# Shaping the future of pharmacoepidemiology in France: recommendations from the SFPT
Pharmacoepidemiology Working Group

Thomas Soeiro, Marion Allouchery, Johana Béné, Julien Bezin, Charles Dolladille, Jean-Luc Faillie, Lamiae Grimaldi, Florentia Kaguelidou, Charles Khouri, Margaux Lafaurie, et al.

► To cite this version:

Thomas Soeiro, Marion Allouchery, Johana Béné, Julien Bezin, Charles Dolladille, et al. Shaping the future of pharmacoepidemiology in France: recommendations from the SFPT Pharmacoepidemiology Working Group. Therapies, 2024, S0040-5957 (24), pp.00213-0. 10.1016/j.therap.2024.12.005. hal-04870620

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PHARMACOEPIDEMIOLOGY

# Shaping the future of pharmacoepidemiology in France: Recommendations from the SFPT Pharmacoepidemiology Working Group

Thomas Soeiro<sup>a,b,*</sup>, Marion Allouchery<sup>c,d,1</sup>, Johana Bene<sup>e,1</sup>, Julien Bezin<sup>f,1</sup>, Charles Dolladille<sup>g,1</sup>, Jean-Luc Faillie<sup>h,i,1</sup>, Lamiae Grimaldi<sup>j,k,1</sup>, Florentia Kaguelidou<sup>l,m,1</sup>, Charles Khouri<sup>n,o,1</sup>, Margaux Lafaurie<sup>p,q,1</sup>, Bérenger Largeau<sup>r,s,1</sup>, François Montastruc<sup>p,q,1</sup>, Lucas Morin<sup>t,1</sup>, Lucie-Marie Scailteux<sup>u,1</sup>, Antoine Pariente<sup>f</sup>, on behalf of the SFPT Pharmacoepidemiology Working Group

<footnote><sup>a</sup> Service de pharmacologie clinique et pharmacosurveillance, AP-HM, 270, boulevard de Sainte-Marguerite, 13009 Marseille, France</footnote>

<footnote><sup>b</sup> Aix-Marseille université, Inserm U1106, 13009 Marseille, France</footnote>

<footnote><sup>c</sup> Service de pharmacologie clinique et vigilances, CHU de Poitiers, 86000 Poitiers, France</footnote>

<footnote><sup>d</sup> ProDiCeT, CHU de Poitiers, université de Poitiers, 86000 Poitiers, France</footnote>

<footnote><sup>e</sup> Centre régional de pharmacovigilance, CHU de Lille, 59000 Lille, France</footnote>

<footnote><sup>f</sup> Équipe AHeaD, CHU de Bordeaux, service de pharmacologie clinique, BPH, université de Bordeaux, Inserm U1219, 33000 Bordeaux, France</footnote>

<footnote><sup>g</sup> Service de pharmacologie, unité de pharmacoépidémiologie, ANTICIPE, université Caen-Normandie, Inserm U1086, 14000 Caen, France</footnote>

<footnote><sup>h</sup> Service de pharmacologie médicale et toxicologie, CHU de Montpellier, 34000 Montpellier, France</footnote>

<footnote><sup>i</sup> IDESP, université de Montpellier, Inserm UMR UA11, 34000 Montpellier, France</footnote>

<footnote><sup>j</sup> Service de pharmacologie, GHU Paris-Saclay, hôpital Bicêtre, AP-HP, 94275 Le Kremlin-Bicêtre, France</footnote>

<footnote>* Corresponding author. Service de pharmacologie clinique et pharmacosurveillance, Assistance publique-Hôpitaux de Marseille, 270, boulevard de Sainte-Marguerite, 13009 Marseille, France.</footnote>

