Search

Introduction Burn eschar removal by enzymatic debridement with NexoBrid® (EDNX) results in a maximum preservation of all viable tissue, which is the main advantage over traditional tangential excision. The authors participated in a marketing authorization holder process to obtain reimbursement from the national health authorities in Belgium. Material and methods The reimbursement process consisted of three phases, as specified by the reimbursement regulations required by the Belgian National Institute for Health and Disability Insurance (NIHDI). Results Forty-one patients with clinically deep 2nd and 3rd degree burns, treated with EDNX in two Belgian burn centers, were included in the registry for the first phase of the reimbursement process. The total success rate of the EDNX treatment was 95.1% (39/41). Over half of the burn wounds treated with NexoBrid® (55.2%) did not require any additional surgical debridement or skin grafting. To obtain definitive reimbursement, an extra 16 patients were included. In this population, 51.4% did not require any surgical intervention. The total success rate of the EDNX debridement in this group was 100%.Based on an estimated market share of 12% and around 75 patients in the third year after final reimbursement, a market access consultant calculated that NexoBrid® will realize yearly savings for the Belgian Healthcare budget of at least €30.000. Conclusion Based on the results of this Belgian registry study in combination with the yearly healthcare budget savings, the NIHDI granted a final reimbursement for EDNX treatment in adults, endorsed by the Minister of Health on November 5th, 2019.

Background Levothyroxine sodium marketed in France was reformulated following a French National Agency for Medicines and Health Products Safety request for a more stringent potency specification. Despite previously established purity and bioequivalence of the new and old formulations, reports of adverse events substantially increased following reformulation. This analysis evaluated the nature and relevance of the medically confirmed safety reports. Methods Spontaneous and solicited individual case safety reports in France were retrieved from 26 March 2015 to 30 June 2016 (old formulation) and 26 March 2017 to 30 June 2018 (new formulation). Rates of reports and adverse events were calculated for the overall patient population and for at-risk subgroups. Adverse events delineated by thyroid-stimulating hormone levels were evaluated. Results A total of 295 and 42 775 reports for the old formulation and new formulation, respectively, were retrieved, with 149 and 5503 medically confirmed. The most common medically confirmed adverse events were consistent with the known safety profile of levothyroxine, with generally comparable rates between both formulations (range of differences, 1.8–4.1%). Most cases were not serious (old formulation, 65.8%; new formulation, 78.7%). Reporting rates were similar or higher for the old formulation within subgroups of at-risk patients. Nature/distributions of adverse events by thyroid-stimulating hormone levels as determined by both the marketing authorization holder of levothyroxine and the French National Agency for Medicines and Health Products Safety were similar. Conclusions The new formulation safety profile aligns with the established profile of the old formulation of levothyroxine. The benefit–risk profile is unchanged, such that the benefits of using the new formulation in the approved indications outweigh the risks associated with the treatment.

The aim of this study is to compare the completeness of relevant structured fields such as age, sex, drug and reaction start dates, time to onset, outcome and drug indication, in serious spontaneous cases reported in Spain depending on whether they have been collected by regional pharmacovigilance centres or by the marketing authorization holders. We analyzed the completeness of key variables for causality assessment related to the patient, the reaction and the suspected drug in all serious cases spontaneously reported and registered in the Spanish Pharmacovilance database, called FEDRA, from 1 January 2011 until 31 December 2018. The completeness scores were calculated according to the type of field and taking into account the VigiGrade tool. Cases were classified according to the reporting pathway, that is whether they were received and transmitted by marketing authorization holder or by regional pharmacovigilance centres. The completeness score of cases collected by regional pharmacovigilance centres was higher in all the studied variables. The main differences were found in drug and reaction start date, and time to onset. This study shows a high completeness score in cases of suspected adverse reactions reported to the regional pharmacovigilance centres with regard to key elements for causality assessment, signal and duplicate detection. In contrast, marketing authorization holder cases show a low completeness score and a decreasing tendency in all the studied variables over the studied period.

