Sunday, February 01, 2015

Adverse Event of Special Interest (AESI), Standardized MedDRA Query (SMQs), Customer Queries (CQs), and SAS Programming

When we perform the safety analyses for clinical trial data or post-marketing pharmacovigilence data, one of the common approach is to identify and summarize the adverse events of special interest (AESI). FDA guidance for industry: E2F Development Safety Update Report defined the AESI as following:
“Adverse event of special interest: An adverse event of special interest (serious or non-serious) is one of scientific and medical concern specific to the sponsor’s product or program, for which ongoing monitoring and rapid communication by the investigator to the sponsor can be appropriate. Such an event might warrant further investigation in order to characterize and understand it. Depending on the nature of the event, rapid communication by the trial sponsor to other parties (e.g., regulators) might also be warranted. (Based on CIOMS VI)”
ICH Topic E2F Development Safety Update Report also indicated the importance of identifying the AESIs:
“If important and appropriate, the report should also include adverse reactions of special interest within the line listings and adverse events of special interest in summary tabulations. The basis for selection of such events/reactions should be explained. “
Since the same AESI may include many verbatim (reported) terms or preferred (coded) terms, the first step of the analysis of AESI is to define the list of terms that will be considered as the specific AESI.

I used to do a large phase III study in Irritable Bowel Syndrome (IBS). The protocol specified the diarrhea and rectal bleeding events as AESI. In developing the statistical analysis plan (SAP), the following tables were included to to identify the diarrhea events and rectal bleeding events. .

Adverse Event of Special Interest
Group term
Preferred term
Diarrhea NOS

Loose stools, stools loose

Loose bowel, loose bowels

Watery diarrhea (diarrhoea)

Stools watery


Gastroenteritis NOS

Gastroenteritis non-infectious
Rectal bleeding
Rectal bleeding

Rectal haemorrhage

Anal haemorrhage

GI h(a)emorrhage

GI h(a)emorrhage NOS

Diarrhea haemorrhagic

Haemorrhage rectum

Blood in stool

Occult blood



Lower GI bleeding (not found)

In 131st Meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) in 2012, the adverse event of special interest regarding autoimmune events was discussed. The meeting minutes explained how the autoimmune events were identified:
"The first was adverse events of special interest. This involved the identification, categorization and analysis of adverse events in the safety database. It was performed using a list of autoimmune and inflammatory conditions. The system was used for all trials in the HEPLISAV clinical program including the Phase 3 trials."
In FDA’s advisory committee meeting to discuss BioMarin Vimizim (elosulfase alfa) for the treatment of Mucopolysaccharidosis Type IVA (Morquio A syndrome), the AESI of hypersensitivity and anaphylactic reaction events was discussed:
“Potential Hypersensitivity AEs were identified by utilizing the broad Anaphylactic Reaction algorithmic Standardized MedDRA query (SMQ) and the broad Angioedema SMQ, which represent a broad range of terms to detect signals possibly indicative of hypersensitivity. Hypersensitivity AEs were reported in 16.2% of subjects in the Proposed Dose Population. No correlation was found between higher titers of anti-BMN 110 antibodies and increased incidence or severity of hypersensitivity AEs. The Warnings and Precautions section of the proposed prescribing information includes language regarding the clinical study experience with anaphylaxis and severe allergic reactions and provides recommended management of and preventive measures for severe allergic-type hypersensitivity reactions. o BioMarin reviewed all reported adverse events against the NIAID/FAAN 2006 criteria for anaphylaxis (Sampson H et al, 2006). Of the 235 subjects exposed to BMN 110 in the development program, the sponsor identified  16 (6.8%) cases consistent with NIAID/FAAN 2006 criteria for anaphylaxis. The reactions were successfully managed with infusion rate adjustments and/or medical intervention, and all but 2 subjects continue to receive subsequent BMN 110 infusions. This rate of anaphylaxis is comparable to other enzyme replacement therapies”
To discuss the AESI, we must know the concept of SMQ. To assist in standardizing the AESI identification process, Standardised MedDRA Queries (SMQs) are developed to facilitate retrieval of MedDRA-coded data as a first step in investigating drug safety issues in pharmacovigilance and clinical development. SMQs are validated, pre-determined sets of MedDRA terms grouped together after extensive review, testing, analysis, and expert discussion. SMQs are a unique feature of MedDRA and provide a strong tool to support safety analysis and reporting. The SMQ topics are intended to address the important pharmacovigilance topics needed by regulatory and industry users. SMQs have been developed with the CIOMS Working Group on Standardised MedDRA Queries that provides pharmacovigilance expertise and validation of SMQs. The SMQs are maintained with each release of MedDRA dictionary by the MSSO.

As of 1 September 2014, there are almost 100 SMQs available. The list of available SMQs can be found here from MSSO website.

If we need to identify a risk or AESI, if SMQ is available, SMQ should be used. If SMQ is not available, the customer-defined list of preferred terms (PTs), so-called CQs (customer queries), will be needed. For three AESIs discussed above, SMQs are available for Diarrhea (as Noninfectious diarrhoea) and Hypersensitivity, but not available for rectal bleeding events. In an ophthalmology paper, both SMQ and customer-defined PTs (CQs) were used to identify various risks. Similarly, in a T2DM study, both SMQ and customer-defined PTs were used to identified various AESIs.

In practice, once we have the database containing all AEs and we have a list of preferred terms (either from SMQ or from the customer-defined [CQs]) to identify the AE of special interest, a simple SAS program with PROC SQL can be used to identify the reported events from the database.

Here the AE database is the base table. SMQ preferred terms or customer-defined preferred terms (CQs) is the look-up table. 

proc sql;
    ***Create a look up table where pt is preferred term;
    create table LookupTable as
    select distinct range, pt
    from smq
    where range = 'Narrow';

    ***Select records based on the look-up table;
    create table matched_terms as
    select subjid, aeterm, pt label='Preferred Term'
    from ae
    where upcase(pt) in (select upcase(pt) from LookupTable);

proc print data=matched_terms label noobs;

The following papers discussed how to use SAS to perform the safety analysis using SMQ.

CDISC “Analysis Data Model (ADaM) Data Structure for Adverse Event Analysis” discussed MedDRA SMQ, included a specific section “4.1.9 MedDRA Query Variables”, and provided an example for analysis of Hemorrhages using SMQ. 

1 comment:

vivek rakha said...

Thanks! Very informative.