OpenRIMS-PVM - User Manual Chapter 5

Analytical Portal

At the Home Page of the Analytical Portal, you will be presented with the following options:

●     Spontaneous and Active Reports

●     Spontaneous and Active Analyzer

The analytical portal is the centralized hub for causative drug assessment using traditional recognized rating scales, standardized terminology, and risk detection with exposed versus non-exposed risk ratios. Note: the following roles have access to the analytical portal: ·         Administrator. The administrator has FULL permissions to the analytical portal. ·         Analyst. An analytics user is able to assign terminology, set causality and run analysis on collected data.

Click on the user profile menu option which appears when clicking on the profile icon to view roles and facilities you currently have access to.

Spontaneous Reporting

Spontaneous reports are termed spontaneous as they take place during the clinician’s normal diagnostic appraisal of a patient, when the clinician is drawing the conclusion that the drug may be implicated in the causality of the event.

Spontaneous reporting system relies on vigilant physicians, other healthcare professionals, and patients who not only generate a suspicion of an ADR, but also report it.

It is an important source of regulatory actions such as taking a drug off the market or a label change due to safety problems. Spontaneous reporting is the core data-generating system of international pharmacovigilance, relying on healthcare professionals (and, in some countries, consumers) to identify and report any adverse events to their national pharmacovigilance center.

Spontaneous reports are, by definition, submitted voluntarily.

PViMS facilitates a public facing interface that allows clinicians or the public itself to spontaneously report on adverse event related data. See chapter 8 for more information.

Active Reporting

Active surveillance for monitoring the safety and effectiveness of medical products is increasingly recognized as a complement to spontaneous reporting commonly used by pharmacovigilance systems. Integrated mechanisms and processes for monitoring the safety of medicines are essential to a well-functioning pharmaceutical sector. A positive benefit-to-risk balance should precede access to market; however, most regulatory decisions take place early in the product lifecycle and are based on limited data from clinical trials that may be of relatively short duration with limited numbers and types of subjects.

It is critical, therefore, that medicines continue to be monitored for safety and effectiveness once they enter the market under real-life conditions. For some medicines, issues will only emerge under real-world conditions as a result of prolonged use, use in specific subpopulations or in patients with multiple comorbidities, or use in combination with other medicines. In some cases, rare adverse effects only emerge after a product is used for many years, by large numbers of patients, or both.

Active surveillance is particularly important to support the introduction of new essential medicines in LMICs whose regulatory systems are being developed and are in need of support. In resource-limited settings, active surveillance can help determine the real-life frequency, risk factors, and impact of clinically significant adverse medicine events on treatment outcomes.

Pharmacovigilance Activities

This section describes the common processes adopted by the pharmacovigilance unit in responding to both spontaneous and active reports submitted through PViMS. PLEASE NOTE: In relation to spontaneous reports, the patient identified in the report does NOT form part of the active reporting patient dataset. Therefore, spontaneous reports do not form part of any analysis conducted through the analyzer. The following activities are facilitated in the Analytical portal: ·         Verify quality of report data ·         Set terminology for adverse drug reaction (MedDRA) ·         Set causality per drug (Naranjo or WHO) ·         Create and update E2B files (Export to XML) ·         Generate a patient summary

Terminology

Causality Assessment Scale or Terms. The assessment scales or terms were developed to help standardize assessment of causality for all adverse drug reactions. The result is determined by an algorithm designed by Naranjo or WHO for determining the likelihood of whether an adverse drug event is actually due to the drug rather than the result of other factors. Probability is assigned via a score termed definite, probable, possible or doubtful (Naranjo) or certain, probable/likely, possible, unlikely, conditional, unassessable or unclassified (WHO). Values obtained from this algorithm are sometimes used in peer reviews to verify the validity of author's conclusions regarding adverse drug reactions.

