Within-subject pharmacokinetic variability has a strong influence on individual exposure ratios in bioequivalence studies, hence on drug formulation interchangeability.

INTRODUCTION: Bioequivalence between a reference and a generic drug is based on the hypothesis that a ± 20% change in blood exposure (or ± 10% for drugs with narrow therapeutic index, NTI) following the generic/reference switch will not have any therapeutic consequences. However, the individual exposure ratio between generic and reference can be higher than 1.20 (or 1.10). This study aims to analyse the different parameters influencing the individual exposure ratio, hence the conditions for reference/generic interchangeability. METHODS: Bioequivalence studies with a double cross-over design for a virtual drug were simulated using 100 random sets of 12, 24, 48 or 100 pairs of areas under the curve (AUC), varying the generic/reference AUC geometric mean ratios between 0.80 and 1.25 and the within-subject exposure variance of the reference and the generic formulations. RESULTS: The proportion of subjects with an exposure generic/reference ratio outside the ± 10% or ± 20% acceptance intervals increases when (1) the reference within-subject variance increases; (2) the ratio of the generic within-subject variance on the reference within-subject variance increases; and (3) the generic/reference mean AUC ratio diverges from 1.0. When only considering replicated administrations of the reference, the individual exposure ratio increases with the within-subject variance, yielding values outside the usually accepted individual exposure ratio range of 0.5 to 2 for drugs with narrow therapeutic index as soon as the within-subject variance standard deviation is ≥ 0.25 (equivalent to within-patient CV% > 25%). CONCLUSIONS: Interchangeability between reference and generic formulations, especially for drugs with narrow therapeutic index can only be assumed if, the within-subject variance of generic is less or equal to the within-subject variance of reference or, if this is not the case, if the distribution of the generic/generic individual exposure ratios is included within the therapeutic margins of the reference drug.

Requests for post-registration studies (PRS), patients follow-up in actual practice: Changes in the role of databases.

Early market access of health products is associated with a larger number of requests for information by the health authorities. Compared with these expectations, the growing expansion of health databases represents an opportunity for responding to questions raised by the authorities. The computerised nature of the health system provides numerous sources of data, and first and foremost medical/administrative databases such as the French National Inter-Scheme Health Insurance Information System (SNIIRAM) database. These databases, although developed for other purposes, have already been used for many years with regard to post-registration studies (PRS). The use thereof will continue to increase with the recent creation of the French National Health Data System (SNDS [2016 health system reform law]). At the same time, other databases are available in France, offering an illustration of "product use under actual practice conditions" by patients and health professionals (cohorts, specific registries, data warehouses, etc.). Based on a preliminary analysis of requests for PRS, approximately two-thirds appeared to have found at least a partial response in existing databases. Using these databases has a number of disadvantages, but also numerous advantages, which are listed. In order to facilitate access and optimise their use, it seemed important to draw up recommendations aiming to facilitate these developments and guarantee the conditions for their technical validity. The recommendations drawn up notably include the need for measures aiming to promote the visibility of research conducted on databases in the field of PRS. Moreover, it seemed worthwhile to promote the interoperability of health data warehouses, to make it possible to match information originating from field studies with information originating from databases, and to develop and share algorithms aiming to identify criteria of interest (proxies). Methodological documents, such as the French National Authority for Health (HAS) recommendations on "Les études post-inscription sur les technologies de santé (médicaments, dispositifs médicaux et actes). Principes et méthodes" [Post-registration studies on health technologies (medicinal products, medical devices and procedures). Principles and methods] should be updated to incorporate these developments.

Hospital-based health technology assessment in France: A focus on medical devices.

Hospital-based health technology assessment (HTA) guides decisions as to whether new healthcare products should be made available within hospital structures. Its extension to medical devices (MDs) makes it possible to analyse several relevant aspects of these healthcare products in addition to their clinical value, and such evaluations are of interest to national health authorities, other healthcare establishments and industry. The aim of this work was to formulate several recommendations for a blueprint for hospital-based HTA for MDs in France. Five themes based on the work of the European Adopting hospital-based HTA in the EU (AdHopHTA) project were defined. Each member of the roundtable was then allocated a documentation task based on their experience of the theme concerned, and a literature review was carried out. An inventory of hospital-based HTA was performed and six recommendations aiming to strengthen and improve this approach were put forward: (1) encouragement of the spread of the hospital-based HTA culture and participation in communications and the promotion of this approach to hospital decision-makers; (2) adaptation of hospital-based HTA to the needs of decision-makers, taking into account the financial timetable and strategic objectives of the healthcare establishment; (3) harmonisation of the dossiers requested from industry between healthcare establishments, based on a common core; (4) promotion of the sharing of hospital-based HTA data under certain conditions, with data dissociable from the HTA report and the use of a validated methodology for the literature review; (5) creation of a composite indicator reflecting data production effort and the sharing of HTA activities, to be taken into account in the distribution of funds allocated for teaching, research and innovation missions considered of general interest; (6) the transmission of information directly from local to national level by pioneering centres. This work highlights the major issues at stake in hospital-based HTA and the need to valorise such activities in France.

