Drug Information Journal, Vol. 34, pp. 693701, 2000 Printed in the USA. All rights reserved.

0092-8615/2000 Copyright 2000 Drug Information Association Inc.

OTCS 2000: ACHIEVEMENTS AND CHALLENGES

R. WILLIAM SOLLER, PHD
Senior Vice President and Director of Science & Technology, Consumer Healthcare Products Association, Washington, District of Columbia

The last 30 years has brought significant changes to self care through responsible self medication. From being essentially unregulated in the 1960s, over-the-counter (OTC) medicines have been transformed by the evolving statutory and regulatory initiatives into a mature market with a high level of consumer confidence in their safety and expected benefits. This paper reviews the legislative/regulatory achievements that have modernized self care with OTCs, including the statutory and regulatory basis for OTCness, the criteria and studies used as a basis for permitting OTC availability, and the paradigm for interaction between regulators and sponsors, as well as the challenges still facing the industry. Key Words: Over-the-counter medicines; Self care

THE FOUNDATION OF OTCNESS THE LAST HALF OF this century has seen a remarkable evolution of social activism and consumer enlightenment. In the health care sector, empowering patients and consumers by educating them about health conditions and possible treatments has been driven as much by changes in technology and the positive patient/consumer feedback on those technological improvements, as it has been on the social conscience about societal risks and the governments response to protect the public. Indeed, American consumers have come to expect that the Food and Drug Administration (FDA) will not just protect the public health by keeping unsafe drugs off the market, but facilitate the availability of safe and effective drugs, improve the health of

Reprint address: R. William Soller, PhD, Senior Vice President and Director of Science & Technology, Consumer Healthcare Products Association, 1150 Connecticut Ave. NW, Washington, DC 20006. E-mail: wsoller @chpa-info.org.

Americans, and provide clear, easily understandable drug information for safe and effective use of prescription and OTC medicines. For OTC medicines, todays age of self care enlightenment started with the amendments to the drug law enacted in 1962, which require that drugs be effective prior to marketing (Prior to 1962, drugs had to be proven safe, but proof of their effectiveness was not required by law). As a result, FDA was then obliged to reexamine all prescription and OTC drugs that had been approved solely on the basis of safety. For OTC drugs, the endeavor involved the review of about 730 active ingredients used in more than 300000 United States drug products by 17 expert advisory panels; these panels made recommendations about their safety, effectiveness, and labeling for their intended uses. In the process, the scientific/regulatory foundation for responsible self care with OTC medicines was created and documented in the extensive public regulatory library known as the Federal Register. Today, OTCness means . . . the widespread availability of safe and effec-

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tive nonprescription medicines for responsible self care by the consumer according to label directions, pursuant to the applicable laws, regulations, and voluntary industry codes affecting manufacturing, packaging, labeling, distribution, and sales of quality products and the advertising of those products in all media (1). At the latter part of the last century, OTCness was simply the widespread availability of proprietary medicines. Thus, todays definition embodies a quarter-century effort by government and industry to meet the needs of progressively sophisticated consumers. This effort has been realized through the legislative and regulatory initiatives that have created an ever improving foundation on which consumer confidence in safe, effective, and welllabeled self-care medicinal products is built. The foundation consists of the definitions and criteria of safety and effectiveness, the development of sound labeling principles, the paradigm for assessing OTCness, an affirmation of the current distribution system, an effective compliance and enforcement program, and a reasonable and workable advertising and promotion framework.

SAFETY, EFFECTIVENESS, AND BENEFIT/RISK As a basis for the OTC Review, FDA took the important and ground-breaking step of defining in regulation the terms safety and effectiveness. Correctly, the definitions are not stated in absolute terms. Safety is not an absence of toxicity, but rather a low incidence of side effects and a low potential for abuse (4). Similarly, effectiveness is not a benefit in all who might try the OTC drug, but rather is defined as a reasonable expectation that the drug will have the effect of the type claimed in the target population (5). Though not defined by regulation, the benefit/risk assessment brings the concepts of safety and effectiveness into balance (6). Usually, this assessment includes answering the question, is the modest, but meaningful, benefit worth the uncommon, but potentially serious, side effect or consequence? This is often the pivotal question for Rx-to-OTC decisions.

