Rational Approaches to the Regulation of Nonprescription Medicines

In recent years, self-medication products have undergone a dramatic change due to the advent of herbal medicines, dietary supplements, nutraceuticals and health foods in addition to traditional nonprescription medicines and the increasing societal preferences towards greater individual control over the use of medicines. Globally, the role and importance of nonprescription medicines in healthcare delivery is also rapidly increasing due to the potential cost-savings. Hence, this area is beginning to receive much attention from regulatory authorities, academia and professional/industry/trade organizations. This dissertation presents a comprehensive analysis of the classification of nonprescription medicines and Rx-to-OTC switch criteria/policy in the United States, United Kingdom, Canada, Japan and Australia. A new approach to investigating US FDA's overall switch regulatory policies through the combined application of casehistory evaluations, electronic survey questionnaire and telephone interviews has been utilized. This investigation was conducted in three phases. Phase-1 involved information retrieval and a critical review of existing literature, phase-2 applied switch case history analyses pertinent to US FDA and phase-3 measured the attitudes/opinions of the academic/professional community and key opinion leaders in nonprescription medicines across the US, Canada, UK and Australia on important questions. The subject matter of this dissertation is of enormous current interest in the global nonprescription medicines arena. The significance of the results presented in this dissertation is amplified as this area has received little academic attention and this is perhaps the first comprehensive treatment of this subject. Overall, inferences based on the information elicited have been summarized to provide data-based responses to questions of global interest in the self-medication arena. This information is especially valuable to the US FDA as they are currently seeking public comment. Data shows that the OTC regulatory model in the United States may be improved. Evidence indicates that principles upon which approaches for improvement of the US regulatory system must be based should include: an objective evaluation of pharmacist class of OTC medicines, development of effective consumer education tools, increase in regulation of non-traditional OTC medicines, acknowledge that not all disease conditions and drug classes are suitable for self-treatment, a collaborative approach by FDA towards switching that includes all stakeholders is more favored, decisions on switch petitions must be case-specific without a presumptive bias and public health benefit must be the paramount evaluation criterion. ACKNOWLEDGMENTS The completion of this dissertation in its final form marks the culmination of a long personal journey that has been enriching and enlightening in so many ways that I cannot even describe. Although this is a personal accomplishment, I could not have done it alone without the support and guidance of many generous individuals. I am most grateful to all of them. I thank my major professor Dr. Christopher Rhodes for his invaluable support and guidance. I am grateful to Dr. Sara Rosenbaum and Dr. James Kowalski for serving on my dissertation committee, they have been very helpful to me. I thank Dr. Mum Nippo for acting as the chairman of the dissertation examination committee and Dr. Cynthia Willey for serving on the dissertation examination committee. Dean Janet Kulberg of the Graduate School offered me wise advice on a very critical occasion, I hold her in high regard. I am most grateful to GlaxoSmithKline Consumer Healthcare, Parsippany, NJ for their support. In particular, Ms. Susan E. James, Mr. Anthony G. Amitrano, Mr. Stanley J. Lech, Mr. Kenneth James, Dr. Prasad Adusumilli at GlaxoSmithKline were most helpful. Mr. Rajan Khade designed and developed the programming for the web questionnaire and automated database for collecting responses, his kind assistance has been very helpful. It is not possible to list here all my friends to whom I am very grateful. I thank Swami Iyer, Bina & Bali Gangadharan, Surabhi & Sudhan Marathe, Ravi Pappu and Kathy Hayes who have been very helpful to me in numerous ways.

: Trends in alternative medicine use in the United States, 1990-1997 34 (data summarized from reference 7) Table 2: Description of scientific evidence necessary for justifying 35 reclassification of an approved prescription drug product to the OTC status in the United States Table 3: Specific issues upon which FDA intends to solicit comments through 37 the over-the-counter drug products public hearing MANUSCRIPT II Table 1: Summary of the schedules relevant to substances for human use as 75 per the Australian classification system Table 2: Summary of the assessment factors used in scheduling 76 nonprescription medicines for human use as per the Australian classification system Table 3: Summary of the factors used for listing drugs for human use in 77 Schedule F (subject to prescription control) as per the Canadian classification system Table 4: Description of factors that serve as the foundational basis for 78 scheduling drugs in Canada Table 5: Summary of suitable evidence required for justification of a 79 rescheduling application submitted to NDPSC review in Australia Table 6: Steps in the regulatory amendment process to de-schedule drugs to 80 nonprescription status at the federal level in Canada Table 7: Summary of data requirements for a reclassification application in 81 The European Union Table 8: Classification of proprietary drugs (nonprescription medicines) m 82 Japan Table 9: Data required for approval of nonprescription drugs in Japan 83 Table 10: Description of clinical trial requirements for nonprescription 84 medicines in Japan MANUSCRIPT III  Figure I: Summary of regulatory mechanisms through which an approved 36 prescription drug product may be reclassified as an OTC drug product. As all prescription drugs are considered to be new drugs, box 2 does not contain any products

INTRODUCTION
In recent years, self-medication products have undergone a dramatic change due to the advent of herbal medicines, dietary supplements, nutraceuticals and health foods in addition to traditional nonprescription medicines and the increasing societal preferences towards greater individual control over the use of medicines (1,2).
Conventional regulations seem inadequate to address the complex challenges and regulatory needs of today's self-medication arena leading to a regulatory vacuum. Some important discrepancies associated with the regulation of nonprescription medicines are: (1) Globally, there exists no uniformity in the classification of nonprescription medicines. For example, over-the-counter (OTC), pharmacy medicine (P) and quasidrugs (QD) are variations of nonprescription drug products available within the developed world.
(2) Scientific methodologies to assess the risks and benefit to individuals/general public health associated with use of OTC drug products (in terms of pharmacological profile of active moieties, their dosage or disease conditions) are unclear. There exist inadequacies to facilitate an efficient Rx-to-OTC switch driven by science-based, datadriven decision making processes.
(3) The role of the US Food and Drug Administration (FDA) in the Rx-to-OTC switch process in the absence of support from a sponsor is unclear.
Globally, the role and importance of nonprescription medicines in healthcare delivery is rapidly increasing due to the shift in societal attitudes towards selfmedication and the associated cost-savings (3). In 1999, global sales of nonprescription medicines grew by 4.7% to US $49.2 billion following the trend in recent years (4). The 2 growing global interest in self-medication and related economic benefits emphasize the importance of and necessity for a regulatory framework developed on the basis of sound scientific principles. Hence, this area is beginning to receive much attention from regulatory authorities, academia and professional/industry/trade organizations.
Also, the US FDA recently initiated a comprehensive review of the Agency's approach to regulating over-the-counter (OTC) drug products, that is ongoing and conducted a public hearing on this subject in June, 2000 (5). The purpose of the hearing was to solicit information from interested persons including scientists, professional groups and consumers. FDA's intention is to elicit comments on general issues regarding the status of OTC drug products, including the criteria the Agency should consider in rendering decisions on OTC availability of drugs, the classes of products, if any, that are not currently available OTC that should or should not be available OTC, how FDA can be assured that consumers understand the issues relating to OTC availability of drug products, how rational treatment decisions are affected by coexisting prescription and OTC therapies for a given disease, whether the current structure for marketing OTC products in the United States is adequate, and FDA's role in switching products from prescription to OTC status.

OBJECTIVES
The salient objectives of this study are listed below: Growing patient involvement in the diagnosis and treatment of common ailments coupled with easy access to reliable information is leading to increasing interest in self-care and the use of nonprescription medicines worldwide.
Nonprescription medicines now account for about 60% of all medications used in the United States and may be used to treat or cure about 400 ailments (1). In 1999, global sales of nonprescription medicines grew by 4.7% to US $49.2 billion in line with the trend in recent years (2). The role and importance of nonprescription medicines in healthcare delivery all over the world is rapidly increasing due to the shift in attitude towards self-medication and the potential cost-savings (3). In recent years, the landscape of self-medication products has undergone a dramatic change due to the rapid advent of herbal medicines, dietary supplements, nutraceuticals and health foods in addition to traditional "pharmaceutical" nonprescription medicines (4). Conventional regulations were not designed to address the complex challenges and regulatory requirements of today's self-medication arena precipitating the need for concomitant evolution in regulatory policies. The growing global interest in self-medication and related economic benefits accentuate the importance of and necessity for a regulatory framework developed on the basis of sound scientific principles. Hence, this area is beginning to receive much attention from global regulatory authorities, academia and related industry/professional organizations. The US Food and Drug Administration (FDA) recently announced a public hearing to evaluate the Agency's approach to regulating over-the-counter (OTC) 11 drug products (5). The purpose of the hearing is to solicit information from interested persons including scientists, professional groups and consumers.
Consequently, an examination of the current global regulatory environment of nonprescription medicines has been undertaken to review and compare the US OTC regulations with those in other comparable developed nations. The central focus of this exegesis is on: (a) classification of medicines (for human use) and the underlying scientific rationale, and (b) regulatory policies affecting prescription to nonprescription reclassification (Rx-to-OTC switch) of medicines, in the United States.

State of nonprescription medicines
The usual perception of nonprescription medicines as pharmaceutical medicines available without a prescription has undergone a dramatic change due to the rapid advent of complementary and alternative medicines (CAM). This shift in societal preferences has increased the scope of nonprescription medicines to include dietary supplements, herbal medicines, folk remedies and other traditional ethnic medicines (6).
Eisenberg et.al. studied the trends in CAM use in the US between 1990 and 1997 (7).
Their results show that CAM use and expenditures substantially increased between 1990 and 1997 attributable primarily to an increase in the proportion of population seeking alternative therapies and the pertinent data is summarized in table 1.
The significance of nonprescription medicines in public health care is also reaching unprecedented levels. In the US, approximately 60% of all medicine dosage units consumed are nonprescription medicines. Of approximately 3.5 billion health problems treated annually in the US, some 2 billion (57%) are treated with a nonprescription medicine. About a third (33%) of all nonprescription medicines are 12 consumed by the rapidly growing demographic group of older Americans. The benefitcost ratio of responsibly used nonprescription medicines is very favorable.
Nonprescription medicines account for less than three cents of every dollar spent on healthcare in the US, yet the benefit derived is vast (8). These observations are in agreement with global trends in support of self-medication. In the United Kingdom, evidence indicates that growing numbers of general practitioners and consumers are in favor of increased responsible self-medication. Positive support by physicians for selfmedication is growing and research shows that more than half the general practitioners expect to increase their recommendations of nonprescription medicines in the next year (9). It is reasonable to conclude that due to the onset of the information age, change in consumer preferences and the availability of new nonprescription medicines that were previously unavailable, the significance of nonprescription medicines in overall health care is bound to increase in the future.

Regulation of nonprescription medicines in the US
In the United States, the original Food and Drugs Act was passed m 1906 prohibiting interstate commerce in misbranded and adulterated foods, drinks and drugs (10,11). This law only ensured purity and did not address the important issue of truthfulness of health claims among other inadequacies. Following the Sulfanilamide tragedy, The Federal Food, Drug and Cosmetic Act (FD&C Act) was passed in 1938 as the foundation of present day drug laws (12). This law contained many new provisions such as, requiring new drugs to be shown safe before marketing (starting a new system of drug regulation), eliminating the earlier requirement to prove intent to defraud in 13 drug misbranding cases, requiring human drugs to bear label warnings against habit formation and requiring FDA to enforce the law.
Arguably, the most important amendment to the FD&C Act in this context is the Durham-Humphrey Amendment of 1951. This amendment clarified the dispensing obligations of the pharmacist by defining the kinds of drugs that cannot be safely used without medical supervision and restricting their sale to prescription by a licensed practitioner (13). This amendment also serves as the foundational basis for the current classification system of drug products in the United States into, prescription medicine and nonprescription medicine (or OTC). Section 503(b)(l) of FD&C Act states: by refilling any such written or oral prescription if such refilling is authorized by the prescriber either in the original prescription or by oral order which is reduced promptly to writing and filed by the pharmacist.
The act of dispensing a drug contrary to the provisions of this paragraph shall be deemed to be an act which results in the drug being misbranded while held for sale. " Hence, the need for medical supervision and prescription requirement for a drug product may arise due to: (a) the drug characteristics or the method of use necessary for its safe use, or, (b) the new drug application (Section 505 of FD&C Act) under which it received approval. An implication of section 503(b )(1) that needs emphasis is that, only 14 drugs meeting above stated conditions reqmre the additional control of medical supervision and prescription requirement, otherwise they may be sold without a prescription. Alternately stated, drug products are inherently presumed to be nonprescription unless otherwise required, as per FD&C Act. This assertion may be tersely stated as, "if it can be OTC, it must be OTC" to illustrate the inherent bias for "nonprescriptionness" arising from the law and is critical in the comprehension of this classification system ( 4).

