Physiologically Based Biopharmaceutics Modeling (PBBM): Best Practices for Drug Product Quality, Regulatory and Industry Perspectives: 2023 Workshop Summary Report.

Physiologically based biopharmaceutics modeling (PBBM) is used to elevate drug product quality by providing a more accurate and holistic understanding of how drugs interact with the human body. These models are based on the integration of physiological, pharmacological, and pharmaceutical data to simulate and predict drug behavior in vivo. Effective utilization of PBBM requires a consistent approach to model development, verification, validation, and application. Currently, only one country has a draft guidance document for PBBM, whereas other major regulatory authorities have had limited experience with the review of PBBM. To address this gap, industry submitted confidential PBBM case studies to be reviewed by the regulatory agencies; software companies committed to training. PBBM cases were independently and collaboratively discussed by regulators, and academic colleagues participated in some of the discussions. Successful bioequivalence "safe space" industry case examples are also presented. Overall, six regulatory agencies were involved in the case study exercises, including ANVISA, FDA, Health Canada, MHRA, PMDA, and EMA (experts from Belgium, Germany, Norway, Portugal, Spain, and Sweden), and we believe this is the first time such a collaboration has taken place. The outcomes were presented at this workshop, together with a participant survey on the utility and experience with PBBM submissions, to discuss the best scientific practices for developing, validating, and applying PBBMs. The PBBM case studies enabled industry to receive constructive feedback from global regulators and highlighted clear direction for future PBBM submissions for regulatory consideration.

Shifting the Focus from Dissolution to Permeation: Introducing the Meso-fluidic Chip for Permeability Assessment (MCPA).

In response to the growing ethical and environmental concerns associated with animal testing, numerous in vitro tools of varying complexity and biorelevance have been developed and adopted in pharmaceutical research and development. In this work, we present one of these tools, i.e., the Meso-fluidic Chip for Permeability Assessment (MCPA), for the first time. The MCPA combines an artificial barrier (PermeaPad®) with an organ-on-chip device (MIVO®) and real-time automated concentration measurements, to yield a sustainable, yet effortless method for permeation testing. The system offers three major physiological aspects, i.e., a biomimetic membrane, an optimal membrane interfacial area-to-donor-volume-ratio (A/V) and a physiological flow on the acceptor/basolateral side, which makes the MPCA an ideal candidate for mechanistic studies and excellent in vivo bioavailability predictions. We validated the method with a handful of assorted drug compounds in unstirred and stirred donor conditions, before exploring its applicability as a tool for dissolution/permeation testing on a BCS class III/I drug (pyrazinamide) crystalline adducts and BCS class II/IV (hydrocortisone) amorphous solid dispersions. The results were highly reproducible and clearly displayed the method's potential for evaluating the performance of enabling formulations, and possibly even predicting in vivo performance. We believe that, upon further development, the MCPA will serve as a useful in vitro tool that could push sustainability into pharmaceutics by refining, reducing and replacing animal testing in early-stage drug development.

Integration of artificial neural network and physiologically based biopharmaceutic models in the development of sustained-release formulations.

Model-informed drug development is an important area recognized by regulatory authorities and is gaining increasing interest from the generic drug industry. Physiologically based biopharmaceutics modeling (PBBM) is a valuable tool to support drug development and bioequivalence assessments. This study aimed to utilize an artificial neural network (ANN) with a multilayer perceptron (MLP) model to develop a sustained-release matrix tablet of metformin HCl 500 mg, and to test the likelihood of the prototype formulation being bioequivalent to Glucophage® XR, using PBBM modeling and virtual bioequivalence (vBE). The ANN with MLP model was used to simultaneously optimize 735 formulations to determine the optimal formulation for Glucophage® XR release. The optimized formulation was evaluated and compared to Glucophage® XR using PBBM modeling and vBE. The optimized formulation consisted of 228 mg of hydroxypropyl methylcellulose (HPMC) and 151 mg of PVP, and exhibited an observed release rate of 42% at 1 h, 47% at 2 h, 55% at 4 h, and 58% at 8 h. The PBBM modeling was effective in assessing the bioequivalence of two formulations of metformin, and the vBE evaluation demonstrated the utility and relevance of translational modeling for bioequivalence assessments. The study demonstrated the effectiveness of using PBBM modeling and model-informed drug development methodologies, such as ANN and MLP, to optimize drug formulations and evaluate bioequivalence. These tools can be utilized by the generic drug industry to support drug development and biopharmaceutics assessments.