THE SCIENTIFIC/MEDICAL BASIS FOR OTCNESS The scientific/medical basis for OTCness is built on the pro-OTC bias in the law that if a drug can be OTC it must be OTC (1). The word can in this concept is defined in terms of the data supporting the safety, effectiveness, and labeling of the active ingredient and dosage form. Therefore, not all switch candidates may be OTCable, dependent on the supportive nature and/or quality of the data. The principles used to assess safety and effectiveness are those found in the disciplines of toxicology, pharmacology, and pharmacoepidemiology, as well as social research relating to consumer attitudes and behavior. For example, safety includes an assessment of: the potential carcinogenic and reproductive toxicological risk; side effects when the product is used as recommended; potential therapeutic hazards including the potential for misdiagnosis, therapeutic failure, and incorrect use (ie, as in overdose and

THE BIAS FOR OTCNESS The original Federal Food, Drug, and Cosmetic Act of 1938 made no clear-cut distinction between prescription (Rx) and OTC drugs. The specific standards for classification were set up in 1951 by the DurhamHumphrey amendments to the act (2), which require drugs that cannot be used safely without professional supervision to be dispensed only by prescription. Such drugs may be deemed unsafe for OTC use because they are habit-forming or toxic, have too great a potential for harmful effects, or are for medical conditions that cannot be readily selfdiagnosed. In other words, drugs are prescription by exception, that is, if a drug can be OTC, it must be OTC (3). The operant word in this still current concept is can, which is interpreted by the generally accepted basis for OTCness (see below).

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abuse); and drug-drug and drug-food interactions (1). The types of studies supporting safety include clinical studies, case reports and series, postmarketing epidemiological studies, and analyses of adverse experience reports. Effectiveness is based on clinical studies in the specified target population(s) using the anticipated OTC dosage regimen(s). The types of studies that are often used to develop data supporting OTCness, particularly for Rx-to-OTC switch, derive from actual use and label comprehension studies. Actual use studies assess use of the candidate drug in a simulated OTC population compared to either placebo (or another OTC drug) in a similar OTC setting, or to a prescription drug in a simulated Rx setting (7). These studies can be quite large, as in the case of the actual use study supporting OTCness for pediatric ibuprofen, which included almost 80000 children to assess rare side effects associated with antipyretic use of acetaminophen (the reference drug) and ibuprofen (the test drug) (8). Label comprehension studies may also be included in the OTC database, particularly for new OTCs introduced as Rx-to-OTC switches (unpublished data, Bowen D, 1994). Such studies usually precede the actual use study and focus on specific aspects of the label (eg, directions or warnings) which are recognized as primary endpoints for the OTCness decision. The benefit/risk assessment integrates safety, effectiveness, and labeling data in an approach that recognizes that these are relative, not absolute, terms (ie, OTCness being a low incidence of safety problems, a reasonable expectation of achieving the effect of the type claimed, and a high percentage of label comprehension and label compliance; see above). Correctly, numerical thresholds of safety, effectiveness, or label comprehension have never been applied as hurdles to overcome for OTCness.

LABELING If OTCness can be likened to a three-legged stool, then the platform of OTC availabil-

ity is supported by safety, effectiveness, and labeling. OTC labeling must be not only . . . clear and truthful in all respects and not misleading in any particular but importantly . . . likely to be read by the ordinary individual . . . (9). In 1973, FDA stated that [T]he Food and Drug Administration is presently engaged in studies to assess the understanding and acceptability by the public of current drug labeling and to develop new labeling formats that can lead to easier reading, improved comprehension, and better use of OTC drug labeling (10). However, it was not until 1990 that the issue of label readability was brought to the national scene through the efforts of the Senior Citizens of California (11). In response, the Consumer Healthcare Products Association created voluntary label readability guidelines and improved the labeling of more than 37500 linear miles of OTC labels (12). On numerous occasions FDA has cited these guidelines for companies to follow in developing OTC labels (13,14). The guidelines stated in 1991 that FDA involvement in label readability was needed for changes in regulations that would simplify and standardize label format and language. On March 17, 1999, after five years of dialogue with the agency, a final rule on OTC label content and format was issued (15). While the rule represents a fit for 75% to 80% of current packages, it is problematic for the remaining current packages because of a six-point type size minimum requirement for body text and a modified format scheme for small size labels that is neither realistic nor reasonable (16). Interestingly, although the agency and industry strive to achieve a data-driven approach to OTC policy issues (see below), the element of the final rule that appears to be so problematic to industry is based principally, if not entirely, on poorly documented subjective comments from consumers about personal preferences for type size (17). The two pivotal studies (18,19) on which FDA relies to support six-point type in fact either provide no supportive data in this regard and/or support less than six-point type as readable.

