unapproved use of a drug becomes widespread, or presents a danger to patients, the FDA has relatively limited options for resolving the issue. The FDA may only deprive a physician of a drug’s use by removing it from the market altogether or restricting the drug’s use to specific physicians or institutions.[153] Generally, the FDA cannot seek sanctions against a physician who prescribes off-label.[154]

1. The 1972 Proposed Rule and Its Impact

The inability of the FDA to regulate off-label prescriptions is largely attributable to the FDA’s own narrow interpretation of its statutory authority under section 355 of the FDCA.[155] In 1972, the FDA’s “Proposed Regulation on Prescribing for Uses Unapproved by the FDA” inferred that the FDA’s statutory authority extended to manufacturers of drugs, but not to the physicians who prescribe them.[156] The FDA concluded that section 355 of the FDCA permits an approved new drug to be shipped in interstate commerce with an approved package insert only if neither the shipper nor the recipient intends that it be used for a nonapproved purpose.[157] Thus, absent such intent, “once the new drug is in a local pharmacy, . . . the physician may, as part of the practice of medicine, lawfully prescribe a different dosage for his patient, or may otherwise vary the conditions of use from those approved in the package insert, without informing or obtaining the approval of the FDA.”[158]

The 1972 Proposed Rule was never adopted, [159] but the FDA reiterated its position that the FDCA allows physicians to prescribe drugs for unlabeled uses in an oft-cited drug bulletin ten years later. [160] The 1982 bulletin emphasized that the FDA condoned off-label use as “accepted medical practice,” and that FDA-approved labeling should be considered “informational only.[161] When the FDA overhauled its IND regulations in 1983, it reiterated the 1982 bulletin's policy that an IND must be filed only if the off-label use “significantly increases the risk associated with use of the drug.[162]

Courts have often cited the 1972 Proposed Rule and the 1982 bulletin in granting physicians broad and unconstrained prescribing autonomy and discretion.[163] In particular, two federal court of appeals cases suggest possible judicial responses to future FDA efforts to regulate off-label prescriptions if the 1972 Proposed Rule were adopted.[164] In United States v. Evers , the government attempted to prevent a physician from prescribing a drug approved as a treatment for lead poisoning to treat arteriosclerosis.[165] The case against Dr. Evers was based on FDCA section 301(k) , which prohibits misbranding of drugs.[166 ] The United States Court of Appeals for the Fifth Circuit held that the misbranding provision, which the government argued banned Dr. Evers’ off-label prescribing, applied only to information provided by manufacturers to physicians, not information provided by physicians to patients. [167] The court also rejected the government’s argument that Dr. Evers “labeled” the drug to the medical community at large through his public promotional and advertising efforts.[168]

Two years later, eight Texas death-row inmates sued the FDA for failing to enforce the 1972 Proposed Rule provision obligating action against unapproved use of a new drug that endangered patients or created a public health hazard.[169] The inmates had petitioned the FDA to block Texas' use of lethal doses of FDA-approved barbiturates and paralytics as capital punishment devices because the drugs' labels indicated no approval for such use. [170] The FDA asserted that it had no jurisdiction over the state-sanctioned use of lethal injections because it fell under the “practice of medicine” by the Texas prison system. [171] The United States Court of Appeals for the District of Columbia Circuit held that the FDA had jurisdiction to regulate use of the capital punishment drugs based on the FDCA's misbranding provisions, [172] and was required to enforce the 1972 Proposed Rule. [173] However, the Chaney court only limited the "practice of medicine" exception to not include executions,[174] leaving the bulk of the exception intact.[175 ] The United States Supreme Court reversed the appellate court on the issue of enforcement discretion, holding that the FDA's decision not to enforce the 1972 Proposed Rule was not subject to judicial review, but declined to address the FDA's power to regulate off-label prescriptions.[176]

Evers and Chaney demonstrate judicial deference to the view that the FDA cannot regulate off-label prescriptions.[177] Dr. Evers, who prescribed off-label to his patients but did not promote or advertise off-label uses to other physicians, was held not to have violated the FDCA. [178] The Chaney court, meanwhile, ordered regulation of off-label use, but only on facts that did not involve the practice of medicine. [179]

Despite the FDA’s and judiciary’s interpretation of section 355, David A. Kessler, prior to his tenure as Commissioner of the FDA, claimed that the legislative history of the 1962 Drug Amendments in fact indicates that the FDA has some authority to regulate off-label prescriptions.[180] According to Kessler, Congress considered the problem of nonapproved drug uses in relation to the manufacturer at the time of the 1962 Amendments.[181] Senator Kefauver expressed concern over the situation in which a drug approved initially for certain illnesses or conditions is subsequently marketed for new indications that have not been approved by the FDA.[182] He was particularly concerned that such action would only violate the FDCA’s misbranding section and the FDA’s enforcement remedies would be limited.[183] Kessler asserted that the Senate report indicates that the members of the Judiciary Committee did not share Senator Kefauver’s interpretation.[184] Instead, the Judiciary Committee interpreted section 355(d) of the FDCA to mean that “it is the use claimed for a drug that determines whether or not it is a new drug and that a new drug is limited to the particular use or uses presented in the application . . . .”[185] The Committee members further cited an FDA regulation that asserted that new drug status could arise by reason of “the newness of use of such drug in diagnosing, curing, mitigating, treating, or preventing a disease, or to affect a structure or function of the body, even though such drug is not a new drug when used in another disease or to affect another structure or function of the body.”[186]

Thus, Kessler maintained that this legislative history casts some doubt on the conclusion that the FDA has no authority to regulate nonapproved uses.[187] The Senate report suggests that the FDA may control the manufacturers’ practice of promoting nonapproved drug uses through section 355 of the FDCA.[188] More significantly, although the report only discusses the problem in relation to manufacturers, the reasoning that a new use of an approved drug constitutes a “new drug” could be equally applicable to the problem of off-label prescriptions by physicians.[189] Kessler’s interpretation would allow the FDA to argue that if a physician wants to avoid a violation of section 355(a), each new indication for a drug that is prescribed requires an NDA.[190] Although the Senate report to the 1962 Amendments is not conclusive, the FDA could also argue that they must be empowered to regulate off-label prescriptions in order to achieve the congressional intent to protect the public health.[191]

While Kessler’s argument is certainly appealing in many respects, the legislative history of the FDCA and the 1962 Drug Amendments indicates a desire to avoid any interference in the practice of medicine. The sponsor of the 1938 FDCA, in response to the concerns of the medical community that the Act would interfere with the “prerogatives of the doctor,” remarked that the bill “makes certain that the medical practitioner shall not be interfered with in his practice.”[192] During discussions of the 1962 Drug Amendments, the following statement was made: “[T]he . . . [FDCA] should not interfere with the professional function of the physician. FDA clearance would assure physicians that a drug effectively produces certain physiological actions, but the physician, not the FDA, would determine whether these specific physiological effects would be useful or beneficial with respect to particular patients.”[193]

Additionally, both the FDA and the courts have come to the conclusion that Congress in fact intended to allow physicians to prescribe off-label if necessary. Contrary to Kessler’s reading of the legislative history of the 1962 Drug Amendments, the FDA believes that the legislative history of the FDCA and the drug amendments supports the right of a physician to prescribe off-label.[194] Specifically, the FDA stated in its 1972 Proposed Regulation that “[t]hroughout the debate leading to enactment, there were repeated statements that Congress did not intend the [FDA] to interfere with medical practice and references to the understanding that the bill did not purport to regulate the practice of medicine as between the physician and the patient.”[195] The courts, relying on the legislative history of the FDCA, have also uniformly recognized patients’ rights to receive medical care in accordance with their licensed physician’s best judgment and physicians’ rights to administer drugs as they see fit.[196] Thus, both the FDA and the judiciary believe that Congress implicitly authorized off-label prescriptions as an accepted medical practice, which are not subject to FDA’s direct regulation.[197]

Due to this apparent regulatory vacuum, physicians can currently prescribe drugs for nonapproved uses with relative impunity.[198] Information on new off-label prescriptions often spread through reports in the medical literature and through discussions by physicians at medical meetings.[199] As a result, some nonapproved uses become widespread among physicians long before the FDA approves the use, while other nonapproved uses become widespread without the FDA ever approving the use at all.[200]

2. FDA’s Authority to Regulate “Go-Pills” Under the 1972 Proposed Rule

If the FDA ever adopted the 1972 Proposed Rule, it may be able to regulate the military’s prescribing of Dexedrine. The 1972 Proposed Rule asserted that the FDA’s jurisdiction would extend to the interstate shipment of drugs that were ordered or shipped with the intention that the drugs be prescribed for nonapproved purposes.[201] In effect, the 1972 Proposed Rule was directed at physicians who either buy large quantities of a drug directly from the manufacturer or cause the pharmacist to order and reorder the drug.[202] The Proposal was not meant to interfere with the individual practitioner who uses a drug for an unapproved use on an occasional basis and did not intend to prescribe the drug for an unapproved use when it was ordered.[203] Thus, the 1972 Proposed Rule may not run counter to the legislative intent behind the FDCA.

In light of the Proposed Rule, it seems fairly clear that the U.S. military ordered Dexedrine with the intention that it was to be prescribed for nonapproved uses. Currently, Dexedrine is indicated for narcolepsy and attention deficit disorder with hyperactivity.[204] It is very unlikely that the military ordered the drug to treat either of these conditions. The military does not allow persons suffering from these illnesses to serve in the military and if a current military member were to be diagnosed with either of these conditions, they would almost certainly be discharged. Therefore, the only possible reason for the military to order this drug would be for fatigue management, a nonapproved use. Thus, if the 1972 Proposed Rule were adopted, the FDA could possibly control the use of Dexedrine to fight fatigue amongst military pilots and soldiers.