Another important legislative development in this context is the Kefauver-Harris
Drug Amendments of 1962, enacted as a result of the Thalidomide disaster (14). As per these amendments, manufacturers were required to prove the safety and efficacy of any new drug before its marketing, and FDA approval of the new drug application (NDA) became a necessary prerequisite to marketing. These amendments required an unprecedented program of accountability from the manufacturers. To fulfill its obligations under these amendments, the FDA contracted with the National Academy of Sciences/National Research Council to evaluate the effectiveness of 4000 drugs approved only on the basis of safety between 1938 and 1962, under the so called Drug Efficacy Study Implementation or DESI Review in 1966 (11).
Further the FDA in 1972, initiated rulemaking procedures to determine which nonprescription medicines (The OTC Drug Review) can be generally recognized among qualified experts as safe and effective and not misbranded under prescribed, recommended, or suggested conditions of use (5). Through the OTC Drug review process, FDA established monographs for classes of nonprescription medicines (such as antacids etc.) that were generally recognized as safe and effective and not misbranded 15 when the products contained the ingredients and are labeled as per the monograph. OTC drug monographs describe the active ingredients, amount of drug, formulation, labeling and other general requirements for drugs to be lawfully sold OTC. In all 722 active ingredients for different uses were reviewed by 17 expert advisory panels through the public review and comment process of OTC Review. About a third of all the drugs reviewed were found to be generally recognized as safe and effective for OTC use (15).
The OTC Drug Review marked the onset of the era of rational regulation of nonprescription medicines on the basis of sound scientific evidence. It is generally agreed that the OTC Review created: (a) a claims structure based on scientific evidence and rational regulatory policy (b) a safety standard that is equal to or higher than that for prescription medicines ( c) an increase in consumer confidence by ensuring nonprescription medicines deliver the benefits advertised, and (d) an emphasis on comprehensive labeling, with clearly defined policies for OTC warnings (4).
Considering the rapidly growmg segment of the nonprescription medicine market that is comprised of CAM, it is important to also discuss the state of their regulation in the US. Kottke has recently published an elaborate review of the scientific basis and the regulatory state of nutraceutical products. It is suggested that readers peruse that report and other references for a comprehensive study of this subject (16,17,18,19). FDA's concern to regulate vitamins and dietary products in a manner similar to drug regulation has been ongoing for many years. But, unfortunately such attempts have only been unsuccessful, for instance, FDA withdrew proposed regulation requiring minimum and maximum levels of dietary supplements in the face of severe consumer protest in 1962 and federal courts disallowed FDA from regulating high 16 dosage vitamins as drugs based on the toxic impacts of such products in late 1970s. An As per DSHEA, a dietary supplement is a product (other than tobacco) that is intended to supplement the diet that bears or contains one or more of the following dietary ingredients: a vitamin, a mineral, an herb or other botanical, an amino acid, a dietary substance for use by man to supplement the diet by increasing the total daily intake, or a concentrate, metabolite, constituent, extract, or combinations of these ingredients. Further, the term is defined to include products such as an approved new drug, certified antibiotic, or licensed biologic that was marketed as a dietary supplement or food before approval, certification, or license. This very broad definition has had the unintended consequence of including even prescription medicines under the term "dietary supplements" raising public health concerns (17,18). Cholestin® is a red yeast rice product marketed as a dietary supplement, and is a natural source of lovastatin which is the active drug in the prescription medicine Mevacor® used for lowering cholesterol levels. Before DSHEA, FDA contended that "labeling" of dietary supplements included not only the actual product label, but also any other written, printed or graphic matter accompanying the product. DSHEA explicitly exempted from "labeling", any such accompanying written matter provided that such written matter is truthful and not misleading, effectively preventing the FDA from regulating It is also hoped that as traditional pharmaceutical companies enter the arena of developing supplement products for economic benefits, they will extend their science-based and data driven product development philosophy to the supplements industry.

Reclassification of medicinal products in the US
Reclassification is the process of removing the prescription requirement and need for medical supervision for a marketed drug product (for human use) that was previously available only through a legitimate prescription and making it available over-the-counter. It is commonly referred to as "Rx-to-OTC switch" or simply "the switch". One major factor responsible for the rapid growth of responsible selfmedication via use of nonprescription medicines is the recent reclassification of previously prescription medicines to OTC status that have been very successful, both medically and commercially. It may be helpful to divide this subject into, (a) regulatory 19 mechanisms through which a marketed prescription drug product may be reclassified as an OTC product, and (b) scientific evidence or data required in support of the petition requesting such a reclassification.
An excellent review of the Rx-to-OTC switch process, related procedures and the underlying statutory scheme has been presented by Wion (23). There are essentially four regulatory mechanisms through which reclassification may be achieved. They are: • filing of an NDA (NDA approach) • filing of a supplement to an approved NDA (sNDA approach) • as per section 503(b)(3) ofFD&C Act (switch regulation approach), and • the OTC Drug Review (monograph approach).
In the NDA approach, either a traditional NDA (per section 505(b)(l) of FD&C Act) or a "paper" NDA (per section 505(b)(2) of FD&C Act) may be filed. The NDA route is suitable in the event where the proposed OTC product is of a lesser strength or for a different indication than its prescription counterpart, in which event efficacy and safety need to be established. The switch of Ibuprofen at the 200 mg dose to OTC status utilized the NDA approach for reclassification. Under the sNDA approach, a supplement to the original NDA under which the drug product was approved may be filed demonstrating the suitability of the product for OTC use to request reclassification.
Benylin® cough syrup containing diphenhydramine hydrochloride was switched to OTC status using the sNDA approach. It must be noted that upon successful reclassification 20 via the NDA approach or sNDA approach, the drug product in the OTC status is considered to be a new drug.
The Durham-Humphrey amendments to the FD&C Act were enacted to state clearly the criteria useful in limiting drug products to sale by prescription only. These amendments eliminated the confusion prevalent before their enactment and are contained in section 503 ofFD&C Act. Section 503(b)(3) of FD&C Act states: Services to remove the prescription requirement and need for medical supervision arising from NDA approval for prescription use (section 505) or for habit-forming drugs (section 502(d)) or the drug characteristics or method of its use necessary for its safe use (section 503(b)(l)) when the determination is made that such requirements are not needed to protect public health. Using this authority, FDA in 1956 issued the so-called "switch regulation" that is now codified in 21 CFR 310.200. Subsection (b) of 21 CFR 310.200 states: "Prescription-exemption procedure.
(b) Prescription-exemption procedure for drugs limited by a new drug application. Any drug limited to prescription use under section 503(b)(J)(C) of the act shall be exempted from prescription-dispensing requirements when the Commissioner finds such requirements are not necessary for the protection of the public health by reason of the drug's toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use, and he finds that the drug is safe and effective for use in self-medication as directed in proposed labeling. A proposal to exempt a drug from the prescription-dispensing requirements of section 503(b)(l)(C) of the act may be initiated by the Commissioner or by any interested person. Any interested person may file a petition seeking such exemption, which petition may be pursuant to part 10 of this chapter, or in the form of a supplement to an approved new drug application. " 21 Hence, using the switch regulation the FDA or any interested person may initiate the reclassification process and drugs so switched to OTC status also are considered to be new drugs (see 21 CFR 310.200(c) Another important factor, the influence of which upon availability of new OTC drug products and reclassification needs to be clarified, is the direct-to-consumer marketing of prescription drug products. Some questions that need to be addressed are: Are any of such drug products suitable candidates for reclassification?; If, only a physician may write a prescription upon diagnosis, why are such promotional activities aimed at consumers creating a "quasi self-medication" possibility?; In the process of a consumer initiated enquiry resulting in a responsible medication choice upon consultation with a physician, can the physician be replaced by the pharmacist, at least in some cases? The Jack of dedicated initiatives aiming at global harmonization of reclassification policy is a cause for concern as globalization is a rising trend among the industry. Subsequently, some key issues that need to be addressed are: Why is there variation in the dosage strength of certain medicines approved for OTC use between nations? Why are certain medicines OTC in some nations, whereas they are prescription only in others? Is it possible to develop and establish globally acceptable monographs for OTC drug products, at least within the developed world? Lastly, the application of information technology to promote and achieve responsible self-medication through enhanced and effective consumer education needs to be explored. The authors intend to address some of the above issues in this, and subsequent articles. Again, use of the "interested persons" terminology perhaps disqualifies FDA from submitting switch proposals via the monograph system and delegates to FDA the role of a facilitator rather than a participant. From this discussion, it may be inferred that FDA has legal authority to promulgate regulation for reclassification to OTC status of prescription medicines only via the switch regulation mechanism under the current legislative framework. At this juncture, it is appropriate to consider the issue of whether FDA should exercise its authority to switch products only in collaboration with the sponsor. In the interest of public health and fairness to industry, the FDA should undertake any initiatives to switch products only in collaboration with the sponsor based on their active support. This approach is most desirable and offers the benefit of FDA being able to utilize the sponsor's vast knowledge database related to the development and marketing of the product.
The undesirable action of FDA switching a product despite the sponsor's objection to do so should be carried out only under very limited and unusual circumstances. Such a situation may be enormous and overwhelming public support for OTC availability of a certain product, assuming it meets all the safety, effectiveness and labeling standards required of OTC products. The inherent difficulty in such an 29 approach would be that the burden of proving suitability for OTC use would lie on FDA and such a task may be formidable in the absence of support from the sponsor. Further, it is very difficult to envision FDA being able to prove suitability for OTC use without access to data from the original NDA (which is the sponsor's intellectual property).
Further, FDA should also present a cogent argument demonstrating the need for such radical regulatory action and subsequent benefit to overall public health. This should be done in an open and transparent process that includes all interested persons prior to such a decision taking effect.

Conclusion
The role and significance of nonprescription medicines in overall health care delivery worldwide is mounting rapidly due to changing social preferences and associated economic benefits. The US FDA has initiated the desirable program of announcing a public hearing to evaluate its approach to regulating OTC products. In this regard, the authors have undertaken a comparative evaluation of regulatory aspects of nonprescription medicines within major developed nations. An examination of the regulatory environment of nonprescription medicines in the United States shows that there exists a wide gap in the scientific basis supporting the regulatory principles for traditional pharmaceutical nonprescription medicines and alternative medicines or herbal remedies. There exist many challenging issues related to the reclassification of products to OTC status in the United States. The authors believe that FDA should invoke its authority to switch products to OTC status in collaboration with the sponsor using their support and expertise. 30 *   Figure 1: Summary of regulatory mechanisms through which an approved prescription drug product may be reclassified as an OTC drug product. As all prescription drugs are considered to be new drugs, box 2 does not contain any products   Consequently, an examination of the current global regulatory environment of nonprescription medicines has been undertaken to review and compare the US OTC regulations with those in other comparable developed nations. The central focus of this exegesis is on: (a) classification of medicines (for human use) and the underlying scientific rationale, and (b) regulatory policies affecting prescription to nonprescription reclassification (Rx-to-OTC switch) of medicines. An earlier article examined the regulatory environment in the United States and this article presents the same in Australia, Canada, European Union, United Kingdom and Japan along with the World Health Organization (WHO) perspective (2). The overall object is to learn from various global regulatory models and draw inferences that may be beneficial when applied in the United States context. 41

Australia
In Australia, the Therapeutic Goods Act of 1989 (TG Act) aims at providing a national framework for the regulation of therapeutic goods to ensure their quality, safety, efficacy and timely availability. The Therapeutic Goods Administration (TGA) as part of the Commonwealth Department of Health and Aged Care has the responsibility for administering the Act and ensuring that the necessary evaluation and assessment procedures are conducted to enable access to the latest treatments available that are safe, effective and of good quality. A general introduction to the regulatory process for all medicines in Australia and other pertinent matters including the role of TGA is presented in one of TGA publications (3).
The TGA uses a risk-management approach to regulating medicines that forms the basis of the Australian classification system. Accordingly, risk is determined by a number of factors such as: (a) the medicine containing a scheduled substance (discussed later) (b) medicine's use can result in significant side-effects ( c) the medicine is used to treat life-threatening or very serious illnesses, and (d) there may be any adverse effects from chronic use or inappropriate self-medication. Essentially, any product for which therapeutic claims may be made must be either listed or registered in the Australian Register of Therapeutic Goods (ARTG) before being marketed in Australia. ARTG was established under Part 3 of the Therapeutic Goods Act to include a computer database of information about therapeutic goods for human use that are approved for supply in, or export from Australia (4).
Listed medicines are considered to be of lower risk than registered medicines, so the regulations allow for sponsors to self-evaluate (in terms of efficacy) their products in some situations and majority of listed medicines are used for self-medication without a prescription being required. Listed medicines only contain well known established ingredients with long history of use, most complementary medicines (such as herbal, vitamin and mineral products), medicines that are intended only for export and if they do not contain any scheduled substances. The TGA assesses listed medicines only for quality, safety and not efficacy, but sponsors are legally mandated to hold information to substantiate their product's claims. Registered medicines are assessed as having a higher level of risk. The degree of assessment and regulation they undergo is rigorous and detailed, with sponsors being required to provide comprehensive safety, quality and efficacy data prior to receiving marketing approval. Registered medicines include both prescription and nonprescription medicines (to include both traditional pharmaceutical OTC products and complementary or alternative medicines). In rare instances, some products may qualify for exemption from being listed or registered in the ARTG.
The registration process for entry into ARTG is determined in part by the household chemicals in addition to human drugs). The SUSDP includes a number of provisions (such as labeling, packaging and advertising) that relate to the level of control intended to apply to the scheduled substances (3,5). NDPSC decisions have no effect and do not attract controls until they are included in state and territory legislation.
While generally, NDPSC decisions are automatically adopted by reference in most jurisdictions (unless action is specifically taken not to accept a specific scheduling decision), others require publication in the Australian Gazette before scheduling decisions come into force.

