13

Seriousness, Expectedness, and Causality

The drug safety staff involved in individual case evaluation generally have to make several decisions regarding each case. These decisions must be made rapidly on receipt of an individual case safety report because this determines how the case is handled in the drug safety department and whether, how, and when it is reported to health agencies and business partners.

The generally accepted definition of seriousness is as follows:

Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the previous definition. These should also usually be considered serious.

“Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or development of drug dependency or drug abuse” (ICH E2A).

The European Union also notes that any suspected transmission via a medicinal product of an infectious agent is also considered serious (Volume 9A, page 200).

Note that the FDA slightly altered the definition of “serious” effective March 2011 for clinical trials by adding the concept of “disability” directly into the definition, including the phrase: “substantial disruption of the ability to conduct normal life functions”.

Over the years, these definitions have been discussed, parsed, and clarified by health agencies, companies, and other interested observers. In general, the most conservative interpretation is the one drug safety groups should use. Some comments follow:

• Death: Although one would believe this binary concept (alive–dead) would be rather straightforward, there have been some discussions relating to the timing of the death and the circumstances around the AE and the death.
  
• It is fairly clear that if a patient has a myocardial infarction (the SAE) and then over the next several hours or days goes into shock, has severe arrhythmias, and dies, this death is related to the SAE and this is a “fatal myocardial infarction.” It gets trickier, however, if the patient has a myocardial infarction and during a cardiac catheterization goes into an intractable ventricular arrhythmia and dies. Is the myocardial infarction to be classified as a fatal one or is the death a sequelum of the catheterization? There is no clear answer, and it may vary from case to case. The most conservative call is often used by drug safety units; that is, the death is a part of (or consequence of) the SAE. However, if a medically defensible call is made that is less conservative, this should be noted somewhere in the case along with the reasoning behind this decision.

Another example would be that of a fall. If a patient trips while walking on a level surface, falls, and scrapes his or her knee, this is most probably a nonserious AE. If, however, he or she falls while standing on a ledge or walking down a staircase and dies as a result of the fall, the case should be reported as a serious and fatal case but how to classify it is tricky. The fall may be nonserious, but the sum of the case is clearly serious and fatal because of the fatality occurring after the fall, not the actual fall. Again, there is no clear answer; many would take the conservative approach and consider this case (if occurring during a clinical trial) as a serious, fatal, unlabeled fall (presuming “fatal fall” is not in the investigator brochure), and unrelated to the study drug (unless it is believed to be related, perhaps due to accompanying dizziness, which should also be coded). Others would argue that the AE was the fall and everything that happened after it was due to the circumstances of standing near the ledge. Had the fall occurred on the level surface none of the events leading to the death would have occurred.

• In a 1996 report on a survey done at the United States and European Union Drug Information Association meetings in 1993, Dr. Win Castle and Dr. George Phillips reported marked transatlantic differences in the interpretation of seriousness and expectedness. For example, “total blindness for 30 minutes” was believed to be serious by 89% in the European Union survey and 44% in the United States survey compared with “mild anaphylaxis,” which was believed to be serious by 37% of the European Union responders and 98% of the United States responders. Whether this is still the case remains to be seen, but the results nonetheless are most interesting and suggest the need for harmonization and training of safety reviewers (Castle, Phillips, Standardizing “expectedness” and “seriousness” for adverse experience case reporting. Drug Inform J 1996;30:73–81).
  
• Life-threatening: This concept also has interpretation issues revolving around whether the SAE would truly kill the patient if untreated. A mild myocardial infarction with no cardiac function compromise or arrhythmias might be considered serious (medically significant if not hospitalized) but not life-threatening, whereas a myocardial infarction that progresses over the next hour or two to pulmonary edema would be considered lifethreatening. This definition thus may overlap to a degree with “medically significant.” Again, most would take a conservative approach. Note that FDA changed the definition effective March 2011 to include the requirement that the idea of whether an AE is life-threatening should be commented upon by both the investigator and the sponsor and that if either one feels it is, then the AE should be so considered.
  
• Hospitalization: Much debate occurred over what actually constitutes “hospitalization” or “inpatient hospitalization.” Some patients may be kept overnight (even up to 24–36 hours) in the emergency department for observation and treatment but not “formally” admitted to the hospital as an inpatient. Thus, this patient would not qualify as serious based on a stay in the emergency room (see the Food and Drug Administration’s 2001 draft guidance on AE reporting, Section IV.A.3. Web Resource 13-1). In the European Union Directive 2001/83/EC and Volume 9A, refer to the definition of serious adverse reaction, including “inpatient” hospitalization.
  