Between 2015 and 2017, a marked increase of anaphylactic-like reactions after intravenous administration of gentamicin was observed first in horses and, later, also in humans. This worldwide issue led to safety measures including product recalls and safety warnings. Here, a German Marketing Authorization Holder (MAH) of an early and intensely affected veterinary product containing gentamicin describes the clinical approach of the company to analyze the root cause and identify the causative agent in the active pharmaceutical ingredient (API). The pharmacovigilance data of the MAH are presented, along with pharmacovigilance phenomena observed during the affected period. An overview is given on further investigations of the API manufacturer and measures taken by all parties involved, including competent authorities to reestablish a safe use of gentamicin products. The histamine contamination of gentamicin was an exceptional incident of global extent, affecting not only veterinary but also human drug safety. The reactions in horses transpired to also be an indicator of a human health threat, which ultimately contributed to an improvement in the safety of human and veterinary medicinal products containing fermentative APIs. The extreme dimensions of this issue emphasise the important role that veterinary clinicians and practitioners play in spontaneous reporting based pharmacovigilance systems and, by this, in drug safety.

A retrospective observational study evaluated the direct healthcare professional communication (DHPC) letters disseminated by the Saudi Food and Drug Authority (SFDA) and their compliance with the pharmacovigilance guidelines. The study was utilized all DHPC letters available on the SFDA website, which is intended to communicate drug safety information to healthcare professionals (HCPs). Then, the letters were evaluated based on DHPC letter requirements approved in the European Medicines Agency (EMA) pharmacovigilance guidelines. Statistical analyses were conducted utilizing statistical analysis software (SAS® version 9.4). In June 2020, 169 letters were retrieved from the SFDA website. Most of the letters had the marketing authorization holder's logo (97%) and mentioned the date of letter issuance (98.8%). The most frequently discussed safety issues were hyperkalemia risk associated with combining renin–angiotensin–aldosterone system (RAAS) medications (10.6%) and cardiac risks (9%). Antineoplastic and immunosuppressant classes were associated with a majority of DHPC letters (15% for each category). A significant percentage of DHPC letters (10%) did not mention an agreement statement with SFDA, and 42 letters did not include marketing authorization holders (MAHs) contact information. The qualified persons responsible for pharmacovigilance and medical directors had signed most of the DHPC letters (51% and 46%, respectively). Many letters mentioned the details of reporting information to both SFDA and an MAH (82%). Moreover, 66% of the DHPC letters presented safety information within the 2‐page limit. In conclusion, the DHPC letters disseminated by MAHs in Saudi Arabia have an acceptable level of compliance with the guidelines.

Marketing authorization holder (MAH)-sponsored patient support programs (PSPs) are a major source of adverse event (AE) reports. The impact of reports from PSPs on the ability to detect AE signals is unclear. We compared signal detection performance using data from PSPs vs. non-PSP sources, and between PSPs providing clinical services vs. PSPs not providing clinical services.Data were obtained from an internal safety database for a global pharmaceutical company 2015-2017. We assessed whether signals were detected for the reference drug-AE pairs using data from PSPs vs. non-PSP sources, and among different PSP services. The performance was evaluated by four measures including area under the receiver operating characteristic curve (AUC) and time-to-signal detection.While the majority of reports were from PSPs, non-PSP sources were better and faster at detecting signals (AUC 0.63 vs. 0.41,Reports of AEs from PSPs had worse signal detection performance compared to non-PSP sources. Pharmacovigilance experts should be mindful when using databases that contain reports from PSPs for signal detection.