3. Regulating Amphetamine Use Through Total Withdrawal and Limited Distribution: Alternative Approaches of the 1972 Proposed Rule

While the FDA’s ability to directly regulate physicians’ prescribing activities is severely limited, the FDA has never abdicated the position that indirect regulation of off-label prescribing is within its power.[205] The 1972 Proposed Rule listed several alternatives the FDA might pursue when confronted with a widespread, nonapproved use of a drug that might endanger patients or the public health.[206] The most drastic of these alternatives included revoking approval of the underlying NDA and limiting the distribution of the drug.[207]

a. Total Withdrawal

If the FDA believed that the off-label prescription of a drug posed a health risk to patients, it could seek to withdraw its previous approval of the drug.[208] FDCA section 355(e) grants the FDA power, through the Secretary of HEW, to revoke an NDA and thereby remove a drug from the market if it can “show that such drug is unsafe for use under the conditions of use upon the basis of which the application was approved.”[209] On its face, this provision seems inapplicable to the problem of off-label prescription. A showing that a drug is unsafe under conditions of use not a part of the initial application would not, it appears, permit the FDA to withdraw the drug.[210]

Notwithstanding the language of the FDCA, the Secretary of HEW has exercised his power to withdraw a drug from the market where improper prescription posed a danger to public health.[211] In one particular case, the FDA initially approved a drug called phenformin for adult-onset diabetes patients who were neither insulin-dependent nor able to reduce caloric intake.[212] Soon after the drug was marketed in 1959, the FDA became aware of reports of fatal lactic acidosis among the patients receiving the drug.[213] By 1976, the FDA had altered the drug’s labeling four times to include relevant warnings concerning lactic acidosis.[214] In January 1977, the FDA further revised the labeling to limit the drug’s indication to those patients whose diabetes was unresponsive to diet and to other drugs.[215] Despite these label changes, the Secretary of HEW decided a few months later that the situation warranted more drastic action and suspended the NDA for phenformin pursuant to the imminent hazard clause contained in section 355(e).[216]

In his order suspending approval of the drug, the Secretary of HEW acknowledged that a few thousand patients could benefit from the drug.[217] However, he determined that under the existing distribution system, phenformin could not effectively be restricted to the relatively small number of patients whose special circumstances justified exposure to its risks.[218] The Secretary felt that even after the FDA had altered the labeling so as to approve uses in only those few patients, physicians would continue to prescribe the drug off-label.[219] Consequently, phenformin was completely withdrawn from the market.

Even if the FDA is able to remove a potentially dangerous drug from the market, total withdrawal seems an unsatisfactory solution to the problem of off-label prescribing. Withdrawal of a drug would mean that the drug would be denied to patients for not only the unapproved use, but for the approved use or uses as well.[220] If the FDA completely withdrew a drug because some physicians prescribed it for off-label uses, it would impose on unfair hardship on those patients who could use the drug safely for its intended use.[221] Thus, withdrawal is neither feasible nor desirable for most instances of the nonapproved use of a drug and the FDA would use this authority only in rare cases where removal of the approved use of a drug would not be detrimental to patients.[222]

Based on this analysis, the FDA would not likely withdraw Dexedrine from the market based on current information. The possible dangers of prescribing the drug to military pilots for fatigue management, which has not been conclusively proven, do not outweigh the beneficial uses for which the drug has been approved. Since removal of Dexedrine would have a harmful impact on patients suffering from narcolepsy or attention deficit disorder, total withdrawal is not an attractive option in dealing with off-label prescription of the drug.

b. Limiting Distribution

A less drastic alternative measure to protect the public health, suggested by the 1972 Proposed Rule, is to limit distribution for certain drugs.[223] This approach would restrict access to a particular drug by specifying which pharmaceutical outlets or physicians are permitted to receive and dispense the drug.[224] However, the FDA’s only notable attempt at limiting the distribution of a drug was rejected in American Pharmaceutical Association v. Weinberger .[225] In this case, the FDA argued that a drug must conform to the conditions that the agency requires as part of the new drug approval process.[226] For a drug that is prescribed off-label or subject to possible diversion or misuse, adherence to the new drug conditions during the testing and approval process would not assure that the drug is “safe for use” unless the distribution of that drug could also be controlled.[227] The FDA concluded that restricted distribution could be considered a “condition” for the safe use of such a drug.[228] The district court held that limitations on distribution were “controls” and that the only “controls” permitted by the FDCA were those expressly stated in FDCA section 355(d)(3).[229] Thus, the FDA was only responsible for the adequacy of premarketing methods and controls during the manufacturing, processing and packaging stages of a new drug.[230] The Court of Appeals affirmed the district court’s decision without issuing an opinion.[231] Judge McGowan, in a concurring opinion, agreed with the result largely because he understood that the FDA’s statutory authority did not grant the agency the power to limit distribution after marketing.[232] If the FDA had the authority to implement post-marketing restrictions to assure the safe use of drugs, it could establish “a comprehensive registration scheme, complete with detailed record-keeping, security, and inspection requirements,” that was possibly as complex as the Controlled Substances Act.[233] Judge McGowan did not believe Congress intended to grant the FDA such sweeping statutory authority.[234]

The FDA’s desire for distribution restrictions to limit improper off-label prescription seems to be based on the belief that such behavior can be better controlled in certain institutions.[235] For example, the existence of hospital drug review procedures certainly exerts pressure on the hospital physician, which the individual practitioner is not subject to.[236] Limiting distribution to those institutions that could better control improper prescriptions would help to protect public health.

However, it may be difficult for the FDA to predict which institutions could better control off-label prescriptions. The military prescribing of Dexedrine provides just one example of this problem. Unlike individual practitioners, military flight doctors are subject to a chain-of-command, which limits their autonomy. On the surface, the military seems to be an ideal institution to control off-label practices due to this strong command structure and its rigid rules. However, this assumes that military commanders have the incentive to control the prescriptions of medicine. Contrary to this assumption, flight doctors might be subject to pressures by commanding officers in a combat situation to keep their pilots flying, which individual practitioners would not be subject to. Historical evidence supports this theory. One U.S. military study of stimulant use in extended flight operations described a history of commander abuse World War II and Vietnam – that instead of allowing reasonable crew rest, commanders relied on stimulants to get superhuman effort out of their subordinates.[237] While Air Force officials currently deny that pilots are forced to ingest go-pills, an agreement to carry them into the cockpit in case they are needed is one of many criteria that may be used by a commander and flight surgeon in approving a pilot for a mission.[238] Air Force commanders have in fact informed flight doctors that pilots could be considered unfit to fly certain missions if they didn't voluntarily take Dexedrine.[239] For example, defense lawyers for the two pilots involved in the friendly-fire incident in Afghanistan have stated that the pilots were told by superiors they could be found unfit to fly the mission unless they took the pills.[240] Thus, as the foregoing example illustrates, even if the FDA were able to limit the distribution of drugs to certain institutions, the FDA may not always be able to accurately predict which institutions will monitor and prevent dangerous off-label prescriptions.

Limited distribution may also unfairly burden those patients who do not have ready access to the institutions permitted to dispense controlled drugs. So, for example, if the FDA limited distribution of Dexedrine to civilian hospitals based on the assumption that civilian hospitals were better able to control the dispensation of Dexedrine than military hospitals, military personnel would be denied access to the drug. Regardless of whether the military actually prescribes Dexedrine for the approved indications of narcolepsy and attention deficit disorder, there may be other off-label uses for Dexedrine yet to be determined that could be safe and efficacious to treat other diseases within the military. If the FDA chose to limit distribution of a particular drug to civilian hospitals, patients of civilian physicians may benefit from future off-label uses of a particular drug, while military personnel would not receive the same benefit. Thus, limiting distribution, like total withdrawal and the prohibition of off-label prescribing, would be at best a trade-off between the patients who would benefit from the prevention of drug misuse and the patients who would suffer from lack of access to efficacious drugs.[241]

While the 1972 Proposed Rule listed several alternatives the FDA might pursue to regulate amphetamine use in the absence of any statutory authority to regulate off-label prescriptions, these alternatives are not particularly attractive or feasible. Regulating amphetamine use through total withdrawal would have a harmful impact on those patients suffering from the approved indications, namely narcolepsy and attention deficit disorder. Limiting distribution would have a similar adverse impact, albeit to a smaller subset of patients who would not have access to those institutions approved by the FDA to distribute the drug.

C. Arguments For and Against Off-Label Prescriptions

An off-label prescription of a drug for a nonapproved purpose falls squarely between an FDA regulatory scheme intended to protect the public from the untested hazards of new drugs or drug uses and a strongly held ethic that doctors deserve substantial freedom to practice medicine.[242] Thus, many in the medical field contend that off-label prescriptions are both prevalent and essential, while those who support increased regulation argue that lack of regulatory control over off-label prescriptions endangers human health.[243] This section will explore the general arguments both for and against off-label prescribing practices and will apply these considerations to the issue of whether the FDA should be authorized to regulate the military’s use of amphetamines for fatigue management.

1. Arguments Favoring Off-Label Prescriptions

The two most common arguments favoring off-label prescriptions are that they: a) are both prevalent and necessary in the practice of medicine; and b) actually improve the practice of medicine by allowing doctors to make risk/benefit decisions for individual patients and by advancing medical findings and scientific information.

a. Off-Label Prescriptions Are Prevalent and Necessary

Most medical experts agree that significant portions of prescriptions today are off-label.[244 ] The American Medical Association estimates that off-label uses presently account for forty to sixty percent of all prescriptions currently written.[245] Other estimates suggest that off-label uses account for twenty to sixty percent of all prescriptions.[246] A recent study by the Government Accounting Office found off-label prescribing to be the rule for many types of therapy.[247]

Thus, regardless of whether off-label prescriptions are necessary, it appears that it would be prohibitive for the FDA to attempt to regulate the vast number of off-label prescriptions that occur on a daily basis. The FDA would be simply incapable of identifying every off-label prescription. It is likely the FDA would only be able to regulate those incidents of off-label uses that were reported or publicized. In this scenario, the FDA could identify and regulate the military’s use of amphetamines due to the recent media attention given to the friendly-fire incident in Afghanistan. However, there may be many other off-label prescriptions that pose a much greater threat to human life than the prescribing of Dexedrine to military pilots. Without the resources to regulate the entire universe of off-label practices, the FDA may have to resort to regulating the most notorious off-label prescriptions, rather than the most dangerous ones. Thus, attempting to regulate off-label prescriptions, including prescriptions of Dexedrine to military pilots, may not be an efficient use of FDA resources.

