Safety concerns (Important identified risks, important potential risks and missing information) in PBRER/PSUR and RMPs

Safety concerns (risks- important identified risks, important potential risks and missing information) can be considered the most scrutinized and most important part of any safety document such as PSUR/PBRER or RMP.

In PBRER, section 16 (esp 16.1 and 16.4) provide list and discussion on safety concerns whereas in RMP: part II, module SVII Identified and potential risks do.

Safety concerns include important identified and important potential risks, and missing information and in this article I intend to discuss each of them with definitions and examples along with significance, although I have written similarly in one of my previous article, I thought an article focused solely on practical side of providing safety concerns deserves a specific and separate discussion so here we are!

Points to consider for deriving safety concerns:

· One of the most intellectually rigorous task if you are working in DSRM (Drug Safety and Risk Management) verticals (E.g. PSUR and RMP).

· Mostly it is a medical reviewer activity/ duty.

· This is relevant for both RMP and PSUR medics.

· Consultation with manager or even QPPV may be required.

· Clients may at times become ‘protective’ of their molecule, but this is counter-productive big time.

· If a theme of ‘hiding stuff’ is noticed, this would cause major perception deficit when it comes to how methodology and rigor for report are received by regulators.

· The more thorough and evidence-based approach, the better reports are (RMP and PSUR both).

Providing safety concerns for PBRERs and PSURs: from ICHE2C

Summary of important safety concerns at baseline means at the beginning of the reporting interval, against which new information and evaluations can be made.

The following factors should be considered when determining the importance of each risk:

· Medical seriousness of the risk, including the impact on individual patient;

· Its frequency, predictability, preventability, and reversibility;

· Potential impact on public health (frequency; size of treated population);

· Public perception of risk where it may impact public heath, e.g., avoidance of vaccines.

The summary should present the following safety information, as of the beginning of the reporting interval of the current PBRER

• Important identified risks

• Important potential risks

• Important missing information

For products with an existing safety specification (RMP), this will be the same as the safety specification: summary of ICH guideline E2E at the start of the reporting interval

For products without an existing safety specification, this section should provide information on the important identified and potential risks associated with use of the product, based on pre- and post-approval experience.

These may include, for example:

· Important adverse reactions

· Interactions with other medicinal products

· Interactions with foods and other substances

· Medication errors

· Effects of occupational exposure

· Pharmacological class effects

Sections “Risk considered important for inclusion in the list of safety concerns” and “Risk not considered important for inclusion in the list of safety concerns in RMP:

Whether to consider a risk important or no depends on various factors, such as:

- Risk seriousness

- Risk frequency

- The risk-benefit impact of the risks.

For risks not taken forward as safety concerns, the information can be grouped by reasons for not including them as safety concerns.

Safety concerns in RMP: How regulatory thinking evolved

What changed with reference to safety concerns in GVP module 5 Rev 2?

Let’s discuss each subtype of safety concerns individually with examples:

Important identified risks:

· Identified risk is an untoward occurrence for which there is adequate evidence of an association with the medicinal product of interest.

· An identified risk that could have an impact on the risk-benefit balance of the product or have implications for public health is considered important identified risk.

· From all the identified risks of the medicinal product, the RMP should address only the risks that are undesirable clinical outcomes and for which there is sufficient scientific evidence that they are caused by the medicinal product.

· Risk may not be “important” if it is infrequent, non-serious, reversible, and readily managed with no significant impact on the individual patients or public health.

· A common ADR may not constitute an important risk if it is not linked to clinically significant adverse sequelae.

· Not all reported adverse reactions are necessarily considered a relevant risk of the product in a given therapeutic context.

· To be considered as important identified risk, adequate causal association should be indicated in RSI section 4.4 (warning and precautions), 4.5 (drug interactions)/ 4.6 (pregnancy and lactation) AND the event should also be mentioned in section 4.8 (Adverse reactions/undesirable events) of the RSI.

· This is important to understand, inclusion of any event in section 4.8 of the RSI itself is indicative of the fact that cases of the event are already identified.

· If event is not mentioned in 4.8 but just in 4.4/4.5/4.6, we should refrain from considering it as an important identified risk.

