Basics of ICSR (Case processing)-Revision
No matter where you are in your Pharmacovigilance career, almost always your interview will start with ICSR processing questions ( till you specialize or diversify or reach senior leadership position). Although below are key basics but when you are in stressful situations of showcasing your knowledge to either a interviewer or a potential client on your understanding of ICSR it is challenging to address this questions and hence a quick skim of some tricky situations and questions helps.
1. 4 minimum criteria
Tricky scenarios to look out for:
1. An article retrieved with your brand name product which does not specify any patient details but just "number of patients" - is it valid or invalid case and moreover how do you handle this situation.
2. A case downloaded by an SDEA partner on behalf of MAH in another territory and forwarded 15 days late, is serious unlisted in their territory and you are responsible for only US territory- is it expedited case or not?
This are very grey area scenario which will be based on where the MAH has marketing authorization i.e. which regulations are applicable, FDA, GVP etc. And based on this regulations how the internal SOP and process are framed.
So in First scenario- you should first download full text if not already done, try to download the reference data from its original source to get patient details, if not do follow up. As conservative approach you could create a case for safety analysis at the time of signal detection.
2. Decoding the regulations:
Regulatory guidance documents need to be referred on ongoing basis, this are not read once and done kind of study documents. So let go of notion or expectation that you will know all the guidance requirements on tip of your fingers. Each situation is different, but knowing where and which regulations to read is expected from professionals the least.
3. Source of ICSR
Yes we know there are two source of ICSR, Solicited and Unsolicited or Spontaneous. But there are variations which you need to be aware. An non company sponsored trials cannot be solicited unless there is agreement between MAH and third party for data sharing in that case- it will be either unsolicited or solicited but in category of "Other trials". This will depend on safety database you are using what options it has at the backend. Also Partner case, Health authority cases, Compassionate use etc. are also different categories in source of ICSR.
4. Data entry:
This includes seriousness, labelling, expectedness, coding of events and products (MedDRA &WHO-DD), Reportability and narrative.
4. a. Seriousness: Knowing seriousness criteria and using it in real world are two different things. When do we use medically significant? It is not when no other criteria is fulfilled, but in fact when if event left untreated could have led to any of the other 5 criteria. IME or DME list is applicable only when MAH is in that territory or there is explicit mention in the process at SOP level to use this. However in absence of such documented process and clarity, its good to go with conservative approach of upgrading to serious when present in IME list.
4.b. Labelling : Knowing the correct document to use for labelling is the first step, its easier in most situations as there is only one IB, USPI or SmPC.
- It is tricky when you have multiple versions of IB or different labelling documents in various territories. In this tricky situations rely on using the correct one based on date of occurrence, CCDS or any documented process for same.
- It is also important to use the correct sections, e.g. in IB its section 6.5 Reference safety information or section for investigators to assess listedness.
- For the USPI – Use whole label to assess events Include Warnings and Precautions, Adverse Reactions ,Clinical Trials Experience, Post marketing Experience, Use in Specific Populations, Patient Counseling Information, Patient Leaflet
- Overdose section only applies to events reported with overdose.
•
Generally,
if an outcome (e.g., death) reported for adverse event exceeds the usual
outcome for that adverse event as described in the labeling document, the
associated event should be considered unlabeled.
•
Non-specific
terms where the meaning of the adverse event can vary (e.g., feeling abnormal,
drug intolerance) should be considered unlabeled, unless these terms are
present in the labeling document. Additional information should be sought to
obtain clarification.
4.c Causality :
- In spontaneous cases it is implied causality meaning "related" by default however most MAH will leave it blank in event screen in database for both company and reporter unless explicitly stated. The causality can be described with evidence in company comments.
- In clinical trials, its binary causality meaning related and not related. For FDA, Sponsor causality drives reportability and for EMA the highest causality drives reportability.
- MedDRA stands for : Medical Dictionary for Regulatory Activities.
- It is used for coding events, patient history, indications, investigations, product issues, medication errors etc. Soft coding need to be avoided i.e. coding to lesser serious or severe term.
- Abbreviations cannot be subsumed.
- Diagnosis cannot be subsumed based on signs and symptoms are reported.
- Specificity needs to be maintained
- Severity needs to be correctly captured i.e if high blood sugar is reported, Diabetes should not be coded.
- WHO-DD: A drug dictionary proves useful when tabulating medication usage because it classifies the same medication, often known by different names, into a single name. Its used to code suspect, cosuspect, conmeds, treatment medications etc.
- Narratives are expected to be submitted for all cases reported expeditiously to any regulatory authority but are useful and should be made available when needed for other types of reports and purposes
- EU requires narrative for all cases, except non serious but MAH may choose to have narrative for all cases in their database
- Knowing what is most relevant for drug event pair and limiting narratives to that, e.g. history that is closer to event in duration or clinically to be included, conmeds that are most relevant to the drug and event. Lab tests that are repeated multiple times add no value but in that case records first and last day lab tests or those that are clinically relevant only.
- Examples include abuse, misuse, medication errors, overdoes, off label use, product issues etc.
- Knowing when to capture just special situations without AE is important, most MAH will database this case and then do follow up and some may use other database or category to track this.
- This data is required to be summarized in aggregate reports and signal detection
- It provides insights in new indication, quality issue, product usage that impact quality or safety.
- Writing company comment- refer to my blog on this topic for notes
- IND annual safety reporting for US FDA- will cover this topic in another blog. This is summary of index case (Serious unlisted and related by company/sponsor) and other similar cases in safety database. The FDA requires this analysis report for all SUSAR cases within 7 or 15 days to FDA, Investigators and ethics committee to provide most recent and evolving safety profile of investigational product.
- Expedited safety reports with death or life threatening as seriousness criteria= As soon as possible but within 7 days of AE receipt date should be notified to all required stakeholders.
- •Electronic reporting to HA database- XML/Manual via eudravigilance portal
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