[Pharmacological Basis for Therapeutics. Pharmacological Analysis of Summary of Product Characteristics (SPC) for Physicians]. / Les bases pharmacologiques de la thérapeutique. Analyse pharmacologique du résumé des caractéristiques d'un produit ( le « RCP ¼) pour le thérapeute.

The summary of product characteristics, the SPC, is the major annex document of Marketing Authorisation (MA) dossier for a medicine. This document is the reference document for health care professionnals since it contains all necessary and opposable information for its therapeutic use. The SPC is initially submitted by the MA applicant and deeply revised in details by regulatory authorities, the national agencies for national MA, and the European Medicine Agency (EMA) for the european centralized procedures. The SPC presents with 12 sections each one being divided into several paragraphs. Sections 1-3 present the name, dosage, qualitative and quantitative composition, the pharmaceutical form of the medicine. Section 4 contains all the clinical particulars: Therapeutic indications, posology and methods of administration, contra-indications, special warnings and precautions for use, interactions, impact on fertility, contraception, pregnancy, lactation, effects on ability to drive and use machines, undesirable effects and risk associated with overdose. Section 5 describes pharmacological properties (pharmacodynamics and pharmacokinetics) and preclinical safety data. Section 6 describes the pharmaceutical particulars: excipients, incompatibilities, shelf live, nature and content of container, special precautions for disposal. Sections 7-10 are administrative ones (date of MA, MA holder), sections 11 and 12 are specific to radiopharmaceuticals (dosimetry and modalities of preparation). SPC is available free of charge on national regulatory agency websites and on EMA website. Sections of SPC finally have to be considered as the pharmacological basis of therapeutic use for each medicine.

Biosimilars: from Technical to Pharmacoeconomic Considerations.

A biosimilar is a biological medicinal product claimed to be similar to a reference biological medicinal product. Its development plan includes studies comparing it with the reference product in order to confirm its similarity in terms of quality, preclinical safety, clinical efficacy, and clinical safety, including immunogenicity. Biosimilars differ from generics both in their molecular complexity and in the specific requirements that apply to them. Since patents on many biological medicinal products will expire within the next 5 years in major therapeutic areas such as oncology, rheumatology and gastroenterology and as those products are so costly to the French national health insurance system, the availability of biosimilars would have a considerable economic impact. The round table has issued a number of recommendations intended to ensure that the upcoming arrival of biosimilars on the market is a success, in which prescribing physicians would have a central role in informing and reassuring patients, an efficient monitoring of the patients treated with biologicals would be set up and time to market for biosimilars would be speeded up.

Biosimilars: from technical to pharmacoeconomic considerations. 30th Rencontres Nationales de Pharmacologie et Recherche clinique pour l'Innovation et l'Evaluation des Technologies de Santé. Tables rondes.

A biosimilar is a biological medicinal product claimed to be similar to a reference biological medicinal product. Its development plan includes studies comparing it with the reference product in order to confirm its similarity in terms of quality, preclinical safety, clinical efficacy, and clinical safety, including immunogenicity. Biosimilars differ from generics both in their molecular complexity and in the specific requirements that apply to them. Since patents on many biological medicinal products will expire within the next 5 years in major therapeutic areas such as oncology, rheumatology and gastroenterology and as those products are so costly to the French national health insurance system, the availability of biosimilars would have a considerable economic impact. The round table has issued a number of recommendations intended to ensure that the upcoming arrival of biosimilars on the market is a success, in which prescribing physicians would have a central role in informing and reassuring patients, an efficient monitoring of the patients treated with biologicals would be set up and time to market for biosimilars would be speeded up.

Information and communication on risks related to medications and proper use of medications for healthcare professionals and the general public: precautionary principle, risk management, communication during and in the absence of crisis situations.

