Changing the marketing status of a drug from prescription (Rx) to over-the-counter (OTC), known as an Rx-to-OTC switch, can increase drug utilization by an average of 30% (Stomberg et al. 2013). According to the Consumer Healthcare Products Association (CHPA), more than 700 current OTC products contain drugs or dosages that were available only by prescription less than 40 years ago. The increased patient access that comes with an Rx-to-OTC switch can have benefits for patients in terms of health and convenience. A recent study used a cost effectiveness model to estimate that if statins were available OTC, Americans would suffer 252,359 fewer major coronary events, 41,133 fewer strokes, and 135,299 fewer coronary revascularization procedures over 10 years, as well as reduce coronary heart disease- and stroke-related deaths by 68,534 (Stomberg et al. 2016).
Rx-to-OTC Switch: Yet Another Advantage of the 505(b)(2) Pathway
That’s right: the 505(b)(2) regulatory pathway can be used to affect an Rx-to-OTC switch as the switch NDA builds on information from previous regulatory filings and the experience with use of the Rx product, including post-marketing safety surveillance and literature reports. If the product does not meet OTC monograph requirements, a New Drug Application will be required to switch a prescription drug to OTC. There are two options for a sponsor wishing to initiate an Rx-to-OTC switch, depending on similarity to the marketed (approved) product. If there are no changes to the dosage form, route of administration, and indication, an NDA efficacy supplement (requested by the holder of an approved prescription NDA) or a 505(b)(2) application may be submitted. If there are any differences between the marketed product and proposed OTC product, including narrowing the OTC indication, a new NDA will be required. In both cases a 505(b)(2) application is appropriate if the Sponsor is relying on any study or studies not conducted by the Sponsor, for which the Sponsor does not have right of reference. Sponsors are strongly encouraged to request milestone meetings with FDA during Rx-to-OTC switch (e.g., Pre-IND, End of Phase 2, Pre-NDA).
In cases where a Sponsor other than the holder of the approved Rx NDA seeks OTC approval, the switch should be requested through a citizen petition (21 CFR section 10.30). Of course, all studies and data to support the switch must also be submitted.
How to Determine an Appropriate Product Candidate for Rx-to-OTC Switch
To determine which products are suitable for switching to OTC status, an assessment of whether the drug is amenable to self-medication must be made. The following criteria must be met:
- The product has an acceptable safety margin (e.g., benefits of OTC availability outweigh risks).
- The product has low misuse and abuse potential.
- A healthcare practitioner is not needed for the safe and effective use of the product.
- The product has appropriate labeling.
In addition, a Sponsor must adequately establish that consumers can self-diagnose, self-select the medication, self-treat, and self-manage the condition for which the OTC drug is intended.
What is Needed to Make Rx-to-OTC Switch?
To assess the extent to which consumers understand the OTC drug product labeling information and can apply this information, the FDA will likely require consumer studies, including: label comprehension, self-selection, and actual use studies.
Label comprehension studies are conducted first to determine the consumer’s ability to comprehend key facts of an OTC label. These studies typically involve a questionnaire. The label wording is revised until all vital elements of the label are effectively understood.
Next are self-selection studies to determine if consumers can make correct self-selection decisions by applying the OTC label information to their personal medical history in order to make proper self-use safety decisions.
Actual use studies are designed to simulate actual OTC use of the product and help determine whether the consumers will use the drug safely and effectively. Depending on the product, human factors studies may also be required to demonstrate that the consumer can effectively interact with the product.
Are New Safety and Efficacy Studies Required for an Rx-to-OTC Switch?
Beyond the consumer studies described above, the need for safety and efficacy studies depends on whether any changes to the indication or patient population are proposed. If no changes are proposed, the safety and efficacy data established for the prescription product will often be sufficient for the OTC product. However, any changes to the indication or patient population will increase the likelihood that pivotal safety and efficacy studies will be required.
Challenges of an Rx-to-OTC Switch
While most drug products can demonstrate an adequate safety and efficacy profile to meet the FDA’s approval standards, proof that consumers can correctly diagnose and treat their medical condition with minimal professional supervision is often more difficult. There is a need to translate key elements of the prescription label into consumer-friendly terms.
The cholesterol-lowering statin drugs, Mevacor® (lovastatin, Merck) and Pravachol®(pravastatin, Bristol-Myers Squibb), both failed to obtain approval for an Rx-to-OTC switch due primarily to the FDA’s conclusion that patients’ perceptions of their disease and the monitoring necessary for successful disease management were not adequately understood and demonstrated. Well-designed and executed Actual Use Studies can be an important tool to help Sponsors address these issues.
Ideally, a product must be marketed for several years before an Rx-to-OTC switch can be considered. This allows for the accumulation of drug-specific safety data such as adverse events, data on patient interaction with the product, and any issues to be addressed identified from the prescription label and clinical use of the product.
To overcome some of the Rx-to-OTC challenges, in 2012 the FDA announced the Nonprescription Safe Use Regulatory Expansion Initiative (NSURE). The goal of NSURE is to develop a practical regulatory framework, within the existing two-class system of prescription and nonprescription drug classes, that ensures certain drugs will be safe and effective in the nonprescription setting. The NSURE concept aims to use innovative technologies to reduce the under-treatment of conditions that could be safely treated with prescription products if switched to OTC. These technologies could result in pre- or post-purchase education for consumers, or self-administration techniques to increase the likelihood of correct use.
Is New Exclusivity for an Rx-to-OTC Product Possible?
Exclusivity is possible for a 505(b)(2) product, including an Rx-to-OTC switch, depending on the studies that were conducted for approval. If a clinical efficacy or safety study is required for approval, the product is eligible for marketing exclusivity.
Rx-to-OTC switch is a data-driven, scientifically rigorous, and highly regulated process that requires expertise and experience to navigate. If you have questions regarding whether your product is appropriate for an Rx-to-OTC switch, or the most straightforward pathway to achieve the switch, please contact us.
Angela Drew, PhD
Product Ideation Consultant
Stomberg, Chris; Philipson, Tomas; Albaugh, Margaret; Sood, Neeraj (2013): Utilization effects of Rx-OTC switches and implications for future switches. In Health 05 (10), pp. 1667–1680. DOI: 10.4236/health.2013.510225.
Stomberg, Christopher; Albaugh, Margaret; Shiffman, Saul; Sood, Neeraj (2016): A cost-effectiveness analysis of over-the-counter statins. In Am J Manag Care 22 (5), e294-303.