Marketing authorisations for unmet medical needs: A critical appraisal of regulatory pathways in the European Union.

For unmet medical needs, the European Union has established fast-track regulatory pathways for ensuring patients' access to essential treatments. It is the case of the Conditional Marketing Authorisation (CMA) and the Authorisation under "Exceptional Circumstances" (EXC), which can be granted even if the clinical part of a medicinal product's dossier is not yet complete. The article aims to discuss the peculiarity of such regulatory pathways and assess the impact of their application on products' market access and penetration. A review of the regulatory history of medicines authorised with EXC or CMA has been performed on European Institutional databases (e.g., EMA portal, Union Register). Excluding vaccines, 71 CMAs and 51 EXCs were granted in the EU from 2002 and 2006, respectively, to 2022. Most CMAs have been released for the treatment of different types of tumours, while most of EXCs for alimentary tract and metabolism diseases, especially in the paediatric population, addressing unmet medical needs. Therefore, both regulatory pathways are effective for placing on the market essential medicines, preserving the initial positive benefit-risk balance. However, on average, CMAs are converted into "normal" authorisations only after a time which is significantly longer than the provided one-year renewal period, suggesting that such a regulatory pathway is still far from optimized.

Medicinal products meet medical devices: Classification and nomenclature issues arising from their combined use.

When a medicinal product (MP) and a medical device (MD) are combined, their correct classification implies discrimination among different possible scenarios, based on the nature of the combination and the principal mechanism of action. In the European Union (EU), stakeholders deal with a lack of harmonization, which can represent an obstacle toward the development of these products, and a complex nomenclature, emerging from two divergent regulatory philosophies (i.e., that of MPs and that of MDs). In the USA, where the US Food and Drug Administration (FDA) supervises MDs, drugs, and biological products, stakeholders interact with a single authority, where any issue is addressed internally.

Rituximab Therapy for Adults with Nephrotic Syndromes: Standard Schedules or B Cell-Targeted Therapy?

Rituximab is a chimeric anti-CD20 monoclonal antibody. It acts mainly through complement-dependent cytotoxicity on B cells expressing the CD20 marker. In this review, we analyse the efficacy and possible pitfalls of rituximab to treat nephrotic syndromes by taking into account pharmacological considerations and CD19 marker testing utility. Despite the fact that the drug has been in use for years, efficacy and treatment schedules in adults with nephrotic syndrome are still a matter of debate. Clinical trials have proven the efficacy and safety of rituximab in idiopathic membranous nephropathy. Data from observational studies also showed the efficacy of rituximab in minimal change disease and focal segmental glomerulosclerosis. Rituximab use is now widely recommended by new Kidney Disease Improved Outcome (KDIGO) guidelines in membranous nephropathy and in frequent-relapsing, steroid-dependent minimal change disease or focal segmental glomerulosclerosis. However, rituximab response has a large interindividual variability. One reason could be that rituximab is lost in the urine at a higher extent in patients with nonselective nephrotic proteinuria, exposing patients to different rituximab plasma levels. Moreover, the association between CD19+ levels and clinical response or relapses is not always present, making the use of this marker in clinical practice complex. High resolution flow cytometry has increased the capability of detecting residual CD19+ B cells. Moreover, it can identify specific B-cell subsets (including IgG-switched memory B cells), which can repopulate at different rates. Its wider use could become a useful tool for better understanding reasons of rituximab failure or avoiding unnecessary retreatments.

Rationalizing the Design of Hyaluronic Acid-Decorated Liposomes for Targeting Epidermal Layers: A Combination of Molecular Dynamics and Experimental Evidence.

