Waiting for the EMA’s answer

Unfortunately, there are not many updates on the topic. We are still waiting for a response from EMA regarding Medical Literature Monitoring (MLM) and why it does not cover local literature sources after EMA told us that:

“Prior to revising the service, the Agency consulted with the pharmaceutical industry, writing to all MAHs affected by the MLM Service. None of them expressed a desire for the Agency to expand to cover local literature and thus the service specifications were published in their current form.”

This consultation with pharmaceutical industry was not publicly documented so we requested EMA to send us the information. The information request was sent over a year ago. Since, we have followed up on the data request a couple of times only to receive an answer that the request will be answered in due time. EMA is often late with responses, in their words still facing increased workload due to COVID-19.

We launched our data request after EMA’s previous response to our enquiry about why EMA’s Medical Literature Monitoring (MLM) service does not cover national non-indexed medical journals that have to be screened by marketing authorization holders as it is required by the European legislation and tightly enforced by inspectors working on behalf of EMA. With our vast experience in local literature monitoring, we and as we believe, most pharmacovigilance experts know that the process brings very little or no additional value to the monitoring of the safety-benefit profile of a medicinal product.

Updates to Medical Literature Monitoring

During last year, EMA reviewed the scope of MLM and ran a public call for tenders on the service. The process included EMA sending a survey to the QPPVs of MAHs. We described the survey process in our previous blog explaining the situation with local literature screening and MLM. We also tried publicly rally industry stakeholders to use this survey to express their dissatisfaction with the unnecessary rule. This new questionnaire also did not cover anything related to local literature screening, but we wanted people to use the open question fields to highlight the waste of time and money versus little to no new information produced. Eventually we will request the responses to this questionnaire as well. Notably, only 143 of about 4,000 (3.5%) MAHs answered the questionnaire.

The call for tenders ran during 2021 resulted to EMA receiving only two tender bids, from Syneos and IQVIA. Based on publicly available information, it looks like EMA ended up contracting both companies and awarding both Syneos and IQVIA with €15,200,000 contracts over the next 6 years. This means that EMA will be spending over €30 million in the next 6 years or around €5 million per year on MLM and reporting ICSRs to EMA’s safety database, EudraVigilance (EV).

Let’s Look at the Numbers

But, accepting the numbers as they are publicly available, that’s €417,000 a month for global literature monitoring of 309 medicinal product substance groups and 100 herbal substance groups. Historically, this would be about 10,000 ICSRs and 500,000 articles (abstracts) reviewed per year providing a service to about 4,000 MAHs. Notably, all the MAHs in Europe pay for this service in the mandatory annual fees to EMA.

At a quick glance, these seem like high numbers. If you break down 10,000 individual safety reports entered into EudraVigilance per month, that’s about 833 ICSRs. And for the articles it would be 42,000 articles (abstracts) per month. If we imagine that Syneos and IQVIA are splitting these tasks, then one company is receiving €200,000 for processing 833 literature ICSRs which is €240 per case and €200,000 for reviewing 42,000 abstracts: about €5 per article / abstract.

These are unnecessary high numbers, but they are very much the standard rates that big CROs would typically charge pharmaceutical companies for these services.

If EMA was a pharmaceutical company buying services, this would not be such a big issue (leaving aside the fact they’d still be paying way above what today is possible through process streamlining). But EMA is, or at least should be, a public agency acting on behalf of EU citizens. And in this case, instead of acting like a public office, they act like they are a big pharma player paying prices going through the roof, including unjustified mark-up.

Cost to MAHs

The pharmaceutical companies pay a mandatory annual pharmacovigilance fee which covers the MLM activity whether their product is covered by the monitoring or not. There is a standard part of the annual fee that pays for the maintenance of EudraVigilance and MLM which is €71 (€43 or €57 for micro-size and small entities) per chargeable unit. Chargeable unit is:

The Article 57 product data that contains information on authorized medicinal products lists about 155,000 units. Without going into details about the products and their authorization procedures, we can quickly calculate 155,000 x €71 = €11 million. This means that EMA is potentially charging the pharmaceutical companies up to €11 million annually for the pharmacovigilance services.