· Important: Adverse reactions included in section 4.8 of the summary of product characteristics (SmPC) are also considered identified risks (but not all of them are important identified risks).

Examples of important identified risks-

· An adverse reaction adequately demonstrated in non-clinical studies and confirmed by clinical data;

· An adverse reaction observed in well-designed clinical trials or epidemiological studies for which the magnitude of the difference, compared with the comparator group on a parameter of interest suggests a causal relationship;

· An adverse reaction suggested by a number of well-documented spontaneous reports where causality is strongly supported by temporal relationship and biological plausibility, such as anaphylactic reactions or application site reactions

· Non-clinical findings confirmed by clinical data, clinical trials, epidemiological studies, and spontaneous data sources, including published literature.

· They may be linked to situations such as off label use, medication errors or drug interactions.

Events mentioned in SmPC/RSI sections 4.4, 4.5 or 4.6 AND also in 4.8 (Non-negotiable for practical purposes) are important identified risks!

Regulatory thinking on safety concerns:

· As per SCOPE WP8 document, this is what regulators look for while reviewing proposed safety concerns: Ask yourself if the risk is potentially so serious and so frequent that it could impact on the B/R of the product, or that specific guidance/tools are needed to ensure correct use of the medicine.

· A risk may not be “important” if it is infrequent, non-serious, reversible and readily managed with no significant impact on the individual patients or public health.

· A common ADR may not constitute an important risk if it is not linked to clinically significant adverse sequelae.

Important potential risks:

· Any potential risk that could have an impact on the risk-benefit balance of the product or have implications for public health is important potential risk.

· Difference here is there is suspicion of association of the product and an adverse event which is not proven yet for potential risks.

· Identified risk means evidence of association between the drug and event (such as cases/ section 4.8 of RSI), whereas potential risk means suspicion of association between drug and event which is yet to be proven.

Examples of important potential risks:

· Non-clinical evidence of an AE that is not yet proven in clinical trials

· Drug class effects

· ‘Use in risks’ (such as use in special population for example, use in elderly, use in paediatric patients, use in patients with liver impairment, use in patients with renal impairment etc)

· Events mentioned in SmPC/RSI sections 4.4, 4.5 or 4.6 but not in 4.8

Events can occur with the use of molecule but evidence of association is not strong enough (just yet!) and that is the essence of important potential risk!

Missing information:

Not all unknown particulars can be considered as missing information.

Missing information relevant to the risk management planning refers to:

- Critical gaps in knowledge about the safety of a medicinal product for certain anticipated utilization (e.g. long-term use)

- Use in particular patient populations, for which there is insufficient knowledge to determine whether the safety profile differs from that characterized so far.

- To be considered a missing information, sufficient reason should be provided on why safety profile may differ in population (e.g. hepatic/renal impairment, children/elderly or pregnant women).

The absence of data itself (e.g. exclusion of a population from clinical studies) does not automatically constitute a safety concern.

Regulatory thinking on missing information as per SCOPE WP8 document:

  • Usually we only want to specify something as missing information if we want to study exposure in those patient groups further.
  • Subgroups of the targeted populations that are expected to frequently use the product and are not included in the clinical development program can be considered as missing information, e.g. patients with impaired renal and hepatic function, children, elderly, pregnant and lactating women, off-label use.
  • Exclusion criteria should not automatically translate into missing information.
  • The assessor should rather consider clinical relevance and likely real-world use to be of importance for the missing information.
  • If the indication implies chronic use, long-term use should be considered as missing information if not studied.
  • If studies of relevant drug-drug interaction have not been done, this should be considered as possible missing information.

Key sources for proposing safety concerns:

· CmDH (as available from )


· Previous report (PSUR/RMP)

When safety concerns are required to be proposed?

  • If none of the above is available or CCDS is recently updated and RMP is not as per current safety information, medical reviewer may need to propose safety concerns.
  • Safety sections of the RSI provide the basis for safety concerns in such situations.

To sum it up: How (and when) to provide safety concerns for PSUR/PBRER:

  • Check CMDH for the same molecule
  • If safety concerns are available and CMDH is updated recently (let’s say 1–2 years) we can consider the same
  • If not, consider other regulatory website such as EPAR
  • Previous report containing safety concerns such as PSUR or latest RMP
  • If nothing of the above is available, company medical reviewer can provide safety concerns based on applicable RSI, SmPC or CCDS

RSI is the single most important key routine risk minimization tool!