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THE SCIENTIFIC/ REGULATORY PARADIGM The scientific/regulatory paradigm for assessing OTCness evolved as a result of the framework created for reviewing all OTC active ingredients, that is, case-by-case weightof-the-evidence, data-driven, and dialoguedriven (20). The OTC scientific/regulatory paradigm defined by the OTC Panels and used today encompasses the following key principles (20): 1. The concept if it can be OTC, it must be OTC, 2. Use of well-defined tenets of toxicology, clinical pharmacology, epidemiology, and other applied sciences as a basis for switch, 3. Use of a dialogue approach to define appropriate research questions, 4. Use of a case-by-case approach, since each ingredient has molecule-specific potential toxicities and each product may have unique use profiles, 5. Use of weight-of-the-evidence, since not all data are absolute, but may require informed decision-making, and 6. Use of the latest scientific techniques and understanding to ensure that the best science of the day is applied to the OTCness decision. The importance of ensuring the effective practice of this paradigm cannot be underestimated. It is an approach that is consistent with the legal underpinnings of OTCness and encompasses the use of new techniques and principles as science evolves. Indeed, this approach allows Rx-to-OTC switch to be a testable hypothesis. DISTRIBUTION By law, the United States has a two class system of distribution: prescription and nonprescription. In other parts of the world, there exists a pharmacy-only class of drugs (ie, third class of drugs), which permits drugs to be dispensed without a prescription. Early in

the OTC Review (21) in connection with an FDA monograph on OTC antacids, some pharmacy organizations commented that such a third class of drugs should be created. Others, including the Department of Justice, objected to a third class of drugs, stating that it would restrain competition, inconvenience the consumer, depart from United States economic policy, and cause price increases for the consumer with no attending benefit. FDA concluded that no controlled studies or other adequate research data have been supplied to support the position that any class of OTC drugs must be dispensed only by pharmacists in order to ensure their safe use. . . . There is at this time no public health concern that would justify the creation of a third class of drugs to be dispensed only by a pharmacist or in a pharmacy (21). This view remains strongly entrenched in the United States fabric of OTCness today, and was recently reaffirmed by the United States Government Accounting Office (23). CHALLENGES Given OTC medicines are a mature market with a well-defined regulatory structure, what are the future opportunities and challenges to self care with OTC medicines? The future growth of the OTC market is dependent on the Rx-to-OTC switch through the NDA process, not the OTC Review process, principally because the OTC Review provides no post-OTC market exclusivity as a means to recoup the substantial research and development (R&D) costs needed to develop chronic disease categories for future switches. By qualifying for market exclusivity under Waxman-Hatch on the basis of essential studies undertaken to support a supplemental NDA, a company has an opportunity to recover OTC development costs postapproval. The extent to which this might be strengthened through carry-forward tax credits for research done in Phase III or IV of Rx development (24), or other creative means, will be important as OTC R&D costs escalate because of the increased burden for research associated with more complicated switches