Biopharmaceutics Risk Assessment-Connecting Critical Bioavailability Attributes with In Vitro, In Vivo Properties and Physiologically Based Biopharmaceutics Modeling to Enable Generic Regulatory Submissions.

Quality risk assessment following ICH Q9 principles is an important activity to ensure optimal clinical efficacy and safety of a drug product. Typically, risk assessment is focused on product performance wherein critical material attributes, formulation variables, and process parameters are evaluated from a manufacturing perspective. Extending ICH Q9 principles to biopharmaceutics risk assessment to identify factors that can impact in vivo performance is an upcoming area. This is evident by recent regulatory trends wherein a new term critical bioavailability attributes (CBA) has been coined to identify such factors. Although significant work has been performed for biopharmaceutics risk assessment for new molecules, there is a need for harmonized biopharmaceutics risk assessment workflow for generic submissions. In this manuscript, we attempted to provide a framework for performing biopharmaceutics risk assessment for generic regulatory submissions. A detailed workflow for performing biopharmaceutics risk assessment includes identification of initial CBA (iCBA), their confirmatory evaluation followed by definition of the control strategy. Tools for biopharmaceutics risk assessment, i.e., bio-discriminatory dissolution method and physiologically based biopharmaceutics modeling (PBBM) were discussed from a practical perspective. Furthermore, a case study for CBA evaluation using PBBM modeling for an extended-release product for regulatory submission has been described using the proposed workflow. Finally, future directions of integrating CBA evaluation, biopharmaceutics risk assessment to the FDA Knowledge Aided Structured Assessment (KASA) initiative, the necessity of risk assessment templates, and knowledge sharing between industry and academia are discussed. Overall, the work described in this manuscript can facilitate and provide guidance for biopharmaceutics risk assessment for generic submissions.

Combined Liquid-State and Solid-State Nuclear Magnetic Resonance at Natural Abundance for Comparative Higher Order Structure Assessment in the Formulated-State of Biphasic Biopharmaceutics.

A higher-order structure (HOS) is critical to a biopharmaceutical drug as the three-dimensional structure governs its function. Even the partial perturbation in the HOS of the drug can alter the biological efficiency and efficacy. Due to current limitations in analytical technologies, it is imperative to develop a protocol to characterize the HOS of biopharmaceuticals in the native formulated state. This becomes even more challenging for the suspension formulations where solution and solid phases co-exist. Here, we have used a combinatorial approach using liquid (1D 1H) and solid-state (13C CP MAS) NMR methodology to demonstrate the HOS in the biphasic microcrystalline suspension drug in its formulated state. The data were further assessed by principal component analysis and Mahalanobis distance (DM) calculation for quantitative assessment. This approach is sufficient to provide information regarding the protein HOS and the local dynamics of the molecule when combined with orthogonal techniques such as X-ray scattering. Our method can be an elegant tool to investigate batch-to-batch variation in the process of manufacture and storage as well as a biosimilarity comparison study for biphasic/microcrystalline suspension.

Assessment of selected pharmaceuticals in Riyadh wastewater treatment plants, Saudi Arabia: Mass loadings, seasonal variations, removal efficiency and environmental risk.

Despite increasing interest in pharmaceutical emissions worldwide, studies of environmental contamination with pharmaceuticals arising from wastewater discharges in Saudi Arabia are scarce. Therefore, this study examined occurrence, mass loads and removal efficiency for 15 pharmaceuticals and one metabolite (oxypurinol) from different therapeutic classes in three wastewater treatment plants (WWTPs), in Riyadh city in Saudi Arabia. A total of 144 samples were collected from the influents and effluents between March 2018 and July 2019 and analyzed using Solid Phase Extraction followed by triple quadrupole LC-MS/MS. The average concentrations in the influents and effluents were generally higher than their corresponding concentrations found either in previous Saudi Arabian or global studies. The four most dominant compounds in the influent were acetaminophen, ciprofloxacin, caffeine, and diclofenac, with caffeine and acetaminophen having the highest concentrations ranging between 943 and 2282 µg/L. Metformin and ciprofloxacin were the most frequently detected compounds in the effluents at concentrations as high as 33.2 µg/L. Ciprofloxacin had the highest mass load in the effluents of all three WWTPs, ranging between 0.20 and 20.7 mg/day/1000 inhabitants for different WWTPs. The overall average removal efficiency was estimated high (≥80), with no significant different (p > 0.05) between the treatment technology applied. Acetaminophen and caffeine were almost completely eliminated in all three WWTPs. The samples collected in the cold season generally had higher levels of detected compounds than those from the warm seasons, particularly for NSAID and antibiotic compounds. The estimated environmental risk from pharmaceutical compounds in the studied effluents was mostly low, except for antibiotic compounds. Thus, antibiotics should be considered for future monitoring programmes of the aquatic environment in Saudi Arabia.