<footnote>Adresse e-mail : thomas.soeiro@ap-hm.fr (T. Soeiro).</footnote>

<footnote n="1">¹ Contributed equally.</footnote>
k Équipe échappement aux anti-infectieux et pharmacoépidémiologie, Inserm U1018, CESP, 94800 Villejuif, France

l GHU Nord, hôpital Robert-Debré, Inserm CIC1426, AP-HP, 75019 Paris, France

m URP 7323, université Paris Cité, 75006 Paris, France

n Centre régional de pharmacovigilance, CHU Grenoble-Alpes, 38000 Grenoble, France

o Laboratoire HP2, université Grenoble-Alpes, Inserm U1300, 38000 Grenoble, France

p Service de pharmacologie médicale et clinique, CHU de Toulouse, 31000 Toulouse, France

q Équipe PEPSS, CHU de Toulouse, Inserm CIC1436, 31000 Toulouse, France

r Service de pharmacologie médicale et pharmacosurveillance, CHRU de Tours, 37000 Tours, France

s Inserm U1327, ISCHEMIA, université de Tours, 37000 Tours, France

t CESP, HiDiBiostat, Inserm U1018, 94800 Villejuif, France

u EHESP, Inserm U1085, Irset, CHU Rennes, université Rennes, 35000 Rennes, France

Reçu le 26 septembre 2024 ; accepté le 9 décembre 2024

## KEYWORDS

Pharmacoepidemiology ;
Prescription drugs ;
Claims databases ;
Hospital data
warehouses ;
Real-world data

**Summary** The drug authorization process is shifting towards a policy aimed at shortening time-to-market. While this policy facilitates early access to new treatments, it can also result in potentially insufficient knowledge of both efficacy and safety at the time of marketing. The latter is particularly true for long-term outcomes or in specific populations (e.g., children and the elderly). Yet, French pharmacoepidemiology is currently not designed to address these challenges, despite recognized expertise. In this context, we aim: (i) to define a strategy for strengthening pharmacoepidemiology in France; and (ii) to identify the associated human, technical, and financial requirements to ensure its success. In this paper, we present the French Pharmacoepidemiology Initiative (https://frenchpharmacoepi.org/), i.e. a network of independent academic teams to complement existing institutions. It will provide coordinated expertise and a workforce to meet national and regional needs for pharmacoepidemiological monitoring and drug-related decision-making. Leveraging the existing expertise of university hospital pharmacoepidemiology units would enable rapid operational deployment to inform the decisions and policies of national regulatory agencies.

© 2024 Les Auteurs. Published by Elsevier Masson SAS au nom de Société française de pharmacologie et de thérapeutique. This article is published Open Access under a Creative Commons Attribution 4.0 License (http://creativecommons.org/licenses/by/4.0/).

## Abbreviations

**SFPT** French Society of Pharmacology and Therapeutics (Société française de pharmacologie et de thérapeutique)

**SNDS** National Health Data System (Système national des données de santé)

## Introduction

In France, over 25% of people aged 75 years and older use 5 or more drugs daily [1]. Codispensing of contraindicated drugs affects 0.6 to 2 million dispensing per year [2]. Simultaneously, the incidence of hospital admissions due to adverse drug reactions has dramatically increased over the past decade, with an estimate of 212,500 in 2018 [3]. A significant proportion of them are related to new pharmacological classes and considered preventable.

Moreover, the drug authorization process is shifting towards a policy aimed at shortening time-to-market. While this policy facilitates early access to new treatments, it

can also result in potentially insufficient knowledge of both efficacy and safety at the time of marketing. The latter is particularly true for long-term outcomes or in specific populations (e.g., children and the elderly) [4,5].

This context highlights the need to enhance pharmacoepidemiology activities, which aims to monitor drug use, effectiveness, and risks in population, real-world settings [6,7]. Yet, French pharmacoepidemiology is currently not designed to address these challenges, despite recognized expertise. To improve patient care and reduce economic burden, it is crucial to integrate pharmacoepidemiology into the global framework of drug evaluation and monitoring (i.e., clinical pharmacology, pharmacovigilance, and addictovigilance). To this end, we aim: (i) to define a strategy for strengthening pharmacoepidemiology in France; and (ii) to identify the associated human, technical, and financial requirements to ensure its success.

