Confusions in Drug Safety & Pharmacovigilance

Dec 27, 2018
Bart Cobert

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert


I had originally planned to discuss Brexit in this post. A 500 plus page plan for the post-Brexit era after March 29, 2019 was created by the UK and set for a vote by the UK Parliament in mid-December. This was postponed till January. There is no assurance that it will be approved though. This may mean that the UK will exit the EU with “no deal” which many say will be a catastrophe.

In our area of Drug Safety(DS) and Pharmacovigilance(PV), there is talk of drug shortages in the UK and Ireland and perhaps elsewhere. The new/updated drug and PV regulations for the UK and perhaps the EU and some member states should be in place by the changeover date. This has not happened and it’s really unclear as of this writing about what will, in fact, occur. I’ll address it later in 2019 when it becomes clearer or, perhaps, only less unclear.  Companies should prepare to have to deal with separate UK and EU requirements as of March 29, 2019. Hopefully we’ll have better information in the first 100 days of 2019.


So Brexit is our first confusion and probably the biggest one for anyone dealing with pharmaceuticals in the UK and Europe, PV included. Now we’ll address some other confusing areas that are fairly well known to the PV community but are worth a review.


Some Basic Terms

One might think that our terminology would have been standardized by now given the international bodies involved in DS and PV.  However not all terminology has been standardized – perhaps because of these very international bodies!


Approved vs. Authorized  vs. Marketed

Basically approval refers to the acceptance by the government or regulatory authority (agency) that a drug product is allowed to be marketed to the public. The US FDA uses this term. In Europe and elsewhere the term for this is authorized or authorization. The spelling varies in US vs. UK English (“z” in the US – pronounced by Americans as “zee” and by most others as “zed” vs “s” in the EU and elsewhere).

Approval/authorization is not necessarily the same as “marketing.” A drug may be approved by the health agency but further steps may need to be taken before it actually goes on the market. This might include pricing approval, acceptance by insurance companies or other payers such as national health services, business reasons, manufacturing issues, etc. In some cases a product might be approved for a seasonal disease and marketing held until the appropriate time for use,such as influenza vaccines. Most, if not all, periodic reporting (e.g. NDA periodic reports, PSURs, PBRERs etc.) refers to authorization, not marketing.



This term is used in the EU for clinical trial adverse reactions that are EMA that are serious, unexpected not listed (i.e., unexpected), suspected to be due to the drug, adverse reactions in the reference safety information.

In the US, the FDA uses the same/similar concept: suspected, unexpected, serious adverse r However, the two words beginning with “s” are reversed in this terminology. The FDA does not use the term SUSAR!



Date format is an issue that is not limited to DS and PV, but is a global issue in all fields. There are several formats used throughout the world. This is the situation when only numbers are used to express a date rather than the writing the name of the month and using four digits for the year.

There are three basic formats used: YMD, DMY, MDY. Some countries use two formats at the same time (DMY and MDY or DMY and YMD) where Y=Year, M=Month, D=Day.

This obviously can pose problems. For example 10/4/19 would be October 4, 2019 in the US and April 10, 2019 in other countries. If two digits are used (e.g. a leading zero for single digits) this is even more complex: 10/04/12 could be October 4, 2012, April 10, 2012 or April 12, 2010 (or even perhaps the year 1910).

In the US and the Philippines the MDY system is used. The DMY system is used in much of Europe, Russia, Indonesia, Latin America, Australia, India and others. The YMD system is used in China, Canada, Japan, parts of Europe. Other countries use the other format or mixtures. So, in fact, the US style (MDY) is used in countries with only about 450 million people. The DMY system is used by countries with some 3.5 billion people and the YMD system in countries with about 1.8 billion people.

So obviously it is important for companies, governments etc. to straighten out the date format used. In electronic systems such as for DS and PV, a single format can be forced and this is often the case in pharmacovigilance. If need be, the reports generated from the database could use a different format for different countries.

The most difficult situation is in narratives where the writer may use one system in and the reader, in another country, uses a different format and reads the date incorrectly.

This mess cries out for standardization. The International Standards Organization (ISO) has issued a standardization document, ISO 8601 which proposes the YMD standard as well as discussing other special situations such as dates lacking a year or day, etc.

However, the transition from the current systems to this would require massive changes in data, both new and old.  So don’t expect changes anytime soon.

For more information see the articles in Wikipedia (or elsewhere) on “Date format by country” and ISO 8601.


Decimals and Thousands

Two different methods are used to separate the whole number and decimal part:

1.51 vs 1,51.

That is, a period or a comma are both used. In the US, Canada (except francophone Canada), Australia the period is used. Most European countries use the comma as well as some Asian and African countries. Some countries use both! This is much less of a problem (usually) as the context will generally make clear that the number is a decimal.

To complicate matters further the separators for thousands may be either commas or periods or nothing at all. Countries that use commas for the decimal will use periods for the thousands and vice versa.

Examples: 2,543,678.91 vs 2.543.678,91 vs. 2 543 678,91 or 2 543 678.91

These two issues in DS and PV are uncommon. Nevertheless one should be aware of the differences.


Reference Document & Labeled vs Listed

In DS and PV, the term “reference document” is defined to refer to the document that is used to evaluate the safety (adverse events, reactions, SUSARs, etc.) for submission to regulatory authorities as expedited reports and periodic reports (PSURs, PBRERs, etc.). There are several of these, which differ somewhat for approved (marketed) products and unapproved (unauthorised) products in clinical trials.

Clinical Trials: In most clinical trials the reference document is the Investigator Brochure (IB). There is usually only one IB per drug. Complications arise if the product is also marketed and has an approved label (e.g. SmPC in the EU and Package Insert in the US). In some trials the approved label may be the reference document if the trial is being done within the approved patients, dose, etc. In some cases the approved labeling will be incorporated into the Investigator Brochure. One should clearly determine which reference document is being used in a trial and mention that clearly in the protocol or other study documents.

Marketed/Approved Products: The regulator-approved prescribing information (e.g., Package Insert or SmPC, etc.) may vary from jurisdiction to jurisdiction unlike the IB for trials where there is only one IB. So the approved labeling may vary from country to country for marketed drugs. Some SAEs or NSAEs may be in one label and not in another. This or these document(s) are used for determining whether an SAE is expected or unexpected.  This is used for expedited (15 day) reporting.

However since there are multiple labels, the issue of which should be used for aggregate reports such as PSURs and PBRERs arises. Another document was thus created for this called the company’s core safety information (CCSI). This document is created by the company and provided to regulators. The regulators usually do not “approve” it.

The CCSI contains the company position on the minimum safety information that should be in every regulator-approved label wherever the product is authorized for marketing. An event/reaction not found in the CCSI may be included in the regular-approved label, but not vice-versa. If the event/reaction is not found in the SmPC, it is considered unlabeled. If it is not found in the core labeling, i.e., the product’s CCSI, it is unlisted. If it is not found in the PI or SmPC etc. it is unlabeled. The CCSI is used to determine “listedness” for periodic aggregate reports in the post-marketing phase. If no CCSI exists another of the labels may be used with the regulators’ permission.

This system is complex but workable… and confusing.


So there we have it. Confusion in DS and PV. There are other areas that can be confusing and contradictory. If you have any other examples or situations, please feel free to let us know in the comments!


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