Current State and Challenges of Physiologically Based Biopharmaceutics Modeling (PBBM) in Oral Drug Product Development.

Physiologically based biopharmaceutics modeling (PBBM) emphasizes the integration of physicochemical properties of drug substance and formulation characteristics with system physiological parameters to predict the absorption and pharmacokinetics (PK) of a drug product. PBBM has been successfully utilized in drug development from discovery to postapproval stages and covers a variety of applications. The use of PBBM facilitates drug development and can reduce the number of preclinical and clinical studies. In this review, we summarized the major applications of PBBM, which are classified into six categories: formulation selection and development, biopredictive dissolution method development, biopharmaceutics risk assessment, clinically relevant specification settings, food effect evaluation and pH-dependent drug-drug-interaction risk assessment. The current state of PBBM applications is illustrated with examples from published studies for each category of application. Despite the variety of PBBM applications, there are still many hurdles limiting the use of PBBM in drug development, that are associated with the complexity of gastrointestinal and human physiology, the knowledge gap between the in vitro and the in vivo behavior of drug products, the limitations of model interfaces, and the lack of agreed model validation criteria, among other issues. The challenges and essential considerations related to the use of PBBM are discussed in a question-based format along with the scientific thinking on future research directions. We hope this review can foster open discussions between the pharmaceutical industry and regulatory agencies and encourage collaborative research to fill the gaps, with the ultimate goal to maximize the applications of PBBM in oral drug product development.

Development of a Novel Gastric Process Simulation Model: The Successful Assessment of Bioequivalence and Bioinequivalence of a Biopharmaceutics Classification System Class II Weak Acid Drug.

Bioequivalence has been assessed using in vitro dissolution testing, such as in vivo predictive dissolution methodology. However, the assessment of bioequivalence should be performed carefully, considering the effect of the in vivo environment and according to the properties of the drug. The gastric emptying process is a key factor for the assessment of biopharmaceutics classification system class II (BCS class IIa) drugs with acidic properties since they cannot dissolve in the acidic stomach, but do dissolve in the small intestine (SI). The disintegration of a tablet in the stomach affects the distribution/dissolution in the SI due to the difference in the gastric emptying step, which in turn is a result of the varying formulation of the drugs. In this study, we used the reported dynamic pH change method and a novel gastric process simulation (GPS) model, which can compare the gastric emptying of particular-sized drug particles. The in vitro results were compared to clinical data using bioequivalent and bioinequivalent products of candesartan cilexetil. It was revealed that the dynamic pH change method was inappropriate, whereas the amount of filtered drug in GPS studies with 20 and 50 µm pore size filters could reflect the clinical results of all products. The evaluation of the gastric emptying process of drug particles less than 50 µm enabled us to assess the bioequivalence because they probably caused the difference in the distribution in the SI. This study demonstrated the utility of the GPS model for the assessment of bioequivalence of BCS class IIa drugs.

An Assessment of Occasional Bio-Inequivalence for BCS1 and BCS3 Drugs: What are the Underlying Reasons?

Despite having adequate solubility properties, bioequivalence (BE) studies performed on immediate release formulations containing BCS1/3 drugs occasionally fail. By systematically evaluating a set of 17 soluble drugs where unexpected BE failures have been reported and comparing to a set of 29 drugs where no such reports have been documented, a broad assessment of the risk factors leading to BE failure was performed. BE failures for BCS1/3 drugs were predominantly related to changes in Cmax rather than AUC. Cmax changes were typically modest, with minimal clinical significance for most drugs. Overall, drugs with a sharp plasma peak were identified as a key factor in BE failure risk. A new pharmacokinetic term (t½Cmax) is proposed to identify drugs at higher risk due to their peak plasma profile shape. In addition, the analysis revealed that weak acids, and drugs with particularly high gastric solubility are potentially more vulnerable to BE failure, particularly when these features are combined with a sharp Cmax peak. BCS3 drugs, which are often characterised as being more vulnerable to BE failure due to their potential for permeation and transit to be altered, particularly by excipient change, were not in general at greater risk of BE failures. These findings will help to inform how biowaivers may be optimally applied in the future.