## State of pharmacoepidemiology in France

### Current organization

Several reports, including some commissioned by authorities, have consistently advocated for enforcing
<figure><img src="image_3.png" /><figcaption>**Figure 1.** Current status of pharmacoepidemiology in France. Data provided by the French Society of Pharmacology and Therapeutics (Société française de pharmacologie et de thérapeutique) concerning its pharmacoepidemiology activities. The data are not exhaustive of all pharmacoepidemiology activities in France (e.g., three additional Inserm teams allocate part of their research to pharmacoepidemiology, some with both public and private fundings). FTE: full-time equivalent.</figcaption></figure>

pharmacoepidemiology [8,9]. Despite clear recom-
mendations from experts, the organization of
pharmacoepidemiology in France lags behind that of
the Nordic PharmacoEpidemiological Network [10], the
Canadian Network for Observational Drug Effect Studies
[11], or the USA Sentinel Initiative [12].

The current organization of pharmacoepidemiology
in France involves three main types of actors. First,
independent academic teams affiliated with medical phar-
macology departments of university hospitals, which have
derived from pharmacovigilance, addictovigilance, or clini-
cal research centers. While this structure allows integrating
pharmacological expertise into monitoring, it also signifi-
cantly hinders the development of pharmacoepidemiology
due to the lack of dedicated university chairs. Second,
public institutions also play a critical role, particularly the
Scientific Interest Group EPI-PHARE. Established in 2019 by
the French Medicines Agency (Agence nationale de sécurité
du médicament et des produits de santé) and the French
Health Insurance (Caisse nationale de l'Assurance maladie)
[13], EPI-PHARE primarily responds to drug-related safety
alerts. Third, private companies, mainly Contract Research
Organizations, are assigned to conduct pharmacoepidemi-
logy studies to comply with requests from the authorities.
In particular, the French Health Authority (Haute Autorité
de santé) requires pharmaceutical companies to provide
pharmacoepidemiology studies for benefit/risk balance eva-
luations [14].

Academic teams engaged in pharmacoepidemiology are
distributed across most French regions. Areas of expertise
vary among teams and cover a wide range of pharmacologi-
cal fields (Fig. 1). However, the availability of technical staff
trained for the real-world health data (e.g., the National
Health Data System (Système national des données de santé
[SNDS]), hospital data warehouses, and clinical databases)
is inconsistent. This is due to several factors: (i) intense

competition for recruitment and precarious job offers in the
public sector (i.e., underpaid and short-term) despite pre-
vious recommendations [15], making it difficult to attract
skilled technical staff, restricted access to data, which ham-
pers the training of new staff, especially given the long
learning curve for using the SNDS.

The establishment of the Health Data Hub in 2019 aimed
to facilitate data access and address outdated data analysis
tools, but these goals have not been met. The French Agency
for Data Privacy (Commission nationale de l'informatique et
des libertés) denied authorization for the Health Data Hub
to host the SNDS due to its reliance on a USA-based cloud
storage solution [16]. Concurrently, pre-existing solutions
have deteriorated, jeopardizing research efficiency conduc-
ted using the SNDS [17]. Despite these challenges, resource
allocations outside EPI-PHARE and the Health Data Hub have
been minimal, although these institutions often lack the
pharmacological expertise required to achieve the highest
scientific standards in pharmacoepidemiology.

Current process for data access

While rapid data access is a major challenge in pharma-
coepidemiology, the average time to access SNDS data
typically ranged from 10 to 12 months, due to regulatory
requirements and the time required for data extraction by
the French Health Insurance [17]. This delay has hinde-
red French academic teams from participating in calls for
applications from European bodies (e.g. calls for applica-
tions issued by the European Medicines Agency, which often
require results within a year). This has long been a major
threat to French expertise, its contribution to European drug
decision-making, and the positioning of French research in
the field. The involvement of the French Medicines Agency,
the French Health Insurance, and EPI-PHARE has not fully
filled this gap, as their reports may struggle to convince
foreign regulators who typically rely on academic work. However, a legal decree in 2021 granted permanent access to the SNDS for academic researchers, including those in university hospitals, allowing pharmacoepidemiology teams to shorten data access times [18].

