Seriousness, Expectedness and Investigator Brochures

Nov 05, 2014
Bart Cobert

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert

Serious Adverse Events, SAEs, IBs

There is some confusion that I have observed in how Serious Adverse Events (SAEs), Adverse Events (AEs) and expectedness are handled in Investigator Brochures (IBs).

First a quick review of the concept of the IB. The basic requirements are described in ICH E6 which is used in most countries now. FDA issued this as a guidance in 1996. The key points regarding IB safety and AEs are:

  • The IB is a compilation of the clinical and nonclinical data on the investigational product that are relevant to the study of the product in human subjects. Its purpose is to provide the investigators and others involved in the trial with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods of administration, and safety monitoring procedures.
  • The IB should provide a description of the possible risks and adverse drug reactions to be anticipated on the basis of prior experiences with the product under investigation and with related products.
  • There should be a table in Appendix 2 of the safety and efficacy.

AEs and SAEs in the IB

That’s basically it. There is a lot of leeway left to the writer of the IB in terms of what is to be put in regarding safety. Clearly there will be no human AEs/SAEs in the IB that is made for the first in humans study. As experience is gained more and more AEs/SAEs will be noted in the clinical trials and need to be included in the IB.

Sometimes the trials are blinded and until the blinds are broken, it will not be possible to say which AEs/SAEs occurred in the subjects receiving study drug and which occurred in the subjects on comparator or placebo.

Later on, as SUSARs are submitted and blinds broken, some SAEs that were associated with the drug will become known and these should be added to the IB.

As more and more safety data is obtained, the picture becomes more and more detailed and a safety profile begins to develop. So it is clear the IB will need to be updated periodically. The usual rule of thumb is yearly but if important information becomes known in shorter time periods, the IB should be so updated. Any data that the investigator should know to better manage the patient and perform the study should be added as rapidly as feasible.

So what one sees in IBs in the safety and efficacy section can be tables or narratives of:

  • All SAEs seen in blinded clinical trials
  • All SAEs seen in clinical trials with study drug vs comparator / placebo
  • Frequency of SAEs seen with study drug (with or without comparisons to comparator / placebo
  • SAEs by frequency seen with study drug in patients with xxxx disease/indication
  • “Treatment emergent SAEs”
  • “Anticipated SAEs” (This is not advised as “anticipated” is not clear. It could be anticipated due to the drug or due to the disease or comedications etc.)
  • Where appropriate, deaths

In the “Guidance to Investigator” section of the IB at the end, one may see something like: “Treatment-Emergent Adverse Events Reported in 3% or More of the Subjects With in Any Treatment Group in Clinical Trials”.

As noted, lots of choices on what to present and how to present it.

In almost all cases Preferred Terms from MedDRA are used in the tables.


There are, in effect, two types of expectedness here.

The first is “regulatory expectedness”. This refers to the SAEs that the company considers likely/possibly or probably related to the study drug. This list is used to determine whether an SAE is a SUSAR (Suspected, unexpected serious adverse reaction) and thus expeditable to FDA, EMA and other health agencies.

The second we can call “clinical expectedness” which is a listing of SAEs that the investigator and patient may encounter during the trial and should be aware of. They may be due to the drug, the disease, comedications, concomitant illnesses (e.g. the flu) or other causes. These may or may not be the same as the “regulatory expectedness” list of SAEs but are important for the treating physician to be aware of and look for. It may not be possible yet to determine whether the particular SAE is due to the drug or the disease or comedications etc. This may become clearer later in the drug’s lifespan as more data becomes available; but sometimes it does not ever become clear.

Thus an SAE may be on one or both of these lists.

There has been a lot of confusion in this area. Some companies consider (and even write in the IB) that the listing of SAEs are considered to be due to the drug and are used for regulatory reporting. Since the regulations on expedited reporting vary in some regions or countries (e.g. in the US, the sponsor may override the investigator’s causality assessment but in the EU this is not allowed), it would not be judicious to get into the regulatory reporting issues in the IB as the list may vary from country to country. Since the investigator really is not involved in the company’s sending expedited reports, it is not really necessary for the investigator to know if an SAE is on the “regulatory expectedness” list.

Some companies will add every expedited SUSAR submitted to FDA, EU etc. to the IB as an expected event. They will write to all investigators and the health agencies saying, please insert the attached MedWatch/CIOMS I form into the brochure in the safety section as this SAE is now considered expected with the drug.

This is not a good policy and some companies have had their IBs rejected or criticized by the health agencies saying that the criteria for moving an SAE from unexpected (and thus an expedited report) to expected (now reportable only in the annual DSUR) should be “robust”. That is, the agencies expect each newly determined “expected” SAE to have been reviewed by one or more MDs and there usually should be more than one ICSR to become expected. That is, just declaring all expedited SUSARs to be expected is not a good policy without careful physician review to ensure the case or cases are “robust”.

Sometimes single SAEs can be clearly due to the drug (e.g. a tablet lodging in the oral pharynx causing choking or some SAEs that are almost always due to drugs such as Stevens Johnson); but most single cases would not qualify to be called expected without further evidence.

So the bottom line here is that the “regulatory expectedness with the study drug list” should be limited only to those SAEs that have clear, defensible and “robust” evidence to move from the unexpected to expected list. Health agencies are more comfortable with this as they will see the new cases within 15 days of occurrence and not in the annual DSUR.

Another point to keep in mind is that once an SAE gets onto the expected list, it is highly likely that this SAE will ultimately appear in the final approved package insert/SmPC.

In conclusion, preparing the expectedness list is a tricky area. For older drugs with a more fully developed safety profile, it may be possible to clearly indicate with SAEs (and perhaps AEs) now have a reasonably strong causality assigned to the drug and can be considered expected. For equivocal cases, the SAE should remain unexpected.



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