Recent drug crises have highlighted the complexity, benefits and risks of medication communication. The difficulty of this communication is due to the diversity of the sources of information and the target audience, the credibility of spokespersons, the difficulty to communicate on scientific uncertainties and the precautionary principle, which is influenced by variable perceptions and tolerances of the risk. Globally, there is a lack of training in risk management with a tendency of modern society to refuse even the slightest risk. Communication on medications is subject to regulatory or legal requirements, often uses tools and messages that are not adapted to the target audience and is often based on a poor knowledge of communication techniques. In order to improve this situation, the available information must be coordinated by reinforcing the unique medication information website and by coordinating communication between authorities by means of a single spokesperson. A particular effort must be made in the field of training in the proper use and risk of medications for both the general population and patients but also for healthcare professionals, by setting up a unified academic on-line teaching platform for continuing medical education on medications and their proper use.

How can the environmental sustainability of healthcare products be taken into account throughout their life cycle?

Healthcare product procurement accounts for around 50% of the French healthcare system's greenhouse gas emissions. This lesson learned from the publication of the Shift Project's work in November 2021 has been a catalyst within the healthcare system, accelerating the consideration and implementation of actions aimed at reducing the environmental impact of the healthcare system, before, during and after care. In addition to their carbon footprint, healthcare products have a wide range of environmental impacts, including on water, air and soil, throughout their entire life cycle. We have chosen to divide this life cycle into four main stages: from research and development to production, distribution and market access, use and finally end-of-life management. Analysis of the regulatory framework at each stage and of existing initiatives described in the literature or by those in the field have structured and fuelled our thinking. We found that existing regulations focus exclusively on the health risk, with little or no consideration of the environmental risk, which is in itself a health risk. Furthermore, the implementation of certain structuring actions during the first 3 stages of the life cycle would make it possible to simplify or even eliminate the major problem of waste management associated with the end-of-life of healthcare products. With this in mind, we have produced 9 recommendations to ensure that the environmental impact of healthcare products is better taken into account throughout their life cycle.

Hydroxychloroquine in systemic lupus erythematosus: results of a French multicentre controlled trial (PLUS Study).

INTRODUCTION: Hydroxychloroquine (HCQ) is an important medication for treating systemic lupus erythematosus (SLE). Its blood concentration ([HCQ]) varies widely between patients and is a marker and predictor of SLE flares. This prospective randomised, double-blind, placebo-controlled, multicentre study sought to compare standard and adjusted HCQ dosing schedules that target [HCQ] ≥1000 ng/ml to reduce SLE flares. PATIENTS AND METHODS: [HCQ] was measured in 573 patients with SLE (stable disease and SELENA-SLEDAI≤12) treated with HCQ for at least 6 months. Patients with [HCQ] from 100 to 750 ng/ml were randomised to one of two treatment groups: no daily dose change (group 1) or increased HCQ dose to achieve the target [HCQ] (group 2). The primary end point was the number of patients with flares during 7 months of follow-up. RESULTS: Overall, mean [HCQ] was 918±451 ng/ml. Active SLE was less prevalent in patients with higher [HCQ]. A total of 171 patients were randomised and followed for 7 months. SLE flare rates were similar in the two groups (25% in group 1 vs 27.6% in group 2; p=0.7), but a significant spontaneous increase in [HCQ] in both groups between inclusion and randomisation strongly suggested improved treatment adherence. Patients at the therapeutic target throughout follow-up tended to have fewer flares than those with low [HCQ] (20.5% vs 35.1%, p=0.12). CONCLUSIONS: Although low [HCQ] is associated with higher SLE activity, adapting the HCQ dose did not reduce SLE flares over a 7-month follow-up.

How can the quality of medical data in pharmacovigilance, pharmacoepidemiology and clinical studies be guaranteed?

The development of medicinal products is subject to quality standards aimed at guaranteeing that database contents accurately reflect the source documents. Paradoxically, these standards hardly address the quality of the source data itself. The objective of this work was to propose recommendations to improve data quality in three fields (pharmacovigilance, pharmacoepidemiology and clinical studies). The analysis was focused on the data and on the critical stages presenting critical quality problems, for which the current guidelines are insufficiently detailed, unsuitable and/or poorly applied. Finally, recommendations have been proposed, mainly focused on the origin of the data and its transcription.

Drug repurposing: From the discovery of a useful pharmacological effect to making the treatment available to the patient.

The repurposing of a medicine already on the market to a new indication could be an opportunity to respond rapidly to a therapeutic need not yet covered, particularly in the context of rare and neglected diseases, or health emergencies. However, at each stage, difficulties may arise that will prevent the repurposed drug from being provided to patients. Beyond fortuity or a systematic strategy to detect a useful pharmacological effect, the implementation of the preclinical and clinical stages is sometimes complicated by the difficulty of accessing the molecule and its pharmaceutical data. Furthermore, relevant clinical results will not always be sufficient to ensure that a marketing authorisation is obtained or that patients receive satisfactory care. In addition to describing these various obstacles, the round table provided an opportunity to put forward recommendations for overcoming them, in particular the creation of a public-private partnership structure with sufficient funding to be able to offer individualised support for projects up to and including the marketing application.

