Introduction: OTC Drugs
Drugs can be divided into two categories: 1) Prescription (Rx) drugs, which require a physician's or other authorized healthcare provider's prescription to obtain; and 2) over-the-counter (OTC) drugs, which can be purchased without a prescription. While Rx and OTC drugs must both be shown to be safe and effective, OTC differ from Rx drugs in several important ways.
For example, prescription drugs must be approved under section 505 of the Federal Food, Drug, and Cosmetic Act; or Licensed under the licensed under section 351 of the Public Health Services Act, before being introduced into interstate commerce in the U.S. In contrast, OTC drugs (in many cases) need not be approved or licensed. Rather, most OTC drugs come to market through the OTC monograph pathway—although some intended OTC medications that do not fit within the OTC monograph framework come to market through new drug applications (NDAs). These OTC drugs are referred to as Rx-to-OTC switches. OTC drugs which adhere to monograph requirements are generally recognized as safe and effective (GRASE) by the U.S. Food and Drug Administration (FDA).
OTC drugs are limited to medical diseases and conditions for which consumers can self-diagnose, and this has limited the types of drugs that can become OTC drugs. Earlier, we wrote about the FDA issuing a guidance that expands the range of drugs that can become OTC drugs when drug facts labeling (DFL), by itself, is not sufficient to ensure the drug can be used safely and effectively in a non-prescription setting. Digital health technology can bridge the gap when DFL is insufficient.
For example, prior to purchase, a consumer could be instructed to respond to a set of questions on a self-selection test in a mobile application. The outcome of the self-selection test may affirmatively indicate if the consumer is an appropriate candidate to use the OTC drug. Alternatively, prior to purchase, the consumer could be required to view and affirm a video that describes when and how to appropriately use the OTC drug.
The list of Rx drugs that could eventually become OTC drugs is important, and includes cholesterol-lowering medications (e.g., statins), high blood pressure drugs (e.g., ACE inhibitors), asthma drugs (e.g., bronchodilators; inhaled corticosteroids), and antimigraine drugs (e.g., triptans).
The CARES Act, OTC Drugs, and COVID-19
Recently, the Coronavirus Aid, Relief and Economic Security (CARES) Act, was signed into law. As SARS-CoV-2, the causative agent of COVID-19, infections increase, OTC drugs continue to play a limited but important role in helping infected patients treat symptoms of the disease. The CARES Act contains several important provisions relating to OTC drugs, and recently the FDA issued a statement that calls the CARES Act OTC provisions "a landmark step that will have an impact lasting long after the current public health emergency." The statement recites, in part, that:
The law grants the FDA transformative, new authorities that will meaningfully advance our efforts to modernize the OTC drug development and review process to help advance innovative, safe and effective options for consumers and secure a robust OTC marketplace. The FDA is committed to using these new tools to promote innovation and improve the safety and effectiveness of OTC monograph drugs—including products like hand sanitizers and acetaminophen, which are so critical to the public health emergency we face right now. (Emphasis added.)
Here are some of the transformative provisions:
18 Months of New OTC Drug Exclusivity
As described earlier, the FDA is attempting to enlarge the scope of OTC drugs—for example using digital health technologies when DFL alone is not sufficient. The CARES Act furthers that goal by providing 18 months of marketing exclusivity for a first, new active OTC ingredient, or when clinical studies result in an administrative order—based on an essential clinical study—providing for changes in use conditions. In essence, the CARES Act creates yet another new form of market exclusivity—18 months OTC new drug exclusivity.
A final administrative order issued in response to a request under this section shall have the effect of authorizing solely the order requestor (or the licensees, assignees, or successors in interest of such requestor with respect to the subject of such order), for a period of 18 months following the effective date of such final order and beginning on the date the requestor may lawfully market such drugs pursuant to the order, to market drugs … (Emphasis added.)
The CARES Act recites that, in general, only one 18-month period under this subparagraph shall be granted …" (Emphasis added.); "for a drug to contain an active ingredient (including any ester or salt of the active ingredient) not previously incorporated in a drug described in clause (iii)" ; or "provides for a change in the conditions of use of a drug, for which new human data studies conducted or sponsored by the requestor (or for which the requestor has an exclusive right of reference) were essential to the issuance of such order." (Emphasis added.)
Fees and Ability to Request Monograph Changes
Section 3862 of the CARES Act establishes two types of fees associated with OTC drugs. The first fee type is a facilities fee:
Each person that owns a facility identified as an OTC monograph drug facility on December 31 of the fiscal year or at any time during the preceding 12-month period shall be assessed an annual fee for each such facility … (Emphasis added.)
The second type of newly established fee, which is potentially more interesting to OTC drug sponsors wishing to make label changes, is an OTC Monograph Order Request Fee:
Each person that submits an OTC monograph order request shall be subject to a fee for an OTC monograph order request. The amount of such fee shall be—(i) for a Tier 1 OTC monograph order request, $500,000, adjusted for inflation for the fiscal year … ; and (ii) for a Tier 2 OTC monograph order request, $100,000, adjusted for inflation for the fiscal year … The OTC monograph order request fees required under subparagraph (A) shall be due on the date of submission of the OTC monograph order request.
These fees, which are to be used to fund FDA monograph oversite and approval, give some idea about what monograph changes can be requested under the Section 3862 CARES Act. For example, a Tier 2 OTC monograph order request is an order request for:
- the reordering of existing information in the drug facts label of an OTC monograph drug;
- the addition of information to the other information section of the drug facts label of an OTC monograph drug . . . (with limitations);
- modification to the directions for use section of the drug facts label of an OTC monograph drug, if such changes conform to changes made pursuant to section 505G(c)(3)(A);
- the standardization of the concentration or dose of a specific finalized ingredient within a particular finalized monograph; and
- a change to ingredient nomenclature to align with nomenclature of a standards-set ting organization; or
- addition of an interchangeable term in accordance with section 330.1 of title 21 Code of Federal Regulations (or any successor regulations). (Emphasis added.)
And a Tier 1 OTC monograph request order is anything that is not Tier 2.
Misbranding
The CARES Act also establishes that failure to comply with a final monograph results in an OTC drug being misbranded.
A drug that the Secretary has determined not to be generally recognized as safe and effective … under a final determination issued under part 330 of title 21, Code of Federal Regulations, shall be deemed to be a new drug under section 201(p), misbranded under section 502(ee), and subject to the requirement for an approved new drug application under section 505. (Emphasis added.)
GRASE Drugs Can Be Relied upon as Part of a 505(b)(2) Drug Application
The CARES Act recites in part that:
A determination under this section that a drug is not subject to section 503(b)(1), is generally recognized as safe and effective under section 201(p)(1), and is not a new drug under section 201(p) shall constitute a finding that the drug is safe and effective that may be relied upon for purposes of an application under section 505(b)(2), so that the applicant shall be required to submit for purposes of such application only information needed to support any modification of the drug that is not covered by such determination under this section. (Emphasis added.)
A finding that an OTC drug is GRASE can be relied upon in a drug repurposing application.
Conclusion
The CARES Act, among other things, provides further incentives to develop OTC drugs, provides fee driven mechanisms to request OTC drug label changes, creates drug repurposing support, and clarifies when an OTC drug is misbranded.
Charles Andres contributed to the preparation of this Wilson Sonsini alert.
