Clemastine

This paper traces the evolution of prescription-to-over-the-counter (OTC) switch criteria and assesses the impact of new developments in this and related areas, as a means to create a conceptual framework for considering the future of prescription-to-OTC switch. Over the past two decades, switch criteria have evolved from the foundational definitions of safety, effectiveness, and labeling in the OTC Review through the pharmacological interpretations of OTCness in Peck's Principles, to the modern day focus in DeLap's Principles on the consumer as the focal point for studying endpoints of self-care. Today's switch criteria represent a solid regulatory/scientific foundation for the next evolution of OTC drugs: to treat chronic conditions and diseases, which are not being adequately treated with current health care options. Further dialogue on the potential for OTC access to enhance collaborative self-care should be actively considered.

Key Words: Prescription; OTC; Switch criteria; Self-care

OVER THE YEARS, as drug sponsors have sought to expand the OTC market with novel self-care therapeutics, interest has centered on defining the essential criteria for switching drugs from prescription-to-OTC status. The reason for this is simple. Sponsor research and development programs are more efficient if the Food and Drug Administration's (FDA's) decision making process is transparent and predictable. When the frontier of OTCness is pushed in a new way, however, the current switch criteria are reassessed and refined to ensure that the agency's premarketing benefit/risk judgment is appropriately sensitive to account for new methods of intended drug use by consumers. Often, it has been the industry that has pushed the agency to articulate its current thinking on criteria for prescription-to-OTC switch, as a means to stage future discussions on novel switches. This paper traces the evolution of prescription-to-OTC switch criteria and assesses the impact of new developments in this and related areas, as a means to create a conceptual framework for considering the future of prescription-to-OTC switch.

"OTCness means the widespread availability of safe and effective nonprescription medicines for responsible self-care by the consumer according to label directions, pursuant to the applicable laws, regulations, and voluntary industry codes affecting manufacturing, packaging, labeling, distribution, and sales of quality products and the advertising of those products in all media" (1). This definition remains unchanged by the evolving switch criteria, principally because it is the endpoint of the process whereby OTC medicines are made available for widespread use in the United States two-class system of drug distribution. Switch criteria are the basis for the scientific/ medical decision making process that determines OTCness. At the core of the definition of OTCness, however, is the statutory premise that drugs are prescription by exception-an important principle that frames a positive perspective as to whether switch criteria can even be considered for novel self-care conditions, such as chronic disease management. This view was recently interpreted by Center for Drug Evaluation and Research (CDER) director Dr. Janet Woodcock: "[Als written, the default assumption of the Act is for drugs to be marketed OTC without a prescription unless a decision is made that consumers are not able to appropriately diagnose their condition nor able to correctly choose the remedy and safely use it based on OTC labeling. . . " (2). This explicit support by FDA of the default premise for OTCness in the law is relatively new and marks a culmination of 30 years of dialogue and OTC postmarketing experience, over which time the criteria for OTCness and, therefore, prescription-to-OTC switch, have continually evolved.

THE OTC REVIEW

The basis for modern OTCness started in 1972 with the initiation of the OTC Review. At that time, definitions for safety, effectiveness, and labeling, as well as a requirement for a benefit/ risk decision, were set forth as regulatory criteria (3) for determining general recognition of safety and effectiveness (GRAS/E) of ingredients by FDA's 17 OTC advisory panels. These definitions advanced OTCness in a significant way and created the basis for modern switch. Specifically, these definitions established safety and effectiveness in relative terms, meaning a low incidence of side effects, a low potential for abuse, and a reasonable expectation of effectiveness in the target population under conditions of intended use. Further, the definition of labeling not only established the label (not the physician) as the intermediary between the consumer and the drug, but held the basis for the future emphasis on assessments of actual use and label comprehension, with the statement: "labeling... shall be .in such terms as to render them likely to be read and understood by the ordinary individuals, including individuals of low comprehension, under customary conditions of purchase and use" (4). Finally, in using these definitions, the OTC advisory panels developed the still currently used scientific/regulatory paradigm (5) of a case-by-case, weight-of-the-evidence, datadriven, and dialogue-driven approach undertaking a benefit/risk assessment on OTC availability.