Assessment of the health risks related to the presence of drug residues in water for human consumption: application to carbamazepine.

Pharmaceutical residues have been detected at low (usually ng/L) concentrations in drinking water sources. The detection of drugs in water intended for human consumption (WIHC) has raised questions of safety. In the absence of regulatory or other official guidance, water utilities are faced with a problem of which pharmaceutical residues should be monitored and the toxicological limits that should be required. In this essay, we define an approach for the assessment of health risks related to chemicals found in drinking water. We use the examples of carbamazepine and its main metabolite 10,11-epoxycarbamazepine to demonstrate our approach, which involves application of the following algorithm: (1) when there is human or animal toxicity data, a toxicity reference value (TRV) can be calculated; (2) when this is not applicable, an attempt should be made to derive the TRV using known information about the minimum therapeutic dose (MTD); and (3) when no applicable data is available, at all, a threshold of toxicological concern (TTC) should be estimated. In the case of carbamazepine, where relevant toxicological data exists, we derived a TRV, based on the known minimum therapeutic dose (MTD). For carbamazepine's metabolite 10,11-epoxycarbamazepine, there is no toxicological data, so we applied the TTC approach. Using this approach, and combining our estimates with what is known about these chemicals' margin of exposure (MOE), suggests that there is likely to be no appreciable risk to human health exposure to carbamazepine or its major metabolite, even given the inevitable uncertainties in exposure scenarios.

Monoclonal Antibodies for Therapeutic Use: Specific Characteristics of Clinical Development, Evaluation by the Agencies, and Long-term Monitoring of Safety.

Monoclonal antibodies (MoAb) are very different from other drugs. The Round Table aimed to determine whether the specific characteristics of MoAb have repercussions on their clinical development, evaluation by the health authorities, and long-term monitoring. As regards the structure-activity relationship of MoAb, classification according to mechanism of action (neutralising or agonist MoAb, cytolytic MoAb) is more relevant than to their degree of humanisation. Recommendations on their clinical development would be useful since the early phases give rise to a number of problems and are insufficiently codified. The pharmacokinetic profile is very different from that of other drugs. The concentration-effect relationship is difficult to study since the biomarkers may be apparently disconnected from the therapeutic effect. The methodology for evaluation of MoAb by the agencies, and postmarketing surveillance do not differ from the procedures used for other drugs; however, MoAb bring together a number of specific characteristics as compared with other drugs.

Interchangeability between Generic and Reference Products: Limits of Average Bioequivalence Methodology.

Marketing authorisation of generic drugs is based on a demonstration of the "average" bioequivalence (ABE), with acceptance limits of 0.8-1.25 for the 90% confidence interval (CI) of the ratio (generic versus reference) of geometric means of exposure (whole blood, serum or plasma drug concentration). However, when interchangeability of reference by one generic is considered during treatment of a given patient, such methodology cannot guarantee the lack of therapeutic impact especially for drugs with narrow therapeutic index. This review article describes the basis and limits of ABE methodology, and the adaptations that have been proposed by regulatory agencies. For highly variable drugs, given their large therapeutic margin, regulatory agencies even allow widening of the bioequivalence acceptance limits. For drugs with a narrow therapeutic index, the average bioequivalence methodology has been amended differently by regulatory agencies. The European Medicine Agency only requires the narrowing of the ABE acceptance limits to the 0.9-1.10 range. The US Food and Drug Administration (FDA) has proposed to narrow the ABE acceptance limits according to the reference within-subject variance. The FDA requires a fully replicate cross-over study (with four periods) which allows one to compare the within-subject variance between generic and reference drug, and to detect any subject-by-formulation interaction. Indeed, any within-subject variance difference or subject by formulation interaction is an obstacle to interchangeability at the individual level. These amendments for the ABE do not fundamentally change the fact that individual ratios of exposure (generic/reference) will vary to a larger extent than the ratio of their means. For these reasons, since true individual bioequivalence studies cannot be performed for practical reasons and statistical issues, one can suggest that, in addition to the usual average bioequivalence criteria, the limits of the 95% confidence interval of the individual generic/reference exposure ratios could be used to allow interchangeability during treatment (at least for narrow therapeutic index drugs). Limit values of such CI for interchangeability acceptance should be scaled to the therapeutic margin of the reference drug. Regulatory agencies could conduct calculations based on real datasets of bioequivalence studies to determine if such criteria could be acceptable to allow interchangeability.