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(see below). In addition, the ability to define consumer behavior studies as essential to approval under Waxman-Hatch, which would require a legislative approach, would help incentivize switch. Furthermore, while the switch regulatory process via the New Drug Application (NDA) route is well in place, despite the need for procedural refinements to optimize review times, the industrys and FDAs perspectives of what products might be switched often differ at this time. At the core of the discussion are the following issues: the competing interests within companies in switching versus maintaining Rx markets, use of OTCs for chronic conditions, and dietary supplements. Further, the globalization of the consumer marketplace will place strains on the current drug development and review process. First, there is not necessarily a consistent view among companies that all OTCs that can be switched should be switched. A number of factors may work in opposition to switch from a company perspective, including, among others: Emerging longitudinal data demonstrating the long-term medical and cost benefits of Rx therapy thereby fueling penetration and persistence of Rx therapies, Greater resourcefulness of Rx managers in managing the Rx life cycle through directto-consumer (DTC) advertising, Increasing clinical costs and preapproval marketing, Expense to switch, The difficulty in differentiating in crowded switch categories, The continuing postmarketing clinical costs to remain competitive, Company familiarity with the Rx versus OTC side of drug development and delivery, and Safety issues unfavorable to a regulatory switch decision. On the other hand, factors favoring an OTC perspective in a companys life cycle management of its products are:

Increasingly rapid brand erosion after patent expiration, Interest by industryas a groupin assessing switches for a broad range of potential OTC categories, particularly those for chronic conditions (see below), and Growing appreciation of the need for Rx life cycle extension strategies. How industry responds to the challenge to find new ways to incentivize OTC R&D through postapproval pay-backs, as mentioned above, will be an important determinate to the future of switch. A second issue relates to differing perspectives between industry and FDA on what is OTCable. About 80 different ingredients, dosages, and dosage forms have been switched since the start of the OTC Review in 1972, in categories both established by the OTC Review (eg, chlorpheniramine as an antihistamine for cough/cold and allergy symptoms, ibuprofen as an internal analgesic/antipyretic, and fluoride for oral care, etc.) and new self care categories (eg, minoxidil for hair growth, miconazole for vaginal candidiasis, and bentoquantam for poison ivy protection, etc.; see Table 1). About 40 active ingredients have been cited in the trade or popular press and at Consumer Healthcare Products Association scientific/regulatory meetings as possible future candidates for switch (25,26). Many of these possible switches would significantly expand the frontier of self care, involving the use of OTCs for chronic conditions such as hormone replacement therapy, cholesterol lowering, and viral infections. While FDA has denied the approval of OTC antihypercholestrolemics (27) and sided with its advisory committee recommendation against the switch of antivirals for herpes labialis (28,29), companies remain interested in these potential OTC categories. A core question for such switches is whether the quality of medical care is considered optimal by the health profession for a particular switch category. For example, for nicotine replacement therapy (NRT), the quit rate in a highly supportive Rx setting is in the range of 50%, while that

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R. William Soller TABLE 1 Ingredients & Dosages Transferred From Rx-to-OTC Status (or New OTC Approvals) by the Food and Drug Administration Since 1975

Category/Ingredient

Action

Approval Date May 27, 1980 May 27, 1980 May 27, 1980 September 9, 1976 September 9, 1976 September 9, 1976 September 9, 1976 September 9, 1976 September 9, 1976 July 23, 1981 July 23, 1981 August 7, 1981 September 3, 1982 September 3, 1982 November 26, 1982 January 15, 1985 January 15, 1985 June 17, 1985 June 17, 1985 May 22, 1987 August 12, 1987 August 24, 1987 August 21, 1992 August 21, 1992 December 9, 1992 January 6, 1997 February 28, 1989 August 1, 1986 April 30, 1987 March 3, 1988 April 28, 1995 June 19, 1995 December 19, 1995 May 9, 1996 June 26, 1997 February 26, 1998 July 9, 1999 May 18, 1984 January 11, 1994 June 16, 1995 October 16, 1995 January 14, 1998 November 29, 1999 May 30, 1986 June 8, 1994 July 11, 1994