Canada
The Health Protection Branch (HPB) of Health Canada is responsible for drug quality, safety and efficacy. It regulates drugs imported into and manufactured for sale in Canada, and drug distribution including conditions of sale. At the federal level, drug products are classified into prescription and nonprescription products (7). Schedule F to the Food and Drug Regulations is a listing of chemical entities or classes of drugs that, with exceptions, are required by regulation to be sold under prescription (8). The factors that are used by HPB to restrict drugs to Schedule Fare presented in table 3.
Additionally, Provincial Pharmacy Acts, enforced by provincial pharmacy regulatory authorities (PRAs ), regulate the profession and the practice of pharmacy and may further specify conditions of sale. Within these acts, drugs are classified into categories (called drug schedules) with conditions imposed on their sale (9). Prior to 1995, five provinces had provisions in their Pharmacy Acts controlling the distribution of drugs that provided additional levels of control to those already contained in the federal legislation and they did not regulate additional location of sale. This situation led to disharmony in how drugs were scheduled and controlled across Canada.
The necessity for drug schedule harmonization in Canada was addressed and the Canadian Pharmaceutical Association (CPhA) proposed a mechanism be established to assess the existing scheduling system and consider the benefits derived from greater consistency in drug scheduling. This proposal also recommended the assessment of the 45 legislation, procedures and criteria generating these schedules. Subsequently, as a result of the collaborative efforts between HPB, PRAs, CPhA and other interested parties the final report "Harmonized Drug Schedules in Canada" was  Thus, the Directive implicitly states that medicinal products should be subject to a prescription only when they meet the specifically defined criteria. Hence, the European Union classifies medicinal products into two categories, prescription medicines and nonprescription medicines, with the prescription requirement being applicable only when medicines meet certain defined criteria.  Proprietary drugs are divided into six classes according to conditions in the approval application (such as ingredients, quantity, indications) and have been summarized in table 8 (16,17). Also, the data requirements and clinical trial data necessary for the registration for each class of proprietary drugs have been presented in 51 tables 9 and 10 respectively. Quasi-drugs as stipulated by the law are: (a) products having fixed purposes of use (b) products having a mild action on the human body, and (c) products other than instruments and apparatus. For a product to be designated as a quasi-drug all three conditions must be satisfied (18). Quasi-drugs have been specified for: To facilitate rapid examination of proprietary drug approval applications, the MHW at the national level has been transferring the authority to prefectural governors, provided they adhere to uniform examinations as per established standards. Only the MHW may approve prescription medicines and quasi-drugs whereas nonprescription medicines may be approved either by the MHW or by the prefectural governments (15).

The United Kingdom
Recently, the MHW approved fifteen categories of medicines under the quasi-drug status. These products are for minor ailments (sore throat, stomach discomfort), vitamins/minerals and for external use (topical ointments) in general. The distribution system in Japan is rather unique as about 66% of all prescription medicines are both 52 written and dispensed by physicians or dentists and only 1 in 3 prescription medicines is dispensed by pharmacists. Quasi-drugs may be sold at any retail outlet. Nonprescription medicines are sold through a variety of outlets such as a pharmacy, drugstore with a pharmacist and drugstore without a pharmacist. Additionally, outlets with special limited license and for household distribution also exist but are relatively uncommon.

Australia
Reclassification (or rescheduling) of medicines in Australia is also governed by NDPSC guidelines for classification of medicines and poisons (6). The process of rescheduling may be initiated by the evaluating Agency (TGA), product sponsor, state and territory authorities and occasionally by NDPSC itself. If an applicant believes that they can justify an alternative schedule entry for any medicine, an application may be submitted for review to the NDPSC with suitable evidence. For rescheduling of a drug substance from prescription only (S4) to a lower nonprescription (S2 or S3) or exempt from scheduling, NDPSC usually requires at least two years of local clinical use or local post-marketing surveillance of the drug substance before the proposal is considered.

Canada
Reclassification (or de-scheduling) to nonprescription status in Canada has been addressed by the HPB in an information letter issued in June-1990 (19). The purpose of this information letter was to inform interested parties of the data requirements for applications to remove drugs for human use from Schedule F to the Food and Drug Regulations and outline the internal mechanism for handling such applications.
Applications must demonstrate that a favorable ratio exists between the benefit to patients that will occur versus the risk to their health that may be inherent in permitting the nonprescription sale of the drug product. HPB requests the following information for assessment of the reclassification applications: • Efficacy data f or new indications and safety data Efficacy data will be required if the indications of use or dosage differ from those approved fo r prescription use. A summary of all animal and human clinical safety data, including data that may have been part of an original submission and the data accumulated after the product's introduction.
• Drug adverse reaction data A summary of all known domestic and foreign adverse drug reaction reports since the introduction of the medicinal ingredient, adverse effects with their frequency and the dose at which they occurred. Any adverse effects that could require patient 54 • • • monitoring by a physician should be clearly described. Any potential for misuse or abuse and actual occurrences should also be discussed.

Labeling
All proposed nonprescription labeling and promotional material demonstrating that the safe and effective use of the product can be assured by nonprescription labeling rather than depending upon the professional judgment of a physician. Appropriate cautions and contraindications must be addressed in lay terms.

Chemistry and manufacturing data
Differences from the original submission and supplements must be identified.
Chemistry and manufacturing data will be required where they differ from the prescription drug.

Market data
Date of introduction of the prescription drug in the Canadian market and a summary of sales data must be included. If the product in consideration was not the first product introduced as a prescription drug, then date of introduction of the first product also must be provided. A summary of international market status (countries where requests for prescription or nonprescription status have been made, approved, rejected or are pending) is required. If a request has been refused, the reason for refusal is required. If the request was approved, the date of introduction in that market and confirmation that the product is currently marketed is required.
Additionally, the Drug Evaluation Unit of the HPB also published an information pamphlet on the subject of prescription to nonprescription switches in April-1999 (20). In this publication, HPB took the position that the switch process be 55 initiated by the manufacturer only, through the filing a supplemental new drug submission (SNDS) with HPB performing the assessment of the evidence provided to determine the suitability of the product and its indication for OTC use. The factors to be considered while evaluating the suitability for a switch and the data requirements for switch SNDS have also been briefly listed in this pamphlet. Also, HPB recently finalized revised guidelines for preparing submissions seeking to change the status of a drug from prescription to nonprescription. These guidelines for a switch divide switches into two types, Type I and Type II, based on the nature of the switch and complexity of the review.
Type I switch is for drugs which have same strength, dose, dosage form, indication and route of administration as the prescription product. Type I switches usually do not require the submission of new clinical trials or chemistry and manufacturing data. The review is mainly of the safety profile and whether selfmedication is effective. Type II switch is for drugs which have a change in, the indication, dosage form, strength or dose, route of administration, relative to the prescription product. Hence, a type II switch request requires data from clinical trials to support the new strength or dosage formulation as a nonprescription product.
Removal of drugs from Schedule F, or addition of a qualifier to Schedule F (for dual status products) requires the promulgation of a regulatory amendment which is subject to federal regulatory process and involves several stages and levels of approvals, that include the Minister and the Governor-in-Council who are advised by the Special Committee of c · ounc1l (SCC). The steps involved in the regulatory amendment process are outlined in table 6. A switch becomes law at the federal level once registered at the 56 SCC. After the drug is reclassified at the federal level, each province must then determine how the product will be sold and this determination is made by the National Drug Scheduling Advisory Committee (NDSAC) at the provincial level as discussed earlier.

The European Union
Reclassification within the EU has been addressed by the issuance of a guideline on changing the cl assification for the supply of a medicinal product for human use in September-1998 (2 1 ). This guideline is divided into two parts. Part one concerns the criteria for classifying a medicinal product as subject to medical prescription or not. Part two describes the data requirements for an application requesting reclassification of a prescription product to nonprescription status. As per this guideline, suitability of a medicinal product for nonprescription status is elaborated by examining the converse of each criterion (discussed earlier) that justifies the prescription requirement. Nonprescription medicines should be approved primarily for short-term treatment when the possibility of "masking" could occur.
No increased risk of resistance to product with a wider use of a product within the general population to such an extent that the usefulness of any medicinal product is likely to be compromised.

Self-assessment
• Conditions or symptoms should be such that can be correctly assessed by the patient and the product can be used without medical supervision. Consumer communication may be facilitated by the use of written information, advice of pharmacist and other appropriate sources.
• The natural course of the disease, the condition, the duration of symptoms and their reoccurrence and consequences should be correctly self-assessable.
• Contraindications, interactions, warnings and precautions should be those that can be understood by the consumer.

Risk and consequences of incorrect use
• Absence of a high incidence of conditions listed as contraindications, precautions or warnings or a high rate of usage of interacting drugs in the population in case of 58 • patients likely to use the medicine that may increase the incidence and risk of misuse.
Low danger to health if the patient uses the product where it is not indicated or uses it for a longer period than recommended or exceeds the recommended dose or fails to heed warnings or contraindications.

Patient information
• Leaflet and label must contribute effectively to safe and effective use of medicine and should be sufficient so that it substitutes for absence of medical supervision. All information should be provided in layman's terms and prominently presented in the leaflet. Leaflet and label should describe in equal prominence when and when not the product should be used.

Known incorrect use
• If known incorrect uses exist, then such a product may not be considered for nonprescription medicine status. Similarly, products with low expenence, where marketing authorization was only recently granted or when further investigation is required should also be not considered for nonprescription medicine status. Further, post-marketing information in an uncontrolled environment should be examined while reclassification. Part two of the EU guideline describes the data requirements and documentation concerning safety and efficacy in support of an application for reclassification. This is usually dependent on the nature of the active substance and the extent of changes to the existing marketing authorization. In all cases, an expert report should be provided taking a clear position and defending the proposal with scientific knowledge and demonstrate why none of the criteria that lead to the prescription requirement should be applicable. In addition to scientific data addressing all points related to determining the suitability of the product for nonprescription status, other requirements summarized in table 7 should also be included in the expert report.

The United Kingdom
In the United Kingdom, two types of reclassification are possible. The first type of reclassification is from prescription only medicine to pharmacy medicine status (POM to P) and the second type is from pharmacy medicine to general sales list (P to GSL). The UK Medicines Control Agency (MCA) has specified a set of guidelines related to each type of reclassification. The POM to P reclassification has been explained in Medicines Act Leaflet 77 (MAL 77) (13) and the P to GSL reclassification is discussed in Medicines Act Leaflet 82 (MAL 82) (22).
For POM to P reclassification, MAL 77 describes the procedure for amendment of the POM Order applying to products that are prescription medicines because they contain one or more substances listed in Schedule 1 to the POM Order. Applications under this procedure may be submitted as a variation or a new abridged application. The variation route is appropriate if the marketing authorization (MA) holder has a product suitable for reclassification, the proposal to amend the POM Order should be accompanied by an application to vary the legal status of the product. Other product particulars may also need to be varied in order for a product to be suitable for reclassification. If reclassification is agreed, amendment to the POM Order will proceed and the MA will be appropriately varied to take effect when the POM Order comes into force. If an MA holder wishes to make a change, for example to introduce a new strength, which requires a new application, a new abridged application should be made.
A new abridged application should also be made if the MA holder wishes to hold a separate MA for the P product. Also, any interested party such as a professional body that does not itself hold an MA may request the reclassification of a substance. The content of the applications should be similar to that of applications from MA holders.
Since, Schedule 1 to the POM Order is substance based, amendment will usually affect the legal classification of products containing that substance. If the MA is in line with the amendment to the POM Order, the product becomes classified as pharmacy medicine. However, MA holders should apply to vary their MAs in accordance with the 61 amendment to the POM Order, and provide appropriately amended labeling and patient information leaflets for approval.
Following assessment of the application, advice from the Committee on Safety of Medicines (CSM) will usually be sought on the proposed reclassification. If the reclassification proposal is supported, wider interests are then consulted. Responses to the consultation are examined by the MCA whose advice is passed to Ministers. It is for the Ministers to determine, in the light of the advice received, whether the POM Order should be amended. If the CSM recommends that a request for reclassification be refused, the originator of the proposal will be notified as to which POM criteria have been considered to apply and the reasons for advising against the change, and will receive a copy of the assessment report.
As stated earlier, the EC Directive on the classification of medicines (92/26/EEC) has been implemented in the United Kingdom and incorporated into section 58A of the Medicines Act, 1968. Although the prescription criteria of Council Directive 92/26/EEC apply to all EC member states, the procedure for assigning prescription classification remains the responsibility of each individual member state. In the United Kingdom, the required documentation in support of a POM to P reclassification request is substantially similar to that described in the EU guidance on the same subject. Applications should contain the following key information that has been discussed in detail in the earlier section in the European Union context. The key elements to be addressed in the expert report must include: MAL 82 provides guidance on pharmacy to general sale list (P to GSL) reclassification procedures and requirements. As discussed earlier, similar procedures, steps and possible routes as for POM to P reclassification also apply to P to GSL reclassification. But, substantial differences exist in the criteria applied to evaluate suitability for GSL and the contents of the supporting application. Criteria applied to evaluate suitability of human medicines for GSL has been defined earlier. The supporting application for a P to GSL reclassification must contain: The guidance states that anthelmintics, parenteral products, drops/ointments for ophthalmic use, enemas, products for irrigation of wounds or of the bladder, vagina or rectum and products for administration to children that are preparations of aloxiprin or aspirin are not included in the GSL.

