A very brief article on medication errors in aggregate reports

A few days ago, I wrote an article on medication misadventures, medication errors and related concepts on Linkedin. If not read already, you can read it here:

Medication misadventures, medication errors and related concepts in PVG | LinkedIn

The article you’re about to read concerns about various ways to present medication errors in PBRERs and nuances thereof.

A slight section may be repeated but a lot (90%) of material is new in this article. Without much adieu, here we go!

Definition of medication errors:

  • A medication error is an unintended failure in the drug treatment process that leads to, or has the potential to lead to, harm to the patient.
  • A medication error is an unintended failure in the drug treatment process that leads to, or has the potential to lead to, harm to the patient.
  • A failure in the drug treatment process does not refer to lack of efficacy of the drug, rather to human or process mediated failures.
  • Medication error is a human or process mediated treatment failure and not due to medicine itself.

Medication errors include any and all of these steps:

  • Prescribing (Drug prescription errors)
  • Storing
  • Dispensing
  • Preparation for administration
  • Administration of a medicinal product
  • Potential medication error

Two types of medication errors:

Active errors:

  • Errors occurring at the point of the interface between humans and a complex system

Latent errors:

  • The hidden problems within healthcare systems that contribute to the event

Medication error section in PBRERs: What the regulators want to see?

What regulators want to see in this section:

  1. The MAH has included and adequately discussed all ME cases
  2. Root cause analysis of types of medication error
  3. How many medication error related cases had AEs
  4. How many medication errors actually caused AEs
  5. MAH comment delineating overall analysis, what is known, what is mentioned in the RSI or other reference document and how the MAH wants to prevent future medication errors.

Search strategy for medication errors and nuances of medical review of the section:

Search strategy:

  • Meddra has an HLGT concerned with medication errors.
  • However, many of the ADR reports with the HLGT term medication error are not medication errors in accordance with the definition (e.g. intentional poisoning, off-label use, interactions, quality issues, irrelevant exposure terms, information of incompatibility etc.)
  • To alleviate this problem, MEDDRA has included SMQs (with broad and narrow scopes) dedicated to Medication error.
  • However, medical reviewer oversight is necessary to identify and include only ‘true’ medication error cases in the PBRER section analysis.
  • Some PTs/ concepts are notorious for being prone to being considered as medication errors when actually they are not.
  • In particular, PTs related to overdose, need careful event-by event consideration for inclusion or exclusion in section 9.2 PBRER.
  • In overdose related PTs found during reporting period, focus should be on intention behind overdose.
  • By definition, medication errors have to be unintentional, hence anyPTs related to intentional overdose would by default be not considered as medication error.
  • On the other hand, PTs such as accidental/unintentional overdose and analogous ones would be considered as medication errors.
  • In PTs simply saying ‘overdose’, thorough review of the whole narrative, ideally by a medical reviewer should be done and decision should be made.

A good example where medical reviewer decisions matter:

  • One gray area would be PT overdose coded in a narrative with patient having a tendency of drug abuse.
  • While theoretically, a patient with drug abuse is prone to accidental overdose due to adverse (massively if I may say so) impact of abused drugs on judgement capacity of an individual and positive reward generated by the human brain during such abuse (such as in ‘Barbiturate fog’ in which patient loses the insight of how many tablets already consumed and keeps on consuming more and more → resulting in unintentional/ accidental overdose and ergo, is a medication error), often co-existing depression and/or suicidality can also mean the overdose can be intentional in such patients.
  • Hence, medical oversight can really make a difference in such medication error cases.

Ways to present medication errors in section 9.2 of PBRERs:

There are multiple ways to discuss and present medication errors in the section 9.2 of the PBRERs.

Basic components of such discussions may include:

  • Total number of medication error cases
  • A brief analysis and categorization of these cases- taking into account- case sources, Case seriousness (non-serious vs serious)
  • How many cases categorized as medication error were with AE as opposed to how many had no associated AE
  • The most frequent PTs, any context thereof (such as mass reports in media etc)
  • Cases ideally in tabular format, for all PTs, their classification in one of the main types of ME (such as drug administration error, drug prescription error and drug dispensing errors)
  • Root cause related to medication error (identified from narrative review with focus on what led to medication error- more on this later)

Medication error cases tabular analysis:

Add alt text

MAH comment for medication error section:

  • Usually drafted by medical reviewer assigned to the PBRER
  • For some clients, may be drafted by PBRER authors however, ultimate ownership lies with the MR

Basic structure of a MAH Comment in ME section:

(a) What is known about medication errors from RP analysis:

  • One or two sentences summarizing overall aggregate analysis of the identified medication errors
  • Sentences about how Mes led to Aes

(b) What was already known (relevant part to ME from RSI goes here)

(c ) Line regarding if any trend or underlying pattern identified about medication error

(d) Line regarding if any new significant safety information related to ME identified

(E) Action proposed by MAH for further future reports if any or a sentence stating the MAH will continue to monitor for ME

Other more subjective ways for presentation of medication errors:

  • While the tabular format is ideal for a higher volume of cases, if PBRER is a short duration PBRER and/or there are less number of medication error cases, more subjective approaches can be considered
  • Old fashioned way would be to discuss individual narratives for medication error cases with focus on medication error itself, related Aes and how Mes led to AES if applicable
  • This individual narrative discussion approach is outdated and feasible in very low volume of cases (ideally if cases during RP are less than 10 or so)
  • In medium or high volume medication error cases in a PBRER, the other and more suitable approach would be tabular analysis or under two separate titles of ME-related cases with harm/AE and those without AE/harm

Risk categorization of medication error:

  • Any risk minimization measures proposed by the MAH to reduce confusion between newly marketed and existing products (where significant changes to the marketing authorisation or line extensions have been introduced) should be discussed in the RMP.