Desenvolvimento de rota sintética da Rosiglitazona em processo batelada e microrreator capilar / Rosiglitazone synthetic route development in batch process and capillary microreactor

Para que os fármacos possam ser comercializados economicamente, a sua escala de produção deve ser aumentada para atender à demanda do mercado. Atualmente, a maior parte dos fármacos são sintetizados em processos batelada que possuem limitações quanto à eficiência de mistura, temperatura e pressão. O uso de microrreatores surge como alternativa na indústria químico-farmacêutica, aumentando a eficiência dos processos de maneira segura. Ferramentas utilizadas no segmento computacional multidisciplinar teórico, como o DFT (Density Functional Theory), podem prever e compreender o comportamento das reações químicas, podendo ter grande utilidade na síntese de novos fármacos economizando tempo, investimento e reduzindo a geração de resíduos. A diabetes mellitus é uma doença de caráter epidêmico, que a cada ano vem aumentando o número de casos. O emprego de fármacos derivados das glitazonas no tratamento de diabetes mellitus tipo 2 é recomendado devido ao excelente controle glicêmico que esta classe de fármacos oferece. Neste trabalho, foi sintetizada a Rosiglitazona, um fármaco derivado das glitazonas, que auxilia no tratamento da diabetes mellitus tipo 2, sendo estudadas duas rotas de síntese distintas, que foram otimizadas com o intuito de maximizar o rendimento de seus intermediários, obtendo a Rosiglitazona com pureza de cerca de 94%. Foi realizada, para os intermediários, aqui denominados, 1R, 2R2 e 3R2 a síntese one-pot e para os intermediários 1R, 2R1 e 3R2 foi realizada a transposição do processo usual em batelada para fluxo contínuo no microrreator, com rendimentos de até 93%. Com o auxílio da química quântica computacional, a reação de síntese do intermediário 1R, foi elucidada teoricamente e determinadas as grandezas termodinâmicas (ΔH‡, ΔG‡ e ΔS‡) no estado de transição, que foram comparadas com os valores experimentais, sendo constatada uma boa concordância, com desvio máximo de 14%

In order for drugs to be commercialized economically, their production scale must be increased to meet market demand. Currently, most drugs are synthesized in batch processes that have limitations in terms of mixing efficiency, temperature and pressure. The use of microreactors appears as an alternative in the chemical-pharmaceutical industry, increasing the efficiency of the synthesis processes in a safe way. Tools used in the theoretical multidisciplinary computational segment, such as DFT (Density Functional Theory), can predict and understand the behavior of chemical reactions, and can be very useful in the synthesis of new drugs, saving time, investment and reducing waste generation. Diabetes mellitus is an epidemic disease that has been increasing the number of cases every year. The use of drugs derived from glitazones in the treatment of type 2 diabetes mellitus is recommended due to the excellent glycemic control that this class of drugs offers. In this work, Rosiglitazone, a drug derived from glitazones, which helps in the treatment of type 2 diabetes mellitus, was synthesized. Two different synthetic routes were studied and optimized in order to maximize the yield of its intermediates, obtaining Rosiglitazone with purity of about 94%. One-pot synthesis was performed to 1R, 2R2 and 3R2 intermediates, and the transposition from the usual batch process to continuous flow in microreactor was performed to 1R, 2R1 and 3R2 intermediates, with yields of up to 93%. With the aid of computational quantum chemistry, the intermediate 1R synthesis reaction was theoretically elucidated and the thermodynamic properties were determined (ΔH‡, ΔG‡ and ΔS‡) in the transition state, which were compared with the experimental results, obtaining good agreement, with a maximum deviation of 14%

Decline in Public Spending on Biopharmaceutics in Brazil

Abstract Biopharmaceuticals, mainly monoclonal antibodies, and fusion proteins are drugs that have gained notoriety in the treatment of various chronic and inflammatory diseases and have high prices. The study aimed to verify which monoclonal antibodies and fusion proteins were most incorporated into the Unified Health System (SUS), which therapeutic indication most benefited from them and to analyze public spending on these biopharmaceuticals from January 2012 to September 2019. This study performed a qualitative and quantitative analysis of biopharmaceuticals incorporated by SUS. The data were collected on the websites of CONITEC and the Health Price Bank. The results demonstrated that subcutaneous adalimumab was most frequently incorporated, and the most requested therapeutic indication was rheumatoid arthritis. Public spending on biopharmaceuticals exceeded R$ 28 billion (more than US$ 140 billion). However, a downward trend was confirmed (-266.7%) in the period evaluated. Despite the increase in demand and public spending on biologics in general, in Brazil and worldwide, the results of this research show that there was a drop in public spending on the biopharmaceuticals studied in the last seven years.

