Furthering the Cause of Self-Medication through

Food and Drug Administration Regulation

Monica Anne Leimone

INTRODUCTION

Ever since the enactment of the Pure Food and Drugs Act of 1906,¹ regulatory policy towards pharmaceutical drugs has been influenced to varying degrees by a perceived right to self-medication. The development of Food and Drug Administration (FDA) authority reveals the tensions inherent in drug regulation; FDA regulations reflect the dual desire to recognize individual autonomy while, at the same time, safeguarding society from potential hazards. The stakes are particularly high in the arena of drug regulation, where the costs and benefits of curtailing risks involve a life or death equation. And, the interests involved in shaping this equation are many and very powerful. At every step of the way, new regulatory developments have involved a fine balance between the perceived interests of different powerful actors: physicians, pharmacists, drug manufacturers, and consumers.² Today, health administrators, such as hospitals and HMOs, have also come to play an important role in the allocation of costs and authority in the health care field.³ As this paper

¹Pub. L. No. 59—384, 34 Stat.768 (1906) [Hereinafter referred to as 1906 ActI.

² The vocal public consists of numerous special interest groups, each with its own prejudices and biases. some of them readily come to mind — consumer activists, members of the regulated industry associations, and citizens' organizations interested in specific issues.. .In the past, one or more of these groups may have had greater access to the Agency and a correspondingly greater voice in its decisions. We are continually working to achieve balance among all of these competing interest groups rather than to let any one dominate or appear to have greater influence. Peter Barton Butt, Philosophy of Regulation under the Federal Food, Drug, and Cosmetic Act, 50 FOOD & DRUG L.J. 101,104 (1995).

³These new actors have introduced pressure f or cost—containment in medical decisionmaking. Often, this means shifting to consumers costs which were traditionally borne by government and private insurance plans. This issue will be explored further in the section on the changing market for pharmaceutical products.

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will demonstrate, the increasing focus on self-medication in FDA regulation of drugs represents an attempt to reconcile these different interests in light of prevailing technological and economic developments.

The Durham-Humphrey Amendment of l951⁴ set the stage for FDA oversight of medicinal drug usage by bifurcating the medicinal drug market into prescription drugs, which can be obtained only with the consent of a physician, and nonprescription or over-the-counter (OTC) drugs, which are readily available to consumers seeking to self—medicate. Prior to 1951, manufacturers of drugs were empowered to make this distinction and, prior to 1938, consumers faced their own decisions about drug purchases, unhampered and unaided by regulation. Today, the sharp distinction between prescription and OTC drugs still exists, as law, and determinations of drug status are made by the FDA. However, new scientific, sociological and economic developments have dramatically altered the factors which traditionally forced classification on one or the other side of this boundary.

Propelled by a combination of market and regulatory factors which will be explored further in this paper, many drug manufacturers have sought to have their products redesignated from prescription-only to OTC. The FDA has been receptive to these changes but they have forced an evolution in the way OTC drugs are regarded. As will be discussed later, refinements in the ability to determine the way consumers actually use these products have bolstered the cause of self-medication and autonomy in health care

⁴Pub. L. No. 82—215, 65 Stat. 648 (1951), as amended, 21 U.S.C. S353 (1982).

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in the United States and blurred some of the distinctions thought necessary in 1951.

After a brief description of the concept of self-medication, this paper will trace the evolution of the regulatory distinction between prescription and OTC drugs by describing the history of such regulation from the Durham-Humphrey Amendment to the present framework for prescription to OTC switches. The focus will be on the different powerful interests involved in the debate and the ways in which these different interests have shaped attitudes towards consumer autonomy. Finally, it will explore the ways in which technological developments, such as the advent of actual use studies and the growing ability to pinpoint chronic drug toxicity, have opened the door for a return to consumer autonomy. This enhanced ability to collect usage data will prove to be more and more important as the restructuring of the health care industry returns to the consumer the onus of the responsibility for his or her own health care decisions.

THE CONCEPT OF SELF-MEDICATION

Although it has seen a resurgence of late, the concept of self-medication is not new. "Self-medication is clearly described in the earliest records uncovered by the historians, for the most primitive archeological remains testify to the use of various plant, mineral and animal materials as medicines."⁵ Americans in the nineteenth century often relied on popular domestic medical manuals by John C. Gunn and Samuel Thomson who declared, "Every

⁵Maurice L. Tainter, Introductory Statement, 27 FOOD DRUG COSM. L. J. 787 (1972).

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man his own physician!"⁶ For the purposes of this paper, I use the term "self-medication" to refer to the circumstances in which a consumer chooses a medicinal drug for the purposes of treating an ailment and then purchases and administers the drug without obtaining a prescription from an intermediary such as a physician or nurse practitioner.⁷ Almost everyone makes the determination at some point to choose an OTC remedy.⁸ Self-medication may or may not involve self-diagnosis of the original ailment.⁹

For a long time, experts on food and drug law have alluded to a "right" to self-medication.¹⁰ There are two reasons why self-medication is seen as a beneficial right. First, there is the idea that consumers are in the best position to make determinations about their own health care. Second, there is the idea that choice has a value in and of itself and that -

⁶ HARVEY YOUNG, PURE FOOD 24 (1989).

⁷Admittedly, even in the case of prescription medications, a consumer faces some degree of autonomy in choosing whether or not to purchase the product and whether or not to adhere to physician directions or the directions in a package insert.

⁸ People with respiratory or musculoskeletal complaints seek medical care less than 4% of the time. A more common strategy, used about 60% of the time, is taking medication, typically non—prescription, for respiratory complaints.. .Discussing symptoms and treatment with family or friends and restricting one's activities are also far more likely strategies than seeing a physician. Chris Anne Raymond, Survey adds evidence that office visits indicate 'just tip of the iceberg' of medical problems, 259 J. AM. MED. ASS'N 647 (1988) (Health in Detroit Study).

⁹1n fact, the ability to self—diagnose a condition seems to have become less important for the purposes of determining OTC status. See Peter Barton Butt, A Legal Framework for Future Decisions on Transferring Drugs from Prescription to Nonprescription Status, 37 FOOD DRUG COSM. L. J. 427, 436 (1982).

¹⁰Tainter, supra note 5, at 787 ("Self-medication is a fundamental human need which, as part of the instinctive self—preservation mechanisms, ranks with hunger and procreation as one of the prime drives that ensure the continuation of the human species. "); Gary L. Yingling, President of the Food and Drug Law Institute, Does Self-Medication Have a Role in Our Society?, 36 FOOD DRUG COSM. L. J. 604,605 (1981)("If you stop for a minute and reflect on the history of man, it is apparent that self—medication serves a fundamental human need and is part of a self—preservation instinct.").

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regardless of the efficacy of the choices consumers make - they are better off for having control over their own health. In the words of Senator Henry Waxman, former Chair of the House Subcommittee on Health and the Environment, "Call it self—care, or call it healthy life-styles. It is an important national objective...Consumers like the opportunity to decide on the medications they take for minor ailments. They like being in control of minor health care decisions."¹¹

Dr. Frank Young, former Commissioner of the FDA, has said that, "Government will continue to emphasize the responsibility of the consumer in maintaining a healthy lifestyle and in handling health problems appropriately. Of course, government will continue to require the large margin of safety that assures consumer protection and that the medicines be effective."¹² This statement lays out the parameters within which government will allow the consumer to operate.

MIT economist Peter Temin analyzes the choices people make regarding their own health¹³ by distinguishing three separate modes of behavior: instrumental, customary and command. A person directly implementing the orders of another individual is in command mode. Customary behavior involves making decisions based on habit, whether one relies on what has worked in the past or what is comfortably assumed. Instrumental behavior involves a

¹¹H.A. Waxman, Self—care: the Legislative Perspective, Remarks at the FDA's and the Proprietary Association's seminar "Self—care/Self—Medication in America's Future," Washington, D.C. (Feb. 8, 1988).

¹²1d. (remarks of F.E. Young, former Commissioner of Food and Drugs, A Theme in Three Parts: Science; Society; the Economy).

'¹³P. TEMIN, TAKING YOUR MEDICINE: A HISTORY OF DRUG REGULATION IN THE UNITED STATES (1980).

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rational analysis of different variables and a determination of what action is in one's own best interest. The classic law and economics framework is built on an assumption that individual actors always employ instrumental behavior.

Temin describes the history of drug regulation in the United States within the context of this behavioral schema. According to him, the post-1951 regulatory framework is premised on the notion that consumers are incapable of demonstrating instrumental behavior in choosing medications and making the choices which are best for their own health care.¹⁴ This view of the consumer justifies a certain degree of paternalism.¹⁵ Based on a belief that consumers are more likely to use the customary mode in their decision making, relying on habit, hearsay, or manipulative marketing, the decision-making function has been relegated to intermediaries such as the FDA and prescribing physicians in order to save consumers from their own poor choices.¹⁶ Temin develops this thesis as it applies to drug regulation up through the 1970s. The current move towards allowing increasing availability of self-medication, viewed in this framework, reflects a growing faith in the consumer's ability to move beyond the customary mode of behavior and employ instrumental decision—making.

¹⁴ id at 17.

¹⁵"We struggle with an acceptable level of paternalism in making our recommendations on these issues." Randy Juhl, Chair Nonprescription Drugs Advisory Committee, The Nonprescription Drugs Advisory Committee and the RXto-OTC Switch Process, Proceedings from a Forum Sponsored by the Tufts Center for the Study of Drug Development, Tufts University (May 24, 1994), in MOVING PRESCRIPTION DRUGS TO THE OVER-THE-COUNTER MARKET: THE IMPACT OF COST CONTAINMENT AND HEALTH CARE REFORM [Hereinafter Tufts Forum] at 33.