MedDRA Terminology. MedDRA or Medical Dictionary for Regulatory Activities is a clinically validated international medical terminology dictionary by regulatory authorities in the pharmaceutical industry during the regulatory process, from pre-marketing to post-marketing activities, and for data entry, retrieval, evaluation, and presentation. In addition, it is the adverse event classification dictionary endorsed by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

E2B. The international standard for transmitting medicine adverse event reports specified by the ICH.

1.3.2       Process Flow

Activity: Start of Process Clinician adds a new adverse event to the patient record. Reporter adds a new spontaneous report. System generates a new report for the PV unit to action: Report has a unique identifier Report has a default activity of Confirm Report Data Report has a sub status of UNCONFIRMED	Confirm Report Data The purpose of this activity is to facilitate the checking, vetting, and updating of the clinical data collected for the adverse event logged. The PV unit will be unable to perform any causality or terminology configurations until the data is confirmed as accurate and comprehensive. The PV specialist has the following options: Delete Report Confirm Report
Activity: Confirm Report Data Step 1: PV specialist and clinician/reporter update clinical data until there is sufficient information to perform causality and terminology configurations. For active reporting the patient record is modified through the clinical portal. For spontaneous reporting the report is modified directly in the analytical portal. Step 2: Once data has been confirmed, the PV specialist will confirm the report is ready for assessment by selecting the Confirm report option. Step 3: The report is moved into a new activity: Set MedDRA and Causality.
Activity: Set MedDRA and Causality Step 1: PV specialist sets the terminology for the adverse event. This will be the terminology used for analysis purposes. Step 2: PV specialist then sets the causality per medication that was in use at the onset date of the adverse event. Please note: the specialist is unable to set causality until the MedDRA term has been selected. Step 3: On completion, the PV specialist confirms causality has been set. Step 4: The report is moved into a new activity: Extract E2B.	Set MedDRA and Causality The purpose of this activity is to facilitate the setting of the MedDRA terminology for the event and to set causality per medication using either the Naranjo or WHO causality scales. The PV specialist has the following options: Set Terminology WHO Causality Naranjo Causality Confirm Causality Set
Activity: Extract E2B Step 1: PV technician creates an E2B XML file for submission. Please note: a patient summary is stored at the time of generating the E2B XML to allow for data verification. Step 2: PV technician then confirms that the E2B XML file has been submitted to WHO. A receipt code and time can be noted here Please note: submission to WHO UMC is a manual process.	Extract E2B The purpose of this activity is to facilitate sharing of E2B adverse drug reactions with the WHO Uppsala Monitoring Centre using the ICH ICSR E2B specification. The PV specialist has the following options: Create E2B Confirm E2B submission
PROCESS COMPLETED

1.3.3       Identifying New Reports

It is possible to identify new active or spontaneous reports using the notification panel in the main system header. A number next to the notification icon indicates you either have a new adverse event report requiring analysis or new terminology has been defined for an existing report.

The number of new reports registered within a pre-defined period of time is displayed as a value in the notification list of menu items.

This alert will vary in count depending on the ReportInstanceNewAlertCount configuration. Please speak to your system administrator to confirm what this value is set to in days.

1.3.4       Search for a Report

In the Reports function for Spontaneous and Active Reporting, you can Search for new reports that have been created. The Reports function can be accessed either through the Spontaneous or Active menu.

There are three ways to search for a report. You can search by:

●     Activity (what stage of analysis the report is currently in)

●     Report date range

●     By a search term

1.3.4.1       Search by Active Work

Searching by activity allows you to search for all incomplete reports by the current stage a report may be in or by listing all new reports that have been identified as per the ReportInstanceNewAlertCount configuration.

·        Select the New Reports button to view a list of new reports within the system

·        Or select the current activity stage if you would like to filter reports based on the stage they are currently in

Confirm Report Data Stage: Search on all reports that are newly submitted and are not yet VERIFIED. Set MedDRA and Causality: Search on all reports that have been VERIFIED and are in the process of being defined through terminology. Extract E2B: Search on all reports that have all terminology defined and are ready to extract information for submission to the WHO Uppsala Monitoring Centre.