This work provides information on the features of low molecular weight hyaluronic acid (HA)-decorated liposomes to target resveratrol (RSV) in the skin. Deformable liposomes were made of soy-phosphatidylcholine with Tween 80 as the fluidizing agent. For HA conjugation, three different phosphoethanolamines were tested: 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). The different phosphoethanolamine-HA conjugates were inserted into the liposome bilayer by hydration (HA on both faces of the bilayer) or by the postinsertion method (HA only on the external face of the bilayer). The effect of these variables on deformability was experimentally assessed by an in-house method (K value, the lower the value, the higher the deformability) and molecular dynamics (MD) simulations. The results showed that the K values of HA-liposomes obtained by hydration were higher than the K values of HA-liposomes prepared by postinsertion, and both were at least 10-fold higher than the K values of the corresponding plain liposomes. The nature of the lipid anchor played a key role in deformability (DMPE > DOPE > DPPE) with high variability in the case of DOPE formulations. These data were justified by the trends found in silico for the bilayer bending modulus and the HA end-to-end distance. In addition to liposome flexibility, the HA extent seems to be the key factor governing the skin penetration of RSV. When the extent is higher, the amount of the drug retained in the skin is larger. Regarding skin permeation, a parabolic trend was recorded, and the optimal amount to favor skin permeation was an approximately 30 HA/phospholipid (µg/mmol) ratio. This study reports the first piece of evidence that it is possible to control drug delivery in the skin by tuning the amount of HA on the vesicle surface.

Community Pharmacist's Role in Detecting Low Back Pain, and Patient Attitudes-A Cross-Sectional Observational Study in Italian Community Pharmacies.

BACKGROUND: Low back pain (LBP) is one of the most frequent diseases for which patients seek advice in a community pharmacy. The study aimed to evaluate the feasibility of the administration by community pharmacists of questionnaires to assess the LBP intensity and disability degree in patients entering community pharmacies and the attitudes they have toward pain management by pharmacological and non-pharmacological strategies. METHODS: An explorative, cross-sectional, observational, and quantitative study was performed. Twelve Italian community pharmacists were asked to submit a questionnaire on LBP to patients visiting their pharmacies. The questionnaire included a pain intensity scale, and two validated tools: the Roland and Morris Disability Questionnaire (RMDQ) and the Start Back Screening Tool (SBST) to determine the degree and risk of patient disability, respectively. RESULTS: 872 patients filled out the questionnaires in 6 months. No statistical differences between genders (p > 0.30) were recorded for pain intensity (Female: median score 6, IQR 4-7; Male: median scores 5, IQR 4-7; p > 0.30) and disability associated with LBP (RMDQ high-disability level: Females, 14.7%, Males, 15.0%; p > 0.90). Most of the patients (69%) reported a low degree of disability, but the risk of disability was medium and high in 36% and 18% of them, respectively (p < 0.05). About 14% of patients declare to never seek for physician's advice despite their medium-high degree of disability. CONCLUSION: The study demonstrated the feasibility of validated tools for assessing the degree and risk of disability in LBP patients administrable in community pharmacies. Moreover, the community pharmacy resulted in an important care portal for patients suffering from moderate LBP and for intercepting patients who suffered from severe LBP but had never reported their problem to their physician.

Old active ingredients in new medicinal products: is the regulatory path coherent with patients' expectations?

The rising costs of new medicinal products are a challenge to the economic sustainability of national healthcare systems in ensuring patients' access to therapies. European Union (EU) and US legislators have provided regulatory pathways aimed at simplifying Marketing Authorization (MA) applications for new medicinal products in cases when safety and efficacy profiles can be derived from the data of already-marketed products. In this review, we discuss the different regulatory pathways towards the MA of new medicinal products containing old drug substances and intended to improve the therapeutic value of a treatment, to obtain a new therapeutic indication (drug repositioning), or to ensure the same therapeutic value of a reference product at lower costs.

Preserving the Integrity of Liposomes Prepared by Ethanol Injection upon Freeze-Drying: Insights from Combined Molecular Dynamics Simulations and Experimental Data.