Japan
The procedures, application format and data requirements for registration and approval of nonprescription medicines, as discussed earlier, apply exactly and in same measure to reclassification application dossiers in Japan (18). The future course of MHw related to reclassification is presently under consideration and additional guidance (15) in the interim may be summarized as: • Upon approval of the switch application, the product may be sold only in a pharmacy or a drugstore with a pharmacist.
• PMS of the prescription product and actual use trials (AUT) should be conducted to support switch applications. PMS should include two kinds of surveillance emphasize actual use/administration of proposed OTC drugs by subjects and adverse reactions documented after the product's launch.
• New clinical trials are required and should be carried out in at least five locations in Japan with not less than 150 cases even ifthe prescription product is considered for switching without any changes.

World Health Organization perspective
The WHO finalized and published guidelines on the regulatory assessment of medicinal products for use in self-medication in March-2000 (23). This guidance states that a medicinal product for self-medication should, at least, meet the following three criteria: If the product meets these criteria, the following additional requirements may be applied: The use of the product has been sufficiently extensive or in high enough volume .
The product has been marketed on prescription for at least five years .
Its adverse events give no cause for concern and their frequency has not increased unduly during the marketing period.
A basic principle for the regulatory assessment, as per WHO guidance, is that the pharmacokinetics, pharmacodynamics, indications, safety, efficacy, toxic or 66 allergenic potential of a medicinal product should have been reasonably well established and documented in humans before its eligibility for use in self-medication can be evaluated. The general regulatory assessment approach should, in detailed terms, investigate the following five complementary aspects:

Drug utilization and consumption data
This is helpful in determining the way in which the product has hitherto been employed by physicians (volume of use, major indications in practice, precautions normally taken) and particularly in interpreting alleged risks.

Reported adverse events/reactions and interactions
This should be examined with respect to their profile, frequency and severity. There is no uniformity among the various regulatory models on the duration for which a drug substance must be marketed as a prescription medicine before it may be considered for reclassification to nonprescription status. That duration in, Australia is two years, Canada is three years Japan is six years, and WHO regulations require five years. The UK and EU regulations also state that any NCE must be marketed as a prescription medicine for a substantial duration before reclassification may be considered. The US position on this issue is unique as no such requirement is explicitly stated, leaving open the possibility of an NCE being marketed directly on OTC status. Reclassification requests in some markets (Australia, Canada and Japan) require approval from regulatory bodies at both federal and state level. In the US and UK such is not the case. Necessity to obtain approval from federal and state level agencies (especially in Canada) is burdensome for the industry. Under the US and UK models, approval is obtained primarily at the federal level which is efficient and desirable.

Conclusion
Nonprescription medicines in major developed nations have been recognized as crucial to efficient public health care. Accordingly, Australia, Canada, the United Kingdom, the European Union and Japan have all established regulatory frameworks 71 based on scientific principles for classifying drug substances under the nonprescription status and reclassifying prescription medicines as nonprescription medicines. However, there exists significant opportunity for improvement of current regulatory systems within these nations to enhance efficiency of regulatory review, convenience to drug manufacturers and consumer access to nonprescription medicines. In this regard, the US OTC regulatory system should seriously consider issuing guidance to industry on specific data requirements for reclassification petitions and investigating the merits of an intermediate pharmacy-class of nonprescription medicines.   . Ailment easily recognized with assistance of a pharmacist • Amenable to short term treatment and monitoring and selfmanl!&_ement b_y_ consumer with assistance of a __Q_harmacist there is a narrow margin of safety between the therapeutic and toxic doses, especially in populations such as geriatrics, children and pregnant or nursing mothers; there are potential or known undesirable or severe side effects at normal therapeutic dosage levels; they are known by experimental data to induce toxicity in animals but have not been in clinical use long enough to establish the pattern or frequency of long-term toxic effects in humans; • they are used in treatment of a serious disease easily misdiagnosed by the public; • their use may mask other ailments; • they have contributed to, or are likely to contribute to, the development of resistant strains of micro-organisms in humans; • they possess a dependence or abuse potential that is likely to lead to harmful non-medical use; • they possess a high level of risk relative to expected benefits; or • they have a therapeutic effect based on recently elucidated pharmacological concepts, the consequences of which have not been established.
Exceptions will be considered for drugs which: • • • are required to be readily available under emergency circumstances where it is not practical to obtain a prescription (such as adrenalin in insect bite kits) ; are rarely used without a practitioner's supervision, and where the need for free availability outweighs the need for protection under Schedule F (such as insulin and nitroglycerin); or have potential to produce dangerous interactions with other drugs or food constituents but effective labeling can minimize the risk. • Indications for use of the drug are identifiable only by the practitioner .
• Use of the drug requires adjunctive therapy or evaluation .
• Use of the drug may produce dependency .
• Serious adverse reactions to the drug are known to occur or have a recognized potential to occur at normal therapeutic dosage levels.
• There exists a narrow margin of safety between the therapeutic and toxic dosages of the drug, either in the general population, or in identified subpopulations, or in patients with multiple medical problems.
• Serious interactions of the drug are known to occur .
• Use of the drug has contributed to, or is likely to contribute to, the development of resistant strains of microorganisms.
• The mechanism of action of the drug is known but the consequences of widespread use are not adequately establ ished.
• The therapeutic effects of a newly released drug are based on new or unknown mechanisms of action, but the cons~uences ofwide~ead use are not a~u ate.!.Y. established.

Schedule II
• The initial need for a drug is normally identified by the practitioner, in addition chronic, recurrent, or subseq uent therapy must be monitored by the pharmacist.
• The drug must be readily available under exceptional circumstances when a prescription is not practical. • The drug is intended for administration in a health care setting or under direction of a health care professional, or is in an injectable dosage form and is not otherwise included in Schedule I.
• Evidence of abuse of the drug has been reported, due to its inherent pharmacological action that has the potentia l for abuse.
• The selection of the drug requires intervention by the pharmacist to confirm that an appropriate selfasse sment has been made by the patient.
• Use of the drug may delay recognition or mask the symptoms of serious disease . • The drug may cause important adverse reactions, including allergies, or interacts with other drugs, foods, or di sease states that cannot be adequately addressed through product labeling.
• Use of the drug requires reinforcement or an expansion of the directions for use, through pharmacistpatient dialogue.
• The drug is a new ingredient for self-medication and monitoring by the pharmacist is necessary to faci li tate observation and reporting of any unexpected event.
• The max imum labeled dosage directions exceed the generally accepted or usual limits for Schedule Ill status.

Schedule Ill
• The initial need for a drug is normally identified by the patient, physician, or pharmacist, but chronic, recurrent, or subsequent therapy can be monitored by the pharmacist.
• The maximum recommended duration of use of the drug is limited and specified on the product label. • The maximum recommended duration of use of the drug is not specified on the label, but continued use may delay recognition or mask the symptoms of serious disease.
• The drug is used to treat a persistent, chronic or recurring condition and the availability of the pharmacist to provide advice can promote appropriate use.
• The drug is used for self-treatment of self-limiting ailments; however, where product selection has been identified as likely to cause patient confusion and the availability of the pharmacist to provide advice can promote appropriate use.
• The drug demonstrates adverse effects, including allergies, or interacts with other drugs, foods, or disease states that can be identified in product labeling, but appropriate product selection and explanation of risk • may require the advice of the pharmacist. The drug is a new ingredient for self-selected self-medication and the availability of the pharmacist to • provide advice can promote appropriate use. The drug has inherent pharmacologic action that has the potential for non-medical use that may result in adverse patient outcomes.
• The maxim um labeled dosage directions exceed the generally accepted or usual limits for unscheduled status.   • Post-marketing experience in wide ranging patient population under prescription status for preferably five years, or shorter period if active substance has been in use as a foodstuff or as a metabolite of a known active substance.
• Adverse reactions information, experience of use without medical supervision from foreign sources, including numbers of patients treated, demographic details, indications for use and dose.
• Safety profile summarized as per EU guidelines, to include: • Post-marketing surveillance study reports .
• Clinical trials and published literature related to safety .
• Discussion of reactions arising from misuse and unknown reasons .
• Data extrapolation from the prescription use population to nonprescription use population.
• Potential and consequences of drug interactions with commonly prescribed drugs .
• Consequences of misuse, abuse or overdose .
• Consequences of consumer using upon misdiagnosis of symptoms .

Efficacy
• When application includes changes in indications or posology, otherwise not needed .
• Justification of a suitable time-period for treatment of the suggested indication(s) .

Product information
• Label and leaflet examined for comprehensive information and effectiveness in protecting consumers from any safety hazards (very important) • Description of use of the product and circumstances when referral for medical advice is appropriate from the label.
• Compliance of labels with requirements as per Council Directive 92/27/EEC on the readability of the label and package leaflet.
• Contraindications and warnings, such as advice limiting duration of treatment or the need to consult a doctor in certain situations.

Package
• Discussion of a chang_e of container when applicable to_g_ether with neces~ documentation . After completion of Post Marketing Surveillance on safety during use of drugs in any one of Classifications, 1, 2, and 3 (collectively hereinafter referred to as "New non-prescription medicines"), drugs which are applied for approval as drugs containing either "New active ingredients" or "New non-prescription ingredients" or "Newly combined ingredients" but which have differences in combination of active ingredients used in already approved OTCs. The differences correspond to the following two cases. However, these drugs shall be limited to those with the same administration and dose, and indications and effects as already approved OTCs, and with the same or slightly different dose forms from already approved OTCs.
(1) When only active ingredients with pharmacological actions different from those of "New active ingredients", "New non-prescription ingredients" or "Newly combined ingredients" are different.
(2) Where ingredients with different pharmacological actions in the case(!) have mild actions with no direct relations to ther'!£_eutic effica~

Class 5
Drugs which belong to the therapeutic categories with the Approval Standards and only whose dose forms are different from those specified in the Approval Standards, and drugs which belong to the therapeutic categories without the Approval Standards and only whose dose forms are different from those of the already approved OTCs in the therapeutic categories in question (Limited to those with ~ecial dose forms}_.

Class 6
Drugs which conform to the Approval Standards, or drugs which do not fall into an_x. one of the Classifications 1 throl!.&_h 5 above.
Key to symbols: o=Required #=Depending on the case x=Not required Clinical trials need to be conducted at more than five medical institutions with more than 150 _£atients Clinical trials need to be conducted at more than five medical institutions with more than 150 patients Note: Clinical data may be reduced to three medical institutions Class 2 with 60 patients for those Rx-to-OTC switch drugs whose safety and efficacy profile for general use has been well demonstrated by clinical investigations or post-market surveillance previously conducted.