Additionally, linking SNDS with external datasets, such as clinical cohorts and hospital data warehouses, is urgently needed due to the critical lack of clinical data in the SNDS. This is crucial to answer questions requiring in-depth clinical information or regarding in-hospital use of drugs. Combined use of these data seems now feasible in a short time, provided the political will that accompanied the creation of the Health Data Hub is maintained. This also requires France to intensify its efforts to participate in international projects aimed at defining methodological standards for linking datasets (e.g., common data models and the European Dataspace Use case) [19].

## Proposition for a French pharmacoepidemiology initiative

### Network structuring, positioning and functioning

To address all previously discussed needs of pharmacoepidemiology in France, we present the French Pharmacoepidemiology Initiative (https://frenchpharmacoepi.org/), i.e. a network of independent academic teams to complement existing institutions (Table 1). It will provide coordinated expertise and a workforce to meet national and regional needs for pharmacoepidemiological monitoring and drug-related decision-making. This initiative follows and extends the Pharmacoepidemiology Working Group of the French Society of Pharmacology and Therapeutics (Société française de pharmacologie et de thérapeutique [SFPT]) [20]. Importantly, it is extensively based on the experience of the aforementioned teams in conducting pharmacoepidemiological studies on the SNDS [21], clinical cohorts [22–25], and hospital data warehouses. In parallel, it is also based on several years of reflections to improve the standards of evidence of pharmacoepidemiological studies in France [26–29].

To ensure complementary expertise within the network, it should be open to anyone from the pharmacological community, or those with strong interactions with it, and involved in public research on drug evaluation in real-world settings (e.g., pharmacologists, epidemiologists, clinicians, biostatisticians, medical informatics engineers).

To fully benefit from access to the SNDS and to hospital data warehouses, the French Pharmacoepidemiology Initiative leverages academic research in pharmacoepidemiology, primarily based within university hospitals. The ultimate goal is for each center to contribute to the network with at least one expert in pharmacoepidemiology, or a pair comprising one expert in pharmacology and one expert in epidemiology, and a data analyst trained in the secondary use of health data (e.g., SNDS, hospital data warehouses). This territorial coverage provides the ideal configuration for collaborations with national regulatory agencies and institutions (e.g. the French Medicines Agency, the French Health

Authority, EPI-PHARE, French Public Health (Santé publique France), and scientific societies) and Regional Health Agencies (Agences régionales de santé). Initially, a federated network of expertise connected by technical support nodes for practical study execution can be envisioned to reduce the risk of isolation among researchers and engineers responsible for data management and analysis.

The network has four main aims: (i) to conduct collaborative research and evaluation projects in pharmacoepidemiology, including in specific areas of expertise or under constrained timelines, by pooling pharmacological, epidemiological, methodological, and technical expertise, and data access; (ii) to facilitate experience sharing among network members through mobility and mentorship programs; (iii) to contribute to theoretical training in pharmacoepidemiology and secondary use of data for pharmacoepidemiological evaluation of drugs; and ultimately (iv) to enhance the visibility and attractiveness of academic research in pharmacoepidemiology in France. All these missions align with an open science approach, including in particular protocol and code sharing (i.e., open source code).

Importantly, we advocate for an independent academic network because public trust can only be achieved if evaluation is free of conflicts of interest with both pharmaceutical companies and national institutions. Moreover, relying heavily on private efforts would be illogical, especially when public expertise is available.

### Network dimensioning and strengthening

As of March 2024, the results of 114 of the post-authorization studies requested by the French Health Authority from pharmaceutical companies are still pending (e.g., from 11 to 19 studies per year over 2020–2023) [30]. This questions the adequacy of the means devoted to conduct these studies. Additionally, Regional Health Agencies will likely require several studies each year to monitor drug concerns specific to their territories and fulfill the commitments of their Regional Health Project (projet régional de santé) and Goals and Resources Contract (contrat pluriannuel d'objectifs et de moyens). Of all the studies that are or will be requested, some might be conducted by private entities with limited potential impact relating to conflicts of interest (e.g., some drug utilization studies). Conversely for others, independent expertise could appear crucial (e.g., benefit/risk balance evaluations).