Anorectal 1. ephedrine sulfate anorectal/vasoconstrictor 2. epinephrine hydrochloride anorectal/vasoconstrictor 3. phenylephrine hydrochloride anorectal/vasoconstrictor Cough/Cold-Allergy 1. brompheniramine maleate antihistamine 2. chlorpheniramine maleate antihistamine 3. oxymetazoline HCl nasal decongestant 4. pseudoephedrine HCl nasal decongestant 5. pseudoephedrine sulfate nasal decongestant 6. xylometazoline HCl nasal decongestant 7. chlorpheniramine maleate* antihistamine 8. phenylpropanolamine HCl* nasal decongestant 9. diphenhydramine HCl* antitussive 10. dexbrompheniramine maleate* antihistamine 11. pseudoephedrine sulfate* nasal decongestant 12. triprolidine HCl antihistamine 13. dexbrompheniramine maleate antihistamine 14. diphenhydramine HCl antihistamine 15. pseudoephedrine HCl* nasal decongestant 16. triprolidine HCl* antihistamine 17. dexbrompheniramine maleate* antihistamine 18. chlophedianol HCl antitussive 19. doxylamine succinate antihistamine 20. clemastine fumarate* antihistamine 21. clemastine fumarate w/PPA* antihistamine/decongestant 22. dexchlorpheniramine maleate+ antihistamine 23. cromolyn sodium* allergy prevention/treatment Gastrointestinal 1. hydrogenated soybean oil & lecithin cholecystokinetic 2. pyrantel pamoate anthelmintic 3. phenhydramine HCl antiemetic 4. loperamide* antidiarrheal 5. famotidine* acid reducer 6. cimetidine* acid reducer 7. ranitidine* acid reducer 8. nizatidine* acid reducer 9. loperamide/simethicone* antidiarrheal/antigas 10. ranitidine* acid reducer 11. cimetidine suspension* acid reducer Internal Analgesic/Antipyretic/Antiinflammatory 1. ibuprofen* analgesic/antipyretic 2. naproxen sodium* analgesic/antipyretic 3. pediatric ibuprofen suspension* analgesic/antipyretic 4. ketoprofen* analgesic 5. aspirin/caffeine/acetaminophen* migraine treatment 6. naproxen Na, pseudoephedrine HCl* analgesic/decongestant Ophthalmic 1. oxymetazoline HCl* occular vasoconstrictor 2. pheniramine maleate with ophthalmic antihistamine/ naphazoline HCl* decongestant 3. antazoline phosphate with ophthalmic antihistamine/ naphazoline HCl* decongestant

OTCs 2000: Achievements and Challenges TABLE 1 Continued Category/Ingredient Oral Care 1. acidulated phosphate fluoride 2. sodium fluoride 3. stannous fluoride 4. stannous fluoride 5. dyclonine HCl 6. triclosan (dentifrice)* Sleep Aid 1. doxylamine succinate* 2. diphenhydramine HCl 3. diphenhydramine monocitrate Smoking Cessation 1. nicotine polacrilex* 2. nicotine transdermal system* 3. nicotine transdermal system* Topicals 1. hydrocortisone 2. hydrocortisone acetate 3. haloprogin 4. miconazole nitrate 5. povidone iodine sponge* 6. clotrimazole* 7. permethrin* 8. hydrocortisone 9. hydrocortisone acetate 10. minoxidil* 11. bentoquatam* 12. terbinafine hydrochloride* 13. ketoconazole* 14. minoxidil* Womens Health 1. clotrimazole* 2. miconazole nitrate 3. butoconazole nitrate* 4. miconazole nitrate* 5. clotrimazole* 6. miconazole nitrate* 7. tioconazole* Action dental rinse dental rinse anticaries gel dental rinse oral anesthetic antigingivitis treatment sleep-aid sleep-aid sleep-aid smoking cessation smoking cessation smoking cessation antipruritic (anti-itch) antipruritic (anti-itch) antifungal antifungal antimicrobial antifungal pediculicide (head lice) antipruritic (anti-itch) antipruritic (anti-itch) hair grower poison ivy protection antifungal dandruff shampoo hair grower anticandidal anticandidal anticandidal anticandidal anticandidal anticandidal anticandidal

699

Approval Date March 28, 1980 March 28, 1980 March 28, 1980 March 28, 1980 May 25, 1982 July 11, 1997 October 18, 1978 April 23, 1982 April 23, 1982 February 9, 1996 July 3, 1996 August 2, 1996 December 4, 1979+ December 4, 1979+ March 23, 1982 March 23, 1982 January 7, 1987 October 23, 1989 May 5, 1990 August 30, 1991+ August 30, 1991+ February 9, 1996 August 26, 1996 March 9, 1999 October 10, 1997 November 17, 1997 November 30, 1990 March 13, 1991 December 26, 1995 April 16, 1996 July 29, 1996 March 30, 1998 February 11, 1997

