The reporting of adverse events (AEs) and serious adverse events (SAEs) is not widely understood in the US because there are different requirements for different products depending upon how they became over-the-counter (OTC) products.
A brief review of how a drug can get onto the market as an OTC in the US is in order.
Firstly, what is an OTC? It is a product that is marketed in the US without a prescription and, importantly, without medical intervention. Thus the patient makes the diagnosis and decides on the treatment him or herself with no pharmacist, nurse, NP, PA or physician involved. Actually, some products are so-called “behind the counter” products whereby one must ask the pharmacist (or at least the person behind the counter in the pharmacy – who may be a non-medical technician) for the product. So, in theory at least, there is some medical intervention. To be an OTC product means the drug should have a clearly positive benefit-risk profile and a wide therapeutic index (that is, the lowest toxic dose should be well above the therapeutic dose. Then the risk of safety problems is low – particularly if too much is taken by the patient).
Drugs can be marketed OTC via two main routes. The first is the “monograph” route which is the most common route to market. An OTC drug monograph (CFR Title 21 sections 300 and beyond) describes what kind of ingredients may be used in the product along with the appropriate dose and instructions for use. There are some 80 categories of monograph drugs. If the manufacturer strictly follows the monograph for the product, the drug may be marketed without FDA review or approval. The FDA actually calls the OTC drug monographs a kind of “recipe book” covering acceptable ingredients, doses, formulations, and labeling. These are drugs that are “generally recognized as safe and effective (GRAS/E)”. See https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/Over-the-CounterDrugs/default.htm for more information on this.
The second major route is the so-called “Rx to OTC Switch”. This is a smaller number of products which originally required a prescription and for which the sponsor submitted an application to the FDA to have the drug sold OTC. Usually it involves doing one or more clinical trials sometimes at a lower dose than the prescription dose. Sometimes the indications for the OTC are different from the prescription product’s approved indications. Examples include antihistamines, PPI and H2 blocker acid reducers, laxatives, topicals, vaginal antifungals and others. When these drugs are approved they still have open NDAs/ANDAs and thus must still submit adverse events and do all necessary safety reporting as before unless special arrangements or waivers are agreed upon by the FDA.
So now the question becomes what are the safety requirements for reporting SAEs and AEs. As noted above, the Rx-to-OTC switch products generally have to follow the usual NDA/ANDA rules. The monograph products have a totally different set of rules.
In fact, up until 2007 reporting AEs/SAEs on monograph products was not required though FDA encouraged reporting of SAEs. Some manufacturers did so voluntarily but many, perhaps most, did not. In 2006, Congress amended the law to require safety reporting for OTC products without NDAs/ANDAs starting in 2007. In 2009 FDA issued a guidance covering this. See www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM171672.pdf
The law and guidance require:
- The manufacturer, packer or distributor must now report SAEs. The submitter is referred to as the “responsible person”. The retailer who functions as the distributor may authorize the manufacturer or packer to handle this reporting.
- The responsible person must submit to FDA all SAEs when the product is used in the US. Note that this does not require a determination of causality or expectedness (labeledness).
- All follow-up reports of new information received within one year of the initial report must also be submitted to FDA. FDA recommends that all follow up be submitted even if received after one year though the law only specifies for one year.
- The timeframe for such submissions is 15 business days. Note that, also unlike NDA drugs, this is 15 business days not 15 calendar days.
- For each initial (but not follow up) submission, a copy of the label which is “the full outer carton/container label and immediate container label (including the Drug Facts panel and the principal display panel) that are the same as the label on the drug product used, or most likely used, by the patient.” The most current label should be sent.
- The submission should be on an FDA MedWatch Form 3500A or the electronic equivalent.
- Reasonable attempts must be made to obtain follow up. “FDA encourages responsible persons to use trained health care practitioners to query reporters, computer-assisted interview technology, targeted questionnaires, and/or other methods developed to target specific events that help focus the line of questioning.”
- If the reporter is a consumer or patient, the responsible person should attempt to contact the heath care provider who is familiar with the event (if there is one).
- The usual four elements (patient, reporter, drug, SAE) must be present for a valid report. Efforts should be made to get this information and they should be documented. When all four elements are present, the regulatory clock starts.
- In terms of drug identification, which may be hard for “families” of drugs where the same brand name is used, the specific name or formulation is needed for a valid report. If multiple drugs are involved all of which are manufactured by the same “responsible person” only one case should be submitted using the most suspect drug as defined by the reporter. If that is not defined, then use the drug product that is first alphabetically. If the drugs are from different manufacturers, the initial receiver should submit the case to FDA with a copy to the other manufacturer(s) who should also report the case and cross reference each other.
- Case records must be made and retained for at least 6 years.
- If the case actually belongs to another manufacturer, then the initial receiver should forward the case to that other manufacturer (this is not obligatory but FDA does recommend).
- New information should be incorporated into the narrative “to present an accurate and comprehensive, but concisely written, description of the event as it is understood at the time of the follow up report.”
- New or corrected information should be highlighted with an asterisk or underlining or other method to draw attention.
- Source or supporting documents (e.g. hospital discharge summaries, lab results) should be submitted.
- A manufacturer’s identification number should be created for the initial report and used on subsequent follow up submissions without change.
- Details on filling out the MedWatch form are included and the reader should refer to the guidance.
- Electronic submissions are possible and information can be obtained from the FDA website for this. Note that requirements often change and the website should be referred to. See: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/UCM085361#Postmarketing
No aggregate reporting is required in the US.
Outside the US the rules vary. In general, some regions, such as the EU, do not make distinctions between prescription drugs and OTC products as all these products have approved marketing authorizations and thus the safety reporting is the same whether OTC or not. Check with each country or region.
Bottom line: Initial and follow up SAEs on monograph OTC products have to be reported to FDA within 15 business days of receipt of a valid report. Since SAEs are not really expected for such “benign” drugs, each SAE should be scrutinized by the responsible person. Presumably, FDA will do the same.