¹⁶TEMIN, supra note 13, at 54-55 (viewing this regulation in the context of other post—Depression, New Deal regulation to address perceived failures in the market economy' s ability to protect citizens).

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Most recently, the emphasis on self-medication has surfaced in the context of prescription to OTC switches. The hearings concerning the - as yet, unsuccessful - switch of acyclovir (a topical herpes medication) from prescription to OTC status provide a dramatic example of this type of language.

[W]e were dealing with people taking control of their own health, being involved in their own health care. We discussed the increasing sophistication of the population. By making the drug available OTC, we would be allowing patients to make a diagnosis and to treat a condition with their own knowledge. At the same time, we were exploring a new role for doctors, pharmacists, and nurses, that of teacher as opposed to what might be characterized as a more traditional, parental role. ¹⁷

As more and more prescription drugs become eligible for a switch, the strict boundary between prescription and nonprescription drugs laid out by the Durham-Humphrey Amendments faces some pressure.

What we were doing at that meeting [the open meeting of the Non-prescription Drugs and the Anti-Viral Drugs Advisory Committees regarding the potential switch to OTC status of the drug acyclovir] was exploring the flexibility in the Durham-Humphrey Amendments to the Food, Drug and Cosmetics Act. We believed that the

¹⁷Tufts Forum, supra note 15, at 17 (remarks of Michael Weintraub, Director, Office of OTC Drug Evaluation).

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principles embodied in the amendments were so important

that a public hearing was appropriate.¹⁸

With health care costs skyrocketing, health care management has moved to a framework which places cost—management on a par with health management. Technological advances and industry restructuring since the early 1980s have forced changes in the regulatory environment; it is no longer merely expedient to allow consumer involvement in health care processes. In the earlier part of the century, lack of knowledge formed a dual-edged sword for consumer autonomy. Consumers, in general, did not have the type of information they needed in order to make sound decisions about a wide range of pharmaceutical products and their therapeutic effects. Regulators, for their part, had a less sophisticated knowledge of pharmaceutical science than it is possible to obtain today. More importantly, they did not have the tools to enable them to understand the customer intimately enough to be able to develop effective ways to convey information about pharmaceutical drug usage. In such an environment, consumers could not be expected to behave in an instrumental fashion. Today, the prognosis for self-medication is more optimistic.

It is clear that the prescription/OTC dividing line of the Durham-Humphrey Amendments is being strained. In order to understand this structure and the subsequent pressures, it is important to look to the factors which led up to the 1951 legislation. The legislative history of the different major drug

¹⁸"But what is perhaps most interesting is that these medications are changing the boundaries of the Durham-Humphrey Amendments and are pushing the intent of the amendments to the very limit." Id. at 21.

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regulation bills indicates that each of these bills was designed with an eye to the potential effects on the right of self-medication.

HISTORY

The 1906 Act

Regulation of the American drug manufacturing industry began with the Pure Food and Drugs Act of 1906¹⁹ (1906 Act) which prohibited the shipment or delivery in interstate commerce of adulterated or misbranded goods. Consumers of the time were faced with an array of so-called "patent" medicines which often contained little more than colored water with opium or alcohol.²⁰ In the early part of the century, the AMA had made sporadic attempts to crack down on the sale and usage of nostrums but it had yet to seriously attempt to thwart this practice.²¹ State criminal statutes of the time attempted to prevent the retail sale of adulterated or misbranded drugs but they were ineffective against goods manufactured in another state and shipped in unbroken packages.²² A national statute was needed to reach those deleterious substances which escaped state jurisdiction. The dawn of the Progressive Era provided a ripe setting for such legislation.

¹⁹Pub. L. No. 59-384, 34 Stat.768 (1906) [Hereinafter referred to as 1906 Act].

²⁰ 59 CONG. REC. 8905—8909 (1906).

²¹TEMIN, supra note 13, at 29. In fact, up until 1905, the Journal of the American Medical Association contained advertisements for many of these questionable products. YOUNG, supra note 6, at 188.

²² 59 CONG. REC. 2723 (1906) (states see themselves as Constitutionally constrained, by the Interstate Commerce Clause, from exercising jurisdiction over such products).

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Harvey Wiley, Chief Chemist of the United States Department of Agriculture (USDA), played an instrumental role in marshaling support for the passage of the 1906 Act which eventually delegated authority for enforcement of its provisions to the Bureau of Chemistry within the USDA.²³ Concern about drug adulteration and about dangerous or addictive substances in "patent" medicines had begun to take hold along with concerns about adulteration of food products in the United States. Equipped with both an M.D. and a B.S. in chemistry, Wiley made a crusade out of his concerns over adulteration of food and drugs. He appealed to various segments of society, eventually garnering support from groups as diverse as the Women's Christian Temperance Union²⁴ and the distillers of "pure" whiskey.²⁵

A series of pure food bills were introduced into Congress with notable consistency, beginning in the latter part of the 19th century.²⁶ These bills faced opposition from manufacturers such as the baking powder companies and the makers of such products as blended whiskey and oleomargarine.²⁷ The Paddock Bill had managed to pass the Senate in 1892²⁸ but serious interest in such

²³The Bureau of Chemistry was renamed the Food, Drug, and Insecticide Administration in 1927, which was shortened to the the Food and Drug Administration in 1930. The FDA moved from the Department of Agriculture to the Federal Security Administration(FSA) in 1940, which became a part of the Department of Health, Education and Welfare (HEW)in 1953. HEW was redesignated the Department of Health and Human Services (BBS) in 1979 pursuant to Public Law No. 96—88, S508, 93 Stat. 692 (1979). See Michael Brannon, Organizing and Reorganizing FDA, in FOOD AND DRUG LAW 113 (Richard M. Cooper ed., 1991).

²⁴ YOUNG, supra note 6, at 186.

²⁵ Id. at 167.

²⁶Twenty—seven bills were introduced in Senate and twenty—nine in the House over the course of eighteen years. Federal Food and Drugs Act and Decisions, USDA OFFICE OF THE SOLICITOR, FOOD & DRUGS ACT (C.A. Gwinn ed., 1914) 810-811.

²⁷YOUNG, supra note 6, at 168.

²⁸USDA OFFICE OF THE SOLICITOR, FOOD & DRUGS ACT, supra note 26, at 810.

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proposals was not reignited until 1902 with the 57th Congress. Twice during the 57th and 58th Congress, after extensive hearings in both the House and the Senate, the House passed a bill and the Senate refused to bring it to a vote.²⁹

A combination of factors coalesced in early 1906 to move Senator Heyburn's version³⁰ of a pure food and drugs bill through the 59th Congress. A series of compromises with different industries, often negotiated by Harvey Wiley, had paved the way for smoother passage. The Proprietary Association³¹ opposed regulations requiring disclosure of the formulas in drugs and had successfully managed to constrain earlier versions of the bill to only those drugs listed in the Pharmacopoeia of the United States (USP).³² The American Pharmaceutical Association (APA), as well as the national associations of wholesale and retail dealers, supported this narrow definition.³³ By the time the 1906 Act was being debated in the House, the more reputable manufacturers of proprietary drugs realized that they had much to gain from an expanded definition which would burden their less-scrupulous competitors.³⁴ The expanded definition included in the Heyburn

²⁹YOUNG, supra note 6, at 157.

³⁰ 59th Cong., 1st Sess. (1905).

³¹The Proprietary Association, an organization of drug manufacturers is known today as the Nonprescription Drug Manufacturers Association (NDMA). Hereinafter, the organization will be referred to by its name during the time period being discussed.

³²YOUNG, supra note 6, at 169.

³³J. YOUNG, THE TOADSTOOL MILLIONAIRES: A SOCIAL HISTORY OF PATENT MEDICINES IN AMERICA BEFORE FEDERAL REGULATION 67-98 (1961).

³⁴[A]mong the most reputable and financially powerful pharmaceutical manufacturers in the United States, and for that matter, in the world, are now making it a business policy to make know to the public the contents of their remedies. Notable among these concerns are Parke, Davis & Co., Fred K. Stearns Company, Detroit; Sharpe & Dobme, Baltimore; Schierfelin & Co., New York; E.R. Squibb & Sons, New York; Fairchilds Brothers & Foster, New York; and Henry K. Wampole & Co., Philadelphia. 59 CONG. REC. 9072 (1906).

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Bill brought all proprietary drugs under its umbrella since it required all drugs to match the standard of strength and purity set forth by the manufacturer on the label.³⁵ In the end, the 1906 Act covered the drugs in included in the USP and the National Formulary (NF) as well as "any substance or mixture of substances intended to be used for the cure, mitigation, or prevention of disease of either man or other animals."³⁶

President Roosevelt initiated the 59th congress with a State of the Union address that contained a brief endorsement of the pure food cause.³⁷ The AMA sent a lukewarm statement to Congress establishing its support for the new bill in February of 1906.³⁸ However, it was the ground swell of support from the public which provided the necessary momentum to move the bill forward. The publication of Upton Sinclair's best-selling book, The Jungle, in February 1906, stimulated outrage over the conditions in Chicago meat packing plants and led to greater public concern over food purity.³⁹ In addition, Samuel Hopkins Adams of Collier's Weekly magazine conducted a series of investigations about the various nostrums available on the market and the potential dangers inherent in such products.⁴⁰ This survey, consisting of numerous accounts of young children being poisoned by "soothing sirup" and

³⁵ 59 CONG. REC. 2721—2722 (1906).