However, the overwhelming emphasis by the agency and industry at the time of the OTC Review was on acute, self-limiting conditions requiring no physician intervention (eg, tension headache, cold and flu symptoms, athlete's foot, etc.), although certain exceptions (ie, asthma) were permitted despite requiring a physician's diagnosis prior to self-care use. To a large extent, at that time companies wanted to ensure that their products made it through the OTC Review process and remained on the market. Indeed, many drugs marketed OTC prior to the initiation of the OTC Review met monograph requirements for OTCness, including aspirin, magnesium hydroxide, and psyllium, among many others. Others were switched under these early criteria for OTCness, including chlorpheniramine, pseudoephedrine, 0.5% hydrocortisone, and stannous fluoride, among others.

In fact, in looking at the number of switches per year over the last 30 years (Figure 1), the monograph system of the OTC Review created 33 OTC ingredients, dosage forms, and dosages, and this yield extended into the mid to late 1980s as the OTC Review final monographs continued to move through the required lengthy public review and comment process. (Note: here switch is not defined only as the transfer of the prescription drug active in the exact dosage, dosage form, and strength, but also per common parlance the transfer of any one of these parameters as well as a condition of use, such as migraine.)

As the OTC Review process moved from its initial advisory panel phase to its public review phase in the late 1970s and early 1980s, industry's attention turned to opening new OTC markets. Ibuprofen heralded this movement in 1984, and, although in many respects it was a switch into an existing category, the ibuprofen switch foreshadowed the extensive database that would be required a decade later for the novel switches of the 1990s. Often forgotten, the ibuprofen switch also required the first label comprehension study (never published in toto or presented publicly), which assessed the comparative understanding of a label with an extensive "laundry list" of all possible warnings about the OTC ingredient versus a label with only the most important warnings. FDA concluded: "[T]he results showed that the `laundry list' version was more often misinterpreted than the general warning" (6). However, it was the dialogue surrounding the potential switches of vaginal antifungals and H2 blockers that led to the first articulation of modern (ie, post OTC Review) switch criteria by FDA.

As a means to engage the agency in a dialogue on switch, the Consumer Healthcare Products Association invited CDER director Carl Peck, MD, to speak at its 1989 annual scientific/regulatory conference, asking Dr. Peck to survey CDER office and division directors for the principle criteria for switching products from prescription to OTC status. The result is a list of 13 criteria, known as Peck's Principles (see Table 1), which like other later statements about switch criteria draw on recent and current experience and thus represent a state-of-the-art summary of current criteria, as opposed to a future vision of switch. This was the first public articulation of switch criteria by FDA and was generally regarded by industry as helpful guidance for the selection and development of prescription-to-OTC switch candidates. While these principles are still useful points to consider when assessing a switch candidate, they are taken from the perspective of the switch candidate, and therefore, do not include future refinements of switch criteria, which emphasize the condition, consumer understanding of product use, and conditions of actual use (see below). Nonetheless, Peck's Principles helped to advance switch, and in the period after their issuance FDA approved the vaginal antifungals, loperamide, 1% hydrocortisone, permethrin, and clemastine.

In 1992, after establishing an Office of OTC Drugs (now a division), FDA convened the Nonprescription Drugs Advisory Committee. During next five years, 23 switches were approved (Figure 1). In many respects, this was a golden era for switch with many approvals and the evolution of switch criteria to emphasize the consumer as the focal point for scientific/medical decision making for (or against) OTCness. While actual use studies were not new to the OTC arena at this time, having been discussed in depth during the development of the vaginal contraceptive monograph, the application of in-use studies in simulated OTC settings and label comprehension studies allowed complex questions about consumer behavior to be answered during the approval process. As the chief OTC drug review executives in the OTC office at that time, Dr. Michael Weintraub and Dr. Debra Bowen were leading contributors to this evolution in FDA's articulation of switch criteria, which placed the emphasis of switch criteria on the consumer and conditions of use. However, it was not until 1998, when Dr. Robert DeLap (then, director, Office of Drug Evaluation V) was asked to provide his version of switch criteria at the annual Consumer Healthcare Products Association scientific/regulatory conference, that the philosophical construct of the consumer as a primary focus of switch criteria was publicly articulated by FDA.

