Analysis of reasons for screening failure of healthy subjects in clinical trials of orally inhaled drug products / 中国临床药理学与治疗学

AIM: To explore the reasons for screening failure of healthy subjects in clinical trials of orally inhaled drug products (OIDPs). METHODS: Screening data of 1 432 healthy subjects who participated in clinical trials of OIDPs were collected. The main reasons for the screening failure, gender differences in screening failure rate and the correlation between age and screening failure rate were summarized and analyzed. RESULTS: The screening failure rate was 72.4 % and increased with age. The failure rate was slightly higher in females than in males. Besides abnormal vital signs (17.3%), abnormal laboratory test results (16.5%) and withdrawal of consent (7.6%), poor venous condition (13.9%), positive for cigarette test results (12.6%) and failure in inhalation training (7.1%) were also the other three main reasons affecting the screening success rate. Abnormal vital signs and poor venous conditions were the primary screening failure reasons for males and females, respectively. CONCLUSION: The screening success rate could be improved by informing fully and communicating effectively, selecting young subjects with strong understanding abilities, and enhancing the training skills of investigators.

Safety analysis on bioequivalence studies of orally inhaled drug products in healthy Chinese subjects / 中国临床药理学与治疗学

AIM: To investigate the safety of bioequivalence (BE) studies of orally inhaled drug products (OIDPs) conducted by Phase I clinical Research Center of our hospital. METHODS: The safety data were collected from 482 healthy subjects enrolled in 20 OIDPs BE studies in Wuxi People's hospital from 2017 to 2022. The difference of adverse events (AEs) between test preparation and reference preparation were compared, as well as the influence of gender, age, mechanism of drug action and device type on AE were analyzed. RESULTS: A total of 102 cases of AEs were occurred in 77 subjects (16.0%, 77/482), 87 cases of AEs were related to experimental drugs, all AEs were mild or moderate, and no serious adverse events occurred. There was no difference in the incidence of AE between test preparation and reference preparation. In addition, gender, age, mechanism of drug action and device type had no significant effects on AEs. CONCLUSION: In 20 bioequivalence studies of OIDPs, OIDPs were safe and well tolerated in healthy subjects after dosing, and safety features of generic OIDPs and original drug were basically similar.

Application and progress of pharmacodynamics study in bioequivalence evaluation of orally inhaled drug products / 中国临床药理学与治疗学

Orally inhaled drug products (OIDPs) play a great role in the pharmacological treatment of chronic obstructive pulmonary disease (COPD) and asthma. There is an unmet clinical need for OIDPs. Pharmacodynamics-Bioequivalence studies (PD-BE) are recommended by several national guidelines as important research methods for bioequivalence study of OIDPs. It can effectively bridge the gap between in vitro studies and PK-BE studies in evaluating the efficacy and safety consistency of generic drugs with the original drugs. There are two research methods for PD-BE, using a diastolic model or an excitation model. The different methods use different metrics to evaluate efficacy. The more commonly used metrics include Forced Expiratory Volume in the First Second (FEV1), Specific Airway Conductance (sGaw), Peripheral Airway Resistance (R5-20), and stimulant concentration/dose (PC20/PD20). PD-BE studies using FEV1 as an efficacy metric is also recommended by the FDA (Food and Drug Administration), EMA (European Medicines Agency) and NMPA (National Medical Products Administration) guidelines and is widely accepted by investigators. In such PD-BE studies, the trial protocols for different OIDPs drugs are relatively consistent in terms of trial design, trial data processing, and equivalence evaluation criteria, while there are detailed differences in terms of target population, single/multiple dosing, dose administration, and collection site design. This paper reviews the progress of PD-BE studies in the bioequivalence evaluation of OIDPs by combining national guidelines and PD-BE-related studies of OIDPs published in the last five years, with a view to providing important theoretical information for PD-BE studies of OIDPs.

Application and progress of pharmacokinetics study in bioequivalence evaluation of orally inhaled drug products / 中国临床药理学与治疗学

Orally inhaled drug products (OIDPs) have a pivotal position and great clinical demand in the treatment of asthma and chronic obstructive pulmonary disease. The development of local generic drugs which are bioequivalent to branded drugs in efficacy and safety while with less price will not only help to solve the problem of drug accessibility, but also greatly reduce the public health burden.OIDPs are complex combinations of formulation and device, and have special drug delivery route and characteristic of local release. Thus, generic drugs of OIDPs are difficult to develop and get registration. Until now, Food and Drug Administration (FDA), European Medicines Association (EMA), Health Canada (HC) and National Medical Products Administration (NMPA) all consider that pharmacokinetics (PK) method can be used to evaluate systemic exposure (safety) in human bioequivalence (BE) study of OIDPs, but there is no consensus on its role in the evaluation of pulmonary deposition (efficacy). The possible reason lies in that the efficacy of OIDPs is determined by both the amount and the region of drug pulmonary deposition. Nevertheless, PK study is still more sensitive and economical in assessing potential differences among products, when compared with pharmacodynamics or clinical endpoint study. Here we mainly compared the domestic and international guidelines and evaluation methods of OIDPs BE study, and introduced the experimental design of PK study and its application and progress in lung deposition study.