³⁶ 34 Stat. 768 S6 (1906).

³⁷YOUNG, supra note 6, at 204.

³⁸"[the bill] would afford adequate protection to honest manufacturers of and dealers in such products, and security against imposition, fraud, or danger to the buyer." Action of the American Medical Association on the Heyburn Pure Food and Drug Bill, 59 CONG. REC. 2721 (1906).

³⁹YOUNG, supra note 6, at 6.

⁴⁰ 59 CONG. REC. 8905 (1906).

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adults unwittingly developing harrowing addictions to opium, received considerable attention in Congressional debate about the drug provisions in the bill. Riding this tide of consumer progressivism, the Food and Drugs Act was finally passed by both houses of Congress and signed into law on June 30, 1906.⁴¹

The new law promoted market competition and facilitated consumer purchasing of food and drugs by making information about these purchases more reliable.⁴² Labels were required to carry truthful information which consumers could depend upon. The 1906 Act specified that a drug would be deemed misbranded

First. If it be an imitation of or offered for sale under the name of another article. Second. If the contents of the original package shall have been removed, in whole or in part, and other contents shall have been placed in such package, or if it fail to bear a statement on the label of the quantity or proportion of any alcohol, morphine, opium, cocaine, heroin, alpha or beta eucaine, chloroform, cannabis indica, chloral hydrate, or acetanilide, or any derivative or preparation of any such substances contained therein.⁴³

In general, misbranding referred to "any statement...which shall be false or misleading in any particular."⁴⁴ Senator Heyburn referred to the bill as "an act to compel the telling of the truth in regard to the business in which men are engaged."⁴⁵ Thus, the

⁴¹ 59 CONG. REC. 9655, 9740 (1906).

⁴²TEMIN, supra note 13, at 31.

⁴³ 1906 Act S8.

⁴⁴ id.

⁴⁵ 59 CONG. REC. 2721 (1906).

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1906 Act aided the cause of consumer autonomy and consumer self-medication.

An analysis of the debate in both houses of Congress demonstrates that the legislators saw the consumer as a responsible, instrumental actor. Self-medication was not explicitly referenced because it was inherent in the nature of the legislation which allowed consumers access to all - appropriately labeled - drug products. In fact, it was assumed that if harmful substances were clearly labeled, consumers would respond appropriately and cease to purchase the product.⁴⁶ The federal government, under the new Act, would ensure proper information, not limited access. "It will not deny men the privilege of getting drunk on bitters, if they choose to do so; but it does say that they shall not be deceived into intoxication in the belief that they are taking harmless medicines."⁴⁷ This response addressed the concerns of the multitude of American citizens whose sad tales of misfortune were reprinted in the Congressional Record: "'She declared that, had she known the preparation contained morphine, she would never have used it' ... 'I would not have taken acetanilide, knowing it to be such, on any account' ... 'I truly believe that people are daily using these drugs innocently; they know not what they are. '"⁴⁸

⁴⁶ Senator by indirection is going to utterly destroy the so-called 'patent medicine business.' If that is the purpose of the bill, why not state it?" Id. 2722 (statement of Sen. Gallinger).

⁴⁷ 59 CONG. REC. 8988 (1906). Similar sentiments were echoed throughout the debate: "We do not want to interfere with the sale of proprietary pharmacopoeial remedies under their own proper names." Id. at 8996. "The general purpose of this bill is to protect the public health, and it is to secure honesty in trade and to enable people to know just exactly what they get." Id. at 8998.

⁴⁸1d at 8907—8908.

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The 1906 Act dealt primarily with representations on drugs. FDA concerns about safety were embedded in the provisions on misbranding; if a drug was not safe for human consumption, than any indications on the label comprised misbranding. Concerns about drug efficacy surfaced in 1914, with the refinements contained in the Sherley Amendment.⁴⁹ This amendment specified that fraudulent false therapeutic claims would be considered misbranding. Congress was responding to a Supreme Court decision in which Justice Holmes held that the 1906 Act did not prohibit false health claims even when the manufacturer knew them to be false.⁵⁰ The Sherley Amendment's requirement of proof of scienter severely weakened the provision since manufacturers could always evade liability by claiming ignorance of their products' shortcomings.⁵¹ The 1906 Act was amended three more times,⁵² but it was not until 1938 that the FDA acquired the administrative authority necessary to develop a more comprehensive scheme of drug regulation and move the agency beyond the role of mere "policing organization. "⁵³

⁴⁹Pub. L. No. 62—301, 37 Stat. 416 (1912).

⁵⁰United States v. Johnson, 221 U.S. 488 (1911).

⁵¹TEMIN, supra note 13, at 42.

⁵² 37 Stat. 732 (1913), 46 Stat. 1019 (1930), 48 Stat. 1204 (1934), and 49 Stat. 871 (1935).

⁵³David F. Cavers, The Food, Drug and Cosmetic Act of 1938: Its Legislative History and Its Substantive Provisions, 6 LAW & CONTEMP. PROBS. 2, 6 (1939).

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The 1938 Act

The Food, Drug and Cosmetics Act of l938⁵⁴ (FDCA) was first considered in 1933, when Senator Royal Copeland introduced into the Senate a bill referred to as the "Tugwell Bill"⁵⁵ after Franklin D. Roosevelt's Undersecretary of Agriculture, Rexford Tugwell. Tugwell, member of a task force organized under President Roosevelt to revise the 1906 Act,⁵⁶ came to be associated with the bill in much the same way as Wiley had come to be associated with the 1906 Act. To the general public, the Tugwell Bill symbolized the newly emergent New Deal legislation, replete with all its controversy.⁵⁷ Congress struggled with different versions of the bill for five years; a deep distrust of New Deal administrators such as Mr. Tugwell weighed against the need for enhanced regulation of food and drugs.⁵⁸ The original task force proposal contained a broad expansion of the FDA's administrative authority by granting the Secretary of Agriculture greater discretion in promulgating regulations which were to have the "force and effect of law."⁵⁹ Much of the debate over this bill and its successors⁶⁰ centered around the nature of procedural protections for industry in the face of FDA rulemaking.⁶¹

⁵⁴Pub. L. No. 75-717, 52 Stat. 1040 (1938) [hereinafter referred to as FDCA].

⁵⁵ S. 1944, 73d Cong., 1st Sess. S 23 (1933).

⁵⁶Joel E. Hoffman, The Food and Drug Administration's Administrative Procedures , in FOOD AND DRUG LAW 1, 5 (Richard M. Cooper ed., 1991).

⁵⁷TEMIN, supra note 13, at 41.

⁵⁸5ee Hoffman, supra note 56.

⁵⁹ s.1944, 73d Cong., 1st Sess. S23(a) (1933), reprinted in FEDERAL FOOD DRUG AND COSMETIC ACT: A STATEMENT OF ITS LEGISLATIVE RECORD 49 (Charles W. Dunn ed., 1938) [hereinafter referred to as 1938 HISTORY].

⁶⁰S.2000, 73d Cong., 2d Sess. (1934); S.2800, 73d Cong., 2d Sess. (1934); S.5, 74th Cong., 1st and 2d Sess. (1935), 75th Cong., 1st and 3d Sess. (1937)

⁶¹Cavers, supra note 53, at 9.

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Congressmen put forth a series of amendments to the first two versions of the bill providing for independent administrative oversight of the FDA;⁶² opponents of later versions favored strict statutory standards rather than administrative discretion at any level.⁶³

As in the case of the 1906 Act, most of the support for the new legislation came from within the government. The drug manufacturers refrained from vigorous protest of the legislation, not wanting to diminish consumer goodwill they had built up over the years.⁶⁴ They preferred instead to support the passage of a law which contained provisions more favorable to the industry.⁶⁵ The Proprietary Association objected to the FDA's power to make "multiple seizures" of an adulterated product, an enforcement mechanism which had proved to be particularly burdensome to the industry.⁶⁶ Additional objections involved the scope of Federal Trade Commission (FTC) and FDA jurisdiction over advertising.⁶⁷ Manufacturers of drug products were also concerned about their ability to challenge FDA rulings under the evidentiary standard laid out in the original Tugwell Bill,⁶⁸ and carried forward in its successors, which declared that findings of fact would be conclusive. The final legislation provided that "the

⁶²Hoffman, supra note 56, at 8.

⁶³1d. at 8; 1938 HISTORY, supra note 59, at 391.

⁶⁴Cavers, supra note 53, at 4.

⁶⁵1d at 5.

⁶⁶1d at 13.

⁶⁷1d. at 14 (The Proprietary Association, as well as the United Medicine Manufacturers of America and the Institute of Medicine Manufacturers favored FTC jurisdiction).

⁶⁸ S.1944 S23(c), 73d Cong., 1st Sess. (1933)reprinted in 1938 HISTORY, supra note 59, at 49.

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Secretary...or any interested industry or substantial portion thereof" could initiate a hearing of any proposal to issue, amend, or repeal a regulation.⁶⁹ In such hearings, the findings of the Secretary would be conclusive only if "supported by substantial evidence. "⁷⁰

Surprisingly, consumer advocacy groups were of limited use in providing support to the different bills, preferring to protest their perceived inadequacies.⁷¹ The AMA threw its support behind the bill in Congressional testimony in 1935 but was not instrumental in urging its passage.⁷² A bill was finally pushed through Congress in 1938, on the heels of the "Elixir Sulfanilamide" tragedy of 1937, in which at least 73 people died from ingesting Massengill's sulfanilamide in a lethal solution of diethylene glycol.⁷³ This tragedy, which could only be addressed by the FDA in the context of its provisions on misbranding⁷⁴, underscored the limitations of the 1906 Act. Ultimately, the Act granted the FDA authority to enact rules directly regulating the industries within its jurisdiction. Congress passed a law in 1938 which allowed the FDA to promulgate rules specifying standards of drug strength, quality, and purity⁷⁵ and allowed the FDA to

⁶⁹FDCA S701(e) reprinted in 1938 HISTORY, supra note 59, atl8.