Many in the medical community also argue that off-label prescriptions are prevalent because they are often among the most effective means of treatment for a number of diseases. The frequency and effectiveness of off-label cancer drugs tends to support this position.[248] Off-label prescriptions likewise dominate other areas of medicine. For example, the vast majority of drugs prescribed for the healing of wounds are approved and labeled only for other conditions.[249] Yet perhaps the most dramatic impact of off-label prescriptions has been in the treatment of AIDS.[250] Experts suggest that between ninety and one hundred percent of applications, including all of the revolutionary antiretroviral combination therapies, are off-label. [251]

While the success of off-label prescriptions in treating cancer and AIDS certainly cautions against banning off-label prescriptions entirely, it does not preclude the possibility of regulating particular off-label prescriptions that demonstrate significant hazards to public health. The FDA’s ability to regulate amphetamine use for fatigue management, if such use is proven to be extremely dangerous, need not have any impact on a physician’s ability to use experimental therapies for cancer and AIDS treatment.

b. Off-Label Prescriptions Improve the Practice of Medicine

The preceding section noted that off-label prescription is very common and that proponents suggest that it improves the quality of medical care, particularly in the treatment of cancer and AIDS. This section examines the theoretical underpinnings of this argument. Generally, proponents emphasize that off-label prescriptions improve the practice of medicine by allowing physicians to make individual risk/benefit decisions and expediting medical findings and the distribution of scientific information.

i. Individual Risk/Benefit Decisions

The risk/benefit ratio of a drug might be favorable for a single patient, given that patient’s unique needs, even though the risk/benefit decision for a class of similar patients might not be favorable.[252] When the FDA approves a drug as safe and efficacious for the treatment of a particular illness, the agency has decided that there is reliable evidence that a doctor can safely prescribe that drug to any patient with that illness.[253] Thus, the FDA’s analysis is based on a risk/benefit decision for an entire class of patients.[254]

The FDA’s decision to approve the use of a particular drug for an entire class of patients is likely to be much more conservative than an individual practitioner’s decision to prescribe that drug off-label to an individual patient.[255] In other words, there are a number of factors that the FDA must consider before approving a drug that an individual physician does not have to face. First, once a drug has been approved, the FDA can only withdraw the drug from the market through lengthy legal procedures.[256] Second, most medical experts agree that the U.S. lacks a dependable reporting system for a drug’s adverse effects.[257] As a result, the FDA often does not learn about dangers posed by a drug until some time after those dangers pose a significant health threat.[258] Finally, FDA officials know that they will be vulnerable to political criticism and public outrage if they incorrectly approve a drug.[259]

In contrast, a single physician is making a decision to use a drug only for one patient or a small group of patients, instead of the large class of patients for which the FDA is making such a decision.[260] Thus, the physician may view the use of a drug as safe and effective for a particular patient before the time the FDA would be ready to make a similar decision for an entire class of patients.[261] The decision to prescribe a drug off-label to a single patient is not necessarily inappropriate due to these differences in the functions of individual physicians and the FDA. These differences in function are one reason why the FDA has not tried to reserve the authority to completely ban all off-label prescriptions.[262]

Proponents of the use of amphetamines in the military can point to these differences in function between individual physicians and the FDA to make their case. While the FDA has not explicitly determined whether Dexedrine is safe to prescribe to a general class of patients who suffer from fatigue, various military studies have determined that Dexedrine would be safe and effective for pilots to combat fatigue.[263] Furthermore, flight doctors prescribe Dexedrine off-label based on the unique risk/benefit ratios for military pilots. In contrast, if the FDA were to decide whether to approve Dexedrine for fatigue management, it would have to consider the widespread legal, health, and political consequences of its decision for a larger class of patients without necessarily considering the uniqueness of military pilots.

ii. Expedition of Medical Findings and Innovation

Proponents of off-label prescriptions also argue that individual physicians are instrumental in the rapid development of new medical findings. First, there are simply far fewer research facilities than there are medical clinics and offices.[264] Moreover, most research facilities employ exacting and therefore time-consuming methodologies. [265] When the scarcity of research facilities is combined with rigorous and protracted methods, the development of new medical findings will be slow in the absence of individual physician ingenuity.[266] Second, individual physicians are less likely to be subjected to bureaucratic constraints and institutional pressures in regard to their findings.[267 ] In a related argument, the medical community claims that FDA regulation of off-label prescriptions would chill innovation and reduce medicine to "cookbook" therapy. [268] Those factors which have led the FDA to be overcautious in approving drugs likewise would lead the agency, in the promotion of greater safety, to needlessly overuse its authority to limit prescribing.[269]

There is some evidence that the off-label prescription of Dexedrine to military pilots was able to quickly remedy the catastrophic problem of exhaustion on lengthy combat missions. One Air Force study found that fatigue was a factor in 101 accidents from 1977 to 1997.[270] To date, there are no confirmed accidents caused by amphetamine use in the cockpit.[271] During Desert Storm, many Air Force pilots reported that Dexedrine increased their alertness, with little or no side effects.[272] In particular, one F-15 squadron that prescribed Dexedrine extensively reported that the squadron could not have maintained its level of flight operations without the medication.[273] It is notable that this F-15 squadron had the fewest pilots assigned to it in Desert Storm, yet flew more flight hours and shot down more aircraft than any other F-15 squadron in the Persian Gulf.[274]

While it cannot be conclusively proven, it is possible that without the option of off-label prescription of Dexedrine, the performance of U.S. Air Force pilots in Desert Storm would have suffered. Additionally, a meticulous and time-consuming study, much like the testing done in the FDA drug approval process, may have precluded the use of Dexedrine in combat, possibly resulting in an increase in the number of accidents due to fatigue. Thus, the expedition of medical findings can be an important benefit of off-label prescriptions.

2. Arguments Disfavoring Off-Label Prescriptions

The three most common arguments disfavoring off-label prescriptions are that they: a) endanger human health; b) are akin to experimental treatments and should be treated as such; and c) are the result of conflicts of interest for physicians.

a. Lack of Regulatory Control Over Off-Label Prescriptions Endangers Human Health

Opponents of off-label prescriptions argue that these types of prescriptions lack the crucial FDA imprimatur, and therefore also lack the consumer safeguards we usually associate with prescription drugs. As discussed earlier with the FDA drug approval process, the law requires that the sponsor of a new drug must submit substantial evidence of safety and efficacy to receive approval to market a drug for uses listed in the labeling.[275] At the heart of the FDA’s evaluation of an NDA is an assessment of the risks and benefits associated with the approved use of a new drug.[276] Although such risks and benefits will vary as the drug is prescribed for different uses, no such requirement for substantial evidence of safety and efficacy is imposed for subsequent, off-label prescriptions. Accordingly, physicians need not collect or record such information regarding proper dosage or drug safety for the off-label prescription.[277]

Since an off-label use of a drug does not require substantial evidence of safety and efficacy, normal sources of prescribing information are not available. Neither drug labels nor other drug advertisements may contain any information about uses not approved by the FDA.[278] To replace these sources of information, the physician has a couple of options. First, the physician can extrapolate the requisite information from the labeling data for the approved purpose.[279] A physician, however, may lack the necessary expertise to make these extrapolations.[280] Second, the physician could look to medical journal articles or past clinical studies, but the physician lacking expertise in clinical pharmacology may not be able to make any independent judgment about the quality of the work reported in the articles or studies.[281] Furthermore, studies have shown that some medical journal articles have reported research that was not scientifically rigorous enough to be considered reliable.[282]

Many physicians believe that the requirement for such scientific rigor cannot be overemphasized.[283] As one medical expert noted, “the only accurate way to decide on the efficacy of a drug is to treat patients under conditions that will control as many variables as possible and to determine whether statistically significant differences can be obtained between patients who have received the drug and those who have not.”[284] This necessity for scientific rigor also means that even if a physician successfully prescribes off-label, the drug in the future still may not be safe or efficacious for all similarly situated patients.[285] This situation has led to concerns “that physicians and consumers will be misled into relying on scientific logic or scanty data supporting a particular use, without adequate well-controlled clinical trials that prove definitively that the drug works.[286] Thus, the patient and the public in general are left unprotected in the absence of an FDA assessment of risks and benefits with respect to each use.[287]

The potential hazards of off-label drug usage are exemplified by the once-popular obesity treatment known as “fen-phen,” a combination of phentermine and fenfluramine.[288] The FDA had approved each drug for short-term use to treat obesity.[289] The drugs were prescribed off-label in combination for persons overweight but not obese, and for longer periods than the approved period.[290] The FDA conservatively estimates that 285,000 fen-phen users suffered damage to heart valves during the brief period in which the combination was widely prescribed. [291]

This enormous increase in off-label fenfluramine prescriptions predated the legalization of off-label marketing. [292] In other words, doctors began prescribing fenfluramine in combination with phentermine not because manufacturers pressured them with advertising, but primarily because the doctors read about the scientific evidence in primary and secondary sources, or heard about the scientific evidence through word of mouth.[293] Additionally, physicians were pressured by patients to prescribe the drugs for individuals who wanted help in losing weight and were not truly obese.[294] Based on the fen-phen debacle, off-label prescription, even without off-label marketing, can cause tremendous injury to the public health.[295]

The off-label prescription of Dexedrine for fatigue management can be analogized to the off-label prescription of fenfluramine and phentermine. All of these drugs were prescribed off-label for conditions that were “lesser” forms of the conditions that the drugs were approved for. Fenfluramine and phentermine were both approved for the treatment of people who were extremely obese, but were prescribed for people who were merely overweight. Likewise, Dexedrine has been approved for the treatment of narcolepsy,[296] but was prescribed by the military for fatigue, a condition much less severe than narcolepsy. Although Dexedrine was not prescribed in combination with another drug and has not been known to cause the extensive harm that fen-phen did, flight doctors did rely on data that was not supported by well-controlled clinical trials that proved definitively that the drug was safe. Thus, the military continues to prescribe Dexedrine without the safeguards that FDA-approved testing would provide.

b. Off-Label Prescriptions Are the Equivalent of Experimental Treatments and Should Be Treated as Such

Opponents have also argued that off-label prescriptions essentially subject the public to the equivalent of experimental drugs.[297] This experimental drug analogy is based on a characteristic shared by non-FDA approved new drugs and off-label prescriptions of FDA approved drugs.[298] In each case, the drug use has never undergone the rigorous testing as required by the agency.[299] From the patients’ perspective, an off-label prescription of approved drugs is arguably indistinguishable from the prescription of entirely unapproved drugs.[300] Therefore, off-label prescriptions should be subject to the same requirements as investigational or experimental drugs.

Current U.S. statutory law requires that informed consent be obtained for all “investigational purposes” of drugs.[301] Thus, if military prescriptions of amphetamines are analogized to prescriptions of experimental drugs, critics may argue that the military should only be permitted to prescribe these drugs off-label with a pilot’s informed consent.

Currently, the military does require pilots who are prescribed Dexedrine to sign an “Operational Use Consent Form.”[302] However, there are serious concerns as to whether the signing of these forms is truly “informed” or “consensual.”