[A Basis for Pharmaceutical Sciences "Quality Assurance": Quality Assurance of Health Foods, Foods with Health Claims, and Pharmaceutics].

The author believes that the three pillars of pharmaceutical sciences (PS) in Japan are drug development science, medical pharmacy, and quality management science. Of these, the most PS-like science is quality management science, both historically and presently. Considering the balance of safety and efficacy is the basis of PS. The definition of "quality" is the degree to which a set of inherent properties of a product, system, or process fulfills requirements in Q9 of International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). In our society, pharmaceutical science graduates including pharmacists, are active participants, not only in the pharmaceutical industry, including a pharmacy, but also in the food industry, especially for quality assurance and quality control. This report presents a focused overview of quality in health foods, foods with health claims, and pharmaceutical products and discusses the importance of a curriculum focusing on quality assurance, control, and management in pharmaceutical education.

Biorreactores de un solo uso en la industria biofarmacéutica y su uso en la producción de candidatos vacunales contra SARS- COV-2. Artículo de revisión / Single-use systems bioreactors in the biopharmaceutical industry and its use in SARS-CoV-2 vaccine's candidates production. A review

Los biorreactores de sistemas de un solo uso (SUSs), también conocidos como biorreactores desechables, se han convertido en una parte integral de las instalaciones biotecnológicas de fabricación para bioproductos con un mercado potencial que espera una tasa de crecimiento de casi el 15,5% durante el período pronosticado: 2018 a 2023. Los biorreactores SUSs son más seguros, simples y flexibles al compararlos con sus contrapartes, biorreactores de acero inoxidable, por lo que su uso se está incrementando en la industria biofarmacéutica principalmente en la planificación de vías rápidas de proyectos complejos, incluidos los relacionados con la pandemia de SARS-CoV-2. Así, el uso de SUS se ha convertido en una alternativa eficaz para la producción rápida de candidatos a vacunas. Pero algunas desventajas técnicas y operativas aún obstaculizan su uso en todo el mundo. Esta revisión brinda una visión racional del uso, los tipos, los parámetros operativos y las nuevas aplicaciones de los biorreactores SUSs en la industria biofarmacéutica. Asimismo, también se discuten los parámetros apropiados y las limitaciones de este equipo, enfocándose en su uso para la producción de vacunas contra COVID-19

Single-Use-Systems (SUSs) Bioreactors, also known as disposable bioreactors, have become an integral part of biotechnology manufacturing facilities for bioproducts with a potential market expecting a growth rate of nearly 15.5% over the forecast period: 2018 to 2023. SUSs bioreactors are comparatively safe, simple, and flexible than their stainless-steel bioreactors counterparts thus, their usage is being augmented in the biopharmaceutical industry mainly in planning fast tracks of complex projects, including those related to the SARS-CoV-2 pandemic. Thus, the use of SUSs has become an effective alternative for the rapid production of vaccine candidates. However, some technical and operational disadvantages still hamper their worldwide use. This review gives a rational insight into SUSs bioreactors use, types, operational parameters and new applications in the biopharmaceutical industry. Likewise, the appropriate parameters and limitations of this equipment, focusing on its use for vaccine production against COVID-19 are also discussed

In vitro and In silico biopharmaceutic regulatory guidelines for generic bioequivalence for oral products: Comparison among various regulatory agencies.