The decision whether to classify the adverse outcome due to a medication error as an important risk will depend on:

1- The number of cases reported in clinical trials or in post marketing use

2- The level of risk associated with this error

When to make medication error potential risk?

  • Situations where medication errors may occur but where the impact of medication errors occurring is uncertain may represent a potential risk


  • Risk of overdose resulting from inaccurate dosing of an oral liquid medication
  • Risk of decreased efficacy resulting from difficulty using the administration device

ME can occur but impact uncertain → Potential risk

When to consider medication error as identified risk

  • Where reports of medication errors have been received which have resulted in adverse outcomes, medication error (specifying the adverse outcome) should be considered an identified risk
  • So cases identified due to medication error → Identified risk

When to consider medication error as an important safety concern:

  • A medication error leading to a risk which impacts on the benefit-risk balance of the product or which has implications for public health may be considered an important safety concern and included in the RMP.
  • Both routine and additional risk minimization measures may be implemented to reduce the risk of medication errors.

MAH obligations for medication errors:

  • To describe and discuss patterns of medication errors and potential medication errors within every periodic safety update report (PSUR), even when these are not associated with adverse outcomes.
  • Development safety update reports (DSURs) should also include any evidence of clinically significant medication errors.
  • During the product development process, applicants should consider the various sources of medication error, their relevance for the product and the likely impact on the balance of risks and benefits
  • Once the product is marketed, MAHs should consider whether any significant changes to the marketing authorization.

The context of reports of medication errors in aggregate reports and RMP:

The context of product use should be considered and discussed in relation to these reports, including:

  • The setting of use
  • Stage of medication process
  • Category (type) of medication error
  • Contributing factors
  • Medicinal products involved
  • Variables amongst the treated population
  • Patient outcome
  • Seriousness
  • Region/country of occurrence
  • Mitigating factors

EMA Regulations regarding medication errors:

  • EMA’s role is to coordinate the EU pharmacovigilance network and to support pharmacovigilance through standards, systems (including EudraVigilance) and services.
  • EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) is responsible for the coordinating the assessment and monitoring of safety issues and all aspects of risk management planning. The PRAC’s responsibilities in relation to medication errors include:
  • Assessing potential medication errors at all stages of a medicine’s product life-cycle in risk management plans (RMP), including errors during product development;
  • Providing recommendations for regulatory action on safety issues arising from errors associated with the use of medicines authorized in the EU;
  • Monitoring the effectiveness of specific measures to prevent or minimize the risk of medication errors, as described in the RMP;
  • Including data on any medication errors in the reporting period in each periodic safety update report regardless of whether it is associated with adverse reaction(s). This information feeds into the continuous evaluation of the benefits and risks of a medicine.
  • In addition, EMA’s Name Review Group routinely assesses whether the (invented) name of a medicine as proposed by the manufacturer could create a public-health concern or potential safety risk, including medication errors.

Approaches by the FDA:

  • The US Food and Drug Administration (FDA) has issued guidance on safety considerations for product design to minimize medication errors
  • This guidance is complementary to EU guidance and is not binding in the EU, but may be useful to consider:

The FDA guidance recommends two tools in particular:

1- FMEA “failure mode and effects analysis”

2- Human factors: “simulated use testing” (also known as “human factors” or “usability” or “user” testing)

  • However, other risk management tools are available, including the “Fault-Tree-Analysis” and “Hazard Analysis”, which may be equally effective in the management of risks

Failure mode and effects analysis (FMEA):

  • The Institute for Safe Medication Practices (ISMP) has issued guidance on the principles of conducting failure mode and effects analysis (FMEA)
  • FMEA involves analysis of all the potential sources of medication error before they occur, in the situations under which they may occur (e.g. prescribing, dispensing, preparation and administration).

Points considered for FMEA of Medication errors:

· The processes in each situation

· Possible failures (what might happen)

· The possible causes

· The effects on the patients

· The severity of the effect on the patient

· The probability the error may occur (which collectively suggest how much of a hazard is presented)

· The proposed actions to reduce the occurrence of failures

Human factors testing

  • Human factors testing can explore whether instructions for use can be adequately understood and followed by users
  • Where simulated use testing has been performed, the results of this can be provided as supporting evidence in EU marketing authorisation applications
  • Such data may also be requested during the assessment of the application if assessors have concerns over the risk of medication errors

Human factor analysis methods for ME:

Other methods of human factor engineering to inspect the usability of the product:

1- Cognitive walkthrough

2- Heuristic evaluation

Task analysis methods such as:

  • PCA- The “perception-cognition-action” (PCA) analysis
  • Can be carried in the earlier stages of product development to reduce risk of medication error

General considerations for potential sources of medication error:

Product design:

  • Applicants should proactively consider all aspects of the design of the product
  • How it will be used (how)
  • In which environment it will be used (where)
  • Who will use it (who)
  • Conduct a suitable analysis of the potential for medication errors

MAH should think Who, how and where of use and plan analysis accordingly

This was the one brief, to-the point article on medication errors, way to present them in aggregate reports and other information, that too on my birthday!

I hope you liked this article and look forward to know and discuss your thoughts in the comments section below!

Happy learning!

Recommended further reading:

Read the first medication article here:

Medication misadventures, medication errors and related concepts in PVG

Medication misadventures, medication errors and related concepts in PVG | LinkedIn



🏳️‍🌈 Aditi Sheth 🏳️‍🌈

🏳️‍🌈📚 Bookworm fueled by curiosity | 750+ Certificates | PBRER | Aggregate reports | Artificial Intelligence | Trained Psychologist | Introvert | ISFJ |MBBS