Validation of methodology for assay, pharmaceutical equivalence, and comparative dissolution profile for tablets containing amlodipine besylate

The amlodipine besylate is indicated as a first choice in the treatment of hypertension. Many similar and generic drugproducts companies were able to bring out to the market dosage forms containing amlodipine besylate with lowerprices. In this context, the aim of this work was to validate a simple method for the determination of amlodipinecontent in tablets by ultraviolet spectrophotometry and to perform pharmaceutical equivalence and dissolution profilestudies for three similar and one generic drug products and their respective innovator tablet containing amlodipine(5 mg). The developed method for the determination of amlodipine content proved to be linear, precise, accurate,robust, and appropriate for employment in the quality control of tablets containing amlodipine besylate. The reference(R), similar (S1, S2, and S3), and generic (G) drug products all fulfilled the specifications for the tests of identification,average weight, hardness, friability, disintegration, drug content, content uniformity, and dissolution. However, incomparative dissolution profile studies, the dissolution efficiency of products G and S2 was statistically different fromproduct R, which may indirectly lead to the unsuitable bioavailability and therapeutic inefficacy. Thus, there is a needfor tighter legislation and inspection regarding the quality of pharmaceutical products already on the market.

Topical ophthalmic antimicrobials: unfulfilled demands and possibility of new investments in Brazil and in the United States

In general, topical ophthalmic drug products, especially those used for treating infections, present low effectiveness because of various reasons, from unfavorable drug physicochemical properties to physiological protective mechanisms of the eye. The fact is such group of products holds room for improvement, which could mean the development of better drugs or dosage forms. To achieve this, the knowledge of market composition is essential. The present work studied and compared the antimicrobial ophthalmic markets of Brazil and of the United States (US). Official databank of Brazilian Health Regulatory Agency and of US Food and Drug Administration were assessed for registered antimicrobial topical ophthalmic drug products. Brazilian market has registered greater number of drug products (119) than the US (94), but the latter involves more variety of substances and dosage forms. In both countries, non-innovative products registered as solutions of antibacterials, especially fluoroquinolones and aminoglycosides lead the market. Despite the clinical demand, the US has only one group of antimycotics (polyenes) registered, while in Brazil, there is not any ophthalmic antimycotic product marketed. This study evidences there is not only space for development of newer drugs and formulations but also a demand for already existing technologies and products in both countries.

Intercambialidade entre medicamentos genéricos e similares de um mesmo medicamento de referência / Interchangeability among generic and similar drug products of a same reference drug product