⁷⁰FDCA S701(f)(3) reprinted in 1938 HISTORY, supra note 59, at 18, as amended 21 U.S.C. S371(f) (1982).

⁷¹Cavers, supra note 53, at 11.

⁷²TEMIN, supra note 13, at 41.

⁷³shayne C. Gad and Christopher P. Chengelis, Human Pharmaceuticals and Medical Devices, REGULATORY TOXICOLOGY 14 (Christopher P. Chengelis, Joseph F. Holson, and Shayne C. Gad eds., 1995).

⁷⁴The term "elixir" could only legally be applied to a mixture containing alcohol; thus, the product was misbranded under the 1906 Act.

⁷⁵FDCA SSO1(b).

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exercise pre-market review authority over new drugs, subject to certain procedural requirements.⁷⁶

The FDCA was more comprehensive than the 1906 Act and it required far more stringent standards for avoiding the prohibition against misbranding, basically outlawing unsafe drug products as "misbranded." Section 502 laid out the strictures for a new labeling requirement. Section 502 (b) required the label to state the name and place of business of the manufacturer and the quantity of contents; Section 502(e) provided that the name or active ingredients be listed on the label; and, Section 502(d) required a warning on the label of hypnotic drugs. Under Section 503(b), a manufacturer could bypass the 502(b) and 502(e) requirements by requiring the drug to be dispensed only on written prescription. If the prescription contained writing prohibiting refills, the product was exempt from the 502(d) warning requirement as well. Congress also required that the manufacturers provide detailed directions to consumers. Under Section 502(f), all drugs on the market were required to bear labeling with "adequate directions for use."⁷⁷ The general

⁷⁶New drugs could not be marketed without FDA approval of a manufacturer's New Drug Application (NDA) demonstrating that the drug could safely be used for the indications described on the label. NDAs not rejected within 180 after submission were deemed automatically approved. FDCA S505.
A drug or device shall be deemed to be misbranded... (f) unless its labeling bears (1)adequate directions for use; and (2)such adequate warnings against use in those pathological conditions or by children where its use may be dangerous to health, or against safe dosage or methods or duration of administration or application, in such manner and form, as are necessary for the protection of users: Provided, that where any resuirement of clause (1) of this paragraph, as applied to any drug or device, is not necessary for the protection of the public health, the Secretary shall promulgate regulations exempting such drug or device from such requirement.
FDCA §502.

⁷⁷ Id.

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prescription exemption of Section 503(b) did not apply to the Section 502(f) directions in the 1938 Act.

The FDA did not promulgate regulations with clear indications of which drugs would fall within each category; it allowed the manufacturers to make these designations. The FDCA respected the right to self-medication by allowing consumers to choose among the available drug products on the market.⁷⁸ The issue of a right to self-medication had become even more important in the debate over this legislation than it had been in l9O6.⁷⁹ This is an understandable response to the comprehensive measures for drug regulation which were being proposed.⁸⁰ Walter Campbell, Chief of the FDA, was careful to state that the provisions on misbranding in the original Tugwell Bill were not developed with an intent to interfere in consumers' rights:

There is no issue, as I have told you previously, from the standpoint of the enforcement of the Food and Drugs

⁷⁸ Even though the 1938 Law restricted the range of drugs that could be offered on the market and mandated that information about them be supplied to the consumer, it appeared to leave the eventual choice of drugs — among those available, to be sure — to the consumer himself. This was stated publicly to be the aim of the FDA in proposing and supporting the legislation. Self-medication was to be improved and facilitated, not hampered.
TEMIN, supra note 13, at 45.

⁷⁹ THE EFFICACY OF SELF-MEDICATION (Joseph D. Cooper, ed., 1972) 15 (Comments of Vincent Kleinfeld).

⁸⁰ In spite of material support, this measure, as was to be expected, aroused bitter opposition from certain trade elements, particularly the proprietary-medicine industry and sections of the advertising profession which saw in the passage of such legislation a curb on lucrative practices heretofore indulged in with impunity. A vast amount of misinformation to the effect that the bill if passed would result in destruction of legitimate industries, interfere with the right of self—medication, and deny manufacturers their constitutional rights, was disseminated not only among the industries but among the public.
Annual Report of the FDA (June 30, 1934) at 14-15 reprinted in 1938 HISTORY, supra note 59, at 190.

21

Act about self-medication. This bill does not contemplate its prevention at all. If it did, a single short section in the measure could have been drawn up to that effect. But what is desired by this particular paragraph and by others which impose restrictions on statements made about the remedial properties of drugs is to make self—medication safe. There will always be self—medication to some extent. As I have said, from our law enforcement standpoint, we do not object to it, but it should be intelligent.⁸¹

Mr. Campbell reiterated the FDA's stance on self-medication in Senate hearings on S.2800, referring to the need for a misbranding provision, "if the public is to be given even a modicum of information that will permit the intelligent and safe use of drugs for self-medication,"⁸² and in support of S.5, "such provision is essential, not only for the protection of the public, but for the purpose of making self-medication safe."⁸³ A House Report on the Senate bill 5.5 stated, "The bill is not intended to restrict in any way the availability of drugs for self-medication. On the contrary, it is intended to make self-medication safer and more effective. "⁸⁴

⁸¹Hearings on S.194 4 Before the Subcomm. of the Senate Comm. on Commerce, 73d Cong., 2d Sess. (1933) reprinted in 1938 HISTORY, supra note 59, at1083—1084(statement of Walter G. Campbell, Chief of the FDA of the Department of Agriculture).

⁸²Hearings on S.2800 Before the Senate Comm. on Commerce, 73d Cong., 2d Sess. (1934) reprinted in 1938 HISTORY, supra note 59, at 1195(statement of Walter G. Campbell).

⁸³Hearings on S.2800 Before a Subcomm. of the House Comm. on Interstate and Foreign Commerce, 74th Cong., 1st Sess. (1935) reprinted in 1938 HISTORY, supra note 59, at 1238 (statement of Walter G. Campbell).

⁸⁴H.R.Rep. 2139, 75th Cong., 3d Sess. reprinted in 1938 HISTORY, supra note59, at 822.

22

Although Congress had designed the FDCA with an intent to assist the right of self-medication, FDA regulations promulgated soon after the FDCA empowered new agents to assist the consumer. These regulations carved out an exemption to the S502(f) requirement of labeling containing adequate directions for use:

if the label of such drug or device bears the statement "Caution: To be used only by or on the prescription of a " (the blank to be filled in by the word "Physician," "Dentist," or "Veterinarian," or any combination of such words), and all representations or suggestions contained in the labeling thereof with respect to the conditions for which such drug or device is to be used appear only in such medical terms as are not likely to be understood by the ordinary individual, and if such shipment or delivery is made for use exclusively by, or on the prescription of, physicians, dentists, or veterinarians licensed by law to administer or apply such drug or device; but such exemption shall expire when such shipment or delivery, or any part thereof is offered or otherwise disposed of for any use other than by or on the prescription of such a physician, dentist or veterinarian.⁸⁵

In the wake of this regulation, drug manufacturers would withhold certain products from the OTC market, acting under the shadow of potential FDA enforcement actions. And, a physician's assistance was required in order to obtain certain kinds of drugs.

⁸⁵Promulgation of Regulations under the Federal Food, Drug, and Cosmetic Act, 3 Fed. Reg. 3168 (December 28, 1938).

23

Prior to this regulation, consumers could purchase any drugs which they wanted, except for narcotics, unassisted. Physicians could write a prescription, which would exempt a drug from certain label requirements, but patients were not required to obtain a prescription for a drug purchase. The FDA, through this regulation, was demonstrating its lack of faith in the manufacturers' ability to produce adequate directions for the layman for certain drugs. By appointing these two new agents for the consumer (manufacturers and physicians), it imposed indirect limitations on the consumer's ability to make OTC purchases. This regulatory stance, so soon after the passage of the 1938 Act, seems at odds with the emphasis on self-medication in the legislative history of the Act.

The Durham-Humphrey Amendment of 1951

Soon after the enactment of the 1938 Act, certain limitations on the FDA'S regulatory capability began to make themselves apparent. Rapid technological advancement in the drug manufacturing industry, together with the constraints of enforcement litigation, limited the FDA'S ability to monitor drug safety.⁸⁶ The 1940s saw unprecedented advances in the development and marketing of drugs such as insulin and antibiotics such as penicillin.⁸⁷ Drug manufacturing had moved beyond the so-called "patent" medicines and nostrums of the early part of the century to enter the modern era. As drug formulations grew in complexity,

⁸⁶Hoffman, supra note 56, at 11.

⁸⁷5ee generally TEMIN, supra note 13, Chapter 4 (documenting the "therapeutic revolution").

24

there was greater need for explicit guidelines to elaborate upon the requirements of the FDCA.