The average completion time of pharmacoepidemiology studies using the SNDS is about 12 person-months, excluding time for data access, when conducted by experienced staff. This includes the time required for researchers (i.e., conception, supervision, interpretation, code review, report writing, and valorization) and staff (i.e., data management, data analysis, and contribution to interpretation, report writing, and valorization). An additional two person-months should be considered for the efforts of scientific committee members.

In summary, the workforce required to meet the above needs in pharmacoepidemiology studies is estimated at 280 person-months per year (i.e., around 20 studies per year, each requiring 14 person-months).
<table><caption>**Table 1** Shaping the future of pharmacoepidemiology in France: expected needs, identified obstacles, proposed solutions, and expected benefits for stakeholders.</caption><thead><tr><td>Expected needs</td><td>Identified obstacles</td><td>Proposed solutions</td><td>Expected benefits for stakeholders</td></tr></thead><tbody><tr><td>Growing need for pharmacoepidemiology studies:<br/>- To monitor drug use and misuse in the population<br/>- To monitor benefit/risk balance of drugs in real-world settings and in vulnerable populations<br/>- To complete clinical evaluation of drugs</td><td>- Lack of organization of pharmacoepidemiology<br/>- Scattered pharmacological expertise<br/>- Lack of trained pharmacoepidemiologist and data analyst<br/>- No protocol and code sharing</td><td>- Create a pharmacoepidemiology network with permanent funding<br/>- Increase the pharmacoepidemiology workforce</td><td>- Meet national and regional needs for pharmacoepidemiological monitoring and drug-related decision-making<br/>- Produce results free of conflicts of interest with pharmaceutical companies<br/>- Cost savings through a more rational use of drugs and a decrease in adverse drug reactions-related costs</td></tr><tr><td>Need to shorten data access and data analysis times to allow providing results more rapidly</td><td>- Average time to access SNDS data typically ranged from 10 to 12 months<br/>- Outdated data analysis tools (both software and hardware)</td><td>- Improve the training of pharmacoepidemiologist and data analyst with permanent access to the SNDS<br/>- Update software and hardware used for data analysis</td><td>Participation to calls for applications from European bodies, including in specific areas of expertise or under constrained timelines</td></tr><tr><td>Need for more clinical, biological, and imaging data in the SNDS</td><td>Need for data standardization according to common data models</td><td>- Participation in international projects aimed at defining methodological standards for linking datasets<br/>- Develop research and training that will enable linking SNDS with external datasets, such as clinical cohorts and hospital data warehouses</td><td>Answering questions requiring in-depth clinical information or regarding in-hospital use of drugs</td></tr><tr><td>Methodological research and training in new methods in statistics and informatics</td><td>Lack of trained pharmacoepidemiologist and data analyst</td><td>Methodological research and training</td><td>Intellectual property-related incomes for drug repurposing</td></tr></tbody></table>

SNDS: National Health Data System (Système national des données de santé).

## Network funding and stabilizing

Permanent funding is crucial to stabilize the federated network, as the needs are permanent and require specific skills and experience. We propose to allocate a percentage of drug expenses to fund their pharmacoepidemiological monitoring. Drug prices could be reduced by 0.05% (e.g., the price of a drug costing 1,000.00 euros per box would be lowered to 999.50 euros). The corresponding amount could be converted into a specific tax to fund pharmacoepidemiology activities, including those required by institutions. The budget would be defined each year based on expenses from the previous year. Any unused funds at the end of the year would be either returned to the funder or invested in structural actions, allowing the network to develop and adapt. Under this system, if the network is tasked with conducting

independent studies, no additional cost would be requested from the concerned pharmaceutical companies.

## Network generated incomes and cost savings for the public funder

The risks of the network not being cost-effective are minimal. Anticipated savings far exceed the network costs, primarily through the reduction of public expenses.