As with Peck's Principles, DeLap's Principles (Table 2) represented a state-of-theart statement of FDA's and industry's recent experience and current thinking. DeLap's Principles, however, reflect not only the emphasis on actual use studies and label comprehension studies in the early to mid 1990s, but also the evolution of the OTC label to include special warning subheadings relating to in-use precautions (eg, in Table 2, see the questions: does the consumer have the ability to assess treatment effect? What is the consumer understanding of what to do if the product isn't working?). Another important expansion in the perspective of OTCness in DeLap's Principles is questions concerning the consumer's expectations of benefits. As considered below, while Peck's Principles are important to consider, DeLap's Principles represent the type of primary focus that will be necessary to consider the more complex switches of the future (see below). In the mid to late 1990s, during which there was a greater expansion of switch in type and number than in any other period (Figure 1), the types of switched products which represent the expression of DeLap's Principles include: 2 blockers for gastric acid reduction and prevention, where consumer understanding of the expected benefit, consumer selfrecognition of when to prevent, and consumer avoidance of drug-drug interactions were important considerations,

* Pediatric ibuprofen, where in-use experience in over 80000 febrile children was used to assess safety relating to rare side effects,

* Nicotine replacement therapy, where in-use studies comparing existing prescription and OTC treatment and associated support programs led to a determination that OTC access would result overall in a higher number of quitters across the population despite a lower quit rate versus prescription use in a high support setting, and

* Migraine remedies, where self-selection and physician diagnosis prior to OTC use was important to resolve before this condition was permitted to be advertised for certain existing OTC analgesics.

In the 1995 to 2000 timeframe, the question of switching prescription antihypercholesterolemic products to OTC status tested the evolving switch criteria. First among the switch candidates was cholestyramine, for which relevant consumer understanding and actual use studies demonstrated a high level of consumer interest in self-treatment of elevated cholesterol and an ability of a significant proportion of the study population to use the product responsibly under conditions of proposed use (7). However, during this period, FDA was evaluating the morbidity/ mortality data of the second generation prescription antihypercholesterolemics (ie, the statins) as well as its public health policy relating to the use of dietary supplements for cholesterol treatment versus maintenance/ promotion of healthy cholesterol levels (8). These considerations, coupled with the limited organoleptic appeal of cholestyramine's liquid suspension form which needed to be prepared prior to each use (versus the single daily dose regimen of tableted statins), led to negative decisions at two advisory committee meetings, resulting in a 1997 policy guidance from FDA (9). This guidance essentially shut off a category from further research and development discussion, providing in the process virtually no direction as to possible future research questions that might need to be answered to satisfy OTC criterion for antihypercholesterolemics and thereby running afoul of the default assumption in the act favoring OTCness (see above). It stated:

OTC drugs generally are used for self-recognizable conditions that are symptomatic, require treatment of short duration, and can be treated without the oversight and intervention of a health care practitioner. Hypercholesterolemia, in contrast, is a chronic, unremitting, asymptomatic condition with life-threatening consequences that can be reduced by some interventions. Treatment of hypercholesterolemia requires both (a) accurate diagnosis and clinical testing and (b) careful health care practitioner-directed medical management, including the choice of appropriate drugs) for the individual patient based on the patient's specific clinical condition.

It is CDER's view that (a) health care practitioner supervision in the diagnosis and ongoing management of hypercholesterolemia is essential for safe and effective use of drug products to treat this condition and (b) this supervision is assured within the context of prescription access to the appropriate drugs) for the individual patient. CDER therefore believes that drugs for the treatment of hypercholesterolemia should not be sold OTC in the United States (9).