A implementação de medicamentos genéricos no Brasil e de programas e políticas para garantir o acesso da população a medicamentos com qualidade, segurança e eficácia resultaram em mais de 3.800 medicamentos genéricos de 445 fármacos registrados na Agência Nacional de Vigilância Sanitária (ANVISA) desde 1999. Os medicamentos genéricos comprovaram a sua equivalência terapêutica e, portanto, intercambialidade com seus respectivos medicamentos de referência por meio de estudos de bioequivalência. Em 2014, a ANVISA estendeu a intercambialidade aos medicamentos similares, aumentando o número de medicamentos intercambiáveis para cada medicamento de referência. As normas para prescrição e dispensação permitem apenas a substituição de medicamento de referência por seu medicamento genérico ou similar intercambiável e vice-versa. Entretanto, o que se observa na prática é a substituição entre medicamentos genéricos e similares de um mesmo fármaco, tanto na rede privada onde os descontos chegam até 90% do preço estabelecido para a venda, como na rede pública, em função da disponibilidade dos medicamentos, visto que as compras públicas se baseiam no menor preço ofertado pelos fabricantes. Entretanto, a bioequivalência e a intercambialidade entre os medicamentos genéricos ou similares de um mesmo referência não pode ser garantida pois os mesmos não foram testados entre si. A ausência de bioequivalência entre medicamentos substituídos pode provocar ineficácia terapêutica ou aparecimento de eventos adversos ou até mesmo intoxicação em pacientes. Consequentemente, podem ocorrer desperdício, gastos com tratamento de eventos adversos, abandono do tratamento e adoção de segunda linha de tratamentos. Este trabalho avaliou a bioequivalência entre os medicamentos genéricos e similares de um mesmo medicamento de referência por meio do método de metanálise, empregando dados de estudos de bioequivalência realizados para o registro de medicamentos genéricos e similares na ANVISA. Foram incluídos na análise estudos de aciclovir, amoxicilina, cefalexina, doxazosina, fenitoína, fluoxetina, levofloxacino e quetiapina. Os resultados demonstraram a ausência de bioequivalência entre a maioria dos medicamentos genéricos e similares contendo o mesmo fármaco. os resultados comprovam que medicamentos genéricos e similares de mesmo fármaco não são obrigatoriamente intercambiáveis e a substituição, principalmente para aqueles usados no tratamento de doenças crônicas, podem trazer graves consequências clínicas. Esta preocupação é aumentada para os fármacos com estreita faixa terapêutica e aqueles com alta variabilidade no processo de absorção. A adoção de uma lista de medicamentos não substituíveis, a exemplo de outros países, e o investimento na divulgação de informações sobre intercambialidade de medicamentos, tanto para profissionais de saúde como para a população, podem contribuir para a redução da substituição entre medicamentos não intercambiáveis, a promoção do uso racional dos medicamentos, a redução de gastos com medicamentos e tratamento de eventos adversos e o aumento da adesão do paciente ao tratamento

The implementation of generic drugs in Brazil, as well as programs and policies to ensure access to medicines with quality, safety and efficacy to the overall population, resulted in more than 3,800 generic drug products of 445 drugs registered in the National Health Surveillance Agency (ANVISA) since 1999. Generic drug products proved their therapeutic equivalence in bioequivalence studies and, therefore, the interchangeability with their respective reference drug product. In 2014, ANVISA expanded the interchangeability to similar drug products, increasing the number of interchangeable drug products for each reference drug product. Regulations for the prescription and dispensation of medicine only allow the substitution of a reference drug product for a generic or an interchangeable similar drug product or vice versa. However, in practice, it appears that there is a substitution between generic and similar drug products of a same reference drug product in private pharmacy chains - where discounts reach up to 90% of the selling price - as well as in public pharmacy, depending on the medicine availability, because public purchases are based on the lower price offered by the manufacturers. Nevertheless, the bioequivalence and interchangeability between generic and similar drug products of the same reference drug product cannot be guaranteed because they haven't been evaluated. Lack of bioequivalence between substituted drug products may result in therapeutic ineffectiveness or the occurrence of adverse events and even to patient intoxication. As a consequence, there might be waste, expenses due to adverse events treatment, no adherence to the treatment or the adoption of second-line treatment. This study evaluated the bioequivalence between generic and similar drugs of the same reference drug product through a meta-analysis, using data from bioequivalence studies carried out for the registration of generic and similar drug products at ANVISA. The drugs included in the study were acyclovir, amoxicillin, cephalexin, doxazosin, phenytoin, fluoxetine, levofloxacin and quetiapine. Results showed lack of bioequivalence between most of the generic and similar drugs containing the same drug and prove that generic and similar drug products of the reference drug product are not necessarily interchangeable. Moreover, the substitution of drugs used for chronic illnesses could lead to serious clinical consequences. This concern increases for drugs with narrow therapeutic index and those with high variable absorption process. The adoption of a list of non-interchangeable medicines - like in other countries - and investment in the dissemination of information about interchangeability between drug products to health professionals and to the population may contribute to reduce the substitution of drugs which are not interchangeable, promote a rational use of medicines, the reduction of expenses with drugs and adverse effects treatment and to improve treatment adherence

Intercambialidade entre medicamentos genéricos e similares de um mesmo medicamento de referência / Interchangeability among generic and similar drug products of a same reference drug product