Class 3
Clinical trials need to be conducted at more than three medical institutions with more than 60 _J>_atients  Rev. Herbert Watson, Jr. , a pastor in East Baltimore and the board chairperson for a program called Heart, Body, and Soul, a cooperative partnership between CURE, a ministerial group in East Baltimore and the Johns Hopkins Center for Health Promotion, who was instrumental in developing a church based smoking cessation program stated his concern about the restrained access for nicotine gum within the prescription setting. He emphasized the need for free and convenient access to nicotine gum, not only in medically underserved communities, but also across the entire nation.
He encouraged the panel to make nicotine gum easily available to communities and individuals who can use it safely and effectively . The sponsor addressed the issue of long-term dependence by arguing that mere long-term use of a medication does not indicate dependence. Additionally, longterm use must be characterized by compulsive use and impaired control, i.e. the drug 91 comes to control your behavior. So long-term use in and of itself does not necessarily mean dependence. Results from the meta-analysis of all the clinical trials that reported long-term use showed that 18% of users still used the gum at the end of six months and this statistic decreased to about one percent in two years. Among the special subgroup of people who quit smoking by using the gum, the percentage using the gum at end of six months was 35% and decreased to 3% in two years. Clearly, there was longer than directed use observed in all the clinical trials. The reasons that the sponsor listed to contend that these results do not represent long-term dependence were as follows: (1) In the clinical trials, the nicotine gum was provided free of cost. A study where people were randomly assigned to differently priced nicotine gum showed that the simple intervention of having to pay for the gum decreased long-term use by two thirds.
(2) Similar users of cocaine and cigarettes upon absence of any intervention showed a very small decrease in the proportion of users over a two-year period, relative to the fall to 3% with the nicotine gum.
(3) Further, there was no dose escalation observed among the long-term users with the nicotine gum. Also, simple reassurance and education of long-term users was adequate to wean them off the nicotine gum.
( 4) The observed long-term use may be attributed to the fear of falling back into the smoking habit having once quit smoking with the nicotine gum and residual craving for nicotine upon smoking cessation that takes a long time to be weaned off completely.
The sponsor contended that the abuse liability associated with Nicorette was minimal and acceptable. They asserted that in the context of abuse liability, more important than the chemical effects of the drug is the drug delivery device. Upon cigarette smoking, nicotine enters the arterial circulation from the pulmonary circulation and goes straight to the brain without being diluted with the venous blood leading to high nicotine concentrations. With the gum, nicotine is absorbed through the buccal membrane and is diluted with the venous blood before entering the brain. Also, inhaling the drug is the fastest way to get it to the brain. Hence, the addiction to nicotine via cigarettes is due to the very rapid onset of the effect. The sponsor argued that the addiction to nicotine via cigarettes is due to the high arterial concentrations, the rapid time to reach the brain, the frequency of use and not due to the chemical per se. Also, when the dose of nicotine (as cigarettes) was increased and the users were asked to rate their liking for nicotine, the liking increased with the dose. With the gum, the response of the users was the opposite as craving for nicotine decreased with higher dose. The differences in the responses between cigarettes and gum were attributed to the different pharmacokinetic characteristics. The potential for abuse by young adults was countered based on the following: (1) Nicotine chewing gum is difficult to chew and does not taste good (but is palatable).
(2) Drug use among teenagers generally is initiated due to peer-pressure, rebelliousness and anti-authoritarianism. Chewing gum is not considered "cool" and does not conform to the badge behavior of being "cool" as is the case with 93 alcohol or cigarettes. Also, increased doses with the nicotine chewing gum do not lead to faster onset of action, but only increased nausea.
Based on this rationale of the benefits arising from increased access, especially for young adults and medically underserved, and the minimal risks of long-term dependence and abuse liability due to the benign pharmacokinetics of the nicotine chewing gum, the sponsor urged the Advisory Committees to favorably consider their OTC switch application.
The labeling for OTC Nicorette was developed based on labeling comprehension studies and was suitable for sixth to seventh grade reading comprehension levels. The marketing plan and associated consumer communication methods proposed for OTC Nicorette were exceptional by any measure. The sponsor claimed that its objective is to help Americans quit smoking and become Nicotine free.
Their two-fold strategy was to very carefully manage the expectations for the OTC product and develop a marketing plan to balance control with the greater access of the OTC product. The Nicorette target consumer was that smoker who has successfully crossed the stages of thinking about quitting, firming up their determination to quit and is ready to take action. The sponsor termed such smokers as "Committed Quitters" and did not wish to speak to smokers in the evolutionary stages before the committed quitter stage in their programs and marketing. The sponsor's advertising plan positioned OTC Nicorette as an aid that can help quit smoking as opposed to a magic bullet. Further, Nicorette OTC product was only one part of the complete package that would consist of a user's guide, an audiotape and a number of program elements that are motivational and can influence the individual's behavioral patterns and ability to successfully quit. 94 The sponsor developed a program called the Committed Quitters (CQ) program. The program becomes apparent immediately upon opening the package and contains an 800 number encouraging the individual to call and enroll in a support program. Upon calling the 800 number, the individual is interviewed to clarify the reasons for their decision to quit and informed of the barriers they need to overcome to successfully quit. Subsequently, a personalized user's guide calendar is put together for the individual with the reasons driving their decision to quit and the barriers they could not overcome in the past. Following initial enrollment in the CQ program, there are about five interventions to help keep the individual from relapsing into smoking. If the individual was chewing too many pieces of gum than recommended, there were also programs that assisted them to wean off the gum, another 800 number is provided to call and talk to a counselor who can assist the individual in weaning off the gum or who has relapsed into smoking. The CQ program of which Nicorette OTC product was only one part, was an active and interactive program for not only helping individuals as a behavioral program but also assist those who have relapsed to smoking.
In terms of merchandising activities, the product would be priced above the impulse level, it would not be sold in vending machines, no free samples would be distributed even to physicians, it would be part of a theft deterrence program and would be sold only to individuals above over 18 years of age. The sponsor also declared that they were working with many insurance companies to urge them to cover this OTC product and said that most insurers agreed to do so. In terms of cultural barriers, stores in predominantly Spanish speaking communities would be provided with special 800 numbers and all the educational material would be in Spanish. As the proposed OTC 95 product was relatively expensive, the sponsor had convened an independent advisory conditions or were pregnant, as subjects understood the label directions but did not obey them.
(2) During the process of refining the label content, evaluative questions for the subjects were phrased and iterated in such a manner to inevitably lead to the desired response. Also, details of demographics were not presented to understand the nature of the subject population. Questioning was leading and did not delve into the attitudes and motivations that affect the actual behavior.
(3) Study methodology and design of questionnaire make it difficult to rely on the results. They do not demonstrate with reasonable confidence that patients who are directed to see a doctor first may do so at a high rate despite the warnings.
The following were comments on the results from two quit rate studies in the prescription setting.
(1) Participants in clinical trials such as those for the NDA are different from consumers in the general OTC population and quit rates may not be representative of the actual results that may be expected in an OTC setting.
(2) The demographic distribution of the study samples also may not be as representative of the smoking population who may elect to use the OTC smoking cessation product.
Commenting on the issue of abuse and dependence, the FDA reviewer summarized that most long-term use is seen in quitters than in non-quitters, who represent the positive outcome. Continued use declines for Nicorette gum generally after six months to one year and there are very few reports at two years. 97 Regulatory options FDA informed the committees and the sponsor that to approve an OTC switch, it is essential that the following two conditions be met: (1) The product is safe and effective under conditions of self-medication when used as directed in the proposed label.
(2) The availability of the product in the OTC environment is of acceptable risk.
Additionally, the law states in this context that neither the toxicity of the drug, the method of use, or any other potential harmful effect of the product necessitate that the product remain prescription only.
These conditions offered the committees the criterion by which they were to judge the suitability of Nicorette as an OTC medicine under the sponsor's plan. The there was empirical evidence that the product was effective in adolescents and a better alternative than cigarettes for pregnant women. There was strong consensus that the efficacy in the 12 to 18 year population needed to be studied. The committees' vote on safety and efficacy ofNicorette in the OTC environment was unanimous in consent.
On question two (need for learned intermediary in special populations) posed to the committees, it was concluded that adolescents, pregnant women and individuals with coronary artery disease might require special physician intervention. During discussion a committee member raised the consequences of making the product OTC in terms of reimbursement. Specifically, the committees were concerned that the access to 99 the OTC product may be diminished due to lack of reimbursement if the prescription product is eliminated. Under present law, it is not possible to classify the same product for the same indications at the same dose simultaneously as OTC and prescription products. Hence, the FDA was urged to retain both prescription and OTC classifications. Also, the sponsor reassured that they would be working with managed care organizations to make the coverage universal and they were in the process of developing a pilot program to identify strategies that would help increase affordability of the product especially to medically under served and poor section parts of our population. The committees did not express any apprehension for misuse or abuse with the exception of individuals chewing the gum longer than directed. However, that was considered a positive cost benefit ratio provided the total tobacco consumption is cut down. Also, the Canadian experience with the 2mg product, where it was OTC since 1993, reinforced the consensus that there was no serious risk of abuse.
Addressing the issue of special protection against abuse by children, the committee strongly recommended the need for the Agency to take active steps in examining the usefulness of nicotine replacement therapies in populations that are beginning to use tobacco. The committees did not regard children as a potential source of abuse for this product, but they were very concerned that the product was not designed to assist children in smoking cessation due to lack of studies and urged the      recently announced a public hearing to evaluate the Agency's approach to regulating over-the-counter (OTC) drug products (1). The purpose of the hearing was to solicit information from, and the views of, interested persons, including scientists, professional groups, and consumers. One specific question that the Agency posed in this context is: should FDA be more active in initiating switches of prescription products to OTC use?
In the development of an objective response to this question, it is helpful to review and evaluate the well-known incident of the metaproterenol switch, when FDA upon its own initiative allowed OTC marketing of metaproterenol and later had to rescind on its decision. In the historical context of examining the application of FD A's OTC switch policy, the metaproterenol case is unique and offers important lessons.
Hence, a detailed examination of the metaproterenol case history is of enormous instructional value.

Background
In Specifically, some of the critical comments received by the FDA were: 1. Recognized experts in the area of allergy treatment either disagreed or were divided in opinion over the safety of metaproterenol under OTC conditions.
2. Pediatricians expressed concern over the potential misuse of OTC metaproterenol by children. Potential for misuse of OTC metaproterenol by asthmatics seeking more relief by exceeding the dose instructions on the OTC label.

Resolution of controversy
In response to these criticisms, FDA arranged a meeting of its P ADAC to discuss the OTC status for metaproterenol. After the P ADAC heard presentations from the proponents, principal critics, FDA staff and the manufacturers who were marketing 111 OTC metaproterenol on an interim basis, and based on its own deliberations, the committee recommended to FDA that it rescind its decision to permit OTC marketing of metaproterenol by a vote of 4 to 3.

FDA response
Following the recommendation of its PADAC, FDA published in the Federal Register on 3 June-1983 that it has concluded that it should accept the advisory committee's recommendation (4). FDA stated that it reached such conclusion based on: 1. Reservations within the medical community about whether metaproterenol sulfate metered dose inhalers can be safely marketed without the safeguard of a prescription limitation and professional supervision of the drug's use in asthmatics. FDA intended to more fully consider such reservations before it could allow metaproterenol to be marketed OTC.
2. The procedure by which metaproterenol was permitted to enter the marketplace as an OTC product led to unintended confusion and controversy that, if allowed to continue may, disrupt the relationship between physicians and their patients and produce unnecessary anxiety among asthma sufferers seeking relief from their symptoms through OTC therapy.
In order to further clarify the Agency's positions on this matter, FDA elaborated its opinion on the safety of OTC metaproterenol and the regulatory mechanism by which it was switched. FDA stated that the decision to switch metaproterenol to OTC status was made in the context of an OTC bronchodilator market in which the only metered dose inhaler products available were epinephrine preparations that the Agency believed to be no safer or less effective than metaproterenol sulfate. FDA asserted that despite the 11 2 advisory committee's recommendation to rescind, it continued to believe that a careful weighing of the risks and benefits supports the proposal that metaproterenol sulfate should be made available without prescription. On the concern that patients may not follow carefully the label directions, FDA believed that asthmatic sufferers are capable of understanding and heeding instructions for safe use of OTC metaproterenol. In relation to potential for abuse by children, the Agency thought that essentially the same potential existed for children using the product without parental supervision whether the product was sold on prescription or OTC. Nevertheless, the Agency was committed to respect the judgment of the specialists in the field who believed OTC metaproterenol posed a public health risk and consequently decided to disallow the OTC marketing of metaproterenol sulfate metered dose inhalers until the safety issues were resolved.
The Agency also explained its interpretation of the regulatory mechanism based on which OTC sale of metaproterenol was allowed.

Conclusion
The case of metaproterenol OTC switch by the FDA upon its own initiative offers valuable information in the comprehension of FD A's application of OTC switch regulatory policy. The FDA is encouraged to initiate switch proposals that it considers to be safe and effective in an OTC environment and offer overall public health benefit.
The learning from the failed metaproterenol switch demonstrates that a collaborative effort with the sponsor and all interested parties is more likely to result in a scientifically robust switch decision. Hence, the Agency must properly manage the consideration of switch proposals that it has initiated by ensuring active participation of all possible stakeholders that may be impacted by its rulemaking.

Introduction
Heart disease is a major cause of mortality among Americans, and the risk factor of cholesterol elevation is well recognized. Hyperlipidemia affects 50 million Americans and the first approach to lowering cholesterol levels is through lifestyle changes. However, most patients are unable to sustain such lifestyle changes over the long term. Making effective drug therapy more readily available to consumers could facilitate improvements in managing this very costly problem. Thus, it has been suggested that making antihyperlipidemic products available over-the-counter (OTC) may contribute a solution.
Attempts to switch two antihyperlipidemic products from the "statins class" of

Efficacy
The benefit of treatment with lovastatin 10 mg daily m the defined OTC population was demonstrated using these approaches (7): • Observing the effect on lipid parameters associated with CHD risk (i.e., TC, LDL-C, HDL-C and ratio of TC/HDL-C).
• Observing the percentage of OTC eligible men and women who attain desirable levels of TC and LDL-C as defined in NCEP ATP-II guidelines. Lovastatin 10 mg/day was the lowest approved prescription dose. Studies in OTC populations revealed that lovastatin favorably modifies lipids by reducing TC-11 %, LDL-C-18% and TC/HDL-C-15% and increasing HDL-C-7%. As the OTCeligible population was defined as having TC<240 mg/dL, LDL-C is expected to be less than 160 mg/dL for a majority of those who are OTC-eligible. With lovastatin 10 mg daily, approximately 70% of OTC eligible men and women could attain levels of LDL-C considered by NCEP-A TP II to be desirable for high risk primary prevention patients (LDL-C <130 mg/dL). The risk of first CHD event was estimated to be reduced by 35% based upon reductions observed in the TC/HDL-C ratio with lovastatin 10 mg daily. 125 Given these data, the sponsor suggested that lovastatin 10 mg/day represents a conservative but effective and appropriate dose for OTC therapy.