The system will display a list of reports according to the filter selected, please note the Unique Identifier of the report in column 2.

1.3.4.2       Search for all Reports within a Date Range

Search by date range searches for all complete and incomplete reports within a given date range.

·        Enter the Search From and Search To date fields for the date range to search.

·        Click the Search button.

The system will display a list of reports according to the filter selected, please note the Unique Identifier of the report in column 2.

1.3.4.3       Search Reports by Term

The Search by term tab allows the user to search for all reports using the following criteria:

·        Patient name

·        MedDRA term as set by the clinician and technician

·        Report identifier

·        Medications

The search function uses a partial term to search all reports on the terms noted above. For instance, searching for the term Accelerated returns all reports that have that partial term in the MedDRA term for the report.

The columns in the report table are described below:

Created	The date and time the report was registered in the analytical portal
Identifier	Unique identifier for the report (system generated)
Patient	Patient name
Medication Summary	Overview of all medications associated with the patient at the time of the event, including the WHO or Naranjo causality assessment outcome once that has been set
Adverse Event	The adverse event experienced by the patient
MedDRA Terminology	The unique and internationally recognized MedDRA term defined for the event
Status	Current status of the report
Actions	Confirm Report Data Stage View Activity History Confirm or Delete Report View Patient (Active Only) View SAE Report or Patient Summary Update Report (Spontaneous Only) Set MedDRA and Causality Stage View Activity History Set Terminology (MedDRA), Naranjo or WHO Causality Term Confirm Causality Set View Patient (Active Only) View SAE Report or Patient Summary Update Report (Spontaneous Only) Extract E2B Stage View Activity History Create or Update an E2B file Prepare or Confirm E2B file for submission Download XML file View Patient (Active Only) View SAE Report or Patient Summary Update Report (Spontaneous Only)

1.4        Pharmacovigilance Activities - General

1.4.1       Viewing Activity History for Report

Irrespective of the stage the report is currently in, you will be able to view a comprehensive history for the report detailing all actions that have occurred, who effected the action, and any additional comments.

Once you have searched for a report, click on the View activity history menu for the associated report you would like to view.

The system will navigate you to the View activity history page.

The columns in the activity history table are described below:

Activity	The primary activity stage performed by the analyst
Execution event	The primary activity performed by the analyst. Activities are dependent on the stage the report is in.
Execution date	The date and time the user executed the activity
Comments	Any comments noted by the user at the point of completing the activity
Receipt date	Particular to the E2B Extract Stage. Confirmation an E2B extract has been received by UMC and this is the associated receipt date
Receipt code	Particular to the E2B Extract Stage. Confirmation an E2B extract has been received by UMC and this is the associated receipt code that may be supplied by UMC
Action	Download summary Download extract Download E2B file

1.4.2       Viewing a Patient Record

The View patient menu allows the user to navigate to the Patient View for the patient so that the analyst may gather additional information to the adverse event.

Once you have searched for a report, click on the View patient menu for the associated report you would like to view.

The system will navigate you to the Patient View page in the Clinical Portal.

This menu item will only be made available under the following circumstances: ·         Active reports only ·         If the user has the Registration Clerk, Data Capture or Clinician role assigned to their user profile

1.4.3       Extracting a Patient Summary

The Download summary menu allows the user to generate an overall summary of the patient clinical record in MS Word format. This is the preferred method of granting access to the clinical record for the analyst.

Once you have searched for a report, click on the Download Summary menu for the associated report you would like to view.

The system generates an extract of the patient summary:

.

If the event is defined as serious, the system will include additional information that explains the seriousness of the report. The heading of the extract will be changed to Serious Adverse Event.

1.4.4       Updating a Spontaneous Report

The Update report menu allows the user to navigate to the spontaneous report for the patient and allow the analyst the ability to amend the report.

Once you have searched for a report, click on the Update report menu for the associated report you would like to amend.

The system will navigate you to the Spontaneous View pop up form for the report.

This menu item will only be available for spontaneous reports.