The freeze-drying of complex formulations, such as liposomes, is challenging, particularly if dispersions contain residual organic solvents. This work aimed to investigate the effects of possible protectants, namely sucrose, trehalose and/or poly(vinyl pyrrolidone) (PVP), on the main features of the dried product using a 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)-based liposomal dispersion prepared by ethanol injection and containing ethanol up to 6%, as a model. The interactions among vesicles and protectants were preliminary screened by Molecular Dynamics (MD) simulations, which have been proved useful in rationalizing the selection of protectant(s). The freeze-drying protocol was based on calorimetric results. Overall data suggested a stronger cryo-protectant effect of trehalose, compared with sucrose, due to stronger interactions with the DPPC bilayer and the formation of highly ordered clusters around the lipids. The effect further improved in the presence of PVP. Differently from the other tested protectants, the selected trehalose/PVP combination allows to preserve liposome size, even in the presence of 6% ethanol, as demonstrated by Nanoparticle Tracking Analysis (NTA). Nevertheless, it should be also underlined that cakes blew out at an ethanol concentration higher than 1% v/v, probably due to the poor cohesion within the cake and solvent vapour pressure upon sublimation.

Mechanisms of ST-segment elevation myocardial infarction in patients with atrial fibrillation, prior stenting and long-standing chronic coronary syndrome.

BACKGROUND: The optimal antithrombotic regimen for patients with atrial fibrillation (AF) and chronic coronary syndromes beyond 1 year after percutaneous coronary intervention (PCI) is a matter of debate. For these patients, guidelines recommend oral anticoagulation (OAC) alone, but the risk of thrombotic complications remains a concern. The aim of this study was to characterize the incidence, presentation and use of antithrombotic therapy in patients with AF, prior stenting > 12 months and new ST-segment elevation myocardial infarction (STEMI). METHODS: Consecutive patients were selected from an institutional registry over a 3-year period if they matched the following criteria: 1) STEMI undergoing primary PCI; 2) AF; 3) chronic coronary syndrome with prior stenting > 12 months. RESULTS: Among 852 consecutive STEMI patients undergoing primary PCI, the prevalence of AF was 4.1%, and 6 (0.9%) patients met all the inclusion criteria. Substantial heterogeneity in antithrombotic treatment for these patients was noted (e.g., OAC alone, OAC plus a single antiplatelet agent, no antithrombotic therapy). In 50% of patients, the STEMI episode was linked to a previously stented lesion or documented plaque. CONCLUSIONS: This case review illustrates the wide heterogeneity in antithrombotic pharmacotherapy among AF patients presenting with STEMI > 12 months after PCI. The underlying reason for STEMI is only partly related to disease progression or stent-related events. This finding suggests that multiple mechanisms of recurrence may be advocated, and are not only limited to antithrombotic therapy but may be explained by the natural history of coronary artery disease in remote vessels.

Regulatory aspects and quality controls of polymer-based parenteral long-acting drug products: the challenge of approving copies.

To assure the safety and the efficacy of a medicinal product, quality and batch-to-batch reproducibility need to be guaranteed. In the case of parenteral long-acting products, the European Union (EU) and US Regulatory Authorities provide different indications, from the classification to the in vitro release assays related to such products. Despite their relevance, there are few in vitro experimental set-ups enabling researchers to discriminate among products with different in vivo behaviors. Consequently, most copies are authorized through hybrid instead of generic applications. Here, we review the actual regulatory frameworks to evaluate the in vitro release of drugs from polymer-based long-acting parenterals to highlight the directions followed by the Regulatory Agencies in the USA and EU.

Glatiramer acetate: A complex drug beyond biologics.

Complex drugs may be either biological, if the active ingredients are derived from a biological source, or non-biological, if obtained by chemical synthesis. In both cases, their quality depends considerably on the manufacturing process. In the case of Non Biological Complex Drugs (NBCDs), complexity may arise either from the active substance, as in the case of glatiramer acetate, or from other sources, such as the formulation, as in the case of liposomes. In this paper, the case of glatiramer acetate (GA) - a NBCD relevant for clinical and economic reasons - is considered and the differences between US and EU regulatory approaches to GA marketing authorization are highlighted. Indeed, though US and EU regulatory agencies have chosen a generic approach integrated with additional data the implementation is different in the two jurisdictions. In the US, the additional data required are listed in a product specific guideline and copies of Copaxone® have been approved as generics. In the EU, instead regulatory agencies followed a hybrid approach requiring an additional comparative study, and interchangeability policies and substitution schemes have been left to national agencies.