First, the consent form does not include all of the foreseeable risks or side effects that are associated with Dexedrine. In seeking informed consent, FDA regulations require a “description of any reasonably foreseeable risks or discomforts” to be provided to the subject.[303] While the consent form includes many of the possible adverse reactions,[304] it is particularly notable that the form fails to include the two adverse reactions that are probably the most pertinent for pilots: overstimulation and dizziness.[305] Perhaps even more importantly, the consent form fails to include the information that “[a]mphetamines may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or vehicles ; the patient should therefore be cautioned accordingly.”[306] The military also never informed its pilots that Dexedrine is strictly banned for commercial airline pilots.[307] Thus, the military’s consent form may not meet the legal standard for “informed consent,” as it does not describe some of the reasonably foreseeable risks.

Second, although the consent form states that the decision to take Dexedrine is voluntary, the pressure put on military pilots to take the drug brings into question how consensual this is. According to FDA regulations, “[a]n investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence.”[308] Although the consent form states that pilots cannot be punished for not taking Dexedrine, it also states that pilots may be considered unfit to fly if they choose not to take the drug.[309] According to the defense lawyers in the Afghanistan friendly-fire case, the two pilots were told by superiors that they could be found unfit to fly the mission unless they took the pills.[310] Thus, in order to perform the long missions that have been assigned to them, military pilots often feel required to take the pills.[311] Military pilots know that if they refuse to take Dexedrine, their fellow pilots, who are already overtasked, will have to shoulder an even heavier flight load.[312] There is also the concern about “command abuse,” with squadron commanders relying on stimulants to keep pilots in the air.[313] The pressure for pilots to keep flying could be construed as coercion or undue influence, and thus violates the FDA’s “informed consent” requirements.

To summarize, many critics argue that off-label prescriptions should be treated like investigational drugs. If off-label prescriptions are indeed the equivalent of experimental treatments, informed consent could have at least some viability regarding problems of nonapproved prescribing. However, as demonstrated by the recent “friendly fire” incident in Afghanistan, informed consent cannot solve every problem.

c. Pressures and Conflicts of Interest for Doctors

Doctors face a number of potential conflicts of interest that may encourage the imprudent off-label prescription of drugs.[314] Some drug manufacturers continue to confer gifts and favors on physicians , who are the legally required intermediaries for the prescription of the manufacturers' drugs.[315 ] Thus, some critics argue that these sorts of gifts and favors could compromise a physician’s decision-making process when it comes to prescribing drugs.

Patients provide another variety of pressure on physicians, as they often visit their physicians with pre-established ideas of the medications they expect to receive.[316] As demonstrated by the fen-phen cases, this pressure by patients to prescribe off-label can have disastrous consequences.[317] It is also clear that as patients become better informed and more empowered, they will become more demanding, placing greater pressures on doctors to prescribe particular drug treatments.[318] As they face larger numbers of learned patients whose patronage provides their livelihood, doctors will have to be very strong to resist pressures to prescribe requested off-label treatments. [319]

As previously mentioned, military consumers of Dexedrine, particular squadron commanders, may place pressure on flight doctors to keep pilots flying.[320] This pressure to prescribe amphetamines off-label could interfere with a physician’s medical judgment and create a significant conflict of interest.


Aside from the legal and medical arguments surrounding the military’s off-label prescription of amphetamines for fatigue management, this practice also raises some serious ethical considerations. With the military already developing a drug that could keep a soldier awake for up to seven days, the question of whether it is ethical to use prescription drugs to gain an edge in combat becomes even more significant. Many people feel that performance enhancement by chemical means is unethical, if not immoral. This sentiment is evident in myriad regulations prohibiting drug use by athletes, where such use would indeed enhance performance.  Also, in light of the current efforts in drug control, some people might accuse the military of imposing a double standard.

There are some realistic ethical concerns, but whether they justify prohibiting the use of amphetamines in the military depends on one’s understanding of the role of the military.  Using drugs to enhance performance in sports may be unethical or immoral, but war is not a sporting event.  Success in combat is not a question of fairness, but of power; military weapons and training are designed to maximize combat power.[321]  Militaries do not seek to equalize each side's chance of success prior to initiating contact (as in sports), but instead seek to obtain every advantage for their armed forces.[322] Thus, there is a strong argument that the U.S. military’s off-label prescription of amphetamines for fatigue management is ethical in light of the unique role of the military.

However, this does not mean that the military should rely upon amphetamine indiscriminately to create a performance edge on every day of combat operations. At a minimum, the costs and benefits of amphetamine use should be considered prior to taking specific actions in various situations. If amphetamine use is determined to be relatively safe and if administration of the drug is well controlled and restricted to those short-term circumstances requiring severely fatigued personnel to perform continuously, the medication may make the difference between a mission completed safely and effectively, and one that ends in tragedy.[323] However, the question remains whether the FDA should play a prominent role in weighing costs and benefits and determining whether such off-label prescriptions of amphetamines are safe and well controlled.

A related concern is the perceived double standard of restricting civilian use of controlled substances, while allowing military use of the same drugs. Military leaders are justifiably concerned about the recent disclosure of the military's use of performance-enhancing drugs and the public reaction to it. In fact, prior to the friendly-fire incident in Afghanistan, prominent military physicians suggested that the military should “classify their involvement with [amphetamines] to avoid media exploitation” or “educate political leaders and the public concerning the unique military value of these medications.”[324] However, now that the proverbial cat is out of the bag, the military should strive to research the military value of amphetamines under the supervision of the FDA and discuss the ethics of using these drugs with civilian leaders. Only an open and rigorous process can determine if the elimination of amphetamine use would put aircrews at increased actual risk for the sake of eliminating theoretical risk.

The need for careful research and an open dialogue about the ethics of amphetamines for fatigue management becomes all the more apparent when one considers the current military trend. Amphetamines are part of a new trend that foresees “performance enhancements” designed to produce “iron bodied and iron willed personnel,” as outlined in one document of the U.S. Special Operations Command.[325] The ability to keep fighting for days at a time without normal periods of rest is seen by military officials as the key to success in future conflicts.[326]

According to the Pentagon’s Defense Advanced Research Projects Agency (DARPA), the military is calling for a “radical approach” to achieve “continuous assisted performance” for up to seven days.[327] This would actually involve much more than the “linear, incremental and . . . limited” approaches of stimulants like caffeine and amphetamines.[328] In a memo outlining technology objectives, the U.S. Special Operations Command notes that the special forces “operator” of the future can expect to rely on “ergogenic substances to manage environmental and mentally induced stress and to enhance the strength and aerobic endurance of the operator.”[329] Additionally, “[o]ther physiological enhancements might include ways to overcome sleep deprivation, ways to adjust the circadian rhythms to reduce jet lag, as well as ways to significantly reduce high altitude/under water acclimatization time by the use of blood doping or other methods.”[330] Thus, the ethical questions surrounding the military’s off-label prescription of amphetamines will only continue to get more complex as the military expands its off-label practices to other drugs.


As previously discussed, the FDA’s only statutory basis for action does not give it the authority necessary to resolve the problem of off-label prescriptions.[331] Additionally, it would be both impossible and imprudent for the FDA to regulate all off-label prescriptions as the practice is very common and many investigative therapies can save or prolong lives.[332] However, as illustrated by the fen-phen tragedy, certain off-label practices may be unethical and can prove to be extremely hazardous to human health.[333] Both political pressure and a concern for public health should require the FDA to respond to the problem of off-label prescriptions in some fashion. The potential responses to the off-label prescription problem listed in the 1972 Proposed Rule, namely total withdrawal and limited distribution, are lacking because they ignore the therapeutic needs of patients unaffected by off-label prescriptions and because they would result in considerable interference with the practice of medicine.[334] Thus, an alternative method to control dangerous off-label prescriptions that does not suffer these faults must be developed.

A. Disapproval of Dangerous Drugs

Former FDA Commissioner David A. Kessler has proposed that the FDA should be given the authority to disapprove particular uses of a drug when the agency encounters widespread off-label uses that can be considered an imminent hazard to the public.[335] Other proposals that would prohibit all off-label uses involve maximum, not minimum interference with medical practice by severely restricting a physician’s choice of uses.[336] In contrast, disapproval of particular off-label uses is a more refined determination that would grant or deny access to a drug based on the propriety of the use and would effectuate congressional intent to avoid interference in the practice of medicine as much as possible.[337]

Kessler’s proposed disapproval process provides a standard for disapproval, the allocation of burdens of proof, and the means of enforcement available to achieve physician compliance with disapproval.[338] An appropriate standard would allow the disapproval of a particular off-label prescription of a drug only if there is a reasonable belief that harm will occur from that use.[339] This standard requires affirmative evidence that the particular off-label prescription has the potential for harm.[340] Although the determination of safety appears to be somewhat discretionary, the former Department of Health, Education and Welfare’s analysis of the drug phenformin suggests safety guidelines could be established.[341] The order that banned phenformin suggested that the number of deaths per thousand patients who used the drug could measure the harm caused by the drug.[342] This measure of harm could be extended to include the number of third-party deaths a particular drug proximately caused. The FDA’s computation of the sufficiency of the harm in the phenformin case, which resulted in the drug’s withdrawal, must also have included a calculation of the benefits to be derived from the drug.[343] The fact that third-party deaths and benefits from the drug may not be quantifiable poses a problem, but there may be no alternative in attempting to balance benefits and risks.[344]

Regarding burdens of proof, Kessler suggests that the FDA be given the same burden for this disapproval process as it has for the withdrawal process, namely that the agency must show initially that the manufacturer or physician has not shown that harm will not occur with a particular off-label use.[345] If the FDA meets its burden, the manufacturer or physician must then prove that no reasonable belief that harm will occur could exist.[346] According to Kessler, this burden of proof would prevent unnecessary interference with medical practice.[347] A more stringent burden, requiring the FDA to first demonstrate that a particular prescription is unsafe, may severely overtax the FDA, as it would be forced to extensively test the large number of drugs thought to present a hazard.[348]

Kessler’s final element of the disapproval process is the means available to the FDA to enforce its disapproval of a particular use. The FDA, with its limited resources, could not be expected to enforce a disapproval plan that requires the monitoring of every doctor in the country.[349] However, if the disapproval of a particular off-label prescription is adequately communicated to physicians through an official compendium, a considerable degree of compliance will voluntarily result.[350] Many physicians will comply because they are concerned for their patients’ health.[351] Other physicians will comply because of the threat of adverse publicity from the FDA, which currently motivates much of the compliance with FDA regulations.[352] Additionally, if the FDA stresses the importance of its disapproval statements because of their scientific reliability, these statements could become important evidence in establishing the standard of care in medical malpractice litigation.[353]

