Are genetically modified protozoa eligible for ATMP status? Concerning the legal categorization of an oncolytic protozoan drug candidate.

Neospora caninum is an obligate intracellular protozoan that affects several animal species. It is not pathogenic for humans, and its ability to infect and lyse a variety of cells and stimulate the immune system makes it an interesting drug candidate in oncology. The intrinsic oncolytic properties of N. caninum have been confirmed in several preclinical models. Moreover, it can be modified to improve its safety and/or efficacy against cancer cells. In this study, we propose the legal categorization of this new biological drug candidate and the impact of modifications, notably the integration of a suicide gene, the deletion of a gene allowing its multiplication in healthy cells, and/or the insertion of a gene coding for a therapeutic protein into its genome. When unmodified, N. caninum can be categorized as a biological medicinal product, whereas modifications aimed at increasing its safety classify it as a Somatic Cell Therapy Medicinal Product, and modifications aiming to increase its efficacy or both safety and efficacy make it as a Gene Therapy Medicinal Product. This categorization is fundamental because it determines the guidelines applicable for preclinical development. These guidelines being numerous and complex, we have focused on the key requirements necessary for the development of the future medicinal product.

The Proposal for a Directive on Defective Products: A Game Changer for Innovative Medicinal Products.

At the end of 2022, the European Commission published a proposal for a directive to revise the strict liability regime introduced in 1985. Although the main goal of this new proposal is to adapt the regulations to information technologies such as artificial intelligence, it has multiple impacts on other economic sectors, including the pharmaceutical market. Therefore, this proposal could change the deal in terms of liability in this specific market. Indeed, the proposal modifies the burden of proof, which can be quite challenging to establish in the case of adverse effects of medicinal products. It introduces a possible presumption of liability for a manufacturer who fails to communicate, to a court, the information they required, which might jeopardise the protection of trade secrets and commercial confidentiality. In addition, the proposal also extends the limitation period, and more importantly, it mandates the application of the 'development risk defence.'

"Regulatory Sandboxes" Could Solve the Regulatory Problems Encountered in Europe and Arising from Innovation in Biological Medicinal Products.

Pharmaceutical innovation can sometimes clash with existing regulations, creating challenges for pioneering medicinal products, especially biologics, as they transition from the research phase to product development and post-approval categorisation. For instance, vaccines and advanced therapy medicinal products must fall under the category of biological medicinal products. However, the ability to chemically synthesise both proteins or mRNA can rule out classifying them as vaccines or advanced therapy medicinal products. Consequently, many organic products face regulatory obstacles when attempting to reach the market owing to their inherent natures or involved technologies. The European Commission's proposal for a directive to overhaul the European Union pharmaceutical legislation brings in a new tool: the regulatory sandboxes. They could be a suitable solution to manufacture pioneering medicinal products. Regulatory sandboxes are a form of legal experimentation helping with the marketing of a medicinal product based on groundbreaking technology as they sidestep current regulations. In essence, a regulatory sandbox is a tailor-made, inherently flexible, and time-limited regulatory framework facilitating the development of a drug outside the standard regulatory framework.

Why is there no biosimilar of Erbitux®?

Monoclonal antibody (mAb)-based therapies have been a major advance in oncology patient care, even though they represent a significant healthcare cost. Biosimilars, launched in Europe in 2004 are an economically attractive alternative to expensive originator biological drugs. They also increase the competitiveness of pharmaceutical development. This article focuses on the case of Erbitux® (cetuximab). This anti-EGFR (Epidermal Growth Factor Receptor) monoclonal antibody is indicated for metastatic colorectal cancer (2004) and squamous cell carcinoma of the head and neck (2006). However, despite the expiration of the patent in Europe in 2014 and estimated annual sales of 1.681 million US dollars in 2022, Erbitux® has not yet faced any approved biosimilar challenges in the United States or in Europe. Here, we outline the unique structural complexity of this antibody highlighted by advanced orthogonal analytical characterization strategies resulting in risks to demonstrate biosimilarity, which may explain the lack of Erbitux® biosimilars in the European and US markets to date. The development of Erbitux® biobetters are also discussed as alternative strategies to biosimilars. These biologics offer expected additional safety and potency benefits over the reference product but require a full pharmaceutical and clinical development as for New Molecular Entities.