In EMA’s budget, the literature monitoring services falls under the category “Scientific studies and services”. This category that also covers studies related to the evaluation of medicinal products and other scientific services has grown from €7.5 million in 2020 to €23 million in 2022. We do not know exactly how much of this €23 million goes to MLM but we know it is at least €5 million. It is also good to remember that of the €400 million annual revenue of EMA, 90% comes from the marketing authorization holders as fees and charges.

Is it worth it?

Let’s assume that the cost of the MLM service is still somehow acceptable. But, when taking into consideration that there are 13,000 unique substances in Article 57 database and MLM covers 400 substance groups (6,000 unique substances or combinations) leaving thousands of substances that are not covered by MLM. This means that majority of marketing authorization holders still must perform weekly global literature screening to fulfill their legal obligations. Out of the 4,000 marketing authorization holders, almost 3,000 have products on the MLM list but only a little over 600 of those marketing authorization holders have solely products that are covered by MLM.

Adding the few keywords covered by the EMA MLM would be a minor additional cost to the companies already paying for literature monitoring, and, knowing the standard practices and lack of guidance by PV providers, in many cases the MAHs tend to include these keywords to their own searches even if they are covered by the MLM. At this point, it’s fair to ask if those €5m per year paid out by pharmaceutical companies and flowing to IQVIA’s and Syneos’ bank accounts in fact add any real value.

Do these prices still make sense?

Local Literature Screening

Shockingly enough, global literature screening is actually the “cheap and easy” part of the regular monitoring, whereas the local literature screening is manual and expensive. Depending on the product and authorization countries, local literature screening can be 10-20 times more expensive than global literature screening.

Finally, the end goal of all this literature monitoring is to detect signals, and out of all the ICSRs in EV, of which literature ICSRs are about 3%, comes about 2,000 potential signals annually, leading to about 40 validated signals – most of them leading to minor changes in product information and handful to an RMP update.

Change is Required

We have pointed out in our previous research into the topic that local literature screening brings very limited additional information regarding the benefit risk profile of medicinal products, but it is one of the largest cost centers for the pharmacovigilance departments of all pharmaceutical companies that have an approved drug in the EU.

The obvious solution to this issue would be to amend the legislation and to remove this one sentence that makes this activity required and has created a whole industry that has no value.

At Tepsivo, we’re part of this industry, but we publicly stated it’s best to get rid of it and we have made calls the most sensible option is to change the legislation. Before that can happen, we need to address it as a stakeholder which is why we have built Tepsivo Literature that works with simple everyday automation and does the mundane keyword searches on behalf of the highly qualified local pharmacovigilance experts who are used for the manual local literature screening.

This type of automation heavily brings down the cost and time effort spent on the activity.

However, the number one rule in any issue solving is to identify the root cause. In this case the root cause is the legislation. Or maybe the true root cause is whatever made the legislators to decide to put in the wording about local journals in the directive? What made them think that journals and other publications that are not submitted for the international medical community would contain information that is not published in the internationally recognized sources?

Learn from Others

Simultaneously, there is another “one-sentence requirement” that is not followed nor enforced by the EMA: the requirement to monitor EudraVigilance for signal detection purposes by license holders. During the signal detection pilot phase, only those companies with products with the highest risk are required to use EVDAS and to regularly look at the cases in EV. This pilot has been extended for yet another year even though EMA reported to European Commission already 3 years ago that the legislation should be amended and the requirement for MAH’s to monitor EudraVigilance removed.

Couldn’t EMA start similar pilot for the local literature? Our suggestion is to include local literature to the MLM using appropriate tools and processes and to expand the scope of the MLM to include also the riskiest products (for example the same list as for signal detection pilot). Meanwhile, there should be a real push from the Agency for a legislation update and remove this redundant requirement.

Also, we can all hope that the language and information managements skills of healthcare professionals and researchers in the EU are developing, hopefully leading to fewer medical publications not indexed in at least one database. There are several organizations working on aggregating European local databases and open access publishing. From our point of view, it is the responsibility of researchers, scientists and healthcare professionals in general to ensure that their publications and results reach the scientific community globally. More importantly, they should always report any adverse events they encounter to competent authorities. While the article most likely takes months to be published, the new information about the benefit-risk profile of the product has reached the competent authorities and the relevant marketing authorization holder(s) immediately.