In 1944, the FDA amended the 1938 regulations to include criteria for determining whether or not "adequate directions" for a layman could be written for a drug, clarifying the prescription/nonprescription distinction created by the 1938 regulations. ⁸⁸ The 1944 regulations defined a prescription drug as any drug which

because 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 generally recognized among experts qualified by scientific training and experience to evaluate its safety and efficacy, as safe and efficacious for use except by or under the supervision of a physician, dentist, or veterinarian.⁸⁹

Over half a century later, debate revolves around the interpretation of this very language which later became codified in the Durham-Humphrey Amendment of 1951.

The Durham-Humphrey Amendment was enacted to address several different problems facing Congress at the time. Pharmacists, concerned about potential liability for misbranded drugs on their shelves, had prompted this new legislation. In 1948, the Commissioner of Food and Drugs had announced to a convention of the National Association of Retail Druggists (NARD) that all

⁸⁸ 9 Fed. Reg. 12,225 (1944).

⁸⁹ 9 Fed. Reg. 12,225 (1944).

25

refills of prescriptions which were not specifically permitted by the prescribing physician would be considered violations of the law.⁹⁰ This newly announced interpretation of the FDCA stunned the audience and added to the anxiety experienced by ~~.⁹¹

Prior to the Durham-Humphrey Amendment, under the stipulations of the FDCA and its regulations described above, individual pharmaceutical manufacturing firms bore the responsibility for determining which drugs should be labeled with detailed instructions for consumer use and which drugs should be furnished by means of physician prescription.⁹² Thus, the same drug could be labeled for OTC use by one manufacturer and set aside for "prescription use only" by a different manufacturer.⁹³ The only constraint on this disparity was ad hoc litigation enforcement by the FDA, deeming certain products as misbranded under the general guidelines laid out in such regulations as the 1944 regulations. The FDA position on the labeling of a particular drug could only be known after the fact, subjecting pharmacists to liability for a variety of products in their inventory.

Senator Durham introduced H.R. 4203 into Congress in 1949, proposing that Section 503(b) be amended to include all of the

⁹⁰James F. Hoge, The Durham-Humphrey Bill, 6 FOOD DRUG COSM. L. J. 135(1951).

⁹¹1d at 136.

⁹²Hoffman, supra note 56, at 12.

⁹³ 97 CONG. REC. 9241, 9321(1951). Apparently, pharmaceutical manufacturers who traditionally catered to physicians in their marketing efforts had an incentive to market drugs under prescription status only. This also exempted them from the responsibility of developing "adequate" directions for use. Id. at 9323.

26

requirements of Section 502 in its broad exemption for prescription drugs.⁹⁴ Thus, even the Section 502(f) requirement of adequate directions could be waived in the case of a properly prescribed drug product. The provisions of the Durham-Humphrey amendment contained measures designed to relieve pharmacists' anxiety over refilling prescriptions bound together with other provisions designed to dramatically increase the scope of the FDA'S regulatory power. In February of 1951, the Food Drug and Cosmetics Law Journal carried an article by James Hoge, partner at a New York law firm and counsel to the Proprietary Association, warning its readers about the impending legislation,

This bill, however, did not stop with a treatment of that problem [the problem of pharmacists' anxiety over refills]. Instead, that problem was availed of for the advancement of a plan for the regulation of the drug industry to an extent never heretofore proposed or contemplated: a plan which not only involved the regulation of the drug business but a plan destined in time to influence, if not regulate, the practice of medicine.⁹⁵

Hoge, and others like him, objected to language in the bill which would allow the FDA to restrict to prescription sale drugs which it determined to be "unsafe or ineffective for use without the professional diagnosis or supervision of a physician or dentist."⁹⁶ Efficacy was added to truthfulness and safety as a

⁹⁴Hoge, supra note 90, at 137.

⁹⁵Id. at 135.

⁹⁶1d at 138.

27

variable which could be examined by the FDA. And, in addition to creating a bifurcation of all medicinal drugs into two distinct classes, the new law was empowering the FDA to oversee the maintenance of the bifurcation, a grant of power which had been rejected in the original "Tugwell Bill" of 1933.⁹⁷ Hoge laid out a frightening scenario for his audience:

Surely it would increasingly restrict the right of self-medication and the choice of remedies, a right which the committee report on the passage of the Federal law stated was not to be restricted but made safe...I have reference to all articles of a medicinal or remedial nature which are now lawfully available to the people. Now the significant thing about that is that if self-medication is prevented, or severely restricted, something must be put in its place. The people must then have medical care to a greater extent and at lower costs than now. Thus a power like the one proposed in this bill could become a handmaiden of socialized medicine.⁹⁸

In other words, if the government were to take away this right to self-medication, it would find itself in the position of having to provide some form of substitute. This concern surfaced in Congressional debate over the Amendment. "[Tihis provision gives the Federal Security Administrator opportunity increasingly to restrict over-the-counter sale of drugs, thereby increasing cost

⁹⁷. id at 139.

⁹⁸Id at 138, 139.

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of medication and creating one more artificial stimulus to the demand for socialized medicine."⁹⁹

The Committee on Interstate and Foreign Commerce voted 19-4 to report the legislation to the House. It was introduced as the embodiment of two specific aims: first, it would strengthen the protection of the public health against dangerous abuses in the sale of potent drugs without a prescription and, secondly, it would relieve the public and retail druggists from unnecessary restrictions on dispensing drugs which could be used safely without medical supervision.¹⁰⁰ The Committee had considered several possible alternatives for accomplishing these aims.¹⁰¹ It considered following the druggist's proposal and codifying the list of prescription drugs but rejected this proposal as too time-consuming and inflexible in the event of scientific or medical developments.¹⁰² It also considered including in the bill a legislative standard for making the distinction between prescription and OTC drugs.

Retail pharmacists wanted an FDA-promulgated list of the drugs which could only be made available through prescription; this was the best way to protect themselves from future liability.¹⁰³ Drug manufacturers objected to this grant of extraordinary power" to Oscar Ewing as Administrator of the FDA,

⁹⁹ 97 CONG. REC. 9236 (1951) (remarks of Rep. Shafer).

¹⁰⁰ 97 CONG. REC. 9235 (1951).

¹⁰¹ 97 CONG. REC. 9321(1951).

¹⁰²Hoffman, supra note 56, at 12.

¹⁰³ 97 CONG. REC. 9235, 9239 (1951). The American Pharmaceutical Association(comprised of academics involved with drug research and closely linked to the drug manufacturing firms) opposed the bill as did the the American Drug Manufacturers. The American Association of Druggists supported the bill, as did the National Association of Retail Druggists. Id. at 9325.

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a man who was "the original sponsor of socialized medicine, as well as a recent advocate of free medical aid for persons over 65 years of age."¹⁰⁴ Although the wording of the bill constrained the Administrator to make determinations formed on the "basis of opinion generally held among experts qualified by scientific training and experience," Congressmen felt that Mr. Ewing could easily find a group of experts willing to declare aspirin a dangerous drug and limit it to prescription use.¹⁰⁵ The Administrator would be subject to appellate review in a federal court of appeals under the "substantial evidence" standard, a standard viewed by some of the legislators as overly deferential. ¹⁰⁶

The AMA filed a statement objecting to the provisions in the bill which ceded authority for the prescription-OTC distinction to the FDA although there was some ambiguity as to how strong the AMA's stance on this issue was, since it did not send representatives to testify before the committee.¹⁰⁷ This negative stance is an interesting position from a group which stood to gain revenue from the increase in physicians' visits required for prescription drugs. Objections to the bill seemed to reflect a generalized fear of bureaucratic intrusion into the medical domain as well as a distrust of Mr. Oscar Ewing. As one Congressman put it, "...the doctors are primarily interested in seeing that no one gets a foot in the door for socialized medicine."¹⁰⁸

¹⁰⁴ at 9237—8.

¹⁰⁵1d. at 9238.

¹⁰⁶ id.at 9336.

¹⁰⁷ at 9323.

¹⁰⁸1d at 9327.

30

The right to self-medication was raised by both supporters and dissenters against the reported measure. Basically, the impact of the bill on the right to self-medication would be determined by whether the new legislation expanded or narrowed the existing range of OTC medications. The 1944 regulations had been promulgated ostensibly to protect safe and efficacious drugs from being swept into the Section 502(f) exemption for prescription drugs. The debate seemed premised on the assumption that the FDA would exercise its authority to narrow the range of drugs available OTC.¹⁰⁹

We are providing in this bill authority for the Federal Security Administrator to regulate 30,000 drugs. If he is not going to go into the field of drugs that are now on a nonprescription basis, why does he want this authority? There is no reason in the world for giving him this authority except on that basis that he will use it to take drugs that have been traditionally sold over the counter ... and put them on the prescription list. If he does not intend to do that, why is he asking Congress for authority to do it?

A Congressman from Indiana read aloud a letter from the dean of the Purdue University School of Pharmacy stating that, "[bjroad powers of this kind might very easily interfere with the proper self-medication for minor symptoms and ailments carried on by the people. "¹¹⁰

¹⁰⁹ Id. at 9329 (remarks of Rep. Bennett).

¹¹⁰1d. at 9326 (letter from Glenn L. Jenkins to Congressman John V. Beamer dated July 20, 1951).

