Four Big Mistakes in Clinical Trials Adverse Event Reporting
Mar 12, 2015 (Posted on LinkedIn) by Dr. Vera M.Madzarevic
Every monitor of clinical trials faces the challenges to determine whether all adverse events were reported to the sponsor. Clinical Trials have two main endpoints, one is efficacy and the other safety, being both of them of equal importance from the regulatory standpoint. Unreported or underreported adverse events are a major problem during regulatory inspections. The monitor has the responsibility to capture any issue with reporting before the inspector does, and ensure compliance.
Adverse event (AE) is an absolute term in function to Good Clinical Practices, defined as “… any untoward medical occurrence in a patient or clinical investigation subject (when) administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment”. This is different from the definition of adverse drug reaction (ADR) that is “…all noxious and unintended responses to a medicinal product related to any dose (…)means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility…”
Having clarified the terms, all adverse events in clinical trials should be reported regardless of relationship and investigators (PI) have to be made aware that reporting is mandatory. Many times we are faced with investigators or sponsors opinions contrary to the requirement mainly because they “assume” and that becomes part of common mistakes in AE reporting.
Note that the analysis of the mistakes below are in function of GCP and do not entertain opinions that may be interpreted otherwise during an inspection.
Mistake #1 “It’s not an adverse event, it is a common progression of the disease”
Monitors may become oblivious of an AE in a clinical trial, because they are not even collected when considered by the investigator as a common progression of the disease.
I have heard this opinion hundreds of times, where investigators as well as sponsors “assume” that if it is disease related, it should not be reported. Many ethics committees also sides with that opinion to reduce the burden of reviewing all the reports. However, there is a good rationale for reporting all AE in a clinical trial regardless of the relationship.
- First, a clinical trial is an experiment that tries to demonstrate a hypothesis. Is not medical care.
- Second, if the clinical trial is blinded, regardless of the treatment groups, there is no possibility that the PI could make the assertion that is not reportable because is the common progression of the disease. What if the study treatment (drug/comparator) is responsible for further accelerating the common progression of the disease? What if that is an early indicator of lack of efficacy? we could never conclude that because the data is not available.
- Lastly, the challenge of “filtering “which AE are going to be reported, biases the safety analysis, downplaying the safety of the product, regardless of what originally could have been agreed with the regulator. Many protocols even establish which adverse events are not going to be collected.
Mistake #2 “It’s not a new AE, it’s the same AE but a bit more severe”
It is obvious that the safety profile of a study drug is going to look weaker if all AE that worsen in time are reported as a new adverse event. The worsening of the severity of an adverse makes it a NEW adverse event. It is very common that monitors overlook this fact, not requiring the PI to report the adverse event that by virtue of severity as a new one instead of the same old one that is ongoing.
Mistake #3 “Lab results are automatically categorized as normal and abnormal by the testing facility, therefore the investigator might not re-classify them further as AEs”
In most of the cases, monitors do not challenge a lab abnormality classification, as well as the investigator only review the lab results in function of the safety of the patient, but not classify abnormalities because considers that all was already electronically classified and submitted by the lab automatically. They might occasionally override an abnormal classification to allow patient eligibility in a clinical trial when the value is not significant.
Here we have several issues.
- First, that the monitor and the investigator may assume that all lab abnormalities have already been classified by the lab, therefore they do not include the clinically significant ones as AE in the report
- Second, that lab abnormalities are not all AE, and further classification as clinically significant and insignificant is to be performed by the PI
- Lab abnormalities are mostly an overridden value by the investigator in function of significance to ensure enrollment
Following are the responsibilities in reporting and verification:
- The investigator is responsible to assign significance to all lab abnormalities and report them in the Case Report Form.
- The monitor should review the lab report, and the classification made by the investigator ensuring that lab AEs are properly reported and classified.
- If lab AE are overridden by the PI, the monitor should investigate and document further to avoid non-compliance. If the lab abnormality meets exclusion, the monitor should procure patient withdrawal.
Lab results are the bulk of safety data, and proper review, classification and reporting should be ensured to avoid overlooking safety signals.
Mistake #4 – “The adverse event is not related to the study drug”
For an adverse event (AE) relationship to study treatment is not relevant in function of reporting by nature of its definition. Nevertheless, we encounter investigators and also sponsors classifying AE as not related to the study treatment without unbinding in function of pre-established rules in the protocol. That misinterpretation in the definition of AE reporting brings up the issue of how to ensure that all AE are reported.
All AE’s should be further classified in function of its relationship to study treatment once the codes are open (in the case of blinded studies) and proper consultation with the investigator and sponsor experts should be sought and documented.
In my opinion, AE drug causality can be assessed either as
- Certain or related, where, event or laboratory test abnormality, with plausible time relationship to drug intake, cannot be explained by disease or other drugs response to withdrawal plausible (pharmacologically, pathologically), event definitive pharmacologically or phenomenologically (i.e. an objective and specific medical disorder or a recognised pharmacological phenomenon), re-challenge satisfactory, if necessary
- Probably/likely, event or laboratory test abnormality, with reasonable time relationship to drug intake, unlikely to be attributed to disease or other drugs, response to withdrawal clinically reasonable, re-challenge not required
- Possibly related, event or laboratory test abnormality, with reasonable time relationship to drug intake, could also be explained by disease or other drugs, information on drug withdrawal may be lacking or unclear
- Unlikely, event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible), disease or other drugs provide plausible explanations.
If we review all the options carefully, the definitions never allow complete disambiguation that the drug in question might have not played a role in the AE. Therefore, we can have different opinions varying from high certainty to low certainty.The causality of AE classification is done in function of the medical opinion of the investigator and in concurrence with the sponsor through the study monitor. Nevertheless, may not be acceptable for the regulator.
The causality of AE classification is done in function of the medical opinion of the investigator and in concurrence with the sponsor through the study monitor. Nevertheless, may not be acceptable for the regulator.
It is very important for the monitor to verify documentation behind the investigators classification before they concur, especially when unlikely is the option. The reason behind it is to allow further reassessment when the clinical trial/study report is written and when submission of safety data is performed.
Also, it is very important to make sure that adverse events do not go unreported or underreported because of an inadequate causality assessment. That may be a red flag in an inspection.
it is very important to make sure that adverse events do not go unreported or underreported because of an inadequate causality assessment. That may be a red flag in an inspection.
Remember that from the legal standpoint, as far as there was study drug in the patient’s circulation during the event, a negative causality assessment would impact on the legal opinion that the drug might not have a role in the AE.
From the legal standpoint, as far as there was study drug in the patient’s circulation during the event, a negative causality assessment would impact on the legal opinion that the drug might not have a role in the AE.