Cobert's Manual Of Drug Safety And Pharmacovigilance (Third Edition). William Gregory

agency indeed makes them into law or regulations. Thus, one must examine the PV requirements in each country or jurisdiction where one is working.

The Practice

      In practice, the laws and regulations often leave areas of ambiguity. No law or regulation is ever able to predict or account for every conceivable circumstance that may arise. Where feasible, a “guidance” or some other agency document is issued to clarify issues. However, it is a complex, time-consuming, and difficult bureaucratic process to create laws, guidances, and regulations, and there is always a time lag between the need for a clarification and the publication of such.

      For example, the definition of serious would seem fairly clear:

      Any adverse drug experience occurring at any dose that results in ... death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity or congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

      In fact, several areas are unclear, and there is a long series of dialogues, publications, and meetings to address such ambiguities:

      Is staying in a hospital emergency room overnight considered inpatient hospitalization (and thus a serious adverse event, SAE)? The consensus: No.

      Is a preplanned inpatient hospitalization that occurs after an adverse event (AE) but perhaps for a totally separate condition considered inpatient hospitalization (and thus a SAE)? The consensus: No.

      What is an “important medical event”? Is thrombocytopenia, if the count is 5,000 platelets per microliter? Yes. 50,000? Probably yes. 350,000 (where the normal is up to 400,000)? Probably no.

      What is “medically important” or “significant”? There is no clear consensus on this. It is left to individual reviewers’ and reporters’ judgments.

      Thus, in circumstances where there is no clear answer, the best approach is to take the most conservative course of action and “overcall”:

      If the question is between serious and non-serious, prefer serious.

      If the question is between reporting and not reporting a case to the health authority, prefer reporting.

      Calls to the agencies are possible to ask such questions, but it is not always possible to reach the right person to have a policy question answered. Most agencies discourage this practice as it would be burdensome to them. If one does succeed in getting an opinion from an agency on a tricky issue, try to get a written confirmation. If that is not possible, write detailed minutes of the telephone call and file them with the case. For cases submitted to multiple health authorities around the world, it is not practical to call each authority to get an answer, and it is possible the answers would be contradictory. Again, the best course of action is the most conservative and, thus, defensible course.

Over-the-Counter Drugs

      Reporting requirements vary from country to country.

United States

      In the United States, an over-the-counter (OTC) product is sold based on whether it got to market via (1) an approved New Drug Application (NDA) (Rx to OTC switch) or an Abbreviated New Drug Application (ANDA), or (2) the OTC drug monograph process. The Time and Extent Application (TEA) is another method to get a product onto the market via the monograph process, but this is rarely used.

      The safety obligations depend on which method is used to get the product to market. If an OTC product has an approved NDA, the requirements are the same as for a prescription product (expedited reports, periodic reports, etc.). For monograph products, the situation is different. Until 2007, there were no obligatory safety reporting requirements, though many manufacturers voluntarily reported SAEs to the FDA.

      The regulations and guidances changed when FDA put forth the following:

      Dietary Supplement and Nonprescription Drug Consumer Protection Act, December 2006 https://www.congress.gov/109/plaws/publ462/PLAW-109publ462.pdf and

      Guidance for Industry Postmarketing Adverse Event Reporting for Nonprescription Human Drug Products Marketed Without an Approved Application, July 2009 https://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/DietarySupplements/ucm171383.htm

      These documents changed the reporting requirements for the monograph products:

      A manufacturer, packer, or distributor whose name is on the label (called the “responsible person”) must submit to FDA all SAEs with a copy of the label within 15 business days.

      All follow-up information received within 1 year of the initial report must be submitted within 15 business days.

      The requirements say 1 year, but FDA wants no time limit. That is, report all follow-ups forever.

      Use E2B (MedWatch forms are not accepted from manufacturers, but can be used by consumers and the healthcare community).

      Use NDA definitions for minimum criteria, reportability, and so forth.

      For brand families need to know the active ingredient to have a reportable drug.

      If multiple suspect drugs, submit Individual Case Safety Report (ICSR) to FDA and to other manufacturers.

      No aggregate reporting requirements, but FDA has occasionally requested ad hoc compilations or reports to address safety concerns.

      Reporting requirements for NDA/ANDA products were unchanged as a result of the changed OTC requirements.

European Union

      In the EU, all marketed drugs (OTC or Rx) have a Marketing Authorization