Finally, Kessler notes a number of difficulties with his proposal. First, propriety of use, although a superior standard than that used for approval of a drug, may not be sufficient for all off-label prescriptions.[354] In certain situations, patients may benefit from an otherwise improper use if the drug is prescribed in conjunction with other therapies and precautions.[355] For example, the safety of amphetamines in the treatment of obesity is somewhat controversial in light of the addiction risk.[356] However, if the drug is used in association with a weight reduction regimen and in such a manner as to minimize drug habituation, the use may be appropriate.[357] Unfortunately, these additional restrictions would further blur the distinction between approval and disapproval, and could constitute a major interference with medical practice.[358] A second difficulty is that disapproval of a particular use will often occur after the drug is on the market.[359] While preclearance testing may uncover some indications for which the drug is unsafe, some dangers will only become evident after physicians widely prescribe the drug.[360] Thus, Kessler’s proposal would require an effective monitoring system to detect improper prescriptions.[361] A final difficulty is that the disapproval procedure would likely require new legislation.[362] Although total withdrawal and limited distribution is currently permitted, no FDCA provision specifically grants the necessary authority for disapproval.[363]

B. Disapproval of Amphetamines for Fatigue Management

Despite the difficulties associated with a disapproval process, Kessler’s proposal is an improvement over the status quo and provides a nice balance between respecting a physician’s ability to practice medicine and regulating hazardous off-label prescriptions. However, the question remains whether Dexedrine, a powerful narcotic deemed too dangerous to fight fatigue for long-haul truckers and civilian airline pilots, should also be disapproved for someone behind the controls of a multi-million dollar military aircraft. In order to determine whether to disapprove the use of Dexedrine for fatigue management, the FDA first would first need to determine how widespread the practice is and whether these off-label prescriptions are an imminent hazard to the public. As to the former consideration, military studies have shown that the use of amphetamines for fatigue management among military pilots is fairly widespread during combat.[364] However, as far as safety guidelines are concerned, it is uncertain how many deaths, if any, have been caused by pilot amphetamine use. While some military studies have indicated that amphetamines are effective in controlling fatigue,[365] these studies may not have been of the same quality and quantity as those conducted by the FDA during the drug approval process. Specifically, the military studies have not tested the effect of amphetamines on a pilot’s decision-making in the cockpit under combat-like stress.[366] Therefore, a joint FDA/military study may be necessary to establish whether Dexedrine use has harmed or clouded the judgment of military pilots, or more importantly, whether such use has harmed innocent bystanders on the ground.

While the possibility of the FDA disapproving Dexedrine for fatigue management would depend on the potential for harm, such disapproval should not be based on the various ethical considerations previously discussed. The FDA has been authorized by Congress to regulate the potentially dangerous use of prescription drugs, not to regulate the practice of medicine.[367] The ethics of using amphetamines for fatigue management in the military should be left to those that practice medicine and to the legislature that has the authority to regulate the practice of medicine. In the absence of specific Congressional authorization in the FDCA, the FDA should base its disapproval decision on safety factors rather than ethical factors.

While off-label prescriptions are necessary to the practice of medicine, the FDA has the responsibility to protect the public from drug prescriptions that are a danger to public health. The FDA’s current regulatory alternatives are either too restrictive or too expansive, with no room to regulate only those off-label uses that are potentially harmful. Disapproval of particular off-label uses would effectively grant or deny drug prescriptions based on a benefit/risk analysis and would effectuate congressional intent to avoid interference in the practice of medicine as much as possible. While the FDA would likely need a more in-depth study on the propriety of prescribing amphetamines for fatigue management to determine whether this military practice is a danger to public health, a disapproval process would at least provide the FDA with a more refined tool to carry out its statutory duties.

[1] Jack Kelly, Did ‘speed’ block pilots’ judgment in deaths of four Canadian soldiers? , Pittsburgh Post-Gazette, Jan. 5, 2003, available at http://www.post-gazette.com/World/20030105dex0105p6.asp .

[2] Id.

[3] Id.

[4] 'Friendly fire' pilots await decision , at http://www.cnn.com/2003/LAW/01/24/mistaken.bombing.ap . (Jan. 24, 2003).

[5] Kelly, supra note 1.

[6] See Prescribing Information, Dexedrine brand of dextroamphetamine sulfate, available at http://us.gsk.com/products/assets/us_dexedrine.pdf . (last visited Feb. 10, 2002); see Michael I. Krauss, Essay, Loosening the FDA’s Drug Certification Monopoly: Implications for Tort Law and Consumer Welfare , 4 Geo. Mason L. Rev. 457, 470 (1996) (referring to off-label prescription as physician’s prescribing drugs for uses other than FDA approved uses).

[7] Thom Shanker & Mary Duenwald, Bombing Error in Afghanistan Puts a Spotlight on Pilots’ Pills , N.Y. Times, Jan. 19, 2003, at A1.

[8] See generally Lt Col Rhonda Cornum, USA, Dr. John Caldwell, & Lt Col Kory Cornum, USAF, Stimulant Use in Extended Flight Operations , Aerospace Power Journal, Spring 1997; see also Performance Maintenance During Continuous Flight Operations: A Guide for Flight Surgeons (NAVMED P-6410), Naval Strike and and Air Warfare Center, 1 Jan 2000 (hereinafter NAVMED Guide).

[9] Shanker, supra note 7.

[10] See Cornum, supra note 8.

[11] Id.

[12] See Cornum, supra note 8.

[13] See M. Prinzmetal & W. Bloomberg, The Use of Benzedrine for the Treatment of Narcolepsy , 105 JAMA 2951 (1935).

[14] See id. at 2951-3054; see also S. C. Harris, A. C. Ivey, and L. M. Searle, The Mechanism of Amphetamine-Induced Loss of Weight: A Consideration of the Theory of Hunger and Appetite , 134 JAMA 1468–75 (1947); Wade & Wood, Prescribing of Drugs Reported to Cause Adverse Reactions , 26 Brit. J. Preventive & Soc. Med. 205, 206 (1972).

[15] R. S. Goodhart, ed., Modern Drug Encyclopedia and Therapeutic Index, 9th ed. (New York: Raven Press, 1975).

[16] Shanker, supra note 7.

[17] Id. (citing study at Columbia University's medical school that tested amphetamines on people undergoing abrupt changes in their sleep patterns. The subjects were kept awake at night for one week, and switched back to a daytime schedule the next. Immediately after making such a shift, the subjects performed poorly on tests of cognitive ability and reaction time. But when given 5- to 10-milligram doses of amphetamines – the size currently prescribed by Air Force flight surgeons – the subjects performed as well as when they are rested).

[18] 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, 702-03 (1978).

[19] See L. Ginspoon & P. Hedbloom, The Speed Culture: Amphetamine Use and Abuse in America 271 (1975).

[20] See Dexedrine Prescribing Information, supra note 6.

[21] J. C. Kramer, V. S. Fischman, and D. C. Littlefield, Amphetamine Abuse: Patterns and Effects of High Doses Taken Intravenously , 201 JAMA 305-09 (1967).

[22] See Dexedrine Prescribing Information, supra note 6.

[23] See id. (listing dextroamphetamine sulfate as a Class II controlled substance); see also 21 U.S.C. §812 (2002) (classifying a Class II controlled substance as: (1) having a high potential for abuse, which may lead to severe physical or psychological dependence and (2) having a currently accepted medical use in treatment in the United States).

[24] L. Grinspoon, Drug Dependence: Non--Narcotic Agents , in Comprehensive Textbook in Psychiatry 1317–31 (A. H. Freedman, H. I. Kaplan, and B. Saddock, eds., 1975); NAVMED Guide at 8 (citing R. Winfield, The Use of Benzedrine to Overcome Fatigue on Operational Flights in Coastal Command , DTIC Technical Report, AD-B953285, Flying Personnel Research Committee, United Kingdom, October 1941; O. Graf, Increase of Efficiency by Means of Pharmaceutics (Stimulants) , German Aviation Medicine World II, Department of the Air Force (1946)).

[25] Cornum, supra note 8.

[26] Cornum, supra note 8 (citing B. Weiss and V. G. Laties, Enhancement of Human Performance by Caffeine and the Amphetamines , 14 Pharmacological Review 1-36 (1962); H. F. Adler et al., Effects of Various Drugs on Psychomotor Performance at Ground Level and Simulated Altitudes of 18,000 Feet in a Low Pressure Chamber , 21 J. Aviation Med. 221-36 (1950); G. T. Hauty and R. B. Payne, Mitigation of Work Decrement , 49 J. Experimental Psych. 6-67 (1955); R. H. Seashore and A. C. Ivey, Effects of Analeptic Drugs in Relieving Fatigue , 67 Psychological Monographs 1-16 (1953); and D. P. Cuthbertson and J. A. Knox, The Effects of Analeptics on the Fatigued Subject , 106 J. Physiology 42-58 (1947).

[27] Id.

[28] See, e.g., G. M. Smith and H. K. Beecher, Amphetamine Sulfate and Athletic Performance, I. Objective Effects , 170 JAMA 542-57 (1959).

[29] See Shanker, supra note 7.

[30] See Cornum, supra note 8.

[31] Id.

[32] Id.

[33] Edward M. Brecher, Licit and Micit Drugs: The Consumers Union Report on Narcotics, Stimulants, Depressants, Inhalants, Halluncinogens, and Marijuana (Little, Brown and Company 1972).

[34] NAVMED Guide at 8.

[35] Cornum, supra note 8.

[36] Id.

[37] NAVMED Guide at 8 (citing Desert Shield/Desert Storm Aerospace Medicine Consolidated After-Action Report).

[38] See Air Force Regulation (AFR) 161-33/TAC Supplement 1.

[39] NAVMED Guide at 8.

[40] See Cornum, supra note 8 (citing Desert Shield, Desert Storm: Aerospace Medicine Consolidated After--Action Report , Proceedings of After--Action Conference, 20–22 May 1991; K. Cornum, Extended Air Combat Operations: F--15s over Iraq , Aviation, Space and Environmental Medicine, May 1994; K. Cornum, R. Cornum, and W. Storm,Use of Psychostimulants in Extended Flight Operations: A Desert Shield Experience , Advisory Group for Aerospace Research and Development Conference Proceedings 579, Neurological Limitations of Aircraft Operations: Human Performance Implications (Papers presented at the Aerospace Medical Panel Symposium, Köln, Germany, 1995), 371–74; and K. Cornum, Eagles over Iraq: A Desert Storm Experience (Paper presented at Seventh Annual Workshop on Space Operation Applications and Research [SOAR], Houston, Tex., August 1993)).

[41] Id. ; NAVMED Guide at 10.

[42] NAVMED Guide at 10.

