Drug-related AEs, AE Causality, AE relationship, and SUSAR

In pre-marketing clinical trials or post-marketing drug uses, adverse events (AEs) can always occur. When AEs are reported, assessments need to be made to judge if the reported AEs are caused by the study drug or study treatment. There are different terms to describe this assessment: drug-related, causality, relationship to the study drug, attributable to the study drug,...

In clinical trials, the causality assessment is made by the investigators. In post-marketing experience (surveillance or spontaneous reporting), all reported AEs are considered as related to the drug - so-called 'adverse drug reaction'. 

In an early post, I discussed "Causality Assessment, Causality Categories for Reporting Adverse Events or Adverse Reactions" and summarized various ways to categorize the AE causality: 

ICH E2B	Not Related, Unlikely Related, Possibly Related, Related)
CDISC	Not Related, Unlikely Related, Possibly Related, Related).
WHO	Certain, Probable/Likely, Possible, Unlikely, Conditional/Unclassified
Other options	None, Unlikely, Possible, Probable, Not assessable

In a recently published CDISC CDASH eCRF form for AEs, the causality is simply assessed as Yes, No.  

For statistical analyses of the AE data, drug-related AEs will usually be summarized and analyzed. Drug-related AEs are usually defined as the AEs with causality assessment at least probably related to the investigational study drug (including the placebo). For example, using ICH2B or CDISC criteria, AEs with causality assessment of 'possibly related', 'related', will be considered as 'drug-related. If CDISC CDASH eCRF is followed, the drug-related AEs will be those with 'Yes' answer to the 'Relationship to Study Treatment' question. Some of my European colleagues once argued that the 'unlikely' category should also be considered as 'drug-related - but I never found any regulatory guidance to support this.  

It is difficult to compare drug-related AEs across different studies that are conducted by different sponsors because the number of causality categories may be different in different studies. The number of categories can be anywhere between 2 (yes/no) to 5 categories. 

In some studies, additional causality assessments may be performed to judge if the AEs are related to the background therapies (especially in studies with add-on design) or related to the medical device (such as inhalation device and infusion pumps). The same AE could be assessed to be related to the study treatment, background therapy, and/or the medical device. 

For the past year, we have seen plenty of headlines about the AE causality assessment in actions in Covid-19 vaccine studies and in gene therapy studies. AE causality can be assessed on an individual case (the unexpected event in AZ's and J&J's Covid-19 vaccine trials) or on an aggregate level (in the case of blood clots by AZ's Covid-19 vaccine). 

Causality assessment based on the individual case:

• AstraZeneca resumes Covid-19 vaccine trials in the U.K. - suspected event of transverse myelitis was assessed not caused by the Covid-19 vaccine
• Johnson & Johnson Prepares to Resume Phase 3 ENSEMBLE Trial of its Janssen COVID-19 Vaccine Candidate in the U.S.

"After a thorough evaluation of a serious medical event experienced by one study participant, no clear cause has been identified. There are many possible factors that could have caused the event. Based on the information gathered to date and the input of independent experts, the Company has found no evidence that the vaccine candidate caused the event."

Causality assessment on an aggregate level: 

•  Covid-19:AstraZeneca vaccine is not linked to increased risk of blood clots, finds European Medicine Agency
• Update on the safety of COVID-19 Vaccine AstraZeneca

"A careful review of all available safety data of more than 17 million people vaccinated in the European Union (EU) and UK with COVID-19 Vaccine AstraZeneca has shown no evidence of an increased risk of pulmonary embolism, deep vein thrombosis (DVT) or thrombocytopenia, in any defined age group, gender, batch or in any particular country.

So far across the EU and UK, there have been 15 events of DVT and 22 events of pulmonary embolism reported among those given the vaccine, based on the number of cases the Company has received as of 8 March. This is much lower than would be expected to occur naturally in a general population of this size and is similar across other licensed COVID-19 vaccines. The monthly safety report will be made public on the European Medicines Agency website in the following week, in line with exceptional transparency measures for COVID-19.

One type of AEs requires special attention and needs to be reported to the regulatory agencies and local IRB/ECs expeditiously. It is called Suspected Unexpected Serious Adverse Reaction (SUSAR). According to FDA guidance Safety Reporting Requirements for INDs and BA/BE Studies, SUSARs are those AEs meeting the following criteria: 

• Serious (S)
• Unexpected (U)
• Suspected Adverse Reactions (SAR)

Fatal or life-threatening SUSAR should be reported to FDA no later than 7 days; Others SUSAR should be reported to FDA no later than 15 days.

We saw the news that Bluebird Bio temporarily suspended their gene therapy clinical trials due to a reported SUSAR of acute myeloid leukemia (AML).

bluebird bio Announces Temporary Suspension on Phase 1/2 and Phase 3 Studies of Lenti Globin Gene Therapy for Sickle Cell Disease (bb1111)

Bluebird bio did their assessment and ruled that Gene Therapy for Sickle Cell Not Linked to Cancer (AML event)

"The company released a statement yesterday (March 10) claiming an investigation has found “it is very unlikely” the AML is related to the therapy and the firm is seeking approval from the US Food and Drug Administration (FDA) to resume the trials.

“VAMP4 has no known association with the development of AML nor with processes such as cellular proliferation or genome stability,” Bluebird’s Chief Scientific Officer Philip Gregory says in the press release. Furthermore, the patient’s cells had mutations in other genes, which are related to leukemia."

Some additional comments on AE causality assessment:

• AEs that occurred prior to the first dose of study treatment (i.e., non-treatment-emergent AEs) should always have the causality 'unrelated' to the study treatment - an edit check should be in place to prevent the investigators to enter a non-TEAE as drug-related. 
• In blinded studies, if a SUSAR event is reported, the individual patient's treatment assignment should be unblinded so that the sponsor can assess the causality and report the SUSAR event appropriately. 
• While drug-related AEs are typically summarized, analyzed, and included in the clinical study report, FDA reviewers will focus their review on all AEs and all SAEs regardless of the causality. Drug-related AEs are usually not included in the drug-label. Instead, the drug label will list the most frequent AEs (whether or not they are drug-related).  
• Sometimes, causality assessment by the investigator may be subjective and arbitrary to some degree. Important events (such as SUSAR and AESI (AE of special interest)) may be further reviewed by the sponsor, data monitoring committee, clinical event adjudication committee, and regulatory agencies. For example, some oncology drugs may induce pneumonitis/interstitial lung disease and these events of pneumonitis/interstitial lung disease can be reviewed and adjudicated by a committee. 
• Statistical summary and analysis of AE causality are always based on the assessment by the investigator that is recorded in the clinical database. Causality assessment by the sponsor and other parties is not part of the clinical database and will be analyzed separately.

Additional References: 

• Reviewer GuidanceConducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review 
• Causality Assessment 
• ICH E2B Electronic Standards
• Guide to Causality Assessment