SOP for Collection, Processing and submission of Individual Case Safety Reports (ICSRs)

Purpose

Purpose of this SOP is to lay down a process for collection, Processing and Submission of Suspected Adverse Drug Reactions for ANDA Holder products to the Regulatory Agency.

As per Legislative regulations of 21CFR314.80, it is responsibility of ANDA Holder.

Scope and Aims

ANDA Holder have legal obligation to maintain the records of all suspected Adverse reactions to their products and maintain a proper pharmacovigilance system to ensure about an appropriate action towards the drug to reduce the Adverse reports occurrence.

This procedure applies to all personnel of ANDA holder, Service providers and affiliates of ANDA holder.

Responsibility

• Data entry Person: Responsible for entering the data from source document into the database structural field.
• Quality Check person: Responsible for performing quality check at data entry level and to evaluate the entire case with no errors.
• Medical Reviewer (MR): Responsible for mentioning the company causality and labelling of the event and event subsuming.

Mentioning the Final medical assessment comment in the narrative

Procedure

Sources of Adverse Event reports:

• Unsolicited reports from health care providers/consumers
• Reports from Regulatory Authorities
• Reports from licensing partners, distributors, and others
• Medical information center reports, fax
• Scientific literature
• Reports from Media (Television, Internet, websites, Newspapers)
• Reports from Non-interventional studies

Note: Apart from Literature, ANDA holder must forward whatever the reports from other sources to XXX within 2 Business days.

Scenarios to be considered as ADRs:

• Unexpected/expected ADRs/Unexpected benefits
• Lack of efficacy cases
• Drug exposure during pregnancy/breast feeding/contraception
• Overdose/misuse/abuse/off-label use
• Medication error/near miss/occupational exposure
• Transmission of suspected infectious agent
• Interactions (drug-drug, drug-food, drug-disease)

Collection and assessment of ADRs:

The minimum criteria to consider a case as valid is

1. Identifiable reporter (HCP or Consumer with contact details)
2. Identifiable Patient (Initials, Date of birth, age, gender, age-group)
3. Suspect drug
4. Suspected Adverse drug reaction

• ANDA holder should not include the names and addresses of individual patients in reports. instead, should assign a unique code for identification of the patient. The applicant should include the name of the reporter from whom the information was received as part of the initial reporter information, even when the reporter is the patient. The names of patients, health care professionals, hospitals, and geographical identifiers in adverse drug experience reports are not releasable to the public under FDA's public information regulations.
• Upon receipt of Adverse Reaction report, duplicate check will be done for the respective case in YYY database. If it was found as duplicate, then this case will be handled as follow-up as per scenario. If no duplicates were found, then a Unique number as (ANDA holder (MMM)-Service Provider (PHC)-Company Receive date (yyyy-mmm-dd)-Source (Lit or spon)-sequence number (0001)) to be given for identification and further references. Eg as: MMM-PHC-2021-Nov-20-LIT-0001
• Cases can also have sequence number as per previous SOP during the YYY set up and transition period.
• All cases must be assessed for Severity and seriousness criteria.
• Seriousness Criteria as follows: Serious adverse drug experience. Any adverse drug experience occurring at any dose that results in any of the following outcomes such as

1. Death,
2. A life-threatening adverse drug experience,
3. Inpatient hospitalization or prolongation of existing hospitalization,
4. A persistent or significant disability/incapacity, or a congenital anomaly/birth defect.
5. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.

• Unexpected adverse drug experience: Any adverse drug experience that is not listed in the current labeling for the drug product. This includes events that may be symptomatically and patho-physiologically related to an event listed in the labeling. but differ from the event because of greater severity or specificity. For example, hepatic necrosis, elevated hepatic enzymes or hepatitis, cerebral thromboembolism, cerebral vasculitis.

Processing of ADRs:

• Day Zero 0 (the clock starts for reporting) is the date of receipt of spontaneous report by any affiliates of ANDA holder. It is CRD (Company Receipt Date).
• Post marketing 15-day Alert reports: The ANDA holder must report each adverse drug experience that is both serious and unexpected, whether foreign or domestic, as soon as possible but no later than 15 calendar days from initial receipt of the information by the applicant. The follow ups for the 15-day alert reports also to be submitted within 15 calendar days of receipt of new information or as requested by FDA. If additional information is not obtainable, records should be maintained.
• XXX must evaluate a case report and send notification about reportable cases to ANDA holder within 7 business days.
• ICSRs for serious, expected, and nonserious adverse drug experiences must be submitted in PADERs.
• The EMEA website will be referred for IME/DME List
• Information to be presented on ICSR as follows:

a. Patient information:

• Patient identification code
• Patient age at the time of adverse drug experience, or date of birth
• Patient gender; and
• Patient weight.

b. Adverse drug experience:

• Outcome attributed to adverse drug experience
• Date of adverse drug experience
• Date of ICSR submission
• Description of adverse drug experience (including a concise medical narrative)
• Adverse drug experience term(s)
• Description of relevant tests, including dates and laboratory data; and
• Other relevant patient history, including preexisting medical conditions.