RNA-based drugs and regulation: Toward a necessary evolution of the definitions issued from the European union legislation.

Many RNA-based drugs, both vaccines and non-vaccines, are under development or even approved. They include coding mRNAs and non-coding (nc) RNAs among them antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), micro-RNAs (miRNAs), small activating RNAs (saRNAs), RNA aptamers and RNA guides. According to the European Union (EU) legislation, these products can be currently categorized into different regulatory statuses, depending, for vaccines, on their target (infectious disease or not) and, for other drugs, on how they are obtained (chemically or biologically). This classification is fundamental to the type of marketing authorization (MA), and therefore to the controls to be performed, from preclinical stages through clinical trials to pharmacovigilance, to meet the safety requirements for patients. However, the current rules raise several problems, in particular the risk, because technology is evolving, to have similar RNA drugs being covered by very different legal statuses and the lack of international harmonization. The objectives of this study are (i) to review how RNA medicinal products are currently legally categorized in the EU and especially whether they fall under the status of gene therapy medicinal products (GTMP), a regulatory status belonging to advanced therapy medicinal products (ATMP), (ii) to discuss the issues generated by this classification, with a focus on the heterogeneity of statuses of these products, the differences with the American and ICH definitions and the potential impact on the safety requirements.

[The pharmacist and informed consent]. / Le pharmacien et le consentement éclairé.

During the implementation of the Covid-19 vaccination, the issue of consent was widely commented upon. Many confusions arose between the withdrawal period, the obligation to collect written consent and many other more or less fanciful concepts. Informed consent is one of the founding stones of health democracy. It deserves to be understood in order to be intelligently applied.

Low Cross-Reactivity Between Cisplatin and Other Platinum Salts.

BACKGROUND: Hypersensitivity reactions to platinum salts (PS) (cisplatin [CI], carboplatin [CA], and oxaliplatin [OX]) can be severe and their incidence is increasing due to their widespread use in cancer treatment. OBJECTIVE: To determine the rate of cross-reactivity between PS and whether CI can be administered without prior allergy testing in patients with a history of CA or OX hypersensitivity. METHODS: From September 2002 to April 2016, patients with suspected immediate PS hypersensitivity were tested and cross-reactivity between the 3 PS was evaluated. We then studied patients who were given CI without desensitization after immediate hypersensitivity to other PS. RESULTS: A total of 155 patients were included. Skin tests were positive in 97 patients (OX: 51, CA: 43, and CI: 3). Cross-reactivity to CA in OX-allergic patients was 45% (23 of 51) (95% confidence interval [CI]: 36% to 66%) and cross-reactivity to OX in CA-allergic patients was 37% (16 of 43) (95% CI: 23% to 53%). In contrast, cross-reactivity to CI was 0% (0 of 51) (95% CI: 0% to 7%) in OX-allergic patients and 7% (3 of 43) (95% CI: 2% to 17%) in CA-allergic patients. All these 3 patients had previously been exposed to CI in previous courses of chemotherapy. CI was initiated in 24 patients with proven hypersensitivity to CA or OX and had no hypersensitivity reactions. CONCLUSION: Initiating CI in patients with proven immediate hypersensitivity to CA or OX appeared to be safe in our study.

[Studying at École de pharmacie de Lille with Alfred Giard in the XIXth century]. / Etudier à 'École de pharmacie de Lille avec Alfred Giard au XIXe siècle.

This article describes a pharmacy student's notebook in Lille in the 1870s. The Medical Natural History course is taught by Alfred Mathieu Giard. Following a brief biography of the latter, excerpts of the manuscript are presented, they reveal the extent of scientific knowledge of the late nineteenth century, especially in the field of Parasitology.