Signal detection and its assessment is the most important aspect in pharmacovigilance which plays a key role in ensuring that patients receive safe drugs. The detection of unknown and unexpected safety signals as early as possible is critical in pharmacovigilance.
The definition of a signal as provided by the Council for International Organizations of Medical Sciences (CIOMS) 8 Working Group:
Information that arises from one or multiple sources (including observations and experiments), which suggests a new potentially causal association, or a new aspect of a known association, between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action.
The strength of a safety signal is determined by several factors of the adverse effect. These include frequency, nature, duration and presence of documented rechallenge/ dechallenge information of the adverse effect.
MedDRA dictionary is standard one which pharmaceutical companies use for event coding.
For safety signals, there are various ways to pull cases out of the safety database using MedDRA after they have been previously coded and entered into the database. One way is to simply search for one or more MedDRA terms and pull the cases that have been coded using these terms (either as AEs, medical history etc.).
Alternatively one may use a Structured MedDRA Query (SMQ). These are groupings of related terms (usually PTs – preferred terms) from all appropriate System Organ Classes (SOCs) as determined by a panel of experts. The terms in an SMQ would cover one medical subject, for example lactic acidosis or acute renal failure, and list signs, symptoms, syndromes, diseases, diagnoses, lab findings etc.
What is soft coding?
Soft coding is selecting a term which is less specific and less severe than another MedDRA term.
Accuracy of event coding is important for detection and evaluation of safety signals.
With MedDRA, each adverse event can be coded as several different terms, for example insomnia can be coded as 11 different preferred terms. Hence specificity (one of the MedDRA guideline) is critical for signal detection. For example, edema can have a very different medical meaning and treatment if it is pulmonary edema (which may be life threatening) or leg edema (which may be only bad circulation and not life threatening).
Below are few examples which can cause signal dilution because of inaccurate event coding:
- Two different LLT might be selected for same event causing two different PT or SOC’s, if LLT not selected correctly as per verbatim and following MedDRA guidelines which effect frequency of events while assessing safety signal.
- Event coding determine severity of case (i.e, IME List event). While assessing safety signals serious events will have high priority as they usually have an increased public health importance compared with non‐serious ones.
- At the end of the clinical trial, data are categorized and summarized, and adverse events are lumped into broad categories for practical reasons. At each of these steps, decisions are made that might impact the overall impression of harms and might lead to important harms being missed, e.g. “gastrointestinal events” may include cases of nausea as well as bleeding ulcers.
- Small deviations from the ideal of objective coding can lead to significantly changed conclusions and are usually impossible for the reader to discover.
Is soft coding way of hiding signals from current surveillance systems?
Let’s see few examples:
1. Paroxetine and suicidal tendency: The antidepressant paroxetine was tested in adolescents in an infamous trial that initially declared that the drug was “generally well tolerated”. The paroxetine group, however, had an overrepresentation of “emotional lability”. After scrutiny by the FDA and independent experts, it turned out that this term was only used when patients had “suicidal tendencies”. Other cases of suicidal tendencies had been coded as aggression or “exacerbation of depression”
2. AstraZeneca Covid-19 vaccine:
According to a participant information sheet dated July 12 that was posted on the ISRCTN clinical-trial registry, one volunteer in AstraZeneca’s U.K. trial had developed symptoms of transverse myelitis. The posting said the cause was being investigated.
An August update of the information sheet removed the reference to transverse myelitis and said the participant developed neurological symptoms that caused the study to be paused, and that the volunteer was later diagnosed with what was described as “an unrelated neurological illness.”
3. HPV Vaccine: More than 100 cases of Complex regional pain syndrome (CRPS) / Chronic Fatigue syndrome (CFS)/ Postural orthostatic tachycardia syndrome (POTS) in the clinical trials of HPV vaccines; 0 shown in the CSR submitted to the regulators for the initial marketing authorization.
Soft coding will lead to non-differential misclassification of adverse events and signal dilution. This will underestimate the relationship and may result in failure to detect important adverse events. To avoid that the coders in a particular organization should standardize on one term and not use all the terms possible to maintain consistency and uniformity.
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