13. Regulatory Reporting

When a healthy volunteer/patient suffers a negative reaction to a drug an adverse event is reported and filed containing various data about the drug, its dose, its purported effect, patient health prior and after an adverse event, patient reaction to the drug prior and after adverse event among others.

Sources of Adverse event reporting: The information about adverse event collected from different sources. Below are types of reports – 

1. Spontaneous / Voluntary reports
2. Clinical trials and Post marketing studies
3. Regulatory reports
4. License partner reports
5. Literature reports

Once report is received it is checked for following four parameters

to consider it as a valid case;

1. Identifiable patient
2. Identifiable reporter
3. The drug suspected of causing reaction/event
4. Adverse event or fatal outcome

Once these conditions are satisfied an ICSR is filed for the adverse event that has occurred. 

The event is categorized based on the level of serious health effect on the affected patient. Events are categorized as Adverse event (AE), Severe adverse event (SAE), Severe adverse reaction (SAR), Suspected unexpected serious adverse reaction (SUSAR), Life-Threatening (LT). Once ICSR assessed for seriousness, causality and labelling, case will be submitted to regulatory authority.

ICSR reporting timelines primarily vary based on the seriousness of an event and the nature of the reporter. Also, timelines in pharmacovigilancemake use of a concept called calendar days rather than weekdays or weekends.

Each Report Can Make a Difference.

Types of reports provided to regulatory authorities:

Pharma companies are required to report safety information to regulatory authorities according to specific timelines. This mandatory reporting includes:

• Expedited Reporting
• Periodic Reporting

What is Expedited Reporting?

• Worldwide regulatory authorities require expedited submission of individual safety reports received by drug companies that meet certain, specific criteria, including criteria for the seriousness of a clinical event, whether or not a report has been previously observed and an assessment of the event’s relatedness to administration of the product.
• The decisions on when and how to report individual case reports are based on the requirements of each country’s local law.

Expedited reporting timelines:

Globally ICSR are reported under 3 categories :

1. Clinical Death/Life threatening cases and SUSAR (Suspected Unexpected Serious Adverse Reaction) cases are reported within 7 calendar days to the NCA (national competent authorities)/HA (health authorities). 
2. Clinical trial other Serious cases and safety issues are reported in 15 days calendar days timeframe.
3. Serious post marketing cases are reported within 15 calendar days to the NCA (national competent authorities)/HA (health authorities)
4. Non-Serious cases are reported within 90 calendar days to the EU health authority (EMA). Not mandatory for non-EU countries.

The clock starts (day 0) on the date when any personnel of the MAH first receive a case report that fulfill the minimum criteria

What is Periodic Safety Reporting?

• Periodic safety reports are submitted to regulatory agencies in accordance with government regulations.
• The purpose of these periodic safety reports is to provide an aggregate review and analysis of all adverse event reports received over a defined time period.
• Periodic reports provide an overall safety re-evaluation at defined time-points and contribute to the ongoing assessment of whether changes should be made to product information or the risk management plan. 
• The timing and content of periodic reports for marketed products are based on local requirements (ie, every 6 months, every year, every 3 years, etc).
• In most countries post-marketing periodic reports are referred to as a Periodic Safety Update Reports (PSURs) or Periodic Benefit Risk Evaluation Reports (PBRER)s. In the United States these reports are referred to as a Periodic Adverse Drug Experience Reports (PADERs).

Drug Safety Update Reports (DSUR): 

• Comprehensive, thoughtful annual review and evaluation of pertinent safety information collected during the reporting period related to a drug under investigation, whether or not it is marketed. 
• DSUR preparation starts after the first authorization of a clinical trial anywhere in the world. This also creates the Developmental International Birthdate (DIBD) for the drug. The DIBD of an authorized drug is the IBD (International Birth Date), the date when the product was first authorized in any country of the world. 
• The Heads of Medicines have concluded in this document that a DSUR should be submitted until the last visit of the last patient in the country(ies) concerned. If the trial has ended in a particular member state the DSUR does not have to be submitted there – only in countries where the study is still actively continuing. If there are several trials going on in that country, the DSUR must be submitted till the last patient’s last visit in the last study.

Periodic Safety Reporting timelines:

EU Periodic reports:

Every 6 months until product marketed for 2 years in EU, then annually for 2 years, then every 3 years

US Periodic reports: 

For 3 years after approval, quarterly periodic report 

After 3 years, annual reports

Regulatory authorities worldwide reviews the results of laboratory, animal, and human clinical testing done by companies for pre marketed products before approving and monitor the benefit/risk balance of marketed drugs, in accordance with each country’s local or regional laws and regulations. 

Regulatory actions:

Based on the reports (ICSR, DSUR and PSUR), regulatory authorities may take actions such as;

• Requesting that drug companies update the information in the drug’s label 
• Conduct additional risk assessment or minimization activities. This may include additional research (REMS or registries etc..) to evaluate a safety risk or communications to health care providers/consumers to bring attention and emphasize the new information included in the updated product label. 
• In some instances, regulatory authorities may decide to directly communicate with the public.
• Product withdrawal