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c. Suspect medical product(s):

• Name
• Dose, frequency, and route of administration used
• Therapy dates
• Diagnosis for use (indication)
• Whether the product is a prescription or nonprescription product
• Whether adverse drug experience abated after drug use stopped or dose  reduced
• Whether adverse drug experience reappeared after reintroduction of drug
• Lot number, Expiration date
• Concomitant medical products and therapy dates.

d. Initial reporter information:

• Name, address, and telephone number
• Whether the initial reporter is a health care professional; and
• Occupation, if a health care professional.
• ANDA holder information, name and contact office address, Telephone number
• Report source, such as spontaneous, literature, or study
• Date the report was received by ANDA holder
• Application number and type
• Whether the ICSR is a 15-day "Alert report"
• Whether the ICSR is an initial report or follow up report; and
• Unique case identification number, which must be the same in the initial report and any subsequent follow up report(s)

All received ADRs must be tracked with identification numbers and must be archived.

Follow-up of ADRs:

• Follow-up of ADRs must be done by timely manner by PV Department.
• First follow-up to be done within 3 business days from CRD.
• Follow-up of cases (serious/non serious) to be made for three attempts in 2 weeks of LRD. If no response received, case can be closed
• It is important to follow up all pregnancy cases where fetus could have been exposed to product. Long half-life must be into consideration while assessing the pregnancy cases.

Case Processing, QC (Quality Check), MR (Medical Review), Submission:

• Case validity checking.
• Duplicate checking: check the YYY Database to identify if any duplicate case or new case.
• The cases must be submitted to the FDA in electronic format through SRP (Safety Reporting Portal) Portal or E2B Gate way via YYY data base.
• The ANDA holder must report each adverse drug experience that is both serious and unexpected, whether foreign or domestic, as soon as possible but no later than 15 calendar days from initial receipt of the information by the applicant. The follow ups for the 15-day alert reports also to be submitted within 15 calendar days of receipt of new information or as requested by FDA. If additional information is not obtainable, records should be maintained.
• ICSRs for serious, unexpected must be processed. Must be submitted in 15 calendar days.
• FDA has accepted electronic submissions of both expedited and non-expedited Individual Case Safety Reports (ICSRs) for human drug and nonvaccine biologic products. To date, FDA has only accepted electronic submissions of ICSRs in the XML format.
• The case data need to be manually entered by the respective users in the YYY Database and submitted to FDA via E2B Gateway. Related source attachments must be in the PDF format.

Case Processing: Cases received from different sources of information.

1. Check the validity of case
2. Case needs to be created in YYY Database if no duplicates
3. A Unique number to be given to identify and track the case
4. All Valid and Reportable cases must be filled and archived
5. Supporting documents to be attached

Quality Check (QC):

• QC findings and corrections must be recorded in the comments section of Database.
• Quality must be maintained not less than 95%. This step will be done at QC level.
• Any Significant errors (errors with respect to 4 Minimum criteria) noted in DE (Data Entry) then, the Quality deduction for each error is 3%
• Any Non-significant errors (errors with respect to other fields) noted in DE, then the Quality deduction for each error is 2%

This evaluation will be tracker in Form 1 (Quality Metrics).

Medical Review:

• Medical Judgement and Causality assessment must be done in Medical Review step and must be recorded in comments section of Database.
• Listedness will be checked as per the product labelling information
• MR refer the WHO Causality assessment guideline as a standard for the causality assessment

Submission:

• Submission of Valid cases through SRP Portal or YYY Database E2B Gateway
• Required supporting documents to be filed in PDF format.

Roles and responsibilities:

Case duplicate check, Data entry (DE), Quality Check, Medical Review and Submission activities are handled by the users who has undergone the project trainings and related activities as per their roles mentioned in the Job Description.

Abbreviations

ANDA-Abbreviated new drug application.

SRP- Safety Reporting Portal.

MR-Medical Review.

WHO- World health organization.

Annexure

Form-1: Quality Metrics

References:

USFDA Guidelines.

Revision History

Nil

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