*Approved as a New Drug Application (NDA) for individual products; all others via OTC Review Monographs + Last Rx-to-OTC Switch via the OTC Review Monographs

in simulated low-support OTC and Rx settings is in the range of 15% to 18%. Yet, prior to NRT switch, access was a problem, since many patients were not obtaining NRT prescriptions; hence OTC availability meant a greater number of users and, despite a lower quit rate in a low-support OTC setting, a greater total number of quitters (30). For antihypercholesterolemics, the question to be de-

bated is how much better, if at all, must Rx cholesterol lowering therapy be before OTC access can be considered as a net benefit to the management of morbidity and mortality associated with elevated cholesterol levels. This matter is the subject of a July 2000 FDA advisory committee hearing. Playing into the future dialogue on OTCs for chronic conditions will be FDAs interest in ensuring a risk

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management approach to drug benefit/risk decisions (31) which will, among other things, focus not only on the consumers ability to monitor and comply with self-care therapy, but also the consumers willingness to accept the risk of the potential consequences of self care for chronic conditions. The passage of the Dietary Supplement and Health Education Act of 1994 (DSHEA) was not just remarkable for what it did to boost the dietary supplement market but, in the process of so doing, it helped define self care as a continuum, spanning Rx and OTC drug treatment and prevention of disease and recurring conditions (eg, tension headache) to health promotion and maintenance through dietary supplements, foods, and other options (eg, diet and exercise). Importantly, DSHEA has sent a significant message to regulatory authorities, that is, consumers demand information on emerging self-care options in order to optimize their health. As FDA deals with the implementation of DSHEA in relation to First Amendment issues, significant scientific agreement as a basis for possible qualified health claims, and structure/function claims, it will be interesting to observe the impact on the OTC market, both in terms of whether dietary supplements are used in place of, and/or in addition to, OTC medicines and in terms of approaches to new OTC products. For example, will OTCs be developed that challenge the target populations now served by dietary supplements (eg, healthy cholesterol maintenance), or will companies seek to further develop the clinical basis for dietary supplementation through studies that support a form of exclusivity through national brandingor both? CONCLUSION The last quarter of the twentieth century has been an era of consumer enlightenment, with consumer product industries meeting the resulting consumer health care demands through Rx-to-OTC switch, dietary supplements, and direct-to-consumer advertising of prescription drugs. The legislative and regulatory initiatives that have been created to

respond to changing consumer demands have also contributed to further strengthening consumer empowerment, and thus form a solid foundation for future expansion of the self-care field. As a result of the still growing impact of the Internet on our daily lives, and with it the globalization of electronic education, advertising, and distribution of self-care products such as OTC medicines, the future demand for novel self-care options will likely be very high. REFERENCES
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Minority Member, Committee on Commerce, House of Representatives. Washington; 1995. 24. Francesco S. OTC switch monitoring and compliance research should quality for a 3 year period of market exclusivity plus access to the monograph system. Switch. (Newsletter) May 1995 (10): 14, 9. 25. Consumer Healthcare Products Association. Ingredients & Dosages Transferred From Rx-to-OTC Status (or New OTC Approvals) by the Food and Drug Administration Since 1975. Washington, DC: Consumer Healthcare Products Association; 1999. 26. Consumer Healthcare Products Association. Rx-toOTC Switch Workshop Materials. Research & Scientific Development Conference. Washington, DC Consumer Healthcare Products Association; October 2829, 1999. 27. Federal Register. 62:5564555646. Washington; 1997.

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28. Food and Drug Administration. Transcript of the Joint Meeting of the Antiviral Drugs Advisory Committee and Nonprescription Drugs Advisory Committee. Docket No. 94N0006, January 1112, 1995. 29. Food and Drug Administration. Draft guidance for industry on OTC treatment of herpes labialis with antiviral agents. www.fda.gov/cder/guidance/index. htm. 30. Soller RW. Rx-to-OTC switchA testable hypothesis. Presented at the Annual AESGP Meeting, Berlin; June 911, 1999. 31. Food and Drug Administration. Managing Risks from medical Product Use: Report to the Commissioner from the Task Group on Risk Management. www.fda.gov/oc/tfrm/riskmanagement.pdf. May 1999.