1.5        Pharmacovigilance Activities – Confirm Report Data

1.5.1       Deleting a Report

The Confirm Report Data stage enforces a process whereby the analyst ensures the necessary clinical data is of sufficient quality to allow terminology and causality to be completed. In the event a report is deemed to be insufficient, inaccurate, or erroneous, a report may be deleted, which will effectively remove it from analysis.

Once you have searched for a report, click on the Delete report menu for the associated report you would like to delete.

The system will navigate you to the Add Activity page.

Specify the reason for deleting the record and click Save to confirm the deletion or Cancel to cancel the action and return to the previous page.

The system will update the status of the report accordingly.

Once a report is deleted, it is not possible to re-include the report for analysis. Please ensure you are correct in deleting the report before committing the action.

1.5.2       Confirming a Report

The Confirm Report Data stage enforces a process whereby the analyst ensures the necessary clinical data is of sufficient quality to allow terminology and causality to be completed. When a report is deemed to be sufficient and accurate, the report should be confirmed, which will effectively allow terminology definition to commence.

Once you have searched for a report, click on the Confirm Report menu for the associated report you would like to confirm.

The system will navigate you to the Add Activity page.

Specify any additional comments for confirming the record and click Save to confirm the deletion or Cancel to cancel the action and return to the previous page.

The system will update the status of the report accordingly.

Confirming a report will move the report into the next stage: Set MedDRA and Causality.

1.6        Pharmacovigilance Activities – Set MedDRA and Causality

1.6.1       Set MedDRA Terminology

The Set MedDRA and Causality stage facilitates the process of confirming the final MedDRA term for the adverse event and allows assignment of causality per relevant medication using either the World Health Organization or the Naranjo Causality Scale.

Once you have searched for a report, click on the Set Terminology menu for the associated report you would like to set terminology for.

The system will pop up a MedDRA Terminology form.

The MedDRA Terminology form displays the adverse event as reported by the clinician and/or reporter.

MedDRA terms can be searched in the following ways:

•           Search by MedDRA Term

•           Search by MedDRA Code

•           Search by MedDRA List

1.6.1.1       Search by MedDRA Term

Searching by a MedDRA term allows you the ability to filter through MedDRA using a partial or fully defined term.

In the Term type field, select the level of specificity for the search (SOC, HLTG, HLT, PT, or LLT).

In the Find by term field, enter the term you are searching for.

It is possible to complete a partial search by entering as few as 3 characters that form part of the overall term.

Click the Select icon next to the term you would like to assign or click the Cancel button to cancel the action and return to the previous page. The report will be updated with the new term accordingly.

1.6.1.2       Search by MedDRA Code

Searching by a MedDRA code allows you the ability to filter through MedDRA using an associated code which can be fully defined or partial in nature.

In the Find by code field, enter the code you are searching for.

It is possible to complete a partial search by entering as few as 4 numerical characters that form part of the overall code.

Click the Select icon next to the term you would like to assign or click the Cancel button to cancel the action and return to the previous page. The report will be updated with the new term accordingly.

1.6.1.3       Search for MedDRA Term by List

The list search function allows the user to navigate the MedDRA dictionary using the hierarchical structure of the dictionary. Select the System Organ Class field to select a SOC.

Continue selecting through the hierarchy (HLGT, HLT, PT) until you have selected the Low-Level Term that matches the adverse event.

Click the Select icon next to the term you would like to assign or click the Cancel button to cancel the action and return to the previous page. The report will be updated with the new term accordingly.

1.6.2       Causality Assessment using the WHO Scale

The Set MedDRA and Causality stage facilitates the process of confirming the final MedDRA term for the adverse event and allows assignment of causality per relevant medication using either the World Health Organization or the Naranjo Causality Scale.

Once the MedDRA terminology for the event has been set, the report will be updated accordingly.

Setting the terminology will further allow the setting of causality per medication. Click on the WHO Causality menu option for the associated report you would like to set causality for.

The system will open up the WHO Causality Assessment pop up form.