Introduction Two risk minimization (RM) tools—a healthcare professional frequently asked questions (HCP-FAQs) brochure and a patient/caregiver information brochure (PCIB)—were developed for HCPs and for adolescents (aged ≥ 13 years) receiving aripiprazole for bipolar I mania and their caregivers. Objectives This study evaluated the effectiveness of these RM tools in improving the awareness and education of HCPs and patients/caregivers. Method The RM tools were distributed to HCPs (identified in agreement with the marketing authorization holder [MAH] and local regulatory authorities), who in turn distributed the PCIBs to patients/caregivers. A web-based survey was then conducted targeting HCPs and patients/caregivers. Results The response rate was low: 118 of 23,282 invited HCPs and 16 patients/caregivers completed the survey. Overall, 42% (49/118) of HCP respondents were aware of aripiprazole RM tools; of these, 59% (29/49) of HCPs read them at least once and 66% (19/29) of these used the RM tools while discussing the benefit–risk profile of aripiprazole with patients/caregivers. In total, 30 of the 118 HCPs (25%) were aware of the PCIB, and 26 distributed it to their patients/caregivers, whereas seven HCPs advised them to read the brochure. Overall, 15 of the 16 patients/caregivers were aware of the PCIB, and 13 read/referred to it. Of these, 12 found the PCIB useful, and five monitored their weight while receiving aripiprazole and reported potential risks immediately to their HCP. Conclusion The response rate to the survey was low, and the tools displayed limited utility and effectiveness in improving awareness and education in a small number of responders. Therefore, the aripiprazole risk management plan was amended, and the tools were discontinued. Electronic supplementary material The online version of this article (10.1007/s40264-018-0662-2) contains supplementary material, which is available to authorized users.

In recent years inhaled systems have shown momentum as patient-personalized therapies emerge. A significant improvement in terms of therapeutic efficacy and/or reduction adverse systemic effects is anticipated from their use owing these systems regional accumulation. Nevertheless, whatever safety and efficacy evidence required for inhaled formulations regulatory approval, it still poses an additional hurdle to gaining market access. In contrast with the formal intravenous medicines approval, the narrower adoption of pulmonary administration might rely on discrepancies in pre-clinical and clinical data provided by the marketing authorization holder to the regulatory authorities. Evidences of a diverse and inconsistent regulatory framework led to concerns over toxicity issues and respiratory safety. However, an overall trend to support general concepts of good practices exists. Current regulatory guidelines1 that supports PK/PD (pharmacokinetics/pharmacodynamic) assessment seeks attention threatening those inhaled formulations set to be approved in the coming years. A more complex scenario arises from the attempt of implementing nanomedicines for pulmonary administration. Cutting-edge image techniques could play a key role in supporting diverse stages of clinical development facilitating this pharmaceutics take off and speed to patients. The ongoing challenge in adapting conventional regulatory frameworks has proven to be tremendously difficult in an environment where market entry relies on multiple collections of evidence. This paper intention is to remind us that an acceptable pre-clinical toxicological program could emerge from, but not only, an accurate and robust data imaging collection. It is our conviction that if implemented, inhaled nanomedicines might have impact in multiple severe conditions, such as lung cancer, by fulfilling the opportunity for developing tailored treatments while solving dose-related toxicity issues; the most limiting threat in conventional lung cancer clinical management.

Pharmacovigilance is an essential part of the post-marketing surveillance of new biologicals. It not only requires a substantial investment of the marketing authorization holder but also of the clinical field to provide accurate safety information. Hence, does pharmacovigilance delivers value for money? This important question needs to be discussed in the light of regulatory requirements, value and cost.