Pharmacology and pharmacokinetics
The sponsor reviewed the human pharmacology and pharmacokinetics of lovastatin to show that, lovastatin is an inactive lactone that, upon hydrolysis, is reassurance to women who are inadvertently exposed to lovastatin during pregnancy, and to the health care professionals responsible for their care. Other lipid-lowering agents (gemfibrozil and niacin) may increase the risk of myopathy through an unknown mechanism in patients taking any of the HMG-CoA reductase inhibitors. Concomitant treatment with potent CYP3A4 inhibitors may increase plasma HMG-CoA reductase inhibitory activity levels, and therefore may increase an individual's risk of myopathy.
The risk of myopathy was very low with lovastatin 10 mg and 20 mg daily regimens, and would be expected to remain low even with concomitant use of a potent CYP3A4 inhibitor. Use of these drugs concomitantly with lovastatin was contraindicated on the nonprescription label.
Long term, chronic use of lovastatin at prescription doses of 10 to 80 mg daily has been well tolerated. In controlled clinical trials, the safety profile of lovastatin 20 mg daily was comparable to that of placebo. Asymptomatic serum transaminase elevations were dose-dependent, and were not proved to progress to clinical liver disease even when drug therapy is continued; the incidence of confirmed ALT elevations (>3 x ULN) was similar with lovastatin 20 mg daily and placebo. Clinically apparent liver disease (hepatitis, hepatic failure) associated with lovastatin use at any dose was very rare. Therefore, the sponsor argued that routine monitoring of LFT was not of value in users of lovastatin 10 mg once daily. Although myopathy, and rhabdomyolysis are considered the adverse experience of primary concern for the HMG-CoA reductase inhibitors, both clinical study expenence and market-use experience indicated that their occurrence is rare. The risk of lovastatin-associated myopathy increased with increasing dose of lovastatin. In postmarketing experience 129 collaboration with healthcare professionals. The ESP focused before purchase, on the infonnation necessary for consumers to make an appropriate purchase decision and, after purchase on the information needed to refine and extend the understanding of the product and its use. The importance of cholesterol testing and monitoring was emphasized both before and after purchase. Before the purchase decision is made, eligibility criteria for the initial selection of the product was introduced through informative advertising which provides the basic information about who should and should not use the product. The carton label then summarized all information necessary for an appropriate purchase decision. After purchase, the consumer has access to several label reinforcement tools contained within the package that refines the product selection decision. More comprehensive information was available after purchase and educates consumers on the importance of a healthy lifestyle and encourages long-term use in order to maintain the benefit. The core elements of the labels specified the age and stage of life when men and women are at increasing risk of CHD and therefore most likely to obtain the benefit. Also listed were specific values for TC and LDL-C and those who should not use the product reflect the warnings from the prescription labeling.
Additional materials called label reinforcement tools were also provided. These real-world conditions. One study was conducted from actual retail pharmacies and allowed long-term use of Mevacor for up to 18 months. Two studies were conducted in rented store space in local shopping centers and tested the toll-free service. Follow-up surveys were conducted in subsets of study participants in order to supplement the information collected from the clinical studies A fourth study, was ended early due to poor enrollment. The sponsor also conducted three label comprehension tests finishing with one round of improvements to create the NDA label. These studies showed that effective labeling guided most consumers to make an appropriate selection decision and that the ESP further improves the correctness of that decision to use the product.
The sponsor asserted that consumer behavior testing showed that, (a) most consumers made an appropriate product selection decision (b) accuracy of the product selection decision was further improved when consumers reviewed the label reinforcement tools contained in the package (c) toll-free telephone label reinforcement service was highly effective as a label reinforcement tool (d) results support the conclusion that the nonprescription lovastatin 10 mg labeling system of communication, education and support effectively guides consumer product selection (e) comprehension testing showed that strong scores were achieved on key messages in the general population and the safety subgroup, and that low literacy subgroup scores were also acceptable.
The sponsor stated that even though excellent label comprehension was achieved, additional minor refinements were made to further enhance the final label submitted in the NDA. These minor refinements included: reformatted liver disease and pregnancy warnings for increased prominence; strengthened drug interaction warning text; doctors and pharmacists added as individuals the consumer can contact to detennine if they are taking a "Do Not Use" medication; and a caution to consumers with continuing medical conditions that they may need further medical care. 133 The sponsor concluded that, (a) consumers maintain or improve eating and exercise habits while taking nonprescription lovastatin 10 mg in a nonprescription setting (b) a substantial segment of interested consumers comply well with long-term daily dosing with nonprescription lovastatin 10 mg to achieve clinically meaningful lipid changes, and ( c) nonprescription lovastatin labeling system encourages collaboration with health care professionals. There were no cases of rhabdomyolysis, myoglobinuria, or liver toxicity reported. At the higher dose of lovastatin, FDA found that consecutive elevations in liver enzymes to more than 3xULN was dose related and at the highest approved dose, the instance was about 1.5 percent, but there were no cases of liver toxicity associated with this enzyme elevation.
FDA contended that the sponsor acknowledged this safety concern, and proposed that this concern can be adequately conveyed to consumers through proper labeling. The sponsors proposal was to warn/advise consumers not to take nonprescription lovastatin if they were on any medications such as erythromycin, clarithromycin, ketoconazole itraconazole, nefazodone, cyclosporin, protease inhibitor, niacin, gemfibrozil, or any other prescription statin drugs. FDA asserted that this was an extensive list and likely to increase as more drugs are approved. So FDA felt that this method of risk communication was challenging to the consumer. This method of risk communication in the prescription setting was apparently not effective enough to avoid some of the drug-related toxicities. So it raised concern that the proposed method of risk communication for OTC lovastatin may also be ineffective.
A comprehensive review of post marketing safety surveillance of all currently available statins in the United States by the FDA led to the conclusion that a significant concern exists over liver failure associated with HMG-CoA reductase inhibitors given that liver transplants, irreversible and fatal hepatic damage, have occurred. Of the liver failure cases, more than 50% of the patients expired while on lipid-lowering therapy consisting of an HMG-CoA reductase inhibitor. Despite this fatal consequence, the labeling in OTC package inserts did not mention liver failure as an adverse reaction to HMG-CoA reductase inhibitor administration. Additionally epidemiological analysis indicated that the reporting rate of liver failure for the HMG-CoA reductase inhibitors exceeds the background rate for liver failure. Based on the severity of liver failure they recommended that liver failure be included as an adverse event in the labeling of package inserts for OTC lovastatin.

FDA's safety review concluded that, "Given the fact that there is very little compliance with liver function test monitoring and this class of drugs have been associated with other potentially serious adverse events (including rhabdomyolysis), and have the potential to cause dangerous drug and drug-food (grapefruit) interactions,
it is prudent to defer any decision on the OTC switch of these drugs (13)." FDA opined 138 that for safety, there are rare, but serious adverse events associated with lovastatin use, particularly that of muscle toxicity which can be potentiated by certain drugs or substances which impair lovastatin's metabolism through the 3A4 isoenzyme. This safety concern was further amplified by the use of lovastatin as a nonprescription drug.
As an OTC drug it would be in an unsupervised setting such that the safety of OTC lovastatin is dependent upon the consumer's comprehension of the label, its use according to label instructions, such that there would be no self-titration to higher doses, and no use by individuals at risk for drug-related toxicities.
In evaluating the prescription to OTC switch of lovastatin 10 milligrams, FDA asked the question: What is the balance of benefit versus risk of nonprescription lovastatin? On the benefit side they found LDL-C reduction and agreed that lovastatin does reduce LDL-C. But stated that the effectiveness of this treatment approach in the OTC population will likely be diminished by poor adherence to drug therapy. Another part of the benefit side was that of clinical cardiovascular benefit. FDA asked if drug treatment, in the OTC target population resulted in reductions in cardiovascular mortality and morbidity? And asserted that there is no evidence from controlled clinical trials to demonstrate that. On the risk side, FDA found the safety concerns to be rare, but believed the seriousness of muscle toxicity potentiated by certain drugs and compounded by the unrestricted, unsupervised use of this product in the OTC environment to be excessive and unacceptable.

Consumer behavior and labeling
An FDA review of the actual use studies conducted by the sponsor led to these observations (14). 3. The labels did not provide sufficient information to use the product effectively. Selfselection errors were too frequent. The safety information was incomplete because laboratory data (especially LFT and creatinine phosphokinase (CPK)) was not provided.

4.
The compliance rate in the OTC setting was poor. This would probably impact on any long-term benefit to be derived from taking lovastatin 10 mg in this population. The committee modified question 6 to, has the sponsor provided sufficient evidence that lovastatin 10 milligrams can be used safely and effectively in an OTC setting? This question was answered in strong dissent by the committee (1-yes; 11-no; I-abstained). In terms of additional studies to demonstrate approvability of OTC lovastatin, the committee made these suggestions:

A long
• Demonstrate efficacy using better defined eligibility criterion and using LDL-C as a surrogate marker relative to prescription lovastatin use.
• Study actual use in a wholly unrestricted manner to demonstrate ability of consumers (to cover minorities, ethnic and low literacy populations) to self-select, self-deselect safely and effectively the proposed OTC medicine.
• Survey large groups to determine their interest in lipid-lowering agents, the obstacles involved with using such drugs and if inadequate medical care is considered an obstacle.
• Study the ability of consumers to self-titrate to larger doses in a safe and effective manner.  2. Statins have been associated with myopathy, including rare cases of rhabdomyolysis, as well as with elevations in hepatic transaminases (although the association between use of these drugs and serious hepatic disease is less clear). lntercurrent illness, undefined individual susceptibility factors, and interactions with other drugs and/or foods may increase the risk for rhabdomyolysis with statins. Taking into account these and other safety issues, has the sponsor presented adequate data to support the safety of lovastatin 10 mg in the target population? a. lfno, what additional data are needed to demonstrate safety? 3. Taking into consideration the balance of risk and benefit, has the sponsor presented data that are adequate to support the use of lovastatin 10 mg in the low-risk population with TC 200-240 mg/dL, LOL-C > 130 mg/dL, regardless of HOL-C level, without CHO or diabetes? a. If no, what additional data are needed to su_0)_ort such an indication?
OTC Considerations 4. Assuming an indication for the use of lovastatin I 0 mg in the proposed target population can be justified based upon an expectation of clinical benefit, has the sponsor adequately demonstrated that consumers can achieve such a clinical benefit in an OTC setting? In responding to this question, please consider the following: a. The abi li ty of consumers to appropriately self-select (and de-select) based upon cholesterol levels and other risk factors. b. The ability of consumers to evaluate response to treatment and to monitor cholesterol levels (including understanding of how to undertake a fast and the frequency of re-testing). c. The ability of consumers to adhere to chronic therapy with lovastatin I 0 mg. d. The need for the physician or other healthcare professional in the effective treatment and follow up of dyslipidemia. e. The capacity of the proposed label to direct consumers in the effective use of lovastatin I 0 mg OTC. 5. Assuming that lovastatin 10 mg is deemed adequately safe when used for the proposed indication in the target population, has the sponsor presented adequate evidence that consumers will be able to use lovastatin I 0 mg safely in an OTC setting? In responding to this question, please consider the following: a. The ability of the consumer to identify adverse reactions to lovastatin and to act appropriately. b. The ability of the consumer to monitor hepatic safety including the need for monitoring of hepatic transami nases and the abi lity of the consumer to perform such monitoring if needed. c. The need for and ability of the consumer to identify and avoid interacting drugs and other substances. Approvabi/i!X._ 6. Assuming that the answer to Question 3 is yes (i.e., the sponsor has provided sufficient information to support the safety and effectiveness of lovastatin IO mg for the proposed indication in the target population), has _the sponsor provided sufficient evidence that lovastatin 10 mg can be used safely and effectively in an OTC setting?
a. If yes, are any additional studies needed post-approval? What are the key messages that need to be conveyed tlo the c~nsumer in the product label (carton and package insert) to provide for the safe and effective use of restricting their sale to prescription by a licensed practitioner (3). An implication of section 503(b )(1) of FDCA, which needs emphasis, is that drug products are inherently presumed to be nonprescription unless otherwise required. This assertion is generally stated as, "if it can be OTC, it must be OTC" to illustrate the inherent bias for "nonprescriptionness" arising from the law and is critical in the context of the current discussion ( 4).
Traditionally, prescription drugs have been reclassified to OTC status via, either the OTC monograph process or an OTC switch petition in the form of an NDA. When FDA initiated the OTC Drug Review in 1972, the monograph process resulted in many drugs being recl assified to OTC status. More recently, drugs have been switched to OTC status upon approval of manufacturer initiated switch petitions (NDA). However, the current request to reclassify certain products of LR, FX and CZ to OTC status did not originate from the manufacturers of these drugs. An independent party, other than the drug manufacturers, requested the FDA to approve the proposed OTC status for these nonsedating antihistamines. This remarkable deviation from conventional practice related to the switch process makes this citizen petition for OTC status of LR, FX and CZ unprecedented in nature. The unparalleled nature of this case raises many significant regulatory, safety and legal issues related to OTC switch process in the United States.

Rationale and basis of citizen petition
The regulatory basis for this citizen petition to request OTC status was for optimal treatment outcomes.
The safety profile of second-generation antihistamines in an OTC setting is not fully known. Although safety is well established for prescription use, significant issues require further study to ensure that equivalent safety would exist without a physician's care. The absence of a physician or pharmacist as an intermediary who would be aware of a patient's concomitant medications is a concern. The pharmacokinetic interaction and safety profile for each of the second-generation antihistamines is different and each of the antihistamines must be considered and evaluated independently. Other aspects of the pharmacologic profile of these drugs also warrant more specific evaluation, particularly were the drugs to be used without physician oversight. The history of this class of drugs is one in which unexpected interactions have been discovered many years after use by millions of patients.
The manufacturer of FX, in contrast to LR's sponsor, did not argue that OTC status was completely inappropriate for FX. Instead, they took the position that it was premature to make an objective assessment of its OTC suitability, as FX was approved only in July-1996 for U.S. marketing. To justify their cautious approach, they cited the example of an earlier non-sedating antihistamine terfenadine (TF is the parent drug that is metabolized to FX). TF was initially approved in the U.S. as a prescription drug and was later considered for OTC status. However, within the first several years of marketing, a serious safety concern related to cardiac arrhythmias eventually resulted in TF being withdrawn from the U.S. market.

