Prescription to over-the-counter switch: a regulatory perspective

CLINICAL THEFtAPEUTICSVVOL.

20, SUPPLEMENT

C, 1998

Prescription to Over-the-Counter Switch: A Regulatory Perspective Randy I? Juhl, PhD, RPh University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania

ABSTRACT This paper discusses the origins of the over-the-counter (OTC) drug category and presents information about the process of switching a drug from prescription (Rx) to OTC status. It also reviews past and current drug laws in terms of how they relate to OTC drugs. Key words: Rx-toOTC switch, self-care, FDA, DurhamHumphrey Amendment.

INTRODUCTION From 1984 to 1994, approximately one prescription (Rx) drug was switched to overthe-counter (OTC) status each year. Some of these switches were blockbusters. The number of switches then increased to six or seven per year from 1995 to 1997, and this trend is expected to continue (table). There are several reasons for this trend. First, the responsibility for health care is being shifted to consumers. The consumers’ desire to be more responsible and

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the “self-care movement” drive this trend from the consumer side; managed care drives it from the other side. The drug manufacturers’ capitalistic motives also contribute to the trend. Companies now consider an OTC component in a product life cycle early in their planning. Most consumers make their first purchase of a switched product in a pharmacy. That business is quickly lost to other outlets, but consumers are curious about these drugs when they are first switched to OTC status, and they view the pharmacist as a primary resource.

HISTORY OF OVER-THECOUNTER DRUGS The history of OTC drugs begins with the 1938 Food, Drug and Cosmetic Act. The elixir of sulfanilamide tragedy, in which more than 100 people died from ingestion of a toxic solvent, provided the primary impetus for the Act. In addition, the Act stated that drug labeling must include “ad-

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Table. The rate of prescription

to over-the-counter

switches over time.

Year

Generic

Brand

1984

Ibuprofen

1985 1986 1987 1988 1989/90

Oxymetazoline Pyrantel pamoate Pseudoephedrine/dexbrompheniramine LoPeramide Clotrimazole

1990 1992 1994 1995

Permethrin Clemastine fumarate Naproxen sodium Famotidine Cimetidine Ranitidine Ibuprofen Ketoprofen

Advil@ Nupri# Afrill@ Antiminth@ Drixoral@ Imodium@ A-D Lotrimin~ Gyne-Louknin@ Nixe Tavist-D@’ Aleve@’ Pepcid Ace’ Tagamet HB@ zantac@ 75 Children’s Motr@ Orudis’s’KT” ActronTM Fernstat@ 3 ocuhist@ Nicoret@’ Rogaine@ Axid@AR Nicotrol” Nicoderme’ Children’s Advil” Monktat@ 3 Nasalcrom” Totala toothpaste Nizoral@ AD shampoo Vagistat@-1 Rogaines Extra Strength Imodium’a Advanced

1996

1997

Butoconazole nitrate PheniramineJnaphazoline Nicotine gum Minoxidil2% Nizatidine Nicotine patches Ibuprofen Miconazole 2% Cromolyn sodium Triclosan + fluoride Ketoconazole 1% Tioconazole 6.5% Minoxidil5% Loperamide/simethicone

equate directions for use,” and that these directions are supposed to appear on the package with “conspicuousness and in terms such as to render it likely to be read and understood by the ordinary individual under customary conditions of purchase

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and use.” These requirements appear to refer to labeling for OTC drugs more than prescription drugs. Thus the first major legislative activity in our country to define how drugs were to be channeled into the marketplace only addressed OTC