Generic drug development is a complex process that involves development of formulation similar to reference product. Because of the complexity associated with generic drug development, many regulatory agencies have come up with various guidelines. Out of many guidelines, the biopharmaceutics classification system that was introduced in 1995 based on aqueous solubility and permeability helped many pharmaceutical scientists across the globe to utilize the tool for formulation development, waiver of in vivo studies. Later on in vitro guidelines based on dissolution and in vitro in vivo correlation were introduced by many regulatory agencies with an intent to reduce number of in vivo human testing thereby facilitating shorter development time and faster approvals and launch. Most recently, understanding the importance in silico approaches such as physiologically based pharmacokinetic modelling, regulatory agencies such as United States Food and Drug Administration (USFDA) and European Middle East and Africa (EMA) came up with modelling guidance documents. Even though consensus exists between guidance documents from various regulatory agencies, still there are many minor to major differences exists between these guidance documents that needs to be considered while submitting a generic drug application. This review aims to compare all the in vitro and in silico guidance documents from major regulatory agencies with emphasis on latest trends and technologies combined with regulatory acceptability with an intention to harmonize regulations. Guidance documents from major regulatory agencies such as USFDA, EMA, World Health Organization, International Council for Harmonization and other emerging markets were compared. Similarities &differences among these guidance documents are critically reviewed to provide the reader a detailed overview of these guidance documents at one place.

A Market Shaping Approach for the Biopharmaceutical Industry: Governing Innovation Towards the Public Interest.

Enhancing research and development and ensuring equitable pricing and access to cutting-edge treatments are both vital to a biopharmaceutical innovation system that works in the public interest. However, despite delivering numerous therapeutic advances, the existing system suffers from major problems: a lack of directionality to meet key needs, inefficient collaboration, high prices that fail to reflect the public contribution, and an overly-financialized business model.

Denaturing and Native Mass Spectrometric Analytics for Biotherapeutic Drug Discovery Research: Historical, Current, and Future Personal Perspectives.

Mass spectrometry (MS) plays a key role throughout all stages of drug development and is now as ubiquitous as other analytical techniques such as surface plasmon resonance, nuclear magnetic resonance, and supercritical fluid chromatography, among others. Herein, we aim to discuss the history of MS, both electrospray and matrix-assisted laser desorption ionization, specifically for the analysis of antibodies, evolving through to denaturing and native-MS analysis of newer biologic moieties such as antibody-drug conjugates, multispecific antibodies, and interfering nucleic acid-based therapies. We discuss challenging therapeutic target characterization such as membrane protein receptors. Importantly, we compare and contrast the MS and hyphenated analytical chromatographic methods used to characterize these therapeutic modalities and targets within biopharmaceutical research and highlight the importance of appropriate MS deconvolution software and its essential contribution to project progression. Finally, we describe emerging applications and MS technologies that are still predominantly within either a development or academic stage of use but are poised to have significant impact on future drug development within the biopharmaceutic industry once matured. The views reflected herein are personal and are not meant to be an exhaustive list of all relevant MS performed within biopharmaceutical research but are what we feel have been historically, are currently, and will be in the future the most impactful for the drug development process.

The Impact of the COVID-19 Pandemic on the Future of Science Careers.

As COVID-19 swept across the world, it created a global pandemic and an unpredictable and challenging job market. This article discusses the future of the 2020-2021 job market in both academia and industry in the midst and aftermath of this pandemic.

Assessment of Canadian patient education material for oncology pharmaceutics.

INTRODUCTION: Health literacy is an individual's ability to access, understand, and utilize information in order to create an informed decision regarding their health. Readability plays an integral role in health literacy as complex health information may be inaccessible to those with low health literacy. The aim of this study is to determine the readability of Canadian patient education material (PEM) for oncology related pharmaceutics. METHODS: Eighty PEMs from Cancer Care Ontario (CCO) and BC Cancer (BCC) were evaluated for their reading level using a Ford, Caylor, Sticht (FORCAST) analysis. Twenty therapies were then randomly selected and converted to plain text to be analyzed further using the Flesch-Kincaid Grade Level (FKGL), the Simple Measure of Gobbledygook (SMOG) Index, the Coleman-Liau Index (CLI), and the Gunning Fog Index (GFI). RESULTS: Both PEMs from CCO and BCC were above the recommended reading level with PEMs from CCO, on average, requiring a higher reading level. Within the text, the section which describes side effects was found to be the most complex section of the representative PEMs from BCC. PEMs from BCC which described antibody-based therapies were, on average, more difficult to read than small molecule-based therapies regardless from which section the PEM was being analyzed. These observations were not seen in CCO PEMs. CONCLUSIONS: Overall, online PEMs from major Canadian cancers associations were written above the recommended reading level. Consideration should be given to revision of these materials, with emphasis on the therapies' side effects, to allow for greater comprehension amongst a wider target audience.