A implementação de medicamentos genéricos no Brasil e de programas e políticas para garantir o acesso da população a medicamentos com qualidade, segurança e eficácia resultaram em mais de 3.800 medicamentos genéricos de 445 fármacos registrados na Agência Nacional de Vigilância Sanitária (ANVISA) desde 1999. Os medicamentos genéricos comprovaram a sua equivalência terapêutica e, portanto, intercambialidade com seus respectivos medicamentos de referência por meio de estudos de bioequivalência. Em 2014, a ANVISA estendeu a intercambialidade aos medicamentos similares, aumentando o número de medicamentos intercambiáveis para cada medicamento de referência. As normas para prescrição e dispensação permitem apenas a substituição de medicamento de referência por seu medicamento genérico ou similar intercambiável e vice-versa. Entretanto, o que se observa na prática é a substituição entre medicamentos genéricos e similares de um mesmo fármaco, tanto na rede privada onde os descontos chegam até 90% do preço estabelecido para a venda, como na rede pública, em função da disponibilidade dos medicamentos, visto que as compras públicas se baseiam no menor preço ofertado pelos fabricantes. Entretanto, a bioequivalência e a intercambialidade entre os medicamentos genéricos ou similares de um mesmo referência não pode ser garantida pois os mesmos não foram testados entre si. A ausência de bioequivalência entre medicamentos substituídos pode provocar ineficácia terapêutica ou aparecimento de eventos adversos ou até mesmo intoxicação em pacientes. Consequentemente, podem ocorrer desperdício, gastos com tratamento de eventos adversos, abandono do tratamento e adoção de segunda linha de tratamentos. Este trabalho avaliou a bioequivalência entre os medicamentos genéricos e similares de um mesmo medicamento de referência por meio do método de metanálise, empregando dados de estudos de bioequivalência realizados para o registro de medicamentos genéricos e similares na ANVISA. Foram incluídos na análise estudos de aciclovir, amoxicilina, cefalexina, doxazosina, fenitoína, fluoxetina, levofloxacino e quetiapina. Os resultados demonstraram a ausência de bioequivalência entre a maioria dos medicamentos genéricos e similares contendo o mesmo fármaco. os resultados comprovam que medicamentos genéricos e similares de mesmo fármaco não são obrigatoriamente intercambiáveis e a substituição, principalmente para aqueles usados no tratamento de doenças crônicas, podem trazer graves consequências clínicas. Esta preocupação é aumentada para os fármacos com estreita faixa terapêutica e aqueles com alta variabilidade no processo de absorção. A adoção de uma lista de medicamentos não substituíveis, a exemplo de outros países, e o investimento na divulgação de informações sobre intercambialidade de medicamentos, tanto para profissionais de saúde como para a população, podem contribuir para a redução da substituição entre medicamentos não intercambiáveis, a promoção do uso racional dos medicamentos, a redução de gastos com medicamentos e tratamento de eventos adversos e o aumento da adesão do paciente ao tratamento

The implementation of generic drugs in Brazil, as well as programs and policies to ensure access to medicines with quality, safety and efficacy to the overall population, resulted in more than 3,800 generic drug products of 445 drugs registered in the National Health Surveillance Agency (ANVISA) since 1999. Generic drug products proved their therapeutic equivalence in bioequivalence studies and, therefore, the interchangeability with their respective reference drug product. In 2014, ANVISA expanded the interchangeability to similar drug products, increasing the number of interchangeable drug products for each reference drug product. Regulations for the prescription and dispensation of medicine only allow the substitution of a reference drug product for a generic or an interchangeable similar drug product or vice versa. However, in practice, it appears that there is a substitution between generic and similar drug products of a same reference drug product in private pharmacy chains - where discounts reach up to 90% of the selling price - as well as in public pharmacy, depending on the medicine availability, because public purchases are based on the lower price offered by the manufacturers. Nevertheless, the bioequivalence and interchangeability between generic and similar drug products of the same reference drug product cannot be guaranteed because they haven't been evaluated. Lack of bioequivalence between substituted drug products may result in therapeutic ineffectiveness or the occurrence of adverse events and even to patient intoxication. As a consequence, there might be waste, expenses due to adverse events treatment, no adherence to the treatment or the adoption of second-line treatment. This study evaluated the bioequivalence between generic and similar drugs of the same reference drug product through a meta-analysis, using data from bioequivalence studies carried out for the registration of generic and similar drug products at ANVISA. The drugs included in the study were acyclovir, amoxicillin, cephalexin, doxazosin, phenytoin, fluoxetine, levofloxacin and quetiapine. Results showed lack of bioequivalence between most of the generic and similar drugs containing the same drug and prove that generic and similar drug products of the reference drug product are not necessarily interchangeable. Moreover, the substitution of drugs used for chronic illnesses could lead to serious clinical consequences. This concern increases for drugs with narrow therapeutic index and those with high variable absorption process. The adoption of a list of non-interchangeable medicines - like in other countries - and investment in the dissemination of information about interchangeability between drug products to health professionals and to the population may contribute to reduce the substitution of drugs which are not interchangeable, promote a rational use of medicines, the reduction of expenses with drugs and adverse effects treatment and to improve treatment adherence

Bioequivalence of Orally Inhaled Drug Products : Focus on Current Regulatory Perspectives.