The WHO Causality Assessment form displays the adverse event as reported by the clinician and/or reporter and the MedDRA Terminology that has been set for the event.

The WHO Causality Assessment form also displays the list of medications that the patient was exposed to at the onset of the adverse event.

The analyst can perform the following actions against each medication the patient was exposed to:

·        Ignore the medication (the medication is definitely not responsible for the adverse event)

·        Set causality for the medication

1.6.2.1       Ignoring the Medication

Ignoring the medication means that a causality assessment need not be set for that medication.

To ignore assigning a WHO causality assessment for this medication, click the Ignore Medication icon. The system will assign Ignored as the causality term.

1.6.2.2       Set Causality

By clicking the Set Causality icon, the system will enable you to set causality for this medication.

The system displays a series of questions for assigning the WHO causality term.

Click the appropriate response (Yes or No) for question 1 and continue to respond to the first five questions.

If responses to all five questions are Yes, the system will assign Certain as the causality term.

Click the Set causality icon next to the causality assessment and the system will assign the term as Certain in the system.

Click the Close button at any time to undo the action and return to the list reports.

If any of the questions in the Certain category have a response of No the system will display questions for the Probable/Likely category.

Continue this process until you have answered Yes to all questions in a specific category. This will result in the classification for that medication being set to that category.

In the event you reach the Unassessable/Unclassified category, if one of the two questions asked in that category is answered as No, the system will trigger an alert.

Once the term has been assigned click the Close button to continue.

1.6.3       Causality Assessment using the Naranjo Scale

The Set MedDRA and Causality stage facilitates the process of confirming the final MedDRA term for the adverse event and allows assignment of causality per relevant medication using either the World Health Organization or the Naranjo Causality Scale.

Once the MedDRA terminology for the event has been set, the report will be updated accordingly.

Setting the terminology will further allow the setting of causality per medication. Click on the Naranjo Causality menu for the associated report you would like to set causality for.

The system will open up the Naranjo Causality Assessment pop up form.

The Naranjo Causality Assessment form displays the adverse event as reported by the clinician and/or reporter and the MedDRA Terminology set.

The Naranjo Causality Assessment form also displays the list of medications that the patient was exposed to at the onset of the adverse event.

The analyst can perform the following actions against each medication the patient was exposed to:

·        Ignore the medication (the medication is definitely not responsible for the adverse event)

·        Set causality for the medication

1.6.3.1       Ignoring the Medication

Ignoring the medication means that a causality assessment need not be set for that medication.

To ignore assigning a Naranjo causality assessment for this medication, click the Ignore Medication icon. The system will assign Ignored as the causality term.

1.6.3.2       Set Causality

By clicking the Set Causality icon, the system will enable you to set causality for this medication.

The system displays a series of questions for calculating the Naranjo causality score.

Click the appropriate response (Yes or No) for question 1 and continue to respond to all remaining questions.  Once all responses have been selected, the system will automatically calculate the causality assessment.

Click the Set causality icon next to the causality assessment and the system will assign the term as per the calculation in the system.

Click the Close button at any time to undo the action and return to the list reports.

1.6.4       Confirming Causality Set

The Set MedDRA and Causality stage facilitates the process of confirming the final MedDRA term for the adverse event and allows assignment of causality per relevant medication using either the World Health Organization or the Naranjo Causality Scale.

Once causality for all medications has been set, the report will be updated accordingly.

Click on the Confirm Causality Set menu for the associated report you would like to confirm causality set for.

The system will navigate you to the Confirm Causality Set form.

Specify any comment if necessary and click Save to confirm the setting of the causality or Cancel to cancel the action and return to the previous page.

The system will update the status of the report accordingly. Please note the report will now be located in the Extract E2B tab.

1.7        Pharmacovigilance Activities – Extract E2B

1.7.1       Create E2B

BUZZWORDS ICH E2B: An E2B dataset facilitates the Electronic Transmission of Individual Case Safety Reports (ICSRs) and can be used to submit such reports to WHO. The E2B dataset within PViMS is implemented using the standard adopted by the ICH1 for electronic transmission of ICSRs according to the ICH E2B(R3) message standard.