Background Cetuximab (CET) in combination with chemotherapy is approved for a once-weekly (q1w) schedule at an initial dose of 400 mg/m², followed by weekly doses of 250 mg/m², in patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC). However in clinical practice, an off-label schedule of CET 500 mg/m2 every-2-weeks (q2w) is frequently used. This pooled analysis of patient-level data aimed to test the noninferiority of the q2w vs q1w schedule on overall survival (OS). Methods All post-authorization studies with patient-level data available to marketing authorization holder at time of study design, in patients with confirmed RAS wt mCRC who received a first-line treatment with CET q1w or q2w in combination with chemotherapy from 2007 to 2018 were included: 2 non-interventional cohort studies (NIS) (EREBUS, ERBITAG) and 3 clinical trials (CEBIFOX, CECOG/CORE 1.2.002, APEC). Patients were categorized into q1w or q2w groups according to the CET schedule planned at initiation. OS was calculated from first CET infusion until all-cause death and censored at the last date patients were known to be alive. The noninferiority of the q2w vs q1w schedule was tested with a hazard ratio (HR) margin of 1.25 using a Cox proportional hazards regression model. Differences in baseline characteristics were accounted for with inverse probability of treatment weighting (IPTW) based on a propensity score. Results 763 (91% from NIS) and 554 (51% from NIS) patients were included in the q1w and q2w groups, respectively. Median (Q1-Q3) age in years was 66 (57-73) for q1w and 60 (53-69) for q2w. Liver-limited disease concerned 42.6% of patients for q1w and 37.9% for q2w. A baseline ECOG Performance Status of 0-1 was reported in 81.8% of q1w and 90.6% of q2w patients. FOLFIRI was most frequently used in combination with q1w (49.4%) and FOLFOX with q2w (59.2%). IPTW-adjusted HRs for OS were in favor of q2w: 0.83 (95% CI, 0.71-0.96) and 0.73 (95% CI, 0.61-0.88) when restricted to NIS. Other efficacy and safety results will be presented in the future. Conclusions This pooled analysis confirmed the noninferiority of CET q2w vs q1w. This result suggests an improved OS with the q2w schedule. Editorial acknowledgement ClinicalThinking, Inc, Hamilton, NJ, USA, funded by Merck Healthcare KGaA, Darmstadt, Germany. Legal entity responsible for the study Merck Healthcare KGaA. Funding Merck Healthcare KGaA. Disclosure S. Kasper: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Aventis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Servier; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly. F. Overkamp: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Chugai; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Cellex; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Gilead; Honoraria (self), Advisory / Consultancy: Hexal; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: Janssen-Cilag; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Novonordisc; Honoraria (self), Advisory / Consultancy: Riemser; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Servier. C. Foch: Full / Part-time employment: Merck Healthcare KGaA. F. Lamy: Full / Part-time employment: Merck Healthcare KGaA. R. Esser: Full / Part-time employment: Merck Healthcare KGaA. D. Messinger: Full / Part-time employment, Prometris provides statistical services for Merck Healthcare KGaA: Merck Healthcare KGaA. V. Rothe: Full / Part-time employment, Prometris provides statistical services for Merck Healthcare KGaA: Merck Healthcare KGaA. W. Chen: Full / Part-time employment: Merck Serono. T. Brodowicz: Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: PharmaMar; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Lilly. C.C. Zielinski: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Imugene; Honoraria (self), Advisory / Consultancy: ARIAD; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Merrimack; Honoraria (self), Advisory / Consultancy: Merck Healthcare KGaA; Honoraria (self), Advisory / Consultancy: FibroGen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: Gilead; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Shire; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Athenex. All other authors have declared no conflicts of interest.

The European Union (EU) is a politico-economic union of twenty-eight member states covering over four million km² and with about 508 million inhabitants. Pharmaceutical regulatory systems in EU comprise of a decentralized body European Medicines Agency (EMA), Heads of Medicines Agencies (HMA), National Competent Authorities (NCAs) and European Directorate for the Quality of Medicines (EDQM). Eudralex is the collection of rules and regulations governing medicinal products in the EU. A medicinal product can be placed in the EU by a Marketing Authorization Holder (MAH) after acquiring a marketing authorization in the EU. The marketing authorization can be obtained by any of the four major procedures: centralized (CP), decentralized (DCP), mutual recognition (MRP), and national procedure. The authorization applied under centralized procedure is granted in all EU member states including the European Economic Area (EEA), whereas marketing authorization under DCP and MRP is approved in EU member states selected by the applicant. The official timeline for the approval of medicinal product under centralized and decentralized procedure is 210 days. EU marketing authorization is generally granted for five years. The marketing authorizations once approved are renewed through a renewal process and any changes to a marketing authorization can be achieved through filing of variation applications. In addition to obtaining and maintaining the marketing authorizations, the MAH is also responsible for meeting the routine batch release and pharmacovigilance obligations.