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agents. None of the labeling was directed to health care professionals, as we are accustomed to today. Each of the Act’s phrases about drug labeling has particular meaning. First, the directions are “likely to be read” means that they cannot be hidden underneath the package, where the consumer might not see them. “Likely to be understood” has become one of the key components in Rxto-OTC switches. The Act does not say that the directions “must” be understood; it says “likely” to be understood. “Ordinary individual under customary conditions of purchase and use” is particularly liberating. If a patient does not speak English, is blind, or has a learning disability, OTC labels will cause problems. Manufacturers are not held responsible for every possible situation that might arise. The legal requirement calls for labeling that accommodates the “ordinary individual.” TESTING DIRECTIONS FOR USE One of the requirements for a drug to be switched from Rx to OTC status is “adequate directions for use.” In Rx-to-OTC switches we remove the physician and the pharmacist from the loop and substitute the words on the label. Can the consumer use the product safely and effectively with the aid of the label only? The issue of “adequate directions for use” can be approached in different ways, such as asking or testing the consumer. Asking the Consumer An “ask the consumer” study titled SelfMedication in the 1990s--Practices and Perception was conducted in 1992 by the

Heller

Research

Group.

The results

showed that 94% of consumers said they would be careful when using an OTC drug; 93% would read the instructions the first time they used the product, and 70% would call a doctor if they had questions. Consumers in general are respectful of the drugs they take. However, we tend to remember the people who did not read the directions and ended up in the emergency room. Overall, “ordinary individuals”-those referred to in the labeling standards-will read and pay attention to product labels. Testing the Consumer Four questions must be answered when testing consumers: (1) Can they read the label? (2) Can they understand the label? (3) Do they follow the label? and (4) Do they achieve the desired outcome? All four levels of inquiry help to determine whether a consumer can use a product and achieve the desired outcome in the absence of a learned intermediary. One example of testing the consumer comes from a project that compared four different OTC labels for a histamine, (I-I& blocker. The test, which was conducted by Walker Information (Indianapolis, Indiana), was to evaluate four ways of presenting information to the consumer. Part of the underlying premise was that it would be good if consumers understood the difference between the clinical response obtained from the active drug compared with the response obtained with the placebo. The question was, how can that information be transmitted to consumers so that they realize that most people with heartburn get better with no treatment, but some feel better with this drug. The folks at Walker were rigorous enough to determine the consumers’ baseline Cl13

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knowledge before moving on to the main part of the test. They asked the subjects to define placebo. The results were that only 46% understood what a placebo was. “Placebo” then is a word that probably should not be on an OTC label. In addition, because of the limited space on an OTC drug label, words must be chosen carefully. Results of the study also showed that text presentations were better than graphic presentations. Most consumers preferred a written sentence over a graph showing placebo versus control. Thus, unlike most health care professionals, who are used to looking at-and often prefer-graphs, laypersons prefer text. This finding provides some idea of the extent to which OTC labels are studied in a test setting. CONSUMERS’ RESPONSES TO DRUG LABELING: ANALGESICS VERSUS HISTAMINE, RECEPTORS An interesting piece of information came to light during a meeting of the US Food and Drug Administration (FDA) Nonprescription Drugs Advisory Committee (Rockville, Maryland, July 13-14, 1995). One day the advisory committee reviewed an application for an oral analgesic; the next day it reviewed an application for an H, blocker. The manufacturers of both products had conducted similar usage studies in which patients received a 30-day supply of medication with the proposed labeling and a diary to record their use of the drug; they were told to use the product as directed on the label. The incidence of overuse of the products was determined from the diaries and was defined as taking two tablets instead of one, not observing the dosing interval, or using more tablets in 24 hours than the label allowed. Cl14