31

The Senate passed a bill which had been amended to remove the provisions granting power to the FDA to determine the prescription/OTC distinction. The final Senate version had one other substantial change - it eliminated the reference to "efficacy" which had appeared in the original House bill.¹¹¹ Safety was to remain the preeminent concern in drug regulation. And, it appeared that the legislature would not consider that allowing a patient to follow a non-efficacious course of treatment, thereby postponing consultation with a physician, could be a significant danger. Thus, the bill moved forward without having delegated substantially more authority to the FDA.¹¹²

The final version of the bill defined a prescription drug as a drug which was either habit-forming,¹¹³ not safe for use except under the supervision of a physician, or limited to prescription sale under a New Drug Application (NDA).¹¹⁴ Although it mandated a strict legal division between prescription and OTC drugs, the final legislation contained only the broad, vague guidelines for differentiation under the second category which had been promulgated in the 1944 regulations: toxicity, other potentiality for harmful effect, and method of use and collateral measures necessary to use. Thus, FDA decisions on the prescription/OTC status of drugs continue to be made on a case by case basis.¹¹⁵ The Durham-Humphrey Amendment did not change the FDCA's default

¹¹¹TEM1N, supra note 13, at 53.

¹¹²Hoffman, supra note 56, at 12.

¹¹³FDCA S502(d) (listing these 17 drugs and their derivatives).

¹¹⁴FDCA S505(c) (NDAs became effective unless diapproved by the FDA within a limited period after filing).

¹¹⁵ Hutt, supra note 9, at 428—9.

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designation of OTC status; it merely laid out the criteria for distinguishing an exception - prescription drugs.¹¹⁶

Despite Congress's reluctance to cede direct authority to the FDA for making prescription/OTC designations, the FDA has managed to achieve similar results by utilizing Section 701(a) of the FDCA which authorizes it to issue regulations for the efficient enforcement of the Act.¹¹⁷ Some have come to regard these interpretive regulations as having the "force and effect of law."¹¹⁸ Still, the FDA has yet to publish regulations which would provide clear and consistent direction in the decisionmaking over prescription/OTC status.¹¹⁹

Post-Durham-Humphrey

The next major step in FDA regulation of prescription and OTC drugs occurred in 1962 with the passage of the Kefauver Amendment to the 1938 Act.¹²⁰ Once again, the issue of the relevance of drug efficacy to FDA regulation had come before Congress and, once again, Congress balked at allowing the Agency too much discretion.¹²¹ Eventually, however, the new Amendment did lead to enhanced authority for the FDA.

The Amendment arose out of the cynicism about the drug market generated by hearings held by Senator Estes Kefauver's

¹¹⁶P.B. Hutt, Remarks at Proprietary Ass'n Symposium: New Resources in Self- Medication (November 2, 1982) in Condensation of Papers and Discussions[hereinafter referred to as PA Symposium] at 45.

¹¹⁷Hoffman, supra note 56, at 13.

"¹¹⁸ Hoffman, supra note 56, at 13.

¹¹⁹Hutt, supra note 9, at 427, 428.

¹²⁰Pub. L. No. 87—781, 76 Stat. 780 (1962)

¹²¹Hoffman, supra note 56, at 17.

33

Subcommittee on Antitrust and Monopoly.¹²² Kefauver was concerned about the pricing structure and efficacy of new drugs on the market. In the wake of the Durham-Humphrey Amendments, prescription drugs were being marketed to physicians who, since they did not ultimately pay the bills for these drugs, had little incentive to minimize costs. In addition, booming technology in patent pharmaceuticals precluded a thorough understanding of the new products by each physician.¹²³ Although it had little relevance to the subject of the Kefauver hearings, the European thalidomide tragedy of the early 1960s stirred up enough public sentiment to assure the bill's passage. ¹²⁴

Several new provisions arose out of this legislation. First, automatic NDA approval was eliminated. New drugs required affirmative FDA approval before they could be marketed. Manufacturers of pharmaceuticals were required to submit to the FDA any procedures for testing an investigational new drug before commencing tests for the NDA. The FDA was empowered to withdraw approval already granted to an NDA. The new law also required that the generic name of a drug be listed on the label. This provision foreshadows much of the revolution in attitudes toward drugs and self-medication that we are beginning to witness today. By requiring that the generic name be provided, the FDA improved the information gathering activities of individual consumers.

¹²² PELTZMAN, REGULATION OF PHARMACEUTICAL INNOVATION: THE 1962 AMENDMENTS6 (1974).

¹²³ id. at 7.

¹²⁴The drug thalidomide had been kept out of the United States market by the FDCA while its dramatic side effects on newborn babies started becoming apparent in Europe. A tragedy in the United States was narrowly adverted by the FDA's hesitation over the adequacy of the manufacturer's data. Id. at 8.

34

Effectiveness as a salient characteristic for regulation had slowly emerged from its disputed relevance during the Senate testimony on the Durham-Humphrey Amendment.¹²⁵ Enhanced technology helped to facilitate this shift, allowing the FDA to require that "substantial evidence" of effectiveness be demonstrated by the manufacturers.¹²⁶ More and more drugs came under the purview of the FDA. If a drug which had previously been generally recognized by experts as safe but not effective for its intended use or effective but not safe, the FDA would classify it as a "new drug" and require pre-market review and approval. ¹²⁷ The FDA was now required to review all drugs marketed during the 1938-1962 period and determine their effectiveness, a process referred to as the Drug Efficacy Study Implementation (DESI). In 1973, the Supreme Court ruled that a drug could escape the "new drug" requirements only if the evidence of its safety and effectiveness was based on the same quantity and quality of data which would support an approved NDA.¹²⁸ This heightened interest in the effectiveness of new drugs demonstrates a move towards the determination of risk/benefit ratios in the regulation of drugs.¹²⁹

Policy towards OTC drugs became more clearly defined in 1972, with the establishment of the OTC Drug Review, separate from the

¹²⁵TEM1N, supra note 13, at 127.

¹²⁶ 1962 Amendment S102(c), 21 U.S.C. S355(d) (1982).

¹²⁷Alan. H. Kaplan, Fifty Years of Drug Amendments Revisited: In Easy-to-Swallow Capsule Form, 50 FOOD & DRUG L. J. 179, 182 (1995).

¹²⁸ at 182.

¹²⁹WALTER S. ROSS, THE LIFE/DEATH RATIO: BENEFITS AND RISKS IN MODERN MEDICINES 4 (1977).

35

DESI.¹³⁰ The OTC Drug Review categorized drugs through a monograph system, evaluating active ingredients, rather than individual drug products.¹³¹ From its incipience, the Review concerned itself with evaluating the status of prescription and nonprescription drugs and considering whether it is appropriate to switch a drug from one status to the other.¹³²

The first phase of the OTC Drug Review consisted of seventeen expert advisory panels which varied in their treatment of this mandate.¹³³ The FDA did not publish any specific criteria for transferring drugs, preferring to allow each panel the discretion to make whatever recommendations appeared appropriate from a medical, scientific and societal standpoint.¹³⁴ The panelists classified the ingredients in three categories: Category I - safe and effective; Category II - unsafe and/or ineffective; and, Category III - ingredients needing further study. Before disbanding in the early 1980s,¹³⁵ the panels reviewed some 700 OTC ingredients and recommended that 37 ingredients be switched from prescription to OTC status.¹³⁶ The OTC Review produced a set of monographs regulating the composition, manufacture and labeling of therapeutic classes of drugs.¹³⁷ The current mechanism for

¹³⁰ 37 Fed. Reg. 85 (Jan. 5, 1972) and 37 Fed. Reg. 9464 (May 11, 1972).

¹³¹Hoffman, supra note 56, at 264.

¹³²Hutt, supra note 9, at 429—430.

¹³³Id. at 430.

¹³⁴Id. at 431.

'¹³⁵ Eve E. Bachrach, The FDA's New Over-the-Counter Drug Office and Advisory

Committee: An Industry Perspective, 48 FOOD & DRUG L.J. 563 (1993).

¹³⁶Tufts Forum, supra note 15, at 30.

¹³⁷PA Symposium, supra note 116, at 3.

36

switching drugs from prescription to OTC has its origins in this Review process. ¹³⁸

Waxman-Hatch

The impetus for many of the current and contemplated prescription to OTC switches of drugs comes from the system of patent protection for pharmaceuticals. Patent protection under Title 35 of the United States Code provides seventeen years of monopoly for new inventions.¹³⁹ In order to receive patent protection for any new product, a company must be the first to file a patent application. Thus, pharmaceutical manufacturers often obtain patents on their new compounds well before they have adequately tested the product and received FDA approval.¹⁴⁰ In an effort to preempt other manufacturers who may be seeking to patent the same compound, pharmaceutical manufacturers may receive a patent well before they are able to market their new product. This serves to reduce the effective patent monopoly term to well below the seventeen years enjoyed by other products.¹⁴¹

New drug development and testing can be expensive and risky. Frustrated with the erosion of patent protection and resultant loss of profit, "pioneer" pharmaceutical manufacturers lobbied Congress for relief. The increasing market share being claimed by

¹³⁸Tufts Forum, supra note 15, at 30.

¹³⁹ 35 U.S.C. 154.

¹⁴⁰Lance W. Rook, Listening to Zantac: the Role of Non-Prescription Drugs in

Health Care Reform and the Federal Tax System, 62 TENN. L. REV. 107, 113

(1994).

¹⁴¹ J. Flannery & P.B. Hutt, Balancing Competition and Patent Protection in the Drug Industry: The Drug Price Competition and Patent Term Restoration Act of 1984, 40 FOOD DRUG COSM. L.J. 269 at 301 (1985).

