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Postmarketing Spontaneous ICSR/SAE Reporting

Postmarketing spontaneous reporting of Individual Case Safety Reports (ICSRs) is the mainstay of drug safety at this time.

The requirements for reporting revolve around ICSRs of various subsets of serious adverse events (SAEs) and then the periodic aggregate reporting of the remaining cases (and some SAEs already reported) with some degree of medical analysis. This system, on its face, is quite extraordinary as it relies on the good will and beneficence of

• healthcare professionals, to voluntarily report bad reactions to drugs that they have prescribed or administered, and who are not compensated for their efforts
  
• patients and consumers

This situation is likely to change over the years for many reasons, including cost and better technology. But for now, this is the system that we use to elucidate the safety profile of marketed drugs.

The regulations governing postmarketing reporting are complex, scattered, and only partially harmonized. Various updates and guidances are published irregularly, often changing the rules significantly. There is no single source tracking all changes, and the changes are often but not always published in English. (Why countries with their own national languages should publish their internal rules in English is another discussion entirely.)

Although postmarketing New Drug Application (NDA) or Marketing Authorization (MA) reporting of SAE reports are conceptually quite similar to premarketing clinical investigation (IND) SAE reports, there are significant differences. The sources and reporters of the events are varied (not just from clinical trial investigators). The handling and reporting to health agencies are also somewhat different. These are explained later.

As with clinical trial reporting, there is an obligation for safety reporting after approval of the NDA or MA. Postmarketing reporting is usually obligatory after approval whether or not the drug is actually marketed (some companies delay marketing for operational or seasonal reasons). In clinical trials, AEs are reported by investigators who are health professionals and usually have a relationship with the company (e.g., sponsored trials). Thus, cooperation and complete medical reports from a healthcare professional are usually ensured. Under governmental regulations, reporting is obligatory for the investigator and the sponsor.

The postmarketing period, however, is quite different. Reports may come from many sources, including patients, families of patients, healthcare professionals, sales representatives, literature reports, news reports, health authorities, the internet, blogs, social media, poison control centers, other pharmaceutical companies, lawyers, and more. Reporting is purely voluntary for everyone except pharmaceutical companies and rests on the goodwill of the reporters. However, sometimes patients that report the AE are upset that the AE happened at all. They may assume that drugs are safe and this AE should not have happened. At least in the United States, they often want their money back and, in fact, may have called the company not to report the AE but rather to get a refund.

Healthcare professionals often contact the health agency or the pharmaceutical company to report an AE and are not quite aware that the company, obliged to follow up and report the case to the authorities, will do extensive follow-up and request copies of reports from the physician’s office, the hospital, the laboratory, and even the ambulance service. Busy pharmacists, nurses, or physicians often do not realize what they are getting into when they simply called to do their duty by making a “quick” report of an AE. They did not want to get burdened down with pulling records from perhaps multiple sources and sending them to the company.

Report quality is also an issue compared with clinical trial reports, as the quality of the postmarketing reports is quite variable, especially when reported by nonmedical people. Consumer reports should have follow-up attempted with the treating physician where possible. The problem is more difficult if the patient used an over-the-counter (OTC) product and self-prescribed; there may be no physician or pharmacist involved at all.

The four elements or criteria for a valid 15-day safety report (sometimes called the minimal data set for reportability) are

1. An identifiable patient
   
2. An identifiable reporter
   
3. A suspect drug(s)
   
4. An AE (or fatal outcome if no AE is reported other than “found dead”)

If these four elements are present, then the case is considered reportable to the U.S. Food and Drug Administration (FDA). If they are not, the company should make due diligent efforts to obtain the missing data. The data should be stored in an electronic database.

An identifiable patient usually means one or more identifiers are present: age, sex, initials, name, and so on. Vague reports such as “I heard there was a patient or two upstate who took drug X and had a stroke” or “a few people had strokes” are not specific enough to meet the criteria for identifiable patient. “A man” or “a young girl” or “six men had strokes” are sufficient to be considered identifiable.

An identifiable reporter is usually clearer. It may be the patient or a family member. As a rule of thumb, an identifiable reporter should be one who can be contacted. Thus, an e-mail AE report where there is no information on the sender other than the e-mail address would be a valid reporter because one can respond to the e-mail and get follow-up.

The suspect drug is also usually not a problem. However, issues do occur:

• Occasionally, someone will send in an AE report and make the comment, “I don’t think this is due to your drug but thought I should report it anyway, just in case.” This should still be considered the suspect drug (unless another one is noted) and the reporter’s comment noted in the narrative.
  
• If it is clear that the drug is the product of another company (e.g., same chemical entity but different manufacturer, whether branded or generic), the case should be sent within 5 days to that manufacturer or company if it is located in the United States; elsewhere rules vary, but in general, the case should go to the manufacturer/MA holder. If, however, it is unclear whether it is the company’s product or another manufacturer’s product, then the company must process it as if it were clearly its own product. The lack of clear “ownership” and product identification should be noted in the report.
  
• Different formulations of the same active moiety must be entered into the database and reported, if appropriate, unless the product is clearly found to be from another company. Thus, a topical version of a company’s product made by another company (but unclear which one) needs to be reported.
  
• Combination products that contain the active moiety should also be reported.

The identifiable AE is also usually clear and relates to any “bad thing.” The AE could include signs, laboratory abnormalities, symptoms, or diseases. More general terms like “experienced unspecified injury” or “irreparable damages” should be excluded. Fatal outcome with no AE should be considered reportable (“found dead in bed”). This is the only instance in which an outcome is considered an AE. Death is an outcome and not an AE unless there is no other AE reported.

One should also be sure to distinguish medication errors and product quality issues. Sometimes two or more things may occur in the same report (“The tablet was blue instead of green and smelled funny; I took two instead of one and then had a bad headache. And I want my money back and I have a question.”). The product quality, medication error, AE, question, and refund issues should each be handled by the appropriate personnel in the company.

In most countries, the company (“applicant,” “sponsor,” or MAH) must report each AE that is serious and unexpected (not in the approved labeling = Package Insert for the United States, the SmPC for the European Union, the product monograph in other countries, etc.), whether domestic or abroad, within 15 calendar days of initial receipt of the information. Note that this is different from the criteria used for clinical trial reporting, which, in most countries, requires three criteria (serious, unexpected, possibly related to the drug). Postmarketing reporting only requires two (serious, unexpected) because it is believed that spontaneous reports have “implied” causality or suspicion. The reporter would not have contacted the health agency or the company to report the case if he or she did not believe there was some level of causal relationship between the drug and the AE.

The company must promptly investigate all serious AEs that produced 15-day alert reports and must submit follow-up reports within 15 calendar days of receipt of new information or as requested by the health agency. If additional information is not obtainable, records of the unsuccessful steps taken to seek additional information should be maintained.

The company selling or making the drug is not the only one obliged to report serious AEs. This requirement also applies to any person or entity whose name appears on the label of an approved drug product as a manufacturer, packer, or distributor. By extension, this applies also to any agent, comarketer, and distributor, that is, anyone or any company or entity that may receive an AE and with which the company has a relationship.

Solicited safety information (e.g., from patient outreach or support programs) should be handled as if this were a postmarketing trial and the three clinical trial reporting criteria are applied: serious, unexpected, and a reasonable possibility that the SAE is related to the drug. That is, the criteria are not those of the postmarketing situation (serious, unexpected) but of the clinical trial situation. There are no 7-day reports in the postmarketing setting.

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