Safety sections of the RSI (4.3 to 4.8) include:

· 4.3 Contraindications

· 4.4 Warnings and precautions

· 4.5 Drug interactions

· 4.6 Pregnancy, lactation and fertility

· 4.7 Effects on ability to drive and use machines

· 4.8 Undesirable effects/ adverse events

Based on inclusion of relevant information in RSI, safety concerns can be proposed accordingly.

All events in section 4.8 of the RSI are by default ‘identified’ (since we have cases known- a prerequisite for inclusion in 4.8 to begin with) but not all of them are important! All events discussed in section 4.4 of the RSI are by default ‘important’ but not all of them are identified (as cases may or may not be reported)!

Proposing/deriving safety concerns based on RSI/SmPC:

We can simplify the formula:

· Section 4.4 + Section 4.8= Important identified risk

· Just section 4.4/ 4.5/ 4.6 or if mentioned as a drug class effect= Important potential risk

· Impact on individual patient is one parameter we need to consider when proposing risk characterization as well.

Formulas for safety concerns:

Section 4.4/4.5/4.6 + Section 4.8= Important identified risk

Just section 4.4/ 4.5/ 4.6 or if mentioned as a drug class effect and NOT in 4.8= Important potential risk

Safety topics (Identified and potential risks) of interest:

Safety topics derived from specific situations/data sources are thought to be of particular interest for the risk identification discussion in module SVII, and should be discussed such as:

· Overdose: Potential harm from overdose, whether intentional or accidental, for example in cases where there is a narrow therapeutic margin or potential for major dose-related toxicity, and/or where there is a high risk of intentional overdose in the treated population (e.g. in depression).

· Medication error: Potential for risks resulting from medication errors, defined as an unintended failure in the drug treatment process that leads to, or has the potential to lead to, harm to the patient. Medication errors leading to important risks, identified during product development including clinical trials, should be discussed and information on the errors, their potential cause(s) and possible remedies given.

· Infection spread: Scenario in which due to the nature of the manufacturing process or the materials involved, inherent chance of infection spread is identified.

· Off-label use: potential for off-label use, when differences in safety concerns between the target and the off-label population are anticipated, the potential risks arising from the off-label use

· Drug class effect risks: If an important identified or potential risk common to other members of the pharmacological class is not thought to be an important identified or important potential risk with the concerned medicinal product, the evidence to support this should be provided and discussed.

· Risks in pregnant and lactating women, e.g. teratogenic risk: Direct or through exposure to semen.

· Effect on fertility — appropriate risk minimization measures should be considered.

· Risks associated with the disposal of the used product (e.g. transdermal patches)

· Risks related to the administration procedure (e.g. risks related to the use of a medical device (malfunction which impacts on the dose administered, risk of variability in complex administrations)

· Paediatric safety issues that are particular causes of concern in paediatric population.

· Drug interactions: important risks related to identified and potential pharmacokinetic and pharmacodynamics interactions should be discussed in relation to the treatments for the condition, but also in relation to commonly used medications in the target population.

Lifecycle of an event in PVG:

- This is a very interesting topic to understand.

- What is the ultimate goal of whole DSRM activity: appropriate inclusion of an event in the RSI/SmPC/PI

- When regulators or MAH become aware of potential association of an event with a drug → Event under monitoring in section 15 of PBRER → Signal → Risk (safety concern) → Variation → Inclusion in the PI/SmPC in an appropriate section.

  • Inclusion of any event in section 4.8 Undesirable events of the RSI/SmPC is the highest degree of PVG by all means!
  • Deriving and providing safety concerns for PSUR/ PBRER or RMP is a scientifically vigorous task and needless to say, highly scrutinized by all stakeholders including QPPV, client and regulators. I hope you liked the article!! Please leave your feedback in the comments and have a great day!
  • Look forward to discussion :-)



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Aditi Sheth

Aditi Sheth

MBBS, Aggregate reports manager based in Bangalore, India, Decent and ambitious, curious reader