Outpatient drug-related expenses amounted to about 33 billion euros in 2022, with an average increase of about 700 million euros per year in France [31]. This is likely to keep growing with the aging population. The economic burden of hospital admissions due to adverse drug reactions is estimated to be at least 420 million euros per year [3]. Esti-
mates of the economic burden of drug misuse, from the cost of unnecessary drugs to the cost of complications, suggest it exceeds 10 billion euros a year [8]. Slowing this increase by only a few percent would result in significant savings.

In addition to the anticipated cost savings through a more rational use of drugs and a decrease in adverse drug reactions-related costs, the network could generate direct incomes by contributing to drug repurposing. Intellectual property-related incomes could be partially attributed to the public funder.

## Prospects

In the coming years, methods used in pharmacoepidemiology are expected to evolve as a consequence of several factors, including standards of evidence, data characteristics, changes in missions, and advances in statistics and informatics.

First, the next standard in drug clinical evaluation will increasingly rely on pharmacoepidemiology to address the limitations of traditional clinical trials. For diseases with a poor short-term prognosis (e.g., cancer) and orphan diseases, the drug authorization process is shifting towards a policy aimed at shortening time-to-market. This involves brief clinical evaluations on small numbers of patients, often based on surrogate endpoints with uncertain long-term clinical significance. While this policy facilitates early access to new treatments, it can also result in potentially insufficient knowledge of both efficacy and safety at the time of marketing. The latter is particularly true for long-term outcomes or in specific populations (e.g., children and the elderly) [4,5]. These promising but poorly developed drugs may achieve a favorable benefit/risk balance primarily due to the high mortality rates in the indicated conditions. Uncertainty about the benefit/risk balance of drugs also stems from the differences in patterns of use (e.g., drug misuse) and characteristics of patients between clinical trials and in real-world settings (e.g., extension of indications). Importantly, when dealing with drugs intended for widespread use, any loss in efficacy or safety will have a significant impact on public health, also resulting in economic burden. In this context, real-word evidence, especially from emulated trials, can supplement clinical trials, assess effectiveness, and clarify the place of drugs in therapeutic strategies [32].

Second, access to data with more clinical information is critical for pharmacoepidemiology. Many European countries have successfully linked medico-administrative data with clinical, biological, and imaging data, allowing: (i) to improve confidence regarding the characteristics of the studied populations and thus, generalizability of results; and (ii) to reduce the need for statistics to ensure the comparability of the studied population for important characteristics. As linked data are not systematically provided in a structured format, new methods tailored to the data format should be employed (e.g., Natural Language Processing for unstructured text from medical reports).

Third, a new mission for pharmacoepidemiology will be to bridge preclinical knowledge and data from real-world evaluation. Along with drug development and preclinical evaluation evolving, there is a shift from animal testing to receptor, cellular, or organoid studies. New translational methods are required to cover the need for drug evaluation

owing to the repositioning of preclinical and post-marketing information. Modeling techniques will be necessary to combine preclinical knowledge with e.g. post-marketing data from other drugs [33]. Similar methods will be needed for drug repurposing before conducting studies that align with the new standards in clinical evaluation. Developing the corresponding research and training to enable effective implementation is crucial.

Finally, advances in statistics and informatics may shift focus towards artificial intelligence methods, especially for large datasets like the SNDS. Methodological research and training will also need to determine the circumstances under which artificial intelligence models provide added value compared to conventional models in pharmacoepidemiology.

## Conclusion

France is currently facing a paradox of having recognized pharmacoepidemiological expertise while having unaddressed needs in pharmacoepidemiological monitoring. To date, no political strategy has been deployed to take advantage of this expertise despite the importance of pharmacoepidemiology for public health. Structuring a pharmacoepidemiology network, highlighted as a critical need in a report to the Ministry of Health 10 years ago [8], is now an urgent priority. If properly implemented, this network will contribute to monitor drug safety and effectiveness, to improve the quality of care, and ultimately to reduce drug-associated costs. Leveraging the existing expertise of university hospital pharmacoepidemiology units would enable rapid operational deployment to inform the decisions and policies of national regulatory agencies.

## Disclosure of interests

The authors declare that they have no competing interest.

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