The Extract E2B stage generates an E2B extract for submission to the World Health Organization Uppsala Monitoring Centre.

By clicking this menu item, the system generates an E2B dataset that is populated with clinical information from the source form. This E2B dataset can be amended by you to reflect additional clinical information pertinent to WHO. This menu item is only available for forms that are in the Extract E2B | NOTGENERATED stage.

Once you have searched for a report, click on the Create E2B menu for the associated report you would like to create E2B for.

Once the system has created the E2B dataset, the status of the report will be updated to E2BINITIATED to indicate the dataset has been created.

The E2B dataset is constructed with the following sections (these sections are based on R2 of the E2B ICH definition):

·        Message Header

·        Safety Report

·        Primary Source

·        Sender

·        Receiver

·        Patient

·        Medical History Episode

·        Past Drug Therapy

·        Patient Death

·        Reaction

·        Test

·        Drug

·        Summary

ICH E2B: Please see the electronic Transmission of Individual Case Safety Reports Message Specification for detail specifications on the above categories. This specification can be found on https://admin.ich.org/sites/default/files/inline-files/ICH_ICSR_Specification_V2-3.pdf

1.7.2       Adding Information to and Updating an E2B File

Once an E2B file is created, the Update E2B menu allows the user to add information to or updating existing information populated in an E2B file.

Once you have searched for a report, click on the Update E2B menu for the associated file you would like to amend.

The system will pop up a E2B ICH Report form for the file.

Once you completed making amendments, click on the Save button to save the changes or the Cancel button to cancel the action and return to the previous page.

1.7.3       Preparing a Report for E2B Submission

The Extract E2B stage facilitates the process of generating an E2B extract for submission to the World Health Organization Uppsala Monitoring Centre.

Once you have created an E2B file and searched for the report, click on the Prepare Report for E2B Submission menu for the associated report you would like to prepare.

The system will navigate you to the Prepare report for E2B submission pop up form.

Specify any additional comments for preparing the record and click Save to confirm the preparation or Cancel to cancel the action and return to the previous page.

The system will update the status of the report accordingly.

It is during this stage that PViMS prepares the XML file for submission. It also prepares an associated patient summary and patient extract that correspond to the clinical data at the point of generating the submission.

1.7.4       Viewing the E2B XML File

Once you have prepared the E2B file for submission and searched for the report, click on the View Activity History menu for the associated report you would like to view the XML file for.

The system will navigate you to the Activities page where you will be able to view a comprehensive history of activities by the analyst against this adverse event.

Locate the E2BGENERATED execution event for the report, click the menu for that event, and select the Download E2B File menu.

The system will automatically generate the XML file for the E2B submission to WHO. Save the file on your local computer for referral when sending to WHO.

The extract below is the XML generated for the Message Header section of the XML file.

1.7.5       Viewing the Clinical Data Associated to the E2B XML File

Once you have prepared the E2B file for submission and searched for the report, click on the View Activity History menu for the associated report you would like to view the XML file for.

The system will navigate you to the Activities page where you will be able to view a comprehensive history of activities by the analyst against this adverse event.

Locate the E2BGENERATED execution event for the report, click the action menu, and select the Download summary or Download extract menu.

If you select the Download summary menu, the system will generate a MS Word extract of the associated clinical data. See Extracting a Patient Summary.

If you select the Download extract menu, the system will generate an MS Excel extract of the associated clinical data.

In both the Patient Extract and Summary above, these files are stored along with the XML file as a reference to the clinical data associated with the XML file at the point the XML file was generated.

1.7.6       Confirming a Report for E2B Submission

Once you have prepared the E2B file for submission and searched for the report, click on the Confirm E2B Submission menu for the associated report you would like to submit.

The system will navigate you to the Confirm E2B Submission pop up form.

Specify any additional comments for confirming the submission and click Save to confirm the submission or Cancel to cancel the action and return to the previous page.