[Analysis of off-label prescriptions of medicines in hospital in adult patients and feasibility study of their detection using CIM-10 coding]. / Analyse des prescriptions hospitalières hors AMM des médicaments chez l'adulte et étude de la faisabilité de leur détection par le codage CIM-10 du PMSI.

Analysis of off-label prescriptions of medicines in hospital in adult patients and study of feasibility of their detection by use of international disease classification, 10th version (IDC-10 codes). CONTEXT: In order to improve the appropriate use of medicines, a method of detection of off label prescriptions, especially in hospitalised patients, should be available. STUDY OBJECTIVES: Evaluate the performance of the detection of off-label prescriptions in hospitalised patients by use of IDC-10 codes. METHODS: Data prescriptions (excluding those directly taken in charge by the national health care system), clinical history and biological results were extracted from Assistance publique des Hôpitaux de Paris (AP-HP) data-warehouse for 108 in-hospital adults patients' journeys. An adjudication committee established the classification reference for the appropriate or off label drug prescriptions status after analysis of medical information for each patient. IDC-10 codification that is performed after every hospitalisation was crossed with those IDC-10 codes that were to be expected corresponding to the marketing authorisation labelling (section 4.1 of specifications of product characteristics [SPC]). Results of IDC-10 coding were compared to the reference for off label use identification. RESULTS: Out of the 1131 analysed prescriptions, 44 (3.9%) were classified as off label by the adjudication committee. Sensitivity of detection by IDC-10 coding was 87 (95% CI [0.73-0.96]) to 92% (95% CI [0.79-0.98]) and specificity 25 (95% CI [0.22-0.27]) to 41% (95% CI [0.38-0.44]) according to the number of characters of ICD-10 that could be used. CONCLUSIONS: Incidence of in-hospital off label use of drugs (restricted to within drug related groups prescriptions) appeared relatively low (3.9%). Its semi-automatic detection by IDC-10 coding appears feasible with a good sensitivity but a low specificity. Such method could be further assessed as a first step detection focusing on one pharmacological class or on one pathologic condition.

Health crisis: What opportunities for clinical drug research?

The COVID-19 pandemic led to the deployment of an unprecedented academic and industrial research effort, the sometimes redundant nature of which is regrettable, as is the lack of both national and international management. However, it must be noted that during this crisis, regulatory procedures were adapted and certain obstacles in the organisation of clinical research were partly removed to contribute to the deployment of trials as close as possible to patients and to facilitate monitoring and control procedures. The digitisation of certain processes and the decentralisation of certain activities were implemented under the cover of a mobilisation of the authorities and all institutional, academic and industrial players. While in the UK, the optimisation of resources through a single platform trial has made it possible to demonstrate or invalidate the efficacy of many treatments, in France the health crisis has highlighted the fragility of the organisation of clinical research, in particular a lack of coordination and funding, difficulties in implementing studies and a certain reluctance to share data. However, the crisis has also revealed the adaptability of the various stakeholders and has led to the improvement of several processes useful for the deployment of therapeutic innovation. Let us hope that the lessons learned during this crisis will allow for greater efficiency in the event of a new pandemic and, above all, that the progress made will continue to apply to all future clinical research activities.

Multidrug resistance-associated protein 4 regulates cAMP-dependent signaling pathways and controls human and rat SMC proliferation.

The second messengers cAMP and cGMP can be degraded by specific members of the phosphodiesterase superfamily or by active efflux transporters, namely the multidrug resistance-associated proteins (MRPs) MRP4 and MRP5. To determine the role of MRP4 and MRP5 in cell signaling, we studied arterial SMCs, in which the effects of cyclic nucleotide levels on SMC proliferation have been well established. We found that MRP4, but not MRP5, was upregulated during proliferation of isolated human coronary artery SMCs and following injury of rat carotid arteries in vivo. MRP4 inhibition significantly increased intracellular cAMP and cGMP levels and was sufficient to block proliferation and to prevent neointimal growth in injured rat carotid arteries. The antiproliferative effect of MRP4 inhibition was related to PKA/CREB pathway activation. Here we provide what we believe to be the first evidence that MRP4 acts as an independent endogenous regulator of intracellular cyclic nucleotide levels and as a mediator of cAMP-dependent signal transduction to the nucleus. We also identify MRP4 inhibition as a potentially new way of preventing abnormal VSMC proliferation.