[43] NAVMED Guide at 8 (citing Summary of the Aeromedical Therapeutics Advisory Committee Meeting with the 58th TFS, Eglin AFB, FL, 1 Oct 91, Naval Aerospace Medical Research Laboratory, Naval Air Station, Pensacola, FL).

[44] NAVMED Guide at 11.

[45] See http://abcnews.go.com/sections/2020/DailyNews/2020_pilotpills021220.html (last visited Feb. 15, 2003) (hereinafter ABC Report).

[46] Cornum, supra note 8.

[47] Id.

[48] Shanker, supra note 7; see also ABC Report, supra note 45 (“In my opinion, if you think you have to take a pill to face something that’s tough, you’re in the wrong business,” McPeak said).

[49] Kelly, supra note 1; Shanker, supra note 7.

[50] Shanker, supra note 7.

[51] Id. (citing a statement by Betty Anne Mauger, a spokeswoman for the Air Force surgeon general).

[52] 21 U.S.C. §353(b)(1) (2000).

[53] DeFreese v. United States , 270 F.2d 730, 733 n. 4 (5th Cir. 1959) (quoting Goodman & Gilman, The Pharmacological Basis of Therapeutics 1759 (2d ed. 1955)).

[54] United States v. Nazir , 211 F. Supp. 2d 1372, 1375 (S.D. Fla. 2002).

[55] See Mary A. McEniry & Sidney H. Willig, The Federal Food, Drug, and Cosmetic Act and the Medical Practitioner , 29 Food Drug Cosm. L.J. 548, 549 (1974).

[56] See id. at 561.

[57] See id. (stating that dentist writing a prescription for contraceptive pills to satisfy his family needs or accommodate a female patient may violate the FDCA).

[58] See Prinzmetal, supra note 13.

[59] See McEniry, supra note 55, at 561; see also 21 U.S.C. §§331, 353(b)(1) (2000) (stating that the act of dispensing a drug without a prescription of a practitioner licensed by law to administer such a drug shall be deemed to be an act which results in the drug being misbranded while held by sale).

[60] See id.

[61] Brown v. United States , 250 F.2d 745, 745 (5th Cir. 1958).

[62] See id. at 747.

[63] Id.

[64] Id.

[65] DeFreese v. United States , 270 F.2d 730, 731 (5th Cir. 1959).

[66] Id.

[67] Id.

[68] Id. at 732.

[69] Nazir , 211 F. Supp. 2d at 1376.

[70] See id. at 1375.

[71] In DeFreese , the doctor distributed 5,000 Benzedrine tablets to one person.

[72] Kelly, supra note 1.

[73] NAVMED Guide at 14.

[74] See ABC Report, supra note 45.

[75] NAVMED Guide at 11.

[76] See, e.g. , Korematsu v. United States , 323 U.S. 214 (1944).

[77] See 21 U.S.C. §801-966 (2000).

[78] See Am. Pharm. Ass’n v. Weinberger , 377 F. Supp. 824, 830 (D. D.C. 1974) (“The Court concludes that Congress intended to create two complementary institutional checks on the production and marketing of new drugs. At the production or pre-marketing stage, the FDA is given the primary responsibility in determining which new drugs should be permitted to enter the flow of commerce. . . . But once a drug is cleared for marketing by way of a NDA-approval, for whatever uses the Commissioner deems appropriate, the question of permissible distribution of the drug, when that drug is a controlled substance, is one clearly within the jurisdiction of the Justice Department . . . according to the scheme of the Controlled Substances Act.”).

[79] 21 U.S.C. §812 (2000).

[80] Id.

[81] 21 U.S.C. §841(a) (2000).

[82] 21 U.S.C. §829 (2000).

[83] See 21 U.S.C. §822 (2000).

[84] See 21 U.S.C. §§802, 829, 841 (2000); United States v. Bartee , 479 F.2d 484, 487 (10th Cir. 1973); see also United States v. Moore , 423 U.S. 122, 140 (1975) (holding that the CSA requires distributions and dispensation of controlled substances to be within the bounds of professional practice); United States v. Collier , 478 F.2d 268, 271-72 (5th Cir. 1973) (“It is apparent that a licensed practitioner is not immune from the act solely due to his status, . . . but rather, because he is expected to prescribe or dispense drugs within the bounds of his professional practice of medicine.”).

[85] 21 C.F.R. §1306.04(a) (1974).

[86] See Kessler, supra note 18, at 696-97.

[87] See id. at 124-25.

[88] See id. at 143-44.

[89] See United States v. Rosenberg , 515 F.2d 190 (9th Cir. 1975) (holding that a doctor is not exempt from the CSA when he distributed dexedrine without a physical examination because the doctor did not in good faith believe that the prescription was for a legitimate medical purpose); United States v. Behrman , 258 U.S. 280, 287 (1922) (“[T]he purpose of the exception is to confine the distribution of these drugs to the regular and lawful course of professional practice.”); Boyd v. United States , 271 U.S. 104, 105 (1926) (“The disputed question was whether the defendant issued the prescriptions in good faith in the course of his professional practice.”)

[90] Kessler, supra note 18, at 697.

[91] Kelly, supra note 1.

[92] See McEniry, supra note 55, at 550.

[93] 21 U.S.C. §824(a) (2000).

[94] 21 U.S.C. §823(b) (2000).

[95] Cornum, supra note 8 (citing J. A. Caldwell et al., Sustaining Helicopter Pilot Performance with Dexedrine during Periods of Sleep Deprivation , 66 Aviation, Space and Environmental Medicine 930–37 (1995); J. Caldwell et al., Sustaining Female UH--60 Helicopter Performance with Dexedrine during Sustained Operations: A Simulator Study, US Army Aeromedical Research Laboratory Report no. 95–27 (Fort Rucker, Ala.: USAARL, July 1995)).

[96] Shanker, supra note 7.

[97] Id.

[98] Id.

[99] See id.

[100] Shanker, supra note 7.

[101] Id.

[102] Brad Knickerbocker, Military looks to drugs for battle readiness , The Christian Science Monitor, Aug. 9, 2002, available at http://www.csmonitor.com/2002/0809/p01s04-usmi.html (last visited on Feb. 16, 2003).

[103] Id. (quoting John Pike, a defense expert with GlobalSecurity.org, as saying: "Given the extent of recreational drug use within the military, and the use of performance-enhancing drugs among athletes, it is very easy to imagine that warriors would consider using any manner of drug they thought would increase their chance of returning home alive.”)

[104] Id.

[105] Id. (quoting Pike).

[106] Cornum, supra note 8.

[107] Id. (citing J. Cole, Clinical Uses of the Amphetamines , in Current Concepts on Amphetamine Abuse 163 (Ellinwood and Cohen eds. 1970)).

[108] Cornum, supra note 8.

[109] See, e.g. , Brian Badura, Navy Medicine Steps Up to Help Curb Ecstasy Abuse , The Waterline, Jan. 18, 2002, available at http://www.dcmilitary.com/navy/seaservices/7_2/national_news/13152-1.html (last visited Feb. 16, 2003).

[110] See NAVMED Guide at 11.

[111] See id.

[112] Cornum, supra note 8.

[113] Id.

[114] Id.

[115] See supra notes 74-75 and accompanying text.

[116] Id.

[117] 21 U.S.C. §355(a) (2000).

[118] 21 U.S.C. §355(d) (2000).

[119] See id.

[120] Id.

[121] 21 C.F.R. §§310-314 (1977).

[122] Sidney A. Shapiro, Limiting Physician Freedom To Prescribe a Drug For Any Purpose: The Need For FDA Regulation , 73 Nw. U. L. Rev. 801, 803-04 (1979).

[123] Id.

[124] 21 C.F.R. §312.1(a)(2) (1998).

[125] 21 C.F.R. §312.21(a)(1)(2) (1998).

[126] Veronica Henry, Off-Label Prescribing Legal Implications , 20 J. Legal Med. 365, 367 (Sept. 1999).

[127] 21 C.F.R. §312.21(b) (1998).

[128] Henry, supra note 126, at 368.

[129] Id.

[130] Id.

[131] 21 C.F.R. §312.21(c) (1998).

[132] 21 C.F.R. §314.1(c)(2) (1998).

[133] 21 U.S.C. §355(d) (2000).

[134] 21 C.F.R. §201.100(c)(1), (d)(1), 202.1(d)(2) (1998).

[135] 21 U.S.C. §505(b) (2000).

[136] 21 C.F.R. §314.70 (1998).

[137] Id.

[138] 21 U.S.C. § 334(a)(1), §355(e) (2000); 21 C.F.R. §201.100(c)-(d) (1998).

[139] Shapiro, supra note 122, at 805 (citing J. Gibson, Medication, Law and Behavior § 8.1.1, at 96).

[140] Shapiro, supra note 122, at 806 (citing U.S. Dep’t of Health, Education, and Welfare, review Panel on New Drug Regulation, Interim Report: Risk, Safety, Efficacy and Benefit 7, 7 (1977)).

[141] Id. (citing Interim Report: Risk at 7).

[142] See supra notes 117-138.

[143] Steven R. Salbu, Off-Label Use, Prescription, and Marketing of FDA-Approved Drugs: An Assessment of Legislative and Regulatory Policy , 51 Fla. L. Rev. 181, 187 (April, 1999); see Lars Noah, The Imperative to Warn: Disentangling the “Right to Know” from the “Need to Know” about Consumer Product Hazards , 11 Yale J. on Reg. 293, 326-33 (1994) (discussing the labeling requirements for prescription drugs).

[144] See Margaret Gilhooley, Learned Intermediaries, Prescription Drugs, and Patient Information , 30 St. Louis U. L.J. 633 (1986).

[145] Edmund Polubinski, III, Note, Closing the Channels of Communication: A First Amendment Analysis of the FDA's Policy on Manufacturer Promotion of "Off-Label" Use , 83 Va. L. Rev. 991, 995 (1997).

[146] Salbu, supra note 143, at 187.

[147] Id.

[148] See William L. Christopher, Off-Label Drug Prescription: Filling the Regulatory Vacuum , 48 Food & Drug L.J. 247, 248 (1993) (supplying the following definition: “Using an approved drug to treat a disease that is not indicated on its label, but is closely related to an indicated disease, treating unrelated, unindicated diseases, and treating the indicated disease but varying from the indicated dosage, regimen, or patient population may all be considered off-label use.”).

[149] Salbu, supra note 143, at 189 (citing Michael E. Petrella, Comment, License to Maim: Federal Preemption and the Medical Device Amendments of 1976 , 6 Health Matrix 349, 368 n.122 (1996)); see also Christopher, supra note 148, at 248.