This policy had a deep chilling effect on the industry, leading to efforts by the Consumer Healthcare Products Association and individual sponsors of statins as OTC cholesterol lowering agents to have the guidance withdrawn. The guidance struck at the very heart of the default assumption that drug products are prescription by exception and indicated that the agency was attempting to create insurmountable barriers to OTCness for whole categories of prospective switch candidates. Despite many submissions from the Consumer Healthcare Products Association to FDA requesting withdrawal of the negative antihypercholesterolemic guidance, it was not until a landmark 1999 Consumer Healthcare Products Association/FDA Switch Summit was convened, in which industry leaders met with CDER Director Janet Woodcock, MD, and seven FDA office and division directors to discuss the future of OTCness through switch, that action was taken. The agency agreed with industry's request that negative opinions on switch petitions should provide explanations as to why the agency disagrees with the data supporting switch, thereby not closing off potential further dialogue on a negative switch decision, thus, allowing the industry to make the decision as to whether the hurdle is or is not worth the march.

Propelled in part by the 1999 Switch Summit, a year later FDA convened its open Part 15 hearing on OTCness and switch, asking for commentary on the criteria for prescription-to-OTC switch. That meeting did little to expand on either Peck's or DeLap's principles, with most attention focusing on a majority of favorable views on emergency oral contraceptives and on such issues as comparative effectiveness evaluations as a part of OTC decisions, nonsponsor initiated switches, and the value of consumer understanding studies. A month later, FDA convened a joint advisory committee meeting to review the switch petitions for the statins Mevaor and Pravachol. While these applications took somewhat different approaches to OTCness, the advisory committee review was generally favorable, leading to heightened expectations that statins would one day be available OTC. Among the issues of concern is whether OTCness for long-term conditions/diseases can be based on clinical trials of surrogate endpoints for disease morbidity/mortality (such as total cholesterol, HDL, and LDL), or whether longterm evaluation of clinical endpoints related specifically to morbidity and mortality is needed to support OTCness. In the case of cholesterol-lowering agents, this matter is of particular importance from a compliance standpoint, since the endpoint of treatment (ie, the user's blood lipid profile) is asymptomatic with no immediate quality of life measures to provide positive feedback to the product's user. This issue will likely gain increased attention as industry continues to push for OTCs for longterm disease management (see below).

More recently, second generation antihistamines have been proposed as switch candidates by Wellpoint, a California-based health care provider, over the wishes of the drugs' sponsors. Much attention was focused by the media on FDA's ability, indeed authority, to force switches over a sponsor's objections. However, apart from this important consideration, two additional criteria for switch were defined through interactions between the Consumer Healthcare Products Association and FDA in preparation for the advisory committee meeting. Specifically, FDA conveyed to each oral presenter at the May 11, 2001 hearing that economic and comparative safety or efficacy assessments are not a part of the agency's switch decisions, consistent with FDC Act (10), as follows: The Agency does not make decisions nor will they discuss what drugs become OTC drugs on the basis of whether the cost to the consumer or providers will change.

The Agency will not be discussing the efficacy of the three drugs (Allegra, Zyrtec, or Claritin). They are all approved and have demonstrated efficacy.

The Agency does not make decisions on what drugs become OTC drugs by comparing drugs. Thus, the Agency will not be discussing comparisons of the efficacy or the safety of any first generation antihistamines to the three second generation (11).

These policy statements effectively answered certain questions raised by FDA at the earlier June 2000 public hearing on OTCness and switch. These statements also focused the agenda in a way favorable to the proswitch view for second generation antihistamines. FDA presentations at the May 11, 2001 hearing clearly showed that the agency was in favor of these switches, particularly as FDA medical reviewers indicated no need for actual use studies or label comprehension studies, which had become a staple component of the data package for most switches in the 1990s. Interestingly, as part of the background materials sent to advisory committee members, FDA chose to emphasize Peck's Principles, which focus on the drug, and not DeLap's Principles, which focus on the consumer and the need to ensure consumer understanding of the label and in-use evaluation of the product prior to switch, thereby helping to guide the advisory committee to limit its discussion of the potential need for consumer (not patient) use data prior to switch.