With the analgesics, the rate of overuse was 40% to 50%, but with the 3 blocker it was 17%. It is likely that consumers have become relatively more sophisticated in the analgesic market. They have heard advertisements for many years encouraging them to use the new “industrial strength” product, and they believe that it is acceptable to take two tablets or capsules instead of one. They know that ibuprofen 200 mg is an OTC drug, but that ibuprofen 400, 600, and 800 mg require prescriptions. They become relatively comfortable with taking more medication than allowed on the package label. The safety question from the public health perspective is, what happens when they do take twice as much or cut back on the interval? We know from experience that analgesics are relatively safe for most patients. However, taking more than the recommended dosage certainly should not be encouraged. Data on the $ blockers suggest a different situation. This study was done before H, blockers were available over the counter. Far fewer people used the drug inappropriately, which probably reflects healthy consumer respect for drugs with which they arc not familiar. If this study were repeated in a couple of years, the results would probably show a higher incidence of people using higher doses of H, blockers than recommended on the label. THE DURHAM-HUMPHREY AMENDMENT OF 1951 The Durham-Humphrey Amendment was the legislation that formalized the prescription category of drugs. Some prescription drugs existed before this amendment (eg, narcotics, as a result of the 1914 Harrison Act). In addition, some states had restrictions, and the FDA actually en-

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forced a restriction that did not exist. For example, although they probably had no legal authority to do so, the FDA told some manufacturers of sulfa drugs that these drugs were going to be dispensed only by prescription. However, the “prescription only” category was not firmly established until 195 1. Thus it appears that the prescription category is an exception and the OTC category is the default. For a drug to be available by prescription only, it must be habit forming or exceptionally toxic, or contain a drug that the FDA approved “for prescription only” because it could not be used safely by the ordinary individual under customary conditions. The caution “Federal law prohibits dispensing without a prescription” came from this 1951 legislation and has recently been eliminated by the FDA Modernization Act. The Durham-Humphrey Amendment also eliminated the 1938 labeling requirements for the new category of prescription drugs. Labeling for these drugs did not have to be understood by the ordinary individual under customary conditions of purchase and use. Instead, the labeling was directed toward the physician and pharmacist. Through the years, and the courts, the term “exceptionally toxic” has been defined for this particular usage. Many of our drugs are exceptionally toxic, but the meaning implied in this case is that more than a remote possibility exists that the drug will cause harm when used in a reasonable manner. In one court case,’ the judge stated that when individuals are self-medicating, they are expected to display “a modicum of common sense.” Therefore, although this is a free country and we have the freedom to do stupid things, when self-medicating

we accept the responsibility either to follow directions or suffer the consequences. Since the adoption of this 195 1 legislation, most new drugs that reached the market have been classified as prescription drugs, although some eventually became eligible for OTC status. THE DRUG AMENDMENTS OF 1962 The next legislative act that affected OTC drugs came in 1962. The primary component of the 1962 amendment was that drugs must be proved effective for their stated therapeutic claims before they can be marketed. Most of the attention focused on prescription drugs through the drug efficacy study implementation process. However, the OTC drug review also grew out of this legislation. The OTC drug review started in 1972 and continues today. Although it is unfinished, many changes have occurred because of this amendment. The net result has been that the public has a more than reasonable expectation that the OTC drugs they purchase are safe and effective when used according to the label. That confidence did not exist before OTC review. Thus the injection of science into the review process for OTC drugs has been beneficial. Over-the-Counter Agents Versus Dietary Supplements The current regulations for OTC drugs are in sharp contrast with those for dietary supplements. No scientific data are required to show that these nutritional supplements are safe and effective. In fact, in many cases the supplement ingredients are unknown. In 1906, the first food and drug law required adherence to standards of identity and purity. We still do not have standards

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for these nondmg supplements. It is important to recognize that dietary supplements are not OTC drugs from a regulatory point of view; they belong to a separate category that is not tightly regulated. REQUIREMENTS FOR PRESCRIPTION TO OVER-THE-COUNTER SWITCHES Currently, drugs should be classified as OTC if they can be safely and effectively used as directed. This involves a question of public access. The law suggests that access to drugs should not be restricted unless it is necessary to do so for the public health. Thus, if the drug can be classified as OTC, it should be. Second, the approach taken by the FDA is “case-by-case weight of the evidence.” A manufacturer that wants to switch a drug from prescription to OTC status usually will do so by means of a new drug application. Clinical trials are required to ensure that the drug is safe and effective in the OTC setting. Studies are also required to refine the labeling so that it delivers a message likely to be understood by an ordinary individual. The kinds of trials differ, depending on the product being studied. For example, the trials designed for nicotine patches were different from those for H, blockers. The studies performed to switch a drug often test the consumer more than they test the drug. We must determine whether consumers can make the decisions necessary to use the drug without a learned intermediary. Finally, in most cases of Rx-to-OTC switches, an FDA advisory committee reviews the data. The FDA has more than 1.5 therapeutic advisory committees that provide independent, expert, scientific advice to the agency. Committees include Cl16