[150] Christopher, supra note 148, at 248.

[151] See Kessler, supra note 18, at 707.

[152] Shapiro, supra note 122, at 807.

[153] McEniry, supra note 55, at 553.

[154] Id.

[155] See generally 21 U.S.C. §355 (2000); see also Kessler, supra note 18, at 699-700.

[156] See Legal Status of Approved Labeling for Prescription Drugs; Prescribing for Uses Unapproved by the Food and Drug Administration, 37 Fed. Reg. 16,503 (proposed July 30, 1972) (to be codified at 21 C.F.R. pt. 130).

[157] Id. ; see Althea Gregory, Denying Protection to Those Most in Need: The FDA’s Unconstitutional Treatment of Children , 8 Alb. L.J. Sci. & Tech. 121 (1997).

[158] Prescribing for Uses Unapproved by the FDA, 37 Fed. Reg. at 16,503.

[159] See Shapiro, supra note 122, at 846-47.

[160] See "Use of Approved Drugs for Unlabeled Indications," 12 FDA Drug Bulletin 4 (April 1982) (“The [Food, Drug and Cosmetic] Act does not, . . . limit the manner in which a physician may use an approved drug. Once a product has been approved for marketing, a physician may prescribe it for uses or in treatment regimens or patient populations that are not included in approved labeling. Such "unapproved" or, more precisely, "unlabeled" uses may be appropriate and rational in certain circumstances, and may, in fact, reflect approaches to drug therapy that have been extensively reported in medical literature.
The term "unapproved uses" is, to some extent, misleading. It includes a variety of situations ranging from unstudied to thoroughly investigated drug uses . . . . [A]ccepted medical practice often includes drug use that is not reflected in approved drug labeling. With respect to its role in medical practice, the package insert is informational only.”).

[161] Id. at 5.

[162] 48 Fed. Reg. 26,720, 26,733.

[163] See e.g. , Rhone-Poulenc Rorer Pharm., Inc. v. Marion Merrell Dow, Inc. , 93 F.3d 511, 514 n.3 (8th Cir. 1996) (“Doctors may prescribe an FDA-approved drug for non-approved uses, but the manufacturer may not promote non-approved uses.”); Weaver v. Reagen , 886 F.2d 194, 198 (8th Cir. 1989); see also Drusilla S. Raiford et al., Determining Appropriate Reimbursement for Prescription Drugs: Off-Label Uses and Investigational Therapies , 49 Food & Drug L.J. 37, 39 (1994).

[164] Christopher, supra note 148, at 252.

[165] United States v. Evers , 643 F.2d 1043, 1044-47 (5th Cir. 1981).

[166] Id. at 1047 (citing 21 U.S.C. §352(f)(1)).

[167] Id. at 1052-53.

[168] Id. at 1053 n.16 (“[The] Act was intended to regulate the distribution of drugs in interstate commerce, not to restrain physicians from public advocacy of medical opinions not shared by the FDA. We believe, therefore, that a doctor who merely advocates to other doctors a lawful prescription drug for a use not approved by the FDA, and does not distribute that drug to other doctors, is not holding that drug for sale within the meaning of the statute and therefore is not in violation of section 301(k) of the Act.”).

[169] Chaney v. Heckler , 718 F.2d 1174, 1176-77 (D.C. Cir. 1983); see also infra notes 194-195 and accompanying text.

[170] Chaney , 718 F.2d at 1176-77.

[171] Id. at 1179.

[172] Id. at 1179-82.

[173] Id. at 1186.

[174] Christopher, supra note 148, at 253 (citing Chaney , 718 F.2d at 1179-80).

[175] Chaney , 718 F.2d at 1182 n. 20 (The court used the “practice of medicine” exception to distinguish Evers , arguing that Dr. Evers was covered by the exception so long as he did not promote off-label use to other physicians).

[176] Heckler v. Chaney , 470 U.S. 821, 828, 837-38 (1985).

[177] Christopher, supra note 148, at 254.

[178] Id.

[179] Id.

[180] See Kessler, supra note 18, at 717-19.

[181] S. Rep. No. 1744, 87th Cong., 2d Sess. 59 (1962) (views of Senators Dirksen and Hruska)).

[182] 108 Cong. Rec. 10,278 (1962).

[183] Id.

[184] Kessler, supra note 18, at 718 (citing S. Rep. No. 1744, 87th Cong. 2d Sess. 59 (1962)).

[185] S. Rep. No. 1744, 87th Cong. 2d Sess. 59 (1962).

[186] S. Rep. No. 1744, 87th Cong. 2d Sess. 60 (1962) (quoting 21 C.F.R. §310.3(h)(4) (1998)).

[187] Kessler, supra note 18, at 718-19.

[188] Id.

[189] Id.

[190] Id.

[191] Id.

[192] 78 Cong. Rec. 2728 (1934) (statement of Senator Copeland).

[193] S. Rep. No. 1552, 87th Cong., 2d Sess. 1998 (1962).

[194] Prescribing for Uses Unapproved by the FDA, 37 Fed. Reg. at 16,503 (“This interpretation of the [FDCA] is consistent with congressional intent as indicated in the legislative history of the 1938 Act and the drug amendments of 1962.”).

[195] Id.

[196] See supra notes 163-179 and accompanying text; see also Doe v. Bolton , 410 U.S. 179, 197 (1973).

[197] See James L.J. Nuzzo, M.D., Independent Prescribing Authority of Advanced Practice Nurses: A Threat to the Public Health? , 53 Food & Drug L.J. 35, 45 (1998).

[198] Id.

[199] Id. at 810 (citing Hearings on Quality of Health Care – Human Experimentation, 1973, before the Subcomm. On Health of the Senate Comm. on Labor & Public Welfare , 93d Cong., 1st Sess. 63 (1973) (testimony of Nathan Kase, M.D.)).

[200] Id. (citing Temple, Legal Implications of the Package Insert , 58 Med. Clin. Am. 1151, 1157 (1974)).

[201] See supra note 157 and accompanying text.

[202] Kessler, supra note 18, at 722.

[203] Id. (citing Fink, Dispensing FDA-approved Drugs for Non-approved Uses , 2 U.S. Pharmacist 24 (1977)).

[204] See Dexedrine Prescribing Information, supra note 6.

[205] Christopher, supra note 148, at 252.

[206] See Prescribing for Uses Unapproved by the FDA, 37 Fed. Reg. at 16,504-05 (Action by the FDA could include: (1) label revisions to warn against the off-label use, (2) requiring the manufacturer to conduct studies to support the off-label use, (3) label revisions to include and define the off-label use (if sufficient data existed), (4) label revisions to forbid refilling of one-time prescriptions, (5) label revisions or investigational new drug (IND) requirements that limit the distribution of the drug to specially qualified physicians, (6) labeling directed at patients rather than physicians, or (7) revocation of approval of the drug).

[207] Id.

[208] Id.

[209] 21 U.S.C. §355(e) (2000).

[210] Kessler, supra note 18, at 733.

[211] Id. at 734.

[212] Id.

[213] Id.

[214] Id.

[215] Id.

[216] Id. at 735 (citing Dep’t of Health, Education, & Welfare, in re New Drug Application for Phenformin, NDA 11-624; NDA 12-752; NDA 17-126; NDA 17-127, Order of the Secretary Suspending Approval (July 25, 1977)).

[217] Id.

[218] Id.

[219] Kessler, supra note 18, at 735 (citing Statement of FDA Commissioner Donald Kennedy, Food and Drug Administration Ad Hoc Professional Meeting (Oct. 18, 1877)).

[220] Shapiro, supra note 122, at 809.

[221] Kessler, supra note 18, at 735.

[222] Shapiro, supra note 122, at 809.

[223] See Prescribing for Uses Unapproved by the FDA, 37 Fed. Reg. at 16,504-05.

[224] Kessler, supra note 18, at 737.

[225] See Amer. Pharm. Ass’n v. Weinberger , 377 F. Supp. 824 (D.D.C. 1974), aff’d sub nom. Amer. Pharm. Ass’n v. Mathews , 530 F.2d 1054 (D.C. Cir. 1976).

[226] Brief for Appellants at 21, Amer. Pharm. Ass’n v. Weinberger , decided sub nom. Amer. Pharm. Ass’n v. Mathews , 530 F.2d 1054 (D.C. Cir. 1976).

[227] Id.

[228] Id.

[229] See Weinberger , 377 F. Supp. at 828.

[230] 21 U.S.C. §355(d)(3) (2000) (“If the Secretary finds . . . [t]he methods used, in, and the facilities and controls used for, the manufacture, processing, and packing of such drug are inadequate to preserve its identity, strength, quality, and purity; he shall issue an order refusing to approve the application.”)

[231] See Mathews , 530 F.2d at 1054.

[232] Id. at 1056.

[233] Id.

[234] Id.

[235] Kessler , supra note 18, at 740.

[236] Id. (citing Wolfe, The Social Responsibility of the Physician in Prescribing Mind-Affecting Drugs , in Social Aspects of the Medical Use of Psychotropic Drugs 57 (R. Cooperstock ed. 1974)).

[237] See Cornum, supra note 8.

[238] See Shanker, supra note 7.

[239] See ABC Report, supra note 45.

[240] Id.

[241] Kessler, supra note 18, at 741.

[242] Shapiro, supra note 122, at 870.

[243] See generally Salbu, supra note 143.

[244] See Martin Page, CBER Status On Reform Initiatives: Industry Reactions and Comments , 52 Food & Drug L.J. 193, 195 (1997).

[245] Henry, supra note 126, at 365 (citing Gorman, Double-Duty Drugs , Time, Sept. 18, 1995, at 96).

[246] See Michael I. Krauss, Essay, Loosening the FDA's Drug Certification Monopoly: Implications for Tort Law and Consumer Welfare , 4 Geo. Mason L. Rev. 457, 472 (1996).

[247] Id.

[248] Salbu, supra note 143, at 193.

[249] Id. at 194 (citing Martin Wright, Prescribing "Off-Label" Drugs for Wound Healing Is Common , Dermatology Times, July 1996, at 35).

[250] Salbu, supra note 143, at 194.