37

manufacturers of generic drugs also put pressure on earnings.¹⁴² These smaller companies benefited from the abbreviated new drug application (ANDA) process, which allowed them to enter into the pharmaceutical market for pre-1962 drugs with little or no expenditure on research and development.¹⁴³ They had been lobbying for progressively greater freedom to enter the market, starting with pre-1962 drugs, moving on to the drugs declared safe and effective under the DESI, and finally, post-1962 drugs.¹⁴⁴ The larger pharmaceutical companies argued that the competition, combined with their diminishing patent terms, limited their incentive to invest in costly research to develop new products.¹⁴⁵

Congress responded to this pressure by passing the Drug Price Competition and Patent Term Restoration Act of 1984 (1984 Act)¹⁴⁶ which is sometimes referred to as the Waxman-Hatch Act after its sponsors, Rep. Henry Waxman (D. Cal.) and Sen. Orrin Hatch (R.Utah). This Act balanced the interests of the large, pioneering drug manufacturers and the smaller manufacturers of generic drugs. It allowed the generics to enter into the market for post-1962 drugs while extending monopoly terms to compensate the "pioneer" manufacturers for all of the time spent in the FDA review process as well as one half of the drug's clinical testing period. These terms of "non-patent market exclusivity" apply to all drugs patented after September 24, 1984 and to some of the drugs

¹⁴²Hoffman, supra note 56, at 18.

¹⁴³Id. at 18.

¹⁴⁴Id. at 18,19.

¹⁴⁵Estimates of the cost of bringing a new drug to market vary widely. Rook, supra note 140, at footnote 38.

¹⁴⁶Pub. L. No. 98—417, 98 Stat. 1585 (1984).

38

patented between January 1, 1982 and September 24, 1984. These extensions are generally limited to five years and patent terms cannot run longer than fourteen years after FDA approval has been granted.¹⁴⁷

Pharmaceutical companies which are able to develop a useful and innovative product stand to reap the rewards of monopoly pricing of their patented product. When the period of monopoly protection is drawing to a close, a company will often look to several different strategies for protecting its market share.¹⁴⁸ An increase in the monopoly term under the 1984 Act may be granted to a company which develops a "novel" improvement on the product which is not "anticipated."¹⁴⁹ Such a change might include a structural change, a change in the chemical formulation or something as simple as a change in the drug's method of delivery.¹⁵⁰ Eventually, however, even extensions under the 1984 Act will run out and the patented product will be subject to competition from lower-priced generic brands.

Although pharmaceutical companies once enjoyed a relatively long-lived and stable market for their brand-name drug products, increasing health care costs have led to an increasing acceptance of generic drug products.¹⁵¹ This growing pressure on the brand-name pharmaceutical market has led many companies to try a new strategy - the prescription to OTC switch. If a company receives

¹⁴⁷ 35 U.S.C. S156(c)(3); 21 U.S.C. S355(j)(4)(D)(i).

¹⁴⁸5ee generally Rook, supra note 140, at 116.

¹⁴⁹ 35 U.S. C. SlOl (1988).

¹⁵⁰Rook, supra note 140, at 116.

¹⁵¹State laws have changed to allow pharmacists to fill brand—name prescriptions with generic products. Hospitals, HMOs and various insurers favor generic products as well. Rook, supra note 140, at 118.

39

FDA approval for such a switch before the end of its patent term, it can utilize its remaining monopoly power in the consumer market rather than the physician market. Such companies pursue aggressive marketing strategies in the hopes that, once the patent expires, they will have captured a sufficiently large share of the consumer market to continue to enjoy high profits. Much of this optimism is based in the notion that consumers demonstrate a high degree of brand loyalty, particularly for their OTC medications.¹⁵²

CHANGING MARKET FOR PHARMACEUTICAL PRODUCTS

A variety of factors have led to the increased number of applications for switch from prescription to OTC status as consumers develop an increased level of interest and awareness of their own health.¹⁵³

The larger health care providers in both the public and private sector managed care plans are facing greater pressure to cut costs. As this pressure increases, more and more of these costs will inevitably be shifted back to the consumer. Much of

¹⁵²Rook, supra note 140, at 119. See also TEMIN, supra note 13, at 152.

¹⁵³ Evidence of the trend is all about us, daily, and can be seen in people running and exercising, in the concern for better nutrition, in the sales of home health care aids.. .We are returning to the self—reliance of the 19th century, when everyone pretty much had to do for themselves, but with a big difference. The difference between 1882 and 1982 is, of course, the amount and quality of the information available to the public for its use, and the number, kind and usefulness of the products available for self-help. These two major trends, the availability of more and better information, and the caring for ourselves, are obviously complementary — we know what is becoming available and how to use it.
PA Symposium, supra note 116, at 2 (remarks of Alexander M. Scbmidt, M.D., Vice Chancellor for Health Affairs, University of Illinois at Chicago).

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the increase in national spending on health care has been attributed to the moral hazard involved in most traditional insurance schemes. When a third party pays the bill for medical care, there is little incentive for either the physician or the patient to economize on treatment. In the case of medical care, where the information is so complex, a patient often does not have the tools to make an informed decision about treatment and must rely on a physician's advice. And, when it comes to such life and death decisions, even the most rational person may hesitate to question the advice of an expert. Thus, the traditional framework for payment of health care costs created an incentive structure which was not conducive to cutting costs. The pharmaceutical companies and other industries in the health care arena were able to capitalize on some of these incentives for a long time.

Shifting costs to the consumer will cut down on the expenditures of managed care but it will also change the market for health care expenditures. A patient/consumer who directly faces the costs of some of his own medical care will have an incentive to alter his behavior and consider the total costs and benefits of his decisions. As one of the largest participants in the market through its Medicare and Medicaid reimbursement programs, the federal government has an interest in promoting this realignment of incentives. Use of OTC drugs for self-medication can provide cost saving advantages beyond the actual cost of the drug product. A study by Kline & Company determined that, in 1987, use of OTCs resulted in a national savings of $10.5 billion in health care costs by cutting down on prescription costs, doctor

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visits, lost time from work, insurance costs and travel.¹⁵⁴ Because they are subject to the constraints of a normal consumer market, OTC costs have not risen as fast as other components of health care spending such as hospital care, physician services, and dental care.¹⁵⁵

The issue of cost—saving is not as straightforward as it might appear at first blU5h.¹⁵⁶ This is because the prescription/OTC dividing line is used by the Internal Revenue Service, as well as many health insurance plans, and federal and state programs, as a convenient boundary line for determining which patient expenses will be reimbursed. Congress designed its medical expense tax deduction policy to cover medical costs which reflect an economic hardship for the taxpayer.¹⁵⁷ In an era when OTC remedies consisted primarily of aspirin, this policy made sense. With today's expanding category of OTC drug products, the dividing line begins to appear anachronistic, particularly for taxpayers with chronic illnesses that require costly maintenance.

Insurance coverage of prescription drugs presents a different problem. Although an OTC remedy may have a lower market price, the fact that a patient could be reimbursed for a similar prescription drug may result in a higher effective price to the patient for the OTC remedy. A patient in a physician's office faced with a choice of purchasing a twenty dollar prescription

¹⁵⁴National Drug Manufacturer's Association "Facts and Figures" fact sheet(November 30, 1995).

¹⁵⁵1d. (citing U.S. Bureau of Labor Statistics).

¹⁵⁶The following discussion draws heavily the ideas of Rook, supra note 140.

¹⁵⁷STAFF OF THE JOINT COMM. ON TAXATION, 97th Cong., 2d Sess., GENERAL EXPLANATION OF THE REVENUE PROVISIONS OF THE TAX EQUITY AND FISCAL RESPONSIBILITY ACT OF 1982, at 24-25 (Comm. Print 1982).

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drug for which she will be reimbursed 90 percent, or a five dollar OTC remedy, will prefer the prescription remedy. In fact, such a patient may pressure the physician to prescribe the more expensive remedy, passing the cost back to the insurer. Cost savings from avoiding a physician visit are not factored in at this point. Alternatively, an indigent patient in a state with a Medicaid reimbursement scheme that only covers prescription drugs may just neglect to purchase the OTC remedy, delaying treatment and potentially exacerbating a treatable condition. These issues need to be addressed concurrently with the expansion of the OTC drug category.

For a long time, physicians resisted recommending OTC remedies to their patients, fearing a loss of the "mystique" associated with their profession and their favorite prescription remedies.¹⁵⁸ Such a recommendation may also run counter to the economic incentives of physicians, since patients will not be required to schedule additional follow-up visits in order to purchase refills of the drug.¹⁵⁹ The growth of HMOs, which pay physicians a monthly capitation fee, reverses these incentives and leads physicians to prefer cheaper remedies and fewer office visits for patients with treatable chronic and minor illnesses.¹⁶⁰ Patient use of OTC remedies cuts down on office visits.¹⁶¹

¹⁵⁸PA Symposium, supra note 116, at 9 (remarks of John F. Morrissey, M.D., Professor and Vice Chairman, Department of Medicine, University of Wisconsin).

¹⁵⁹ Id.

¹⁶⁰ id. at 10.

¹⁶¹ Dr. Simon Rottenberg, Professor of Economics at the University of Massachusetts, has estimated that if only 2% of OTC drug customers in the United States choose to visit primary care practitioners, rather than use self—medication, the annual increase in patients' office visits would be 292 million, a 62% rise.. .we simply cannot afford to pay the bill for the visits. PA Symposium, supra note 116, at 29 (remarks of Donald M. Vickey, M.D.).