Copies of nonbiological complex drugs: generic, hybrid or biosimilar?

The experience gained with biosimilars has made it clear that copies of complex drugs are more challenging to produce and put on the market than generics. In the case of so-called nonbiological complex drugs (NBCDs), the complexity can arise either from a complex active substance or by other factors, such as formulation or route of delivery. Regulatory policies in the USA and the EU for the marketing of NBCD copies are reviewed, using glatiramer acetate copies as a case study. In the USA, they are approved and marketed as generics (although needing additional data), and so they are interchangeable with the originator. In the EU, they are managed with a hybrid application, and their interchangeability and substitution are established by individual member states.

The safety of tattoo inks: Possible options for a common regulatory framework.

Tattoo prevalence has been increasing in the last 25 years, but specific regulations on tattoo inks are still missing. In the European Union, no supranational regulation is available and only few national provisions cover them. In the United States, tattoo inks are classified as cosmetics but are not approved for injection into the dermis. Health risks for consumers may derive from microbiological contamination and the presence of toxic substances or nanomaterials. However, current regulations and non-binding recommendations, where present, only address the microbiological and chemical risks, completely overlooking nanotoxicity. The aim of this paper is to promote awareness of the risks associated with tattoo inks and the nanomaterials contained therein. In particular, the need for a harmonised regulation or, at least, a set of minimal requirements is highlighted to improve the safety of tattoo inks and market surveillance by regulatory authorities.

Do laws impact opioids consumption? A breakpoint analysis based on Italian sales data.

PURPOSE: In Italy, where the adoption of opioid analgesics in pain management has been historically poor, an increase in opioids consumption occurred between 2000 and 2015. The aim of this study is to assess, through specific time series analyses for trend changes, the impact of different intervening factors - such as the availability of new drugs, the observance of clinical guidelines, changes in prescription regulations, and in reimbursement policies - on opioids sales to community pharmacies in Italy, focusing on the time period 2000-2010. MATERIALS AND METHODS: Five opioids were considered: codeine, tramadol, buprenorphine, morphine, and fentanyl. The analysis is based on sales data collected at wholesale distributors. For each one of the five drugs, time series of the number of Defined Daily Doses per thousand inhabitants per day in the period 2000-2010 were analyzed, and an estimation of breakpoints was performed using segmented linear regression. RESULTS: Drug sales underwent a sharp increase in 2000-2010, although on different scales. Segmented regression analysis highlighted different potential breakpoints, corresponding to either a significant change in value and/or in slope. Sales of the five opioids were affected by at least one relevant event, often due to a synergy of regulatory, marketing, and technological factors. The effect of reimbursement changes has proved important. CONCLUSION: Between 2000 and 2010, regulatory, technological, and reimbursement changes significantly influenced opioid sales to community pharmacies in Italy. The sales of relatively new drug products seem to be less influenced by changes in reimbursement and regulatory policies than that of more established products, suggesting that physicians are more comfortable with "old" drugs, since their clinical use is supported by established clinical guidelines and protocols.

Biosimilar switching and related medical liability.

Unlike generics, biosimilars are similar, but not equivalent, to the reference biological medicinal product. Therefore, if a patient experiences an adverse event, or a loss of efficacy, when transitioned to a biosimilar, the distribution of medical liability will be different from the case of both the originator and generics. Moreover, the case of naïve patients is different from that of non-naïve patients. In the case of naïve patients, physicians make their choice from a range of medicinal products that pose the same risk, since it is not possible to know with any certainty the patients' response to each therapeutic option until they have taken the drug. If physicians, instead, switch to a biosimilar for a patient already in treatment with the originator, they are switching from an option where the individual response is known, to an option where it is unknown. Given the evolving framework of biosimilar legislation, sharing choices with patients and obtaining their informed consent when switching to a biosimilar could represent an effective approach on the part of the prescribing physician. Moreover, a supranational database containing real-life data about patients in treatment with biological medicines, including information on the actual biological medicinal products administered, could complement the data obtained from clinical studies.

