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Interpreting fuzzy regulations: What literature should I monitor and how often?
Martti Ahtola | Updated: Oct 21, 2024
We all know that literature screening is required to meet pharmacovigilance obligations. Everyone is doing it. Monitoring of “global” literature happens weekly and usually the “local” literature screening is also performed weekly. Literature screening and review of new information is part of signal detection and Periodic Safety Reports.
But actually:
Is the requirement to monitor literature clear after all?
🧩 What is literally required by the EU legislation related to the literature screening process?
🧩 What is stated in the good pharmacovigilance practice guidelines?
🧩 Are there clarifications on the EMA or national competent authority websites?
EMA Website
On the EMA Medical Literature Monitoring (MLM) website, it is stated:
and also:
But there is no legal reference to this statement. The website says that more information is available at Article 107 of Directive 2001/83/EC.
However, the article 107 of the directive only states:
How should we interpret this article? That local literature screening is required by the companies whose product is included in the MLM? This part seems to be clear and this is how we have interpreted the sentence before.
Companies whose product contains an active substance that is covered by MLM must monitor “other” literature and report any suspected adverse reactions.
But what about those marketing authorization holders whose product is not included in the MLM? It seems that this is not stated in the legislation or if this sentence is supposed to cover this scenario as well, it can be very hard to understand from this sentence only.
Should we just assume that if the MAH whose product is covered by MLM have to perform local literature screening, the MAH whose product is not covered by MLM have to perform local literature screening and also global literature screening?
As mentioned above, this seems to be what everyone is doing.
Other parts of the legislation
By the way, if you’re wondering what the Article 27 of 726/2004 states, it is the following three points on setting up and performing MLM by EMA:
“1. The Agency shall monitor selected medical literature for reports of suspected adverse reactions to medicinal products containing certain active substances. It shall publish the list of active substances being monitored and the medical literature subject to this monitoring.
2. The Agency shall enter into the Eudravigilance database relevant information from the selected medical literature.
3. The Agency shall, in consultation with the Commission, Member States and interested parties, draw up a detailed guide regarding the monitoring of medical literature and the entry of relevant information into the Eudravigilance database.”
It should be noted that EU Directives work in a certain way:
That means that there could be a national version of the legal requirement of Article 107 in the local legislation. However, for example the Finnish legislation contains pretty much the exact same text but in slightly more comprehensible wording, and in the local language.
In the US, there is a legal requirement for the marketing authorization holders to report adverse events found in scientific literature but it is not specified if or how and when the literature screening should be done.
FDA guidelines suggest that marketing authorization holders can use literature surveillance tools to receive relevant articles and FDA reviewers monitor literature for potential signals.
The EU Commission Implementing Regulation No 520/2012 states that signals detected in EudraVigilance should be validated and confirmed using among other things, literature. This legislation also does not state that the literature should be continuously monitored for signal detection purposes.
The EU Commission Implementing Regulation No 520/2012 also lists literature as one of the sections of the PSUR.
Regulation (EU) No 1235/2010 states:
Guidelines
Guideline on good pharmacovigilance practices (GVP) Module VI – Collection, management and submission of reports of suspected adverse reactions to medicinal products states:
“Marketing authorisation holders are therefore expected to maintain awareness of possible publications through a systematic literature review of widely used reference databases (e.g. Medline, Excerpta Medica or Embase) no less frequently than once a week.
The marketing authorisation holder should ensure that the literature review includes the use of reference databases that contain the largest reference of articles in relation to the medicinal product properties. In addition, marketing authorisation holders should have procedures in place to monitor scientific and medical publications in local journals in countries where medicinal products have a marketing authorisation, and to bring them to the attention of the company safety department as appropriate.”
This means that according to the good practices of pharmacovigilance MAHs are expected to monitor certain databases weekly and they should have procedures in place to monitor local journals.
But this still isn’t a legal requirement.
GVP is a set of guidelines that can be followed to achieve a good quality in pharmacovigilance activities, but they are not legally binding documents and the marketing authorization holder can choose to follow alternative processes if they believe that they can produce a higher quality with them.