Medical community's position
The American Academy of Allergy, Asthma and Immunology and the American College of Allergy, Asthma and Immunology were strongly opposed to the nonsedating antihistamines being moved to OTC status. The rationale for their position was as follows (7): Contrary to the purpose of this switch petition, if approved, the placement of these compounds on the OTC market will result in a reduced availability of these valuable medications to patients. The cost of these drugs will likely make them unavailable to those patients who received them through insurance covered formularies.
OTC availability will eliminate the physician from the care process of patients taking antihistamines. The appropriate use of these medications needs the reinforcement of health care providers with expertise about allergic disorders.
Overuse or misuse of this class of drugs for disorders in which they have no proven efficacy will increase health care costs. Conversely, underuse in appropriate allergic disorders will negatively impact their effectiveness and result in poorer outcomes.
Furthermore, the drugs being considered are not necessarily equivalent in their efficacy or their capacity to induce sedation, or cognitive and performance impairments depending on the dose.
• Allergies are not necessarily a self-diagnosable condition. Although 20-30% of the U.S. population suffers from allergic disorders, public surveys indicate that up to 75% of people feel they have allergies. This leads to the overuse of antihistamines for disorders where they have no proven efficacy. By placing these agents in an OTC status this problem will be compounded.
• Subjects with allergic diseases often fail to adequately appreciate the degree of impairment they have from their disease as well as whether treatment impacts upon this impairment. By placing these agents in an OTC status, physicians will not play as active a role as they should in assessing disease status and response to therapy.
By placing these agents in an OTC status, in some cases there may be a resultant 158 trivialization of the disorders for which they should be utilized. Reduced availability or utilization of these drugs without physician evaluation may mask or delay appropriate diagnosis of underlying disorders such as sinusitis, otitis, or asthma. As well, urticaria can be a manifestation of a serious underlying condition, which if left undiagnosed, could lead to substantial morbidity and mortality.
The American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) stated that a physician and pharmacist is necessary in the responsible use of nonsedating antihistamines and did not support the proposed OTC status (8). Further, they opined that allergic rhinitis (AR) may not be self-diagnosed as nasal polyps or tumors could be the problem.

FDA's position
The Agency asserted that AR and related conditions are generally considered amenable to self-diagnosis and self-treatment (9). Antihistamines as a class have a long history of OTC availability and are used in these indications, with correct usage guided by OTC monograph labeling. Hence, FDA reasoned that neither an actual use study nor a label comprehension study was required to support the proposed OTC switch petition for LR, FX and CZ. Further, FDA opined that it is not appropriate that these drugs be switched to OTC status for all age ranges, formulations and/or indications for which they are approved for prescription use. For instance, CIU, an approved prescription indication for all three drugs was not considered to be an appropriate OTC indication.
Also, FDA stated that the efficacy of this class of drug products and the appropriateness of antihistamines in general for OTC marketing is not in question. The Agency took the position that efficacy of these drugs is not in question as there is a long history of OTC marketing of antihistamines.
Hence, FDA's OTC switch review team conducted an extensive review of worldwide safety information related to LR, FX and CZ to determine whether there are safety concerns that might preclude their appropriate use in the OTC marketplace. The safety data for all three drugs were derived from the NDA safety databases, the spontaneous reporting system (AERS) database, and the published literature (10). FDA concluded that a thorough review of all available data, from its own safety information and from countries where LR was available without a prescription, failed to identify conclusive evidence of a causal relationship between use of LR and serious adverse events. It must be clarified that countries where LR is available without a prescription allow for a third class of drugs, which require dispensing, only in a pharmacy under the supervision of a registered pharmacist. Under the current US classification system, there does not exist a comparable class of medicines. Hence, it must be emphasized that even in countries where LR is available without a prescription, the involvement of a learned intermediary is not completely eliminated. Potential safety signals were noted for ventricular arrhythmias and liver failure; however, the data were deemed as inconclusive and suggested that if such events were causally related to LR, they are extremely unusual. A potential association between LR use and seizures was observed, consistent with information contained in the current package insert, and likely consistent with a class effect.
FX is the active metabolite of TF, but lacks the pro-drug's ability to inhibit the main subunit of the potassium channel in vitro, which is felt to be the primary 160 mechanism responsible for cardiac arrhythmias associated with TF use. As the sole active metabolite, FX is predicted to have a non-cardiac adverse events profile reflective of TF, and to be safe from a cardiac perspective. A full safety review of TF, excluding cardiac events, was also conducted by the Agency to supplement the available post-marketing data available for FX. For FX, the Agency concluded that a detailed review of all available safety data did not reveal evidence of a causal association between FX use and serious and/or life threatening adverse events. A possible association between FX use and seizures was noted that is not currently reflected in the package insert. A potential signal of ventricular arrhythmias in association with FX use was detected, however, the data was thought to be inconclusive and the known pharmacologic properties of FX argue against a causal link.
CZ is an active metabolite of hydroxyzine, a currently marketed prescription antihistamine. Upon an extensive review of adverse event reports associated with use of CZ, FDA found possible associations between CZ and sedation, neuropsychiactric events, including seizures, cardiac arrhythmias, and thrombocytopenia. The Agency thought that there is a preponderance of neuropsychiatric adverse events, particularly sedation, which may exceed the rate of reporting of similar events for LR and FX. The Agency reviewers felt that the data were inconclusive with regard to a causal relationship between CZ and arrhythmias and thromobcytopenia.
FDA also reviewed the post-marketing surveillance data related to first generation antihistamines and compared the observations with those of the drugs in question. Overall, the Agency made the inference that although generally accepted as appropriate OTC drugs, the first generation antihistamines agents possess a number of 161 safety concerns, some of which are serious, m addition to their widely recognized sedative and cognition-impairing properties. Although the occurrence rates of adverse events attributable to the OTC antihistamines cannot be directly compared to those of LR, FX or CZ due to many potential confounders, the Agency suggested that these three products might offer certain safety advantages over the currently available first generation antihistamines, primarily with regard to sedation and cognition.
Advisory committees' recommendation has solicited public comment on these two questions (11). In responding to these questions, it is necessary to ascertain if FDA has the statutory right to propose OTC marketing of a drug product. This author opines that FDA has the statutory authority to propose OTC marketing of a drug product. The basis for this opinion is As stated earlier, Section 503(b)(l) of FDCA states the prescription-dispensing requirements and Section 505 of FDCA describes the pre-marketing approval 163 requirements and process for drugs. Additional evidence in favor of this opinion is found in the Agency's response to metaproterenol controversy (12). In 1983, as part of the OTC Drug Review the Agency allowed OTC marketing of metaproterenol sulfate, but later, due to the advisory panel's recommendation against the OTC status for metaproterenol, rescinded upon its earlier decision to allow OTC status for metaproterenol. In explaining that action, FDA wrote that although it agreed with the advisory committee's recommendation on that occasion, it did not believe that all drug decisions require the prior involvement of an advisory panel or notice-and-comment procedures. The Agency asserted that Congress has given the duty of approving drugs to FDA and argued that it has the statutory responsibility to make a broad range of decisions (related to safety, efficacy, prescription or OTC status, indications for use and labeling of drugs) involving the suitability of drugs for use by the American public.
Also, according to FDCA all medicines are inherently assumed to be nonprescription in nature and the prescription restriction is applied only when necessary to safeguard public health. Extending this rationale to the current situation, wherein both the Agency and its advisory committees have endorsed the safety of these drugs in an OTC setting, it is possible to reason that FDA may remove the prescription requirement for LR, FX and CZ. One implication of applying the "if it can be OTC, it must be OTC" rationale to this situation is as follows and deserves explanation. It is well known that descarboethoxyloratidine (DCLR) is a major active metabolite of LR.
If an interested party requests marketing approval for DCLR in a separate NDA to the Agency under prescription category, FDA will then be compelled to grant OTC status for DCLR also. As DCLR and LR have the same pharmacological safety and toxicity 164 profi les, it would be inconsistent if FDA granted OTC status for LR and approved a prescription NDA for marketing DCLR, LR's active metabolite. Based on this reasoning, it may be inferred that FDA has the authority to reclassify drugs to OTC status. But, it remains unclear as to what regulatory mechanism the Agency may employ, should it decide to allow OTC status for these drugs.
In relation to nonsedating antihistamines FDA has taken the position that neither an actual-use study nor a label comprehension study is required as AR is a known selfdiagnosable condition and an OTC antihistamine monograph exists. In the absence of data from an actual-use trial it remains unclear how the target OTC population for these medicines can be determined. Also, the duration of use after which consultation with a physician is required is unknown for these drugs. The use of second-generation antihistamines tends to be chronic in nature and a warning of short duration of use may be inappropriate (9). In this regard, FDA's position presents a dramatic departure from its rigorous data and evidence based decision-making approach that was employed in evaluating recent switch petitions.
The position of this author is that FDA should initiate switch proposals that it considers to be safe and effective in an OTC environment and offer overall public health benefit. Also, the Agency must switch medicines to OTC status by ensuring active participation of all interested parties such as scientific, medical, pharmacist, industry, public and consumer communities in the evaluation of its switch proposals and before reaching a decision to allow OTC marketing. The author believes that the drastic regulatory action of FDA switching a product to OTC status despite the sponsor's objection should be carried out only under very limited and highly unusual 165 circumstances. Such a situation may be an enormous and overwhelming support among the general public and other stakeholders for OTC availability of a certain product, assuming it meets all the safety, effectiveness and labeling standards required of any OTC products.

Conclusion
The citizen petition for OTC status of these nonsedating antihistamines demonstrates a remarkable deviation from common practice related to the switch process in the United States and makes this citizen petition unprecedented in nature.
The unparalleled nature of this case raises many significant regulatory, safety and legal issues related to OTC switch process in the United States.
Based on overall review of the safety profile of LR, FX and CZ, the Agency concluded that these drug products, in the OTC setting, might offer certain safety advantages over the currently available first generation antihistamines, primarily with regard to sedation and cognition. FDA also took the position that no actual use trials or label comprehension trials are needed to support this switch request as they fall under an existing OTC monograph for antihistamine products. The Nonprescription and Pulmonary-Allergy Drugs Advisory Committees to the FDA voted strongly in favor of these drugs meeting the safety profiles required for unsupervised use in an OTC environment.
It may be inferred that FDA has the authority to reclassify drugs to OTC status.
However, it remains unclear as to what regulatory mechanism the Agency may employ, should it decide to allow OTC status for these drugs. This author believes that the drastic regulatory action of FDA switching a product to OTC status despite the 166 sponsor's objection should be carried out only under very limited and highly unusual circumstances. Using the contingency table constructed for each statement, the value of the Chisquare test statistic was computed. The rejection rule was to reject the null hypothesis (the responses are independent of the respondent's country) if the computed test statistic was greater than 12.59 (standard chi-square value for 5% level of significance and six degrees of freedom).

Results
A total of 473 responses were received from United States, Australia, United Kingdom and Canada. Contrarily, there was no clearly inferable opinion from the American respondents on the issue of direct-to-consumer marketing of prescription drug products adversely influencing reclassification to OTC status and availability of new OTC drug products as approximately, 31 % disagreed, 34% were undecided and 35% agreed.

Role of regulatory agency
When asked if their regulatory agency should actively propose OTC marketing of a drug in the absence of support from the sponsor, the response was varied. American were undecided. These responses were found not to be statistically independent of the participant's location.
The respondents almost unanimously (95% of Americans, 93% of Australians, 98% of Britains and 95% of Canadians) stated that the risks and benefits to individuals and public health should be assessed and weighed in any decision on OTC marketing of drug products. 90% of Americans stated that initiatives to market at least some nontraditional medicines (dietary supplements and nutraceuticals) as regular OTC products by subjecting them to the same rigorous premarketing scientific evaluation and clinical review criteria should be promoted. Also, most respondents added that this is perhaps the most important public health issue in the area of OTC medicines regulation

Suitability of drugs for OTC status and disease conditions for self-medication
The majority of Americans (65%), Britains (70%) and Canadians (68%) stated that chronic illnesses (such as asthma) are not suitable for treatment with OTC products.
But, 56% of Australian respondents agreed to the contrary. In Australia, P-agonist inhalation products for asthma are available without a prescription under the pharmacist class of medicines due to which a majority of Australians believed that asthma is suitable for self-medication. A consistent majority across all countries, 59% Americans,

Consumer understanding and behavior
A majority of respondents from all countries, 55% Americans, 55% Australians, 63% Britains and 54% Canadians, rejected the idea that rational selection of treatment regimens by consumers may be ensured when prescription and OTC therapies coexist for a certain disease. Similarly, more than 80% of respondents from all countries thought that patients do not know the best ways to treat their illnesses in an environment with coexisting prescription and OTC therapies for a certain disease. At least 63% of respondents from all countries thought that prevention claims for OTC medicines would encourage ill-advised behavior (such as ignoring smoking cessation and dietary discretion while using an OTC cholesterol-lowering drug, if it were available) among consumers.