We analyze the basic situation of Marketing Authorization Holder (MAH) of drugs in China. Mathematical analysis was carried out on the approval time, product category, dosage form, listing permit holder and production unit of 3239 MAH of drugs in China as of July 31, 2019. We found the following results. The approval time for MAH of drugs was concentrated in 2015, mainly based on chemicals, and the dosage forms were mostly tablets and injections. Furthermore, the number of MAH of drugs varies greatly among different provinces, and the number of Hebei, Guangdong, and Jiangsu ranks in the top three. Thirdly, there are time differences, variety types and geographical differences in the MAH of drugs. This is the application for examination and approval after the full implementation of the MAH of drugs system, and the patent and intellectual property protection in the process of entrusted production technology transfer. The research provides reference for enterprise declaration and regulatory approval management after the full implementation of the MAH system in China.

Desde o acesso ao mercado até o termo da comercialização, os medicamentos percorrem ciclos de valor, que são aferidos pelo desempenho de variáveis endógenas e exógenas ao medicamento. Os ciclos de valor constituem intervalos de tempo durante o qual o valor se mantém constante. A definição do preço dos medicamentos deve ter lugar em função do valor observado em cada ciclo. O contrato como instrumento de regulação das relações jurídicas administrativas com os titulares das autorizações de utilização de medicamentos, dispositivos médicos e outras tecnologias de saúde compromete-os com os objetivos do sistema de saúde em que se inserem, enquadrando as condições de comparticipação ou aquisição mediante avaliação prévia., From access to term of marketing, medicines go through value cycles measured by the performance of endogenous and exogenous variables. Marketing access includes efficacy, safety profile, and therapeutic indications, whereas term of marketing comprises drug life cycle and public health priorities. The value cycles are time intervals during which the value is constant. The setting of the price of pharmaceuticals should occur according to the value observed in each cycle. A system of pricing based on value cycles is dynamic, transparent, and geared towards efficiency and sustainability. Agreement as a regulatory tool of administrative and legal relationship with the marketing authorization holder is committed to the goals of the health care system.

Pharmacovigilance of vaccines is of paramount importance to promote the safe use of vaccines among their recipients. India launched the Adverse Events Following Immunization (AEFI) surveillance program in 1986 for monitoring suspected adverse events following immunization and since then, the AEFI surveillance guideline has been updated periodically, with the latest being in 2015. The successful AEFI surveillance program in India required the concerted effort of all stakeholders such as National AEFI Secretariat, National Technical Collaborating Centre, Central Drug Standard Control Organization, marketing authorization holder, and health-care professionals.