clinicians who take care of patients, researchers who conduct trials and understand how to interpret data, statisticians, and public representatives. They are independent of the FDA in a setting that resembles a PhD dissertation defense. THE F’UTURE OF PRESCRIPTION TO OVER-THE-COUNTER SWITCHES All applications for switches to OTC status undergo rigorous scrutiny. The table lists products that have been switched to date; other applications for switches were not approved. For example, cholestyramine (Questran@‘,Bristol-Myers Squibb, Princeton, New Jersey) for cholesterol reduction has been before the advisory committee twice. The agency recently stated that reduction of cholesterol is not considered to be an “OTCable” indication. Acyclovir (Zovirax@, Glaxo-Wellcome Inc., Research Triangle Park, North Carolina) for recurrent genital herpes was also reviewed twice. In this case, the issue was not the safety and efficacy of the drug in the individual patients who would be taking it, but rather an increasing resistance to the drug in the entire society. Products for asthma have also been considered but will probably not be switched in the near future. Labeling standards will likely be revised. A proposal from the agency is soon expected to revise the format of all OTC labeling. This format change will make better use of the limited space on labels and make them easier to read. It is hoped that the revised labels will transmit messages to consumers more effectively. The changes will be patterned to some extent after the Nutrition Facts that appear on food labels.

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Chronic Conditions Chronic conditions are probably the biggest hurdle for Rx-to-OTC switches. Most of the products in the OTC market are for acute conditions (eg, headaches, colds). Currently, none of the medications approved for OTC use are to be taken for the remainder of a patient’s life. Minoxidil (Rogaine@, Pharmacia & Upjohn, Kalamazoo, Michigan) is perhaps the best example of an OTC drug used for a chronic condition. Chronic use of an OTC drug raises questions about self-monitoring. How much responsibility should be passed on to patients to take care of themselves? For example, OTC cholesterol tests are available to the public; can consumers adequately monitor their condition with such a product? What should we expect of patients, and how much will we continue to rely on the existing health care system? Educutiouul Role of Over-the-Counter Labeling Smoking-cessation products provide the best example of the educational role of OTC labeling. These products include an audiotape, a booklet, and other educational tools that provide the patient with the information necessary to use the product correctly. In addition, 800 numbers are provided for consumers who have questions or concerns, and one company has even developed a “committed quitters” program. The question of whether an OTC drug should be packaged as a compre-

hensive drug therapy program or just as a single product to treat symptoms is being examined by both the pharmaceutical industry and the FDA. Another question concerning the future of Rx-to-OTC switches involves directto-consumer (DTC) advertising and its potential to enhance the climate for switch. Can DTC advertising be designed so that it is educational and prepares the public to better deal with self-management of an illness for which OTC products are not yet available? CONCLUSION The past few years have seen an increase in the number of drugs that have moved from Rx to OTC status. This trend is compatible with a long history of food and drug laws in this country and will continue to the limit of the public’s ability and willingness to accept additional responsibility. An enhanced role for the pharmacist arises from this trend to serve as an additional information source for consumers as they assume greater responsibility for their own health care. Address correspondence to: Randy P Juhl, PhD, RPh, Dean, University of Pittsburgh School of Pharmacy, 1104 Salk Hall, Pittsburgh, PA 15261. REFERENCE 1. United States v Decholin, 264 F Supp 484 (ED 1967).

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