[251] Id. (citing Ramon A. Torres & Michael Barr, Impact of Combination Therapy for HIV Infection on Inpatient Census , 336 New Eng. J. Med. 1531, 1532 (1997) (stating that therapies that combine two nucleoside analogues with a protease inhibitor, first introduced into medical practice in 1995, have been widely hailed as a major breakthrough in HIV and AIDS treatment, resulting in substantial reduction in disease progression and mortality); Robert Steinbrook, Battling HIV on Many Fronts , 337 New Eng. J. Med. 779 (1997) (observing substantial decline in AIDS deaths immediately following the initiation of antiretroviral combination therapies); Kenneth P. Berkowitz et al., Congress Tries to Bridge the "Label Gap," But Nobody Is Cheering , Med. Mktg. & Media, Jan. 1998 (citing panel comments of Steven K. Carter that 90% of AIDS drug use is off-label, as the drugs are approved for single-agent uses at end stages of the disease but often used in combination during earlier stages of the disease; and comments of Mark Smith that off-label use of AIDS treatments is "pretty much 100 percent").

[252] Shapiro, supra note 122, at 813.

[253] Id. at 812.

[254] Id.

[255] Id.

[256] See supra notes 208-222 and accompanying text.

[257] See Finkel, Phase IV Testing FDA Viewpoint and Expectations , 33 Food Drug & Cosm. L.J. 181, 185-88 (1978).

[258] Shapiro, supra note 122, at 813 (citing U.S. Dep’t of Health, Education and Welfare, Review Panel on New Drug Regulation, Final Report 92-93 (1977)).

[259] Id. at 813.

[260] Id. at 814.

[261] See Franklin & Lowell, Unapproved Drugs in the Practice of Medicine: Beclomethasone – A Case In Point , 292 New Eng. J. Med. 1075, 1076 (1975)).

[262] See Crout, In Praise of The Lowly Package Insert , 29 Food Drug & Cosm. L.J. 139, 143-44 (1974); see also supra notes 155-179 and accompanying text.

[263] See NAVMED Guide at 8 (“At low dosages amphetamines primarily increase alertness with significant side effects only beginning as the doses are increased. Well-rested subjects evaluated in the laboratory showed that 5 mg of dextro-amphetamine (Dexedrine) counteracted small performance decrements caused by [fatigue]. An intermittent low dose regimen, therefore, has the capability of maintaining aviator performance yet avoiding undesired medication effects.”).

[264] Salbu, supra note 143, at 196.

[265] Id.

[266] Id. at 197.

[267] Id.

[268] Christopher, supra note 148 (citing 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); Robin Marantz Henig, FDA Assails "Off-Label" Uses of Cosmetic Drugs; Painful Medical Problems Continue for Years, Patients Allege , Wash. Post, June 18, 1991, at Z7).

[269] See, e.g. , Archer, A Guide Into Chaos; Resist It , 227 J.A.M.A. 1297, 1398 (1974).

[270] Shanker, supra note 7 (citing "Air Crew Fatigue as a Human Factor in U.S.A.F. Class A Mishaps — a Twenty-Year Review”).

[271] The current investigation of Majs. Schmidt and Umbach has yet to determine whether amphetamine use was a contributing factor in the accident in Afghansistan.

[272] See NAVMED Guide at 11.

[273] Id. During Desert Storm, this squadron flew approximately 7000 hours in 1200 sorties using a pool of 35 pilots and shot down a total of 16 MiG aircraft.

[274] Id.

[275] See supra notes 117-141 and accompanying text.

[276] Kessler, supra note 18, at 718.

[277] Salbu, supra note 143, at 202 (citing Nancy A. Wynstra, Breast Cancer: Selected Legal Issues , 74 Cancer 491, 505 (1994)).

[278] D’Andrade, Communicating with Physicians: A Regulatory Overview , 29 Food Drug & Cosm. L.J. 154, 157 (1974).

[279] Shapiro, supra note 122, at 816.

[280] Id. (citing B. Barber, Drugs and Society 40 (1967)).

[281] Shapiro, supra note 122, at 817.

[282] Id. ; see also Ball, PSRO – An Alternative To The Medical Malpractice System As a Quality Assurance Mechanism , 36 Md. L. Rev. 566, 582 (1977).

[283] Shapiro, supra note 122, at 817 (citing H. Dowling, Medicines for Man: The Development, Regulation, and Use of Prescription Drugs 127 (1970); Eisenberg, The Social Imperatives of Medical Research , 198 Sci. 1105 (1977)).

[284] Id. (citing H. Dowling at 127).

[285] Id. (citing H. Dowling at 128).

[286] Nancy K. Plant, Prescription Drug Promotion on the Internet: Tool for the Inquisitive or Trap for the Unwary? , 42 St. Louis U. L.J. 89, 129 (1998).

[287] Kessler, supra note 18, at 719.

[288] Henry, supra note 126, at 376.

[289] Id.

[290] Id. ; see also Salbu, supra note 143, at 203.

[291] Salbu, supra note 143, at 203.

[292] Id.

[293] Id.

[294] Henry, supra note 126, at 377.

[295] Salbu, supra note 143, at 203.

[296] See Prescribing Information, supra note 6.

[297] Id. at 204.

[298] Id.

[299] Id.

[300] Id.

[301] See 21 U.S.C. §355(i)(4) (2000); see also 10 U.S.C. §980(a) (“Funds appropriated to the Department of Defense may not be used for research involving a human being as an experimental subject unless (1) the informed consent of the subject is obtained in advance; or (2) in the case of research intended to be beneficial to the subject, the informed consent of the subject or a legal representative of the subject is obtained in advance.”).

[302] NAVMED Guide at 21. The full text of the “Informed Consent for Operational Use of Dexedrine” is as follows:

It has been explained to me and I understand that the US Food and Drug Administration has not approved the use of Dexedrine to manage fatigue. However, I understand that Dexedrine previously has been approved for the treatment of sleeping disorders, obesity, and attention deficit disorder. Subsequently, it has also been found effective in treating the symptoms of chronic fatigue. I understand that it is for the benefit of controlling the symptoms of chronic fatigue that I have been provided a single dosage of the medication. I further understand that the decision to take this medication is mine alone.

In addition, I understand that possible common side effects of Dexedrine include insomnia, nervousness, and appetite loss. Possible gastrointestinal disturbances include diarrhea, constipation, and/or dryness of the mouth. Other known, less common side effects include rapid heartbeat, heart palpitations, elevation of blood pressure, tremor, headache, euphoria, depression. Addiction and tolerance are also risked through prolonged use at increased dosages.

I have also been informed and understand that use of Dexedrine simultaneous with the use of certain other prescription or over-the-counter medications is not advised. I have informed the flight surgeon of any other medications I am taking at this time.

My decision to take Dexedrine is voluntary. I understand that I am not being required to take the medication. Neither can I be punished if I decide not to take Dexedrine. However, should I choose not to take it under circumstances where its use appears indicated, I understand safety considerations may compel my commander, upon advice of the flight surgeon, to determine whether or not I should be considered unfit to fly a given mission.

I understand that a copy of this notice shall be inserted in my medical record. If I have any questions with regards to the administration of Dexedrine, I will raise them with the flight surgeon.

[303] 21 C.F.R. §50.25 (1998).

[304] See NAVMED Guide at 21.

[305] See Dexedrine Prescribing Information, supra note 6.

[306] Id. (emphasis added).

[307] See ABC Report, supra note 45.

[308] 21 C.F.R. §50.20 (1998).

[309] See NAVMED Guide at 21.

[310] See ABC Report,supra note 45.

[311] See id. Capt. Matt Skobel, Umbach's military lawyer, said pilots need the pills in order to complete their difficult missions (“These missions were at the limit of the pilots' physical and mental endurance. And these pills were required to allow them to do it.”).

[312] See id. ("These men are patriots, these men were sent to fight a war and they're put in a situation where it's either take these pills or you don't fly," Skobel said. “For a pilot, it's not a choice at all.").

[313] See supra notes 235-240 and accompanying text.

[314] Salbu, supra note 143, at 207.

[315] See Susan Heilbronner Fisher, Note, The Economic Wisdom of Regulating Pharmaceutical "Freebies," 1991 Duke L.J. 206, 210, 211-12 (noting that pharmaceutical company "retailers" often treat physicians to meals and "freebies," and pharmaceutical companies pay physicians substantial honoraria to speak at company-sponsored conferences and mention the sponsor's product).

[316] Salbu, supra note 143, at 208.

[317] See supra note 295 and accompanying text.

[318] Salbu, supra note 143, at 208.

[319] Id.

[320] See supra notes 235-240 and accompanying text.

[321] Cornum, supra note 8.

[322] Id.

[323] Id.

[324] Id.

[325] Knickerbocker, supra note 102.

[326] Id. (citing document from the Pentagon’s Defense Advanced Research Projects Agency (DARPA), which states “[t]he capability to resist the mental and physiological effects of sleep deprivation will fundamentally change current military concepts of 'operational tempo' and contemporary orders of battle for the military services. In short, the capability to operate effectively, without sleep, is no less than a 21st Century revolution in military affairs that results in operational dominance across the whole range of potential U.S. military employments.").

[327] Id.

[328] Id. (quoting retired Rear Adm. Stephen Baker, the Navy’s former chief of operational testing and evaluation, as stating "[f]uturists say that if anything's going to happen in the way of leaps in technology, it'll be in the field of medicine. This 'better warrior through chemistry' field is being looked at very closely.”).

[329] Knickerbocker, supra note 102.

[330] Id.

[331] See supra notes 52-116 and accompanying text.

[332] See supra notes 242-272 and accompanying text.

[333] See supra notes 273-294 and accompanying text.

[334] Kessler, supra note 18, at 750; see also supra notes 203-239 and accompanying text.

[335] Kessler, supra note 18, at 750.

[336] Id. at 752.

[337] Id. at 750-51.

[338] Id. at 753.

[339] Id.

[340] Id.

[341] Id. at 754.

[342] Id.

[343] Id.

[344] See id.

[345] Id. at 756.

[346] Id.

[347] Id.

[348] Id.

[349] Id.

[350] Id. at 756-57.

[351] Id.

[352] Pines, Regulatory Letters, Publicity and Recalls , 31 Food Drug Cosm. L.J. 352 (1976).

[353] Kessler, supra note 18, at 757.

[354] Id. at 758.

[355] Id.

[356] Id.

[357] Id. (citing H. Conn, Current Therapy 447 (1978)).

[358] Kessler, supra note 18, at 758.

[359] Id . at 758-59.

[360] Id.

[361] Id.

[362] Id. at 759.

[363] Id.

[364] See notes 24-51 and accompanying text.

[365] See Cornum, supra note 8.

[366] This is the crux of Maj. Schmidt and Maj. Umbach’s defense in the Afghanistan friendly-fire incident. See supra notes 1-7 and accompanying text.

[367] See supra notes 155-200 and accompanying text.