• Significant or persistent disability/incapacity: A relatively uncommon criterion in practice. Not formally defined. The FDA gives an interesting example in its 2001 draft guidance:
  
  
  

  Persons incarcerated because of actions allegedly caused by a drug (e.g., psychotropic drugs and rage reactions) have sustained a substantial disruption in their ability to conduct normal life functions. Thus, these adverse experiences would qualify for the significant or persistent disability/incapacity outcome. Note the change referred to earlier in this chapter about FDA’s addition of this concept directly into the definition of “serious.”

  
  
• Congenital anomaly/birth defect: Usually rather straightforward. It would include even mild birth defects. The FDA also notes that this includes those defects “occurring in a fetus,” thus covering abnormalities discovered before birth.
  
• Important medical events (also called “significant medical events”): This criterion has often been difficult to handle for pharmacovigilance departments because the definition relies on medical judgment. The examples given (allergic bronchospasm, blood dyscrasias, or convulsions) do not necessarily help to clarify other less dramatic situations. The FDA also gives the examples of drug dependency or drug abuse as important events.

Often, cases elicit hours of debate in drug safety units on whether to consider them medically important. Is a mild focal seizure medically important? Is a platelet count 10% below the lower level of normal medically important? Other examples abound. Various rules of thumb have developed:

• If it happened to you or a family member, would you consider it important or medically significant?
  
• If you discuss or debate whether a case is medically important, it is.
  
• Another method involves using the FDA’s “always expedited” list (see Chapter 8) as published in “the Tome” (see Chapter 4) or the equivalent lists from other health authorities.
  
• If a member of the marketing or sales department or a nonmedical professional believes it is not important, it is important. (This “rule,” though somewhat jocular and cynical, has developed to note the real observation that sometimes there are nonmedical pressures put on personnel in the safety department to interpret cases or make decisions based on sales, financial, or other nonmedical criteria. This is an unfortunate fact of life—not just in the pharmaceutical world but in the world of clinical medicine, where many judgments are now made on a cost-effectiveness basis. Always keep in mind that the primary mission of the drug safety department is to protect the public health.)

The United States regulations governing expectedness are fairly straightforward:

In the European Union, expectedness is addressed in Directive 2001/20/EC, which simply notes that an unexpected reaction is one “the nature or severity of which is not consistent with the applicable product information (e.g. investigator’s brochure for an unauthorised investigational product or summary of product characteristics for an authorised product).”

In theory, this concept is rather straightforward, but in practice, it becomes somewhat harder when synonyms and overlapping concepts are considered. In the report cited previously by Castle and Phillips, 72% of the European Union responders believed that if the labeled event is “dizziness,” then “vertigo” would also be considered expected (labeled), but only 50% of the United States responders believed vertigo was labeled. Similarly, 18% of the European Union responders and 3% of the United States responders believed that if “hypotension, wheezing, and urticaria” are labeled, then a reported term of anaphylaxis would also be expected. Whether these differences persist, many years after the survey, is unclear. However, it does highlight the fact that well-trained experienced medical personnel doing pharmacovigilance can take the same set of facts and come up with differing and even opposing views.

In general, one should decide expectedness without thought to seriousness. That is, just because a case is nonserious and the AE in question is mildly severe and of little medical import (e.g., a maculopapular rash) compared with a serious AE (e.g., severe hepatitis), the decision on expectedness should be made purely on the basis of the wording in the label and not on the seriousness. Give each AE its due.

With clinical trial drugs, especially those not yet marketed, there may be minimal or no human experience (e.g., the first study in humans or the first phase II study after phase I studies that showed no AEs). In this case, there are no labeled events in the investigator brochure, and everything is thus “new” and unexpected. Anticipated events based on the pharmacologic properties of the drug should not be considered expected until actually reported in a patient and put into the brochure.

In some cases, it is necessary to consider the route of administration’s, dosage’s, or indication’s being studied when assessing the expectedness. This usually depends on how the investigator brochure or marketed labeling is written. Some describe a different set of AEs for different indications, dosages, or routes of administration. Care must be taken to apply the correct label to each case when doing expectedness.

The general advice would be, as with seriousness, to decide on the side of conservatism. Then, if there are questions on whether an AE is expected, consider it unexpected.

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