Currently, two related topics are under discussion within CDER and industry: enhancing risk management in the pre- and post-marketing review of drug safety and expanding OTCness to include consumer selfmanagement of chronic conditions and diseases. First, in the wake of accusations that prescription drug user fees rushed products to market without proper safety reviews, FDA convened a special committee on risk management under the leadership of CDER Director Janet Woodcock, MD. Not only did CDER adequately address the accusations to support the value of user fees in bringing more products with acceptable safety profiles to market sooner, but the center also prepared an in-depth report providing recommendations for a systems approach to prescription drug safety assessments (12). In this timeframe FDA also created the Office of Drug Safety, through which even greater emphasis has been applied to adverse experience reporting as predictors of postmarketing drugrelated risk. Translated to OTCness and other products, the evolving safety perspective is that, if the adverse event is predictable, then it is potentially preventable through specific interventions which can be measured to define their effect and/or the need for alternate interventions. If, however, the adverse event is idiopathic, then depending on the risk, the intervention may mean removal from the market, even if the event is rare.

Also under discussion in this regard is the overall perspective taken by CDER in its report, which focuses on prescription products, specifically on "prescribers" as the primary focal points for postmarketing risk management of drug safety. In contrast, the OTC industry sees the consumer at the center of self-care therapeutics as a "benefit-risk co-manager," with prescribers, pharmacists, nurses, FDA, manufacturers, and other government agencies (eg, Centers for Disease Control and Prevention) also as "benefit-risk co-managers" with the consumer. The importance of placing the consumer at the center of self-care and defining postmarketing risk management as a collaborative process relates not only to considerations of the realities of postmarketing surveillance for OTC drugs, but also to how switch criteria are defined and studies are designed to predict adverse events before marketing in order to support approval of switch candidates. DeLap's Principles have been an important advance in this regard, and should be used as the stepping stone to future refinements to switch criteria.

The second area of current dialogue between CDER and industry relates to the possible use of OTC medicines for management of chronic conditions and diseases. Prevention of disease is not a new concept to nonprescription self-care, with such OTC active ingredients as sodium fluoride for caries prevention, the imidazole derivatives for prevention of fungal infections, and sodium chromolyn for allergy prevention. Prevention of disease progression and long-term treatment of disease, however, represent frontier areas where improved access to therapy has the potential to improve disease therapy and outcomes.

A key driver for engaging the agency in discussions on how to approach the use of OTCs for chronic conditions and diseases is industry's belief that OTC access and consumer support through marketing approaches to targeted OTC audiences have the potential to raise awareness of the condition/disease, emphasize the need for responsible continued self-care, and provide easier access to therapy at lower overall health care costs. For example, underserved populations have been described for hypertension, hyperlipidemia, and urinary incontinence:

* As many as 50% of patients with a known diagnosis of hypertension are not receiving treatment (13). The sixth report of the Joint National Committee on Prevention and Treatment of High Blood Pressure states that only 27% of people who are aware that they had hypertension had their blood pressure controlled (14),

* An evaluation of the third National Health and Nutrition Examination Survey (NHANES 111) revealed that among United States adults without coronary heart disease and with more than two risk factors, 54.6% are not meeting Adult Treatment Panel II (ATP II) treatment goals, and 22.6% qualify for drug therapy. About 37% of United States adults without coronary heart disease and with more than 2 risk factors were not at the desirable LDL cholesterol level of

* While urinary incontinence is common and a burden to many patients, one study found that 72% of those with current urinary incontinence had not told a health care provider (16), while another study reported that health practitioners spontaneously asked about incontinence in only 18% of visits (33% for physician assistants, and 11% for nurse practitioners and family physicians) (17).