Asthma/chronic obstructive pulmonary disease (COPD) medication market is a fast growing market, especially in the emerging markets where drugs have not been launched due to high costs. Use of generic medicines has been increasing in recent years, primarily as a cost saving measure in healthcare provision. Orally inhaled products (OIPs) should continue to remain an attractive clinical proposition. At the same time, establishing bioequivalence of an inhaled therapeutic can be a challenging proposition. The purpose of establishing bioequivalence is to demonstrate equivalence between the generic medicine and the originator medicine in order to allow bridging of the pre-clinical and clinical testing performed on the originator drug. Methodologies to determine bioequivalence are well established for oral, systemically acting formulations. However, for inhaled drugs, there is currently no universally adopted methodology, and regulatory guidance in this area has been subject to debate. There is no one-size-fits-all programme. This review article mainly focused on current regulatory perspectives on bioequivalence of topically acting, orally inhaled drug products.

In vitro release of diclofenac diethylamine from gels: evaluation of generic semisolid drug products in Brazil

In order for the pharmacological action of a topical dermal drug product to occur, the drug must first be released from the vehicle to be available to penetrate the skin layers and reach the site of action. Drug release is mainly dependent on the characteristics of the formulation. Currently, to register a generic or a similar drug product in Brazil performance testing of topical drug products for local action is not required. In this context, this aim of this study was to evaluate the in vitro release of commercial diclofenac diethylamine gel products available on the Brazilian pharmaceutical market, using the vertical diffusion cell method. Factors which may influence the test, such as the type of membrane used, and the effect of the formulation characteristics on the diffusion rate were evaluated. Brazilian legislation currently allows generic drug products to contain excipients other than the reference drug, which may affect the drug release from the vehicle. Only one of the four generic drug products tested could be considered equivalent to the reference Cataflam Emulgel®. The cellulose acetate and polyethersulfone membranes tested were found to be interchangeable in the in vitro release studies carried out on this product.

Para exercer ação farmacológica, medicamentos tópicos de aplicação cutânea precisam, primeiramente, liberar o fármaco do veículo, para que desta forma ele se torne disponível para penetração nas camadas da pele, até atingir seu local de ação. A liberação do fármaco do veículo depende principalmente das características da formulação. Até a presente data, para registrar um medicamento genérico ou similar no Brasil não se exigem testes de desempenho para produtos tópicos de ação local. O presente trabalho teve como objetivo avaliar a liberação in vitro de especialidades farmacêuticas de diclofenaco dietilamônio gel do mercado farmacêutico brasileiro, usando o sistema de célula de difusão vertical. Avaliaram-se fatores que influenciam o teste como o tipo de membrana usada nos ensaios de liberação e características da formulação que impactam a velocidade de difusão. A legislação vigente no País permite que medicamentos genéricos contenham excipientes diferentes do medicamento referência. Esta diferença afetou a liberação do fármaco do veículo. Dos quatro medicamentos genéricos testados apenas um seria considerado equivalente ao medicamento referência Cataflam Emulgel®. As membranas de acetato de celulose e polietersulfona testadas apresentaram-se intercambiáveis nos estudos de liberação desse produto.

Quality problem of drug products produced in hospitals in Thailand.

Problems of drug quality prepared in hospitals in Thailand were collected during January 1990-December 1998. From laboratory findings, evidence of instability in 649 samples were evaluated. Problems were found in various types of pharmaceutical dosage forms (oral liquid preparation 43.8%, parenteral products 21.6%, topical preparation 20.6%) and water samples for pharmaceutical purposes 14.0%. The types of instability were: chemical change 44.8%, microbiological change 25.3%, physical change 17.5% ( appearances 3.8 per cent and properties 13.7 per cent) and a combination of changes 12.4%. In addition, expiration dates were not stated on the labels (94.3 per cent) since these products may be dispensed a short time after preparations, instability was found between 1 month and over 12 months after manufacturing with the highest frequency of occurrence filling within 2-3 months. For the products with a stated shelf-life of 6 months, 1 or 2 years, stability problems of 37 samples occurred between 1 month to 6 months after manufacturing, with maximum occurance at 1 month. Type of containers used were problematic. It was found that 64.5 per cent of problems occurred in transparent glass bottles and 36.7 per cent in semi-transparent plastic bottle packages. To avoid quality problems, the authors suggest that hospitals must be developed and use high-quality active ingredients, water, production process and areas which comply with current Good Manufacturing Practices requirement.