Poly(methyl methacrylate) salt as film forming material to design orodispersible films.

This work aims to evaluate the possible use of a poly(sodium methacrylate, methyl methacrylate) (NaPMM2) plasticized by PEG400 in the design of orodispersible films (ODF). Placebo ODF prepared by solvent casting were intended to study the impact of the polymer/plasticizer ratio and residual moisture on disintegration time, stickiness and mechanical properties. The drug loading capacity was assessed using ketoprofen and paracetamol. Placebo ODF containing PEG400 in the 10-30% w/w range and 10-15% of residual moisture content were easy-to-handle, packed without failures and completely dissolved within 30 s. NaPMM2/PEG400 in 80/20 ratio allowed up to 70% of paracetamol loading, which appeared as the largest value described in literature. This ODF showed good mechanical properties and disintegration time. The same formulation loaded with 25% or 50% ketoprofen (pKa = 4.45) swelled without disintegrating, because of a partial protonation of NaPMM2, as verified by ATR-FTIR spectroscopy. However, the addition of 5% surfactants allowed the formulation of ODF containing 25% ketoprofen that disintegrated within one minute and guaranteed the complete drug dissolution within 5 min. All the presented data, discussed in the framework of information available on such copolymer, highlighted its versatility in the design of orodispersible dosage forms.

Extraction Method and Analysis of Cannabinoids in Cannabis Olive Oil Preparations.

Recently, an increasing number of pharmacists had to supply medicinal products based on Cannabis sativa L. (Cannabaceae), prescribed by physicians to individual patients. Cannabis olive oil preparation is the first choice as a concentrated extract of cannabinoids, even though standardized operative conditions for obtaining it are still not available. In this work, the impact of temperature and extraction time on the concentration of active principles was studied to harmonize the different compounding methods, optimize the extraction process, and reduce the variability among preparations. Moreover, starting from the cannabis inflorescence, the effect of temperature on tetrahydrocannabinolic acid decarboxylation was evaluated. For the analysis, a GC/MS method, as suggested by the Italian Ministry of Health, and a GC/flame ionization detection method were developed, validated, and compared.

Simulation data for an estimation of the maximum theoretical value and confidence interval for the correlation coefficient.

The data presented in this article are related to the article titled "Molecular Dynamics as a tool for in silico screening of skin permeability" (Rocco et al., 2017) [1]. Knowledge of the confidence interval and maximum theoretical value of the correlation coefficient r can prove useful to estimate the reliability of developed predictive models, in particular when there is great variability in compiled experimental datasets. In this Data in Brief article, data from purposely designed numerical simulations are presented to show how much the maximum r value is worsened by increasing the data uncertainty. The corresponding confidence interval of r is determined by using the Fisher r→Z transform.

Molecular Dynamics as a tool for in silico screening of skin permeability.

Prediction of skin permeability can have manifold applications ranging from drug delivery to toxicity prediction. Along with the semi-empirical or mechanistic models proposed in the last decades, Molecular Dynamics simulations have recently become a fruitful tool for investigating membrane permeability, in particular as they allow the involved mechanisms to be modelled at a molecular level. Despite their significant structural complexity, Molecular Dynamics simulations can also be utilized to study permeation through the lipid matrix that characterizes the stratum corneum. In this work, Steered Molecular Dynamics simulations are performed on a suitably developed stratum corneum lipid matrix model. Regardless of their actual tortuous path within the stratum corneum, the permeants, taken from a Fully Validated dataset of 80 compounds of known permeability coefficient, are moved through the bilayer along its normal. This allows the exploration of all the possible conformational and physicochemical constraints the molecule experiences when moving through the bilayer. The so performed Steered Molecular Dynamics simulations are then utilized to extract the corresponding lipophilicity and diffusion parameters as computed by subdividing the entire path in 18 regions of different polarity and composition. Correlative analyses showed that the water-lipids interface is the best performing region and that significant enhancements can be gained by including parameters accounting for the temperature effect. Taken together, the developed models possess an enhanced predictive power compared to the existing equations and statistics are approaching the best possible results, given the uncertainty in the utilized permeability data.