First of all, we thank Dr. Syed Rizwanuddin Ahmad for his well-advised comments [1] and for offering us the opportunity to clarify a number of points from our work [2]. As Dr. Ahmad mentioned in his letter to the editor, even if Australia was one of the first countries to accept patient adverse drug reaction (ADR) reports in 1964, it was the USA that first initiated and developed a drug ADR surveillance programme, in 1956—a few years after the chloramphenicol-associated blood dyscrasia issue. This programme, launched by the US Food and Drug Administration (FDA), started with six hospitals at the beginning, which had to report ADRs on a monthly basis, and then the programme was rapidly expanded to other hospitals in the 1960s [3]. Dr. Ahmad underlined the fact that in the USA, in 2013, the direct patient reporting to health authorities was around 2.5 %, the remainder being indirect reporting. We agree that our paper should have clearly mentioned if the ADR reporting by a patient is direct, i.e. reporting to a health authority (or to a regional pharmacovigilance centre) or indirect via a marketing authorization holder (MAH). The percentage given in Table 1 (the patient reports column) in our paper was, most of the time, direct reporting, except for the USA and Canada, where the majority of ADR reports by patients/consumers are received indirectly via the MAH [4]. Another point addressed by Dr. Ahmad is clarification of the pathway of reporting done by patients or consumers. When our paper mentioned that ‘‘direct patient reporting systems exist in 44 countries out of the 50 surveyed countries’’, it meant that National Health Competent Authorities (NCAs) have implemented tools to directly receive ADR reports from patients or healthcare professionals (HCPs). Moreover, 27 countries (61 %) provide customized patient forms for direct reporting to NCAs, which differ from those intended to be used by HCPs and are easier to understand and complete. However, even if the NCAs of these 27 countries specially provide a separate direct ADR reporting system for patients or consumers, this system is not really dissociated from that set up for HCPs. Indeed, most of the time, the NCA website offers the possibility to report an ADR with a binary input: report as a patient or as an HCP. The direct patient ADR reporting is also subject to the same minimum reporting criteria required by the pharmacovigilance to be validated. Ultimately, the question of direct or indirect reporting (via an MAH) of a ADR by a patient can be raised and, even if it is well established that direct patient reporting to the NCA represents real added value for pharmacovigilance, the essential point is the fact that patients or consumers report ADRs.

Pharmaceuticals and medical devices (PMDs) are regulated by the Pharmaceuticals and Medical Devices Agency (PMDA) under a system that grants marketing approval only when it is indicated that effectiveness and safety are guaranteed [1]. Medical devices (MDs) have been used to treat, diagnose, and prevent disease since ancient times. MDs are classified by design complexity, use characteristics, and, importantly, risk assessment. Currently, a new classification system has been adopted [2]. The level of control, supervision, and data content needed to support the product depends on its classification [3] (Table 1). To register and market a class I device, the marketing authorization holder (MAH) need only file a pre-market notification with the PMDA without an assessment. To register and market a class II device, the MAH must file a pre-market approval application with a registered certification body and obtain certification [4]. This procedure is very similar to the European Conformity marking from a notified body [5]. If no applicable certification standard has been established or if the device is deemed a new MD, the MAH is required to submit an application to the PMDA to obtain approval. To register and market a class III or class IV device, the MAH must file a pre-market approval application with the PMDA and obtain approval.

Background: The package leaflet included in the packaging of all medicinal products plays an important role in the transmission of medicine-related information to patients. Therefore, in 2009, the European Commission published readability guidelines to try to ensure that the information contained in the package leaflet is understood by patients. Objective: The main objective of this study was to calculate and compare the readability levels and length (number of words) of the package leaflets for biological medicines in 2007, 2010, and 2013. Methods: The sample of this study included 36 biological medicine package leaflets that were downloaded from the European Medicines Agency website in three different years: 2007, 2010, and 2013. The readability of the selected package leaflets was obtained using the following readability formulas: SMOG grade, Flesch-Kincaid grade level, and Szigriszt’s perspicuity index. The length (number of words) of the package leaflets was also measured. Afterwards, the relationship between these quantitative variables (three readability indexes and length) and categorical (or qualitative) variables were analyzed. The categorical variables were the year when the package leaflet was downloaded, the package leaflet section, type of medicine, year of authorization of biological medicine, and marketing authorization holder. Results: The readability values of all the package leaflets exceeded the sixth-grade reading level, which is the recommended value for health-related written materials. No statistically significant differences were found between the three years of study in the readability indexes, although differences were observed in the case of the length (P=.002), which increased over the study period. When the relationship between readability indexes and length and the other variables was analyzed, statistically significant differences were found between package leaflet sections (P