The receipt date and code can be used to note correspondence with WHO on the receipt of the E2B XML submission file.

The system will update the status of the report accordingly. Please note that the report is removed from the Extract E2B tab as work for this report is now classified as finished. Use the Search by date or Search by term tabs to locate this report again.

1.8        Analyser

This section is used to generate the relative risk for a specified adverse drug reaction based on an exposed and non-exposed population set over a defined period of time. The analyser user can access the following functionality within the analytical portal: ·         Define population set (cohort or condition group) ·         Define reporting period ·         Specify additional risk factors ·         View risk ratios per exposed drug ·         Download dataset for further analysis

2        

2.1        

2.2        

2.3        

2.4        

2.5        

2.6        

2.7        

2.8        

2.8.1       Methodology

The following formulas, calculations and definitions are used in the calculation of the relative risk for a specific medication and adverse reaction.

1.8.1.1       Incidence Rate

The incidence rate is the number of new cases per population in a given time period

IR = (ADR / Population) * 1000 Where IR = Incidence Rate ADR = Number of adverse drug reactions * Population = Total patient years in reporting period ** Note * Where causality is set to possible, probably/likely or Certain for WHO assessments and where causality is set to possible, probable or definite for Naranjo assessments ** Population is represented in patient years. For example, if the reporting period is 30 days, and 10 patients were on treatment for all 30 days, the total patient years is 300 /365.25 which is 0.82. Example Cases = 11 Non-Cases = 170 Population = 181 (11 + 170) Incidence Rate = 11/181 * 1000 = 60.77

1.8.1.2       Relative Risk

Relative risk is defined as the incidence in the exposed over incidence in the non-exposed.

RR= IR1 / IR2 Where RR = Relative Risk IR1 = Incidence Rate for exposed population. The exposed population is defined as the patient population that have been exposed to a medication in the reporting period. IR2 = Incidence Rate for non-exposed population. The exposed population is defined as the patient population that have NOT been exposed to a medication in the reporting period. Example Incidence Rate Exposed = 60.77 Incidence Rate Non-Exposed = 45.12 RR = 1.35

1.8.1.3       Confidence Interval

A confidence interval is a range of values so defined that there is a specified probability that the value of a parameter lies within it. Most commonly, the 95% confidence interval is used.

Where zα is the standard score for the chosen level of significance and SE the standard error.

1.8.2       Generating Unadjusted Relative Risk Ratios

To implement the methodology for generating an Unadjusted Relative Risk Ratio, the following parameters will need to be specified:

·        The population target (condition group or Cohort)

·        The date range for the analysis

The Analyser function can be accessed through the main menu.

1.8.2.1       Specifying the Population Group

Ensure the Analysis Criteria tab is selected to allow the selection of the patient population.

By selecting a Condition Group or Cohort, you are effectively able to target a specific set of patients for analysis.

To specify a Condition Group, click the Primary Condition Group Risk Factor field and select the primary condition you would like to run analysis against. If this option is selected, all patients that belong to the corresponding Condition Group will be included in the analysis.

To specify a Cohort, click the Cohort field and select the primary cohort you would like to run analysis against. If this option is selected, all patients that belong to the corresponding Cohort will be included in the analysis.

1.8.2.2       Specifying the Date Range for the Analysis

By selecting a Date Range, the system will determine which patients should be included into the analysis from the Patient Population specified in the previous step. Patients that have been actively exposed to medication within that range will be included.

1.8.2.3       Running the Analysis

Once the Patient Population and Date Range parameters have been selected, click on the Analyse button to execute the analysis.

The system will conduct an initial analysis that will identify what Adverse Drug Reactions have been identified over the reporting period. All results are included in the Analysis Results tab. Please note that only adverse drug reactions where a MedDRA term has been selected by the PV technician will be selected.

Select the Adverse Drug Reaction that you would like to detect signals for by clicking on the tab for that reaction. The selected tab will turn a dark blue to signify that it has been selected.

Please note that selecting the Adverse Drug Reaction will enable the Dashboard and Patients tab.