In conclusion, over the past two decades, switch criteria have evolved progressively from the foundational definitions of safety, effectiveness, and labeling related to the initiation of the OTC Review through the pharmacological interpretations of OTCness in Peck's Principles to the modern day focus in DeLap's Principles on the consumer as the focal point for studying endpoints of selfcare. Today's switch criteria represent a solid regulatory/scientific foundation for the next evolution of OTC drugs to treat chronic conditions and diseases, the groundwork for which is currently being laid by ongoing dialogue between FDA and industry. The broader public health discussions on risk management of prescription pharmaceuticals will likely impact this process in a positive way, if the focus of OTC risk management places the consumer at the center of pre- and postmarketing assessments of drug safety and effectiveness, using a collaborative benefit/risk co-management approach to self-care. Clearly, current health care options are not serving all components of the chronic disease populations, and further dialogue on the potential for OTC access to enhance collaborative selfcare should be actively considered.

REFERENCES

1. Soller RW. OTCness. Drug Inf J. 1997;32:555-560.

2. Woodcock J. Statement of Janet Woodcock, M.D.,

Director, Center for Drug Evaluation and Research, FDA for the Hearings on "Recent Developments Which May Impact Consumer Access to, and Demand for, Pharmaceuticals," Subcommittee on Health, House Committee on Energy and Commerce, June 13, 2001.

3. 21 CFR 330.10(a)(4)(i)(ii) and (v). 4.21 CFR 330.10(a)(4)(v).

5. Soler RW. The over-the-counter scientific/regulatory paradigm. Drug Inf J. 1999;33:799-804.

6. US Food and Drug Administration. Ibuprofen in people with mild kidney disease. Talk Paper. Rockville, MD: US Food and Drug Administration; May 2, 1990.

7. US Food and Drug Administration. Transcripts of joint meetings of the Nonprescription Drugs Advisory Committee and Endocrinologic and Metabolic Drugs Advisory Committee dated September 27, 1995, and May 13, 1997. Rockville, MD: US Food and Drug Administration; 1997.

8. US Food and Drug Administration. Regulations on statements made for dietary supplements concerning the effect of the product on the structure or function of the body; Final Rule. Federal Register. 2000;65: 999-1050.

9. US Food and Drug Administration. OTC Treatment of Hypercholesterolemia Guidance for Industry. September 1997. www.fda.gov.

10. Consumer Healthcare Products Association. Written Comments Relating to the June 28-29, 2000 FDA Public Hearing on Over-the-Counter Drug Products. Docket No. OON-1256, submitted August 25, 2000. Washington, DC: Consumer Healthcare Products Association.

11. Titus S. E-mail to Open Hearing Requesters at the May 11, 2001 FDA Advisory Committee Meeting on Switching Second Generation Antihistamines. Docket No. 98P-0610, April 27, 2001.

12. Center for Drug Evaluation and Research Task Group on Risk Management. Managing the Risks From Medical Product Use: Creating a Risk Management Framework. Report to the Commissioner. Rockville, MD: US Food and Drug Administration, Center for Drug Evaluation and Research; May 1999.

13. Munger MA. Critical overview of antihypertensive therapies: what is preventing us from getting there? Am J Manag Care. 2000;6(Suppl):S211-21.

14. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. NIH Publication No. 98-4080. Bethesda, MD: National Institutes of Health; November 1997.

15. Hoerger TJ, Bala MV, Bray JW, Wilcosky TC, Larosa 1. Treatment patterns and distribution of lowdensity lipoprotein cholesterol levels in treatment-- eligible United States adults. Am J Cardiology. 1998; 82:61-65.

16. Lagace EA. Prevalence and severity of urinary incontinence in ambulatory adults: an UPRNet study. J Fam Pract. 1993;36(6):610-614.

17. Jones TV, Brunner SH. Approaches to urinary incontinence in a rural population: a comparison of physician assistants, nurse practitioners, and family physicians. J Am Board Fam Pract. 1998;3:207-215.

R. WILLIAM SOLLER, PHD

Senior Vice President and Director of Science & Technology, Consumer Healthcare Products Association, Washington, Dostrict of Columbia

Reprint address: R. William Soller, Senior Vice President and Director of Science & Technology, Consumer Healthcare Products Association, 1150 Connecticut Ave. NW, Washington, DC 20036. E-mail: wsoller@ chpa-info.org.

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