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The pharmaceutical companies, faced with a dramatic restructuring of their marketing environment, have an incentive to adapt quickly and face a future where physicians will not be the sole decision-makers in the purchase of health care products. Many of these companies are meeting the challenge by switching their products from the prescription to the OTC market.¹⁶² Michael Weintraub, Director of the FDA'S Office of Over the Counter Drug Evaluation, has commented

The amount of time my office is devoting to OTC switch applications is increasing. Overall, we anticipate a 30 percent expansion in our work load over the next two years. In the face of this change, we are trying to restrict meetings with manufacturers and association representatives to only those that we consider crucial. ¹⁶³

OTC SWITCH MECHANISM

In 1991, the Secretary of Health and Human Services commissioned a report evaluating the FDA's mission.¹⁶⁴ In the wake of this report, the FDA created the Office of Over the

¹⁶² In view of these competitive and other healthcare cost containment pressures, pharmaceutical companies also can be expected to consider OTC marketing for appropriate new drug products and drug products not previously available in the United States. As international harmonization efforts proceed, more potential drug candidates for OTC marketing in the United States may become attractive. Stephen Paul Mahinka & Elizabeth Bierman, Direct-to OTC Marketing of Drugs: Possible Approaches, 50 FOOD & DRUG L.J. 49, 50 (1995).

'¹⁶³ Tufts Forum, supra note 15, at 18 (remarks of M. Weintraub).

¹⁶⁴Bachrach, supra note 135 , at 563.

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Counter Drug Evaluation within the Center for Drug Evaluation and Research, elevating the Division of OTC Drugs to the higher visibility of "office" status. Apparently, FDA Commissioner David Kessler was responding to the growing "self-care" movement as well as the higher volume of switch candidates coming before the FDA.¹⁶⁵ The data on OTC drugs which had been collected and evaluated during the OTC Drug Review has led to a much firmer scientific basis for many OTC ingredients and revolutionized the way people view these products.¹⁶⁶

As an aid to the new office, the FDA chartered the Nonprescription Drugs Advisory Committee (NDAC) to review and evaluate scientific data on OTC drugs and focus on the prescription/OTC status of these drugs.¹⁶⁷ This was the first such advisory committee focusing exclusively on OTC drugs since the seventeen OTC Drug Review panels of the seventies and early eighties and its regulations were modeled on those of the earlier panels.¹⁶⁸ The NDAC has a varied membership comprised of individuals with different specialties and including, at one point, clinical pharmacologists, pharmacists, a dermatologist, an epidemiologist, a clinical toxicologist, a pediatrician, and a lay

¹⁶⁵Tufts Forum, supra note 15, at 31.

¹⁶⁶Hoffman, supra note 56, at 266. In a survey conducted by the Heller Research Group in 1992 for the Non—prescription Drug Manufacturers Association, 88% of consumers surveyed said they disagreed with the statement "only prescription medications are effective," and 73% agreed that, "for some medical problems, nonprescription medications are just as effective as prescription medications."

¹⁶⁷Bachrach, supra note 135 , at 563.

¹⁶⁸ 21 C. F.R. pt. 14 (1993). Both the new and the old regulations allow for flexibility and inclusion of a wide variety of experts in the dialogue. Bachrach, supra note 135 , at 563; "[T]here is a fascinating mixture of regulation, capitalism, politics and personal opinion intertwined with our scientific deliberations." Tufts Forum,supra note 15, at 30 (remarks of Randy Juhi).

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member.¹⁶⁹ The NDAC (usually in conjunction with the appropriate therapeutic committee) makes recommendations to the FDA'S Office of Over the Counter Drug Evaluation, which ultimately determines whether a drug may be marketed OTC. These two entities were expected to facilitate and expedite the OTC switch process.¹⁷⁰

Today there are several routes for a company contemplating switching a prescription drug product to OTC status.¹⁷¹ For drugs subject to the OTC Drug Review, the switch can be performed through the review process, initiated by the FDA. Alternatively, a company can petition the FDA to amend the regulations which limit certain drugs to prescription status. These regulations, which are currently being reevaluated, set forth the general conditions for a drug to be recognized as safe, effective, and not misbranded.¹⁷² If a drug is approved through this process, it will be subject to a final regulation (either monograph or nonmonograph) in the Federal Register.

If the drug is a "new drug", the switch can be requested through an NDA or a supplement to an existing NDA. Under either method, the product will be considered a "new drug," subject to pre-market approval and other FDA requirements for new drugs. Where new clinical studies are used to support an NDA, the sponsor of the approved NDA will have marketing exclusivity for several

¹⁶⁹ id. at 31.

¹⁷⁰Whether this has been the case is subject to some debate. See Mahinka & Bierman, supra note 162, at 50 (suggesting that companies consider seeking approval to market on an OTC basis directly in order to circumvent the "apparently conservative" NDAC).

¹⁷¹Prior to the OTC Drug Review, 25 different ingredients were reclassified under a "switch regulation."

¹⁷² 21 C.F.R. SS31O.200—310.201

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years, a factor prompting many of the switches for prescription drugs towards the end of their existing patent terms.

FACTORS TO CONSIDER IN THE RX/OTC SWITCH PROCESS

When the FDA considers a candidate for switch today, it uses the criteria laid out in the Durham-Humphrey Amendment of 1951, bolstered by the information-gathering and analytic capabilities available to it in the 1990s. There is a conscious recognition of the delicate balance being struck between risks and benefits to society.¹⁷³ The variables being considered in this risk/benefit equation are the variables laid out in 1951, in the Durham-Humphrey Amendment. A drug will be limited to prescription sale if it meets one of the three components of the statutory definition of a prescription drug¹⁷⁴ : habit-forming drugs, drugs not safe for use except under the supervision of a physician or other practitioner licensed to administer such drug, and drugs already limited to prescription sale under an NDA.

Consideration of prescription/OTC status relies on the second component¹⁷⁵ and the three factors which determine the necessity for physician involvement: toxicity, potentiality for harmful effect, and method of use or collateral measures necessary to use.¹⁷⁶ These factors are clearly general and subject to flexible interpretation. At a 1994 forum on the Prescription to OTC switch, Weintraub explained that the FDA was focusing on "a solid

¹⁷³Tufts Forum, supra note 15, at 18, 32-34.

¹⁷⁴ 21 U.S.C. S353(b)(1).

'¹⁷⁵ Hutt, supra note 9, at 433.

¹⁷⁶ 21 U.S.C. S353(b)(1)(B).

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OTC indication, an appropriate target population, and labeling that leads to safe and effective use."¹⁷⁷ Dr. Carl Peck, formerly director of the FDA's Center for Drug Evaluation and Research, has suggested a list of principles to be considered in the review of switch candidates:

Does the switch candidate have special toxicity in its

class?

Does the candidate have a large margin of safety? Does candidate's frequency of dosing affect its safe

use?

Has the candidate's safety profile been defined at

high dose?

Has the candidate been used for a sufficiently long

time on the Rx market to enable full characterization of its safety profile?

What is the world-wide marketing experience of the switch candidate?

What foreign countries market the candidate OTC? What

is its experience in those countries?

What do the "use data" show?

Has a vigorous risk analysis been performed?

Has the efficacy literature been reviewed in a way to support the expected usage and labeling of the switch candidate?

Is there a full understanding of the pharmaco—dynamics

of the switch candidate?

¹⁷⁷Tufts Forum, supra note 15, at 19.

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Is the minimally effective dose for the proposed OTC

indication known?

Have possible drug interactions for the switch candidate

been characterized?¹⁷⁸

Typically, FDA clinical investigations involve three phases.¹⁷⁹ In phase I, the drug is administered to a small number of healthy human test subjects to determine such pharmacological information as human toxicity, drug metabolism, absorption and elimination, preferred routes of administration, and safe dosage range. Phase II trials test the drug on a limited number of patients with the actual disease or other indication the drug will be used for. Once the first two phases have provided reasonable assurance of safety and efficacy or suggested that benefits from the product outweigh the risks, a Phase III trial will be performed on a larger population sample to determine an optimal dosage schedule for maximum safety and effectiveness.

A change from prescription to OTC may involve switching an entire product, switching some indications, allowing a higher dosage for a drug which was previously available in a lower dosage OTC, or creating a new, lower dosage, product which is more suitable for OTC use. Notable among the dosage switches has been topical hydrocortisone, an antipriuritic which was moved from the 0.25% to 0.5% strength made available OTC in 1979 to 1.0% in 1991, pending a final monograph.¹⁸⁰ Ibuprofen was introduced to the OTC

¹⁷⁸ Switch Principles Cited by Peck, NDMA EXECUTIVE NEWSLETTER, November 10, 1990 at 3.

~¹⁷⁹ The following discussion is from Hoffman, supra note 56, at 246.

¹⁸⁰William E. Gilbertson, FDA's Review of OTC Drugs, in HANDBOOK OF NONPREScRIPTION DRUGS, 10TH EDITION 21, 30 (1993) (noting that switch was done in response to a citizen petition containing complaints to manufacturers about ineffectiveness at the lower strength).

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market via an NDA, and marketed at a 200-mg strength, a dosage lower than the 300 - 800-mg dosages which had previously been available for prescription use in the United States.¹⁸¹ Although safety for such a product may have been demonstrated by clinical data supporting the NDA for the prescription product, efficacy at the new, lower, dose must be demonstrated by new clinical data.

In addition, the FDA'S Office of OTC Drug Evaluation is turning increasingly to data acquired from "actual use" or "usage" studies.¹⁸² Studying actual use of a drug product is not a new concept,¹⁸³ but FDA emphasis on such data is relatively new. Usually, such a study consists of a late Phase III clinical trial conducted under ordinary conditions of use, examining subjects' multiple use of a test drug.¹⁸⁴ The objectives of the study may vary, depending upon the type of drug being studied but some or all of the following may be included: evaluation of the safety during use for large, representative sample of the population such as a sample of unsc