You are able to now view a 2 by 2 table illustrating relative risk and 95% Confidence Interval for the selected reaction.

·        Incidence Rate for exposed group

·        Incidence Rate for non-exposed group

·        Relative Risk for the associated medication

·        95% Confidence Interval for the associated medication

1.8.2.4       Viewing the Contributing Patient List

Once analysis has been executed, it is possible to view the list of patients that have contributed to the analysis population set through the Patients tab.

The columns in the patient list table are described below:

Patient name	The name of the patient contributing to the patient population
Medication	The drug the patient was exposed to during the period of analysis
Days contributed	The number of days the patient contributed to the patient population
Reaction	Did the patient suffer a reaction during the period of analysis
Risk Factor	Which risk factor does the patient match

1.8.2.5       Resetting Criteria

If at any point you would like to alter the patient population or date range, click the Reset criteria tab alongside the list of Adverse Drug Reactions to reset analysis. Selecting this tab will remove existing analysis and reopen the Analysis Criteria tab for modification.

1.8.3       Generating Adjusted Relative Risk Ratios

To implement the methodology for generating an Adjusted Relative Risk Ratio, the following parameters will need to be specified:

·        The population target (condition group or Cohort)

·        The date range for the analysis

·        The risk factors to be applied

The Analyser function can be accessed through the main menu.

1.8.3.1       Specifying the Population Group

Ensure the Analysis Criteria tab is selected to allow the selection of the patient population.

By selecting a Condition Group or Cohort, you are effectively able to target a specific set of patients for analysis.

To specify a Condition Group, click the Primary Condition Group Risk Factor field and select the primary condition you would like to run analysis against. If this option is selected, all patients that belong to the corresponding Condition Group will be included in the analysis.

To specify a Cohort, click the Cohort field and select the primary cohort you would like to run analysis against. If this option is selected, all patients that belong to the corresponding Cohort will be included in the analysis.

1.8.3.2       Specifying the Date Range for the Analysis

By selecting a Date Range, the system will determine which patients should be included into the analysis from the Patient Population specified in the previous step. Patients that have been actively exposed to medication within that range will be included.

1.8.3.3       Specifying Risk Factors for the Analysis

To specify a Risk Factor, click the Risk factor field and select the risk factor you would like to include into the analysis. Once you have selected the risk factor, select the appropriate option associated to that risk factor and click the add icon to add the risk factor to the selected list.

You are able to add as many risk factors as you would like to include into the analysis by repeating the above process.

By including Risk Factors into the analysis, the system will determine which patients match the criteria stipulated by the set of risk factors and the corresponding Relative Risk Ratio will be adjusted based on the new population set.

1.8.3.4       Running the Analysis

Once the Patient Population, Date Range, and Risk Factor parameters have been selected, click on the Analyse button to execute the analysis.

The system will conduct an initial analysis that will identify what Adverse Drug Reactions have been identified over the reporting period. All results are included in the Analysis Results tab. Please note that only adverse drug reactions where a MedDRA term has been selected by the PV technician will be selected.

Select the Adverse Drug Reaction that you would like to detect signals for by clicking on the tab for that reaction. The selected tab will turn a dark blue to signify that it has been selected.

Please note that selecting the Adverse Drug Reaction will enable the Dashboard and Patients tab.

You are able to now view a 2 by 2 table illustrating relative risk and 95% Confidence Interval for the selected reaction.

·        Incidence Rate for exposed group

·        Incidence Rate for non-exposed group

·        Relative Risk for the associated medication

·        95% Confidence Interval for the associated medication

1.8.4       Downloading a Dataset for Further Analysis

Select the Download Data tab and then click the Download Dataset button to able to download a comprehensive dataset of patient clinical data in XLSX Excel format for importation into a third-party statistical tool.

If you are unable to locate this function, please liaise with your system administrator as the ability to download a dataset for external consumption will need to be assigned to your user profile.

The Excel file password is: rcAHtHx&pN6cE3kL