Approval of new OTC medicines
When asked if the first drug to enter the OTC market should be the "best" drug in terms of benefit-to-risk ratio within a therapeutic class, a majority of respondents concurred. Almost half (49%) of Americans, about 56% Australians, about two-thirds (67%) of Britains and 58% of Canadians were in agreement with the above statement.
In United States, this is not true as the order of availability of new OTC medicines to the general public is decided by the sponsor's willingness to switch and the FDA has no role in this decision. As discussed earlier, the issue of regulatory agencies initiating and pursuing switch proposals in the absence of support from the sponsor is critical in this context. A majority of the respondents from all countries ( 46% Americans, 60% Australians, 63% Britains and 50% Canadians) agreed that the availability of a ''better" OTC product in terms of efficacy or safety should affect the status of products already in the OTC market for treatment of the same condition within a therapeutic class.
Additionally, about two-thirds of the respondents (66% Americans, 67% Australians, 69% Britains and 65% Canadians) believed that when newer nonprescription products become available within a therapeutic class, older therapies that may provide less benefit or more risk should be either removed from the market or their labeling should be revised. These observations must be interpreted cautiously as the decision to remove older OTC medicines upon availability of newer OTC medicines must be considered on a case specific basis. In some cases removal of an OTC medicine (as in the case of phenylpropanolamine in the United States) may be the right course due to public health reasons. However, attempts to extend such a policy universally may be imprudent as individuals do not show a uniform pharmacological response to any medicine and it is 179 necessary to allow for a choice of pharmacological therapies being available to individuals.
There was variability among responses on the issue of direct-to-OTC marketing (a new chemical entity (NCE) is directly granted OTC status without being first marketed as a prescription product for some duration of time

Discussion
Literature m this scientific discipline does not widely document the use of internet, despite its obvious and well-known advantages, for administering a survey.
This study demonstrates the utility of electronic communication in the rapid and effective completion of a global survey. Also, the electronic survey instrument is presented as an efficient alternative to traditional questionnaire-by-mail survey technique.
As with any study, this study is also subject to limitations and the results must important in the context of proposed OTC status for second-generation, non-sedating antihistamines in the United States (7 ,8). Although, this topic has substantial legal complexity and experts in drug law did not participate in this study, it is important for the FDA to consider the opinion of pharmacists and academicians in formulating its regulatory policy on OTC status for non-sedating antihistamines.
It is important to note that responses on statements related to suitability of disease conditions and drugs for self-medication were found to be statistically independent of the country in all but, two cases. The United States has only one class of nonprescription medicines whereas Australia, United Kingdom and Canada have two classes of nonprescription medicines (one that requires consultation with a pharmacist in a pharmacy before purchase and the other that may be purchased anywhere). It has been argued that the existence of the pharmacist-controlled class of nonprescription medicines offers a more efficient approach to manage the risk/benefit ratio associated with potent nonprescription medicines and ensures their safe use. If this hypothesis were true, it is reasonable to expect that the responses of participants from countries with a pharmacist-controlled class of nonprescription medicines might possibly be different from those in United States. However, the results show this trend only in two of the ten statements. Also, a proportion of all respondents stated that their responses on above statements might have been different if a pharmacist-class of nonprescription medicines was available and pharmacist intervention can be frequently exercised.
Hence, it is unclear if a majority of all respondents believe that most of the diseases or drug classes discussed above are unsuitable for self-medication even if a pharmacistcontrolled class of nonprescription medicines were available. Two limitations of this 183 study, the phraseology of the questionnaire not possibly ensunng consistent comprehension by all respondents and the participants not having the opportunity to qualify their responses, are particularly important in this context. It is necessary that subsequent studies designed to specifically test hypotheses such as these must be conducted for an accurate assessment.
Recently, dietary supplements have witnessed a rapid growth in usage (9,10,11,12) and there has been a vocal expression of concern among the professional community over the safety and efficacy of these products and this overall opinion is aligned with the views of the majority of the scientific and medical community (13,14,15,16,17). The responses observed on regulation of dietary supplements imply that such products presently regulated as per the Dietary Supplement Health and Education Act (DSHEA) of 1994 need to be comprehensively reviewed and fundamental changes must be made to the regulatory framework. Observations on the subject of consumer understanding and behavior related to nonprescription medicines indicate that the respondents believe that consumers posses neither the knowledge nor the commitment to correctly select and safely use OTC medicines without being assisted by a learned intermediary. It is vitally important for consumers to responsibly use OTC medicines and effective education of the general public must be accomplished.
The significance of these observations is augmented as it is expected that attempts to make potent prescription medicines available without a prescription will increase in the future. 10. Patients know the best ways to treat their illnesses in an environment with coexisting prescription and nonprescription therapies for a certain disease. 189 11. The risks and benefits to individuals and public health should be assessed and weighed in any decision on nonprescription marketing of drug products (for example, the potential benefits of nonprescription antimicrobial agents with the potential risks to society at large of the development of resistant organisms).
12. Prevention claims for nonprescription medicines encourage ill-advised behavior (for example, use of an nonprescription cholesterol lowering drug would allow patients to ignore other needed interventions such as smoking cessation, dietary discretion and management of other risk factors).
13. Within a therapeutic class, the first drug to enter the nonprescription market should be the "best" drug in terms of the benefit-to-risk ratio.
14. Within a therapeutic class, the availability of a "better'' nonprescription product in terms of efficacy or safety should affect the status of products already on the nonprescription market for treatment of the same condition.
15. When newer nonprescription products become available within a therapeutic class, older therapies that may provide less benefit or more risk should be either removed from the market or their labeling should be revised. 9. Patients know the best ways to treat their illnesses in an environment with coexisting prescription and nonprescription therapies for a certain disease. 12. Within a therapeutic class, the first drug to enter the nonprescription market should be the ''best" drug in terms of the benefit-to-risk ratio.
13. Within a therapeutic class, the availability of a "better" nonprescription product in terms of efficacy or safety should affect the status of products already on the nonprescription market for treatment of the same condition. 193 14. When newer nonprescription products become available within a therapeutic class, older therapies that may provide less benefit or more risk should be either removed from the market or their labeling should be revised.
15. Initiatives to develop and establish globally acceptable monographs for nonprescription drug products, at least, within the developed world should be promoted. 16. Assuming a new chemical entity meets all regulatory requirements necessary for nonprescription classification, it should still be marketed as prescription medicine for a specified duration before reclassification to nonprescription status may be considered.
194     Upon giving their consent, all the participants were interviewed by the author.
Participants were also requested to grant permission for recording the interview for review and transcription purposes by the author only. Participants were assured that their identity and individual responses will be kept anonymous and that only collective data from the interviews will be publicly discussed. Hence, table 1 describes the nature of the participants only in general terms without specific information. The statements for the interview survey questionnaire were adapted from the public hearing notice published by the FDA with a few modifications made to the phraseology as presented by the FDA. Selected questions posed by the FDA were presented as statements during the interview and respondents were asked to state their opinion. The format of the interview was free flowing and the participants were allowed to respond without any restrictions. The set of statements used in the interviews is appended to this article. 203 Data analysis: Data collected through the interviews and the public statements was pooled and qualitatively examined to discern prominent observations and trends. An attempt to make inferences helpful towards formulation of rational regulatory policy was also made.

Results
The opinions of thirty-six stakeholders from United States, Australia, United Accounting Office as evidence for their position. They asserted that this concept restricts access and has been rejected by the FDA. 206 A substantial majority of the respondents interviewed stated that direct-toconsumer advertising of prescription pharmaceuticals does not affect the reclassification of those products to OTC status. Also, they strongly endorsed a proposal to create global OTC monographs so that the scientific basis and knowledge used in approval of OTC products may be efficiently shared across nations. Respondents also supported the issuance of a guidance document prepared by the FDA for sponsors describing the nature and kind of evidence required in switch petitions.

Role of regulatory agency
When asked if their regulatory agency should actively and unilaterally propose OTC marketing of a drug in the absence of support from the sponsor, the responses were assorted. Most of the respondents said that it would be appropriate for a regulatory authority to force a switch against the willingness of a manufacturer if such a move meets public health needs. However, respondents also stated that the most productive and efficient approach to switches would be a collaborative one between the manufacturer and the regulatory authority. The reasons provided to justify a unilateral switch by the regulatory authority were; (a) public health benefit must be the paramount

Criteria for OTC classification
A substantial majority of the participants opined that the current OTCness criterion of safety/efficacy of drug, self-treatment of condition and overall public health benefit of a medicinal product in the absence of a learned intermediary as adequate for making decisions on OTC suitability. However, a reasonable portion of the respondents also stated there were inconsistencies in the implementation of these criterion in the decision making process and evaluating OTC suitability. One participant stated that there should not be any limitations on who can petition for reclassification to OTC status in the US. Also, some respondents requested clarifications in the regulatory process for OTC evaluation of prescription medicines.
CHPA, PhRMA, Kaiser Permanante and Well Point Health Networks agreed that the existing regulatory criteria applicable in the estimation of risk-to-benefit ratio 208 for OTC availability were adequate. The APhA recommended that the FDA must additionally consider the environments surrounding the use of the drug and the disease or symptom for which it is used . Dr. Wolfe suggested that ease of self-diagnosis, selflimited or chronic condition, benefit-to-risk ratio and its evaluation, low potential for abuse, adverse reactions and drug interactions, and long-term prescription use data as six principles that must be used to evaluate potential Rx-to-OTC switch candidates.
A significant theme that was repeatedly observed among the participants was serious concern over the unscientific approval process for non-traditional OTC medicines under the Dietary Supplement Health and Enhancement Act (DSHEA).
Almost all respondents felt that the robust scientific and data-driven decision making process followed for most pharmaceutical OTC products as per the OTC Drug Review was completely eliminated for DSHEA products and such was medically unjustifiable. Overall, the participants felt that complete elimination of a learned intermediary (physician or pharmacist) would be imprudent and supported a collaborative system where a close relationship between the physician and the pharmacist is preserved with the responsibility for maintenance and monitoring of the treatment placed largely on the pharmacist.

Consumer understanding and behavior
A reasonable proportion of the study participants believed that consumers could neither make a rational selection of treatment regimens nor choose the best way to cure their illness, when there are coexisting prescription and OTC therapies for a certain disease. Further, they also thought that prevention claims for OTC medicines might encourage ill-advised behavior among consumers. Respondents reasoned that consumers are neither trained nor qualified to make such decisions and most often do not have the appropriate information to use medicines properly in an OTC environment.
CHP A asserted that its research showed that 95% of consumers read the labels before using OTC medicines and that there is a very high level of label comprehension.

App roval of new OTC medicines
When asked if the first drug to enter the OTC market should be the "best" drug in terms of benefit-to-risk ratio within a therapeutic class, a majority of respondents concurred. A majority of the respondents agreed that the availability of a "better" OTC product in terms of efficacy or safety should not affect the status of products already in the OTC market for treatment of the same condition within a therapeutic class.
Additionally, participants stated that when newer nonprescription products become available within a therapeutic class, older therapies that may provide less benefit or more risk should not be removed from the market or their labeling should not be revised. On the issue of direct-to-OTC marketing (a new chemical entity directly marketed as an OTC product without being a prescription medicine for some duration), there was universal agreement that products must be marketed as a prescription medicine under the supervision of a learned intermediary for some duration before reclassification to OTC status may be considered. Respondents stated that a drug's safety profile cannot be understood based solely on controlled clinical trials during 212 development and surveillance during real-world clinical practice is necessary before OTC status may be considered.

Discussion
As with any study, this study is subject to limitations and the results must only be interpreted within the context of any such limitations. An important limitation of this study is that the study sample population may not accurately represent the overall population of stakeholders. Although attempts were made to interview all stakeholders, it is rarely feasible to fully realize this objective. Also, responses are influenced by the inherent biases of the respondents and must be accounted in analyzing the data. Despite the limitations, these results are useful to discern the attitudes of important stakeholders on regulation of nonprescription medicines. This assertion is reinforced, as the study is exploratory in nature and was not designed to test any specific hypotheses. Moreover, the absence of any information in the global context related to these important issues accentuates the significance of these results.  13. Within a therapeutic class, the first drug to enter the nonprescription market should be the "best" drug in terms of the benefit-to-risk ratio.
14. Within a therapeutic class, the availability of a "better" nonprescription product in terms of efficacy or safety should affect the status of products already on the nonprescription market for treatment of the same condition.
15. When newer nonprescription products become available within a therapeutic class, older therapies that may provide less benefit or more risk should be either removed from the market or their labeling should be revised.     self-treatment, a collaborative approach by FDA towards switching that includes all stakeholders is more favored, decisions on switch petitions must be case-specific without a presumptive bias and public health benefit must be the paramount evaluation criterion.
The significance of information presented in this dissertation is amplified as this area has received little academic attention and information is not readily available. It is proposed that an examination of the interactive effects between scientific, regulatory and economic principles affecting nonprescription medicines and their optimization to maximize public health benefit would be appropriate for subsequent research.

List of conclusions
Presented below in detail are some of the significant and original findings resulting from this study: 1. Globally, healthcare systems are changing significantly to affect the use and attitudes toward over-the-counter (OTC) medicines and interest in self-care is rapidly increasing. In recent years, self-medication has undergone a dramatic change due to the advent of herbal medicines, dietary supplements, nutraceuticals and health foods in addition to traditional nonprescription medicines, and, increasing societal preferences towards greater individual control over the use of medicines. It is widely believed that responsible use of OTC medicines can lead to overall cost savings and public health benefit. Hence, the regulatory framework related to nonprescription medicines has become an important priority for regulatory authorities, academicians and the industry.