Dialog with EMA
To clarify this topic and to confirm our understanding and to make sure that we have not missed some crucial points in the legislation, we decided to contact the EMA.
We asked EMA a two part question, or actually a set of questions, related to the medical literature monitoring:
1. Is there a legal requirement for a marketing authorization holder to continuously monitor literature?
Regulation (EU) No 1235/2010 states:
“Scientific and medical literature is an important source of information on suspected adverse reaction case reports” .
Article 107 of Directive 2010/84/EU states:
“For medicinal products containing the active substances referred to in the list of publications monitored by the Agency pursuant to Article 27 of Regulation (EC) No 726/2004, marketing authorisation holders shall not be required to report to the Eudravigilance database the suspected adverse reactions recorded in the listed medical literature, but they shall monitor all other medical literature and report any suspected adverse reactions.”
➡️ Is there a part of the legislation we have missed as based on these statements, we would understand that MAHs are not required to continuously monitor global medical literature?
2. How should we interpret GVP in this case?
The Module VI of GVP states:
“Marketing authorisation holders are therefore expected to maintain awareness of possible publications through a systematic literature review of widely used reference databases (e.g. Medline, Excerpta Medica or Embase) no less frequently than once a week.”
➡️ With the assumption that modules of GVP are not legally binding documents, is this (“expected to”) a “shall” or “should” requirement?
➡️ If it is a “shall” requirement, to which part of the legislation does it refer to?
➡️ Is the requirement/recommendation applicable to all MAHs or to those MAHs only whose product is not covered by MLM?
After about 4 weeks from sending the questions we received the response from the EMA, which was the following:
Article 107 of Directive 2010/84/EU states:
For medicinal products containing the active substances referred to in the list of publications monitored by the Agency pursuant to Article 27 of Regulation (EC) No 726/2004, marketing authorisation holders shall not be required to report to the Eudravigilance database the suspected adverse reactions recorded in the listed medical literature, but they shall monitor all other medical literature and report any suspected adverse reactions.
In this context “they” refers to marketing authorisation holders and “the list of publications monitored by the Agency pursuant to Article 27 of Regulation (EC) No 726/2004” is the substance groups monitored by the EMA’s Medical Literature Monitoring (MLM) service
This is a crystal clear legal requirement for marketing authorisation holders to monitor the medical literature, except for that which is covered by the MLM service.
If you only have products whose substances are covered by the MLM service, then you do not have to perform global literature monitoring because the MLM Service is doing this for you.
If you have any products containing substances NOT covered by the MLM service, then you DO have to perform global literature monitoring for those substances.
GVP Module VI clarifies that it is expected that the monitoring will take place no less frequently than once a week.
Conclusion
The response from EMA does not exactly clarify our questions, because it refers to the same unclear part of the legislation that we have discussed earlier in the post. So we are quite far from a “crystal clear” legal requirement, but we can read between the lines from this response that the expectation of EMA is that weekly literature monitoring is performed.
The weekly frequency is a good practice recommended by the EMA. If the product is covered by the MLM, global literature monitoring is not required by the MAH, but local literature screening is required. If the product is not in the MLM list, both global and local literature screening are required.
The general understanding is that literature monitoring is a required part of the PV System in the EU and usually in all other regions as well. In the EU it is considered to be a good practice to monitor scientific weekly. This is what Tepsivo has been stating in our previous blog posts, and in our service offering.
To meet this requirement we have built an automation tool called Tepsivo Literature to help out marketing authorization holders to simplify the literature screening process and simultaneously cut down the costs.
Traditionally literature monitoring consists of Global Literature and Local Literature Monitoring, but Tepsivo Literature runs daily automations across both global and local sources. Local literature screening can be especially expensive when a large group of local experts are assigned to continuously monitor local publications that are not indexed in PubMed.
Now, this was our in-depth examination of the available regulations. How do you feel about their clarity – is your understanding and experience similar to what we get to in this blog post?
Or do you think the reality is different?
Let us know, we feel that if the PV industry wants to improve, discussions like this one are much needed.
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