Assessment of Prescribability and Switchability by Using Multiple Bioequivalence Assessment Approaches.

BACKGROUND: In the drug development process, an assessment of bioequivalence is an integral part. For the evaluation of generics against the comparator, average bioequivalence approach is the gold standard method. In the recent past, there were many discussions on whether we have the adequate tool to evaluate generics and thereby drug interchangeability (prescribability and switchability) issue is addressed as average bioequivalence approach just considers population mean. Hence, the alternative approaches like population bioequivalence and individual bioequivalence assessment approaches arise as different variances like inter/ intra-subject variance and subject- by-formulation variance along with population mean are considered. OBJECTIVE: Methoxsalen, in combination with long-wave UVA radiation, is used in the symptomatic management certain psoriasis. The study was aimed to establish the bioequivalence (BE) of a newly developed methoxsalen capsule (MTX test) with that of a reference methoxsalen capsule (MTX reference) using multiple BE methods (i.e., average [ABE], population [PBE], and individual [IBE]) by utilizing a new LC-MS/MS method. METHODS: This is an open-label, randomized, balanced, two-treatment, three-period, three-sequence, crossover, single-dose (20 mg, 2 × 10 mg capsules), comparative, oral BE study conducted in 52 healthy, adult males under fasting conditions. Along with various pharmacokinetic (PK) parameters ABE, PBE, and IBE were also determined in the single study. RESULTS: A non-compartmental model best described the concentration-time data of both MTX test and reference. Both the formulations demonstrated nearly similar values of BE parameters (i.e., AUCo-t, AUC0-∞, Cmax, Tmax, and t1/2). For MTX test, the observed Cmax, AUC0-t, and AUC0- ∞ were 125.16±81.53 ng/mL, 313.73±260.86 ng h/mL, and 321.25±271.85 ng h/mL, respectively. For MTX reference, the values were 127.63±71.60 ng/mL, 329.11±252.91 ng h/mL, and 335.48±264.54 ng h/mL, respectively. The bioanalytical method was validated over the concentration range 0.100-100.00ng/mL and the coefficient of determination (r2) was ≥ 0.9991. The sensitivity of the method was 0.100 ng/mL with the accuracy and precision values of 115% and 10.54%, respectively. CONCLUSION: A single dose of MTX test met the ABE criteria of 80.00% -125.00% for Cmax, AUCo- t, and AUC0-∞, against MTX reference. The study outcome by PBE and IBE approaches proved that MTX Test was bio-inequivalent to MTX reference. Using multiple BE assessment methods in a single BE study is a novel approach and may overcome shortcomings of conventional bioequivalence assessment methods.

Has the Time Come to Employ Population and Individual Bioequivalence for the Evaluation of Generics?

BACKGROUND: Bioequivalence studies are a vital part of drug development. The average bioequivalence approach is the standard method of assessment to conclude whether the generic product is bioequivalent to the innovator product. Of late, debates are on whether the average bioequivalence approach adequately addresses drug interchangeability as it considers only population mean for the evaluation especially when highly variable drug products and narrow therapeutic index drugs are dealt with. Hence, the alternative approaches like population bioequivalence and individual bioequivalence assessment approaches emerge as they consider inter/intra-subject variance and subject- by-formulation variance along with population mean. OBJECTIVES: The objective of the study was to apply different bioequivalence assessment approaches in a replicate bioequivalence study to evaluate the drug interchangeability. METHODS: This was an open-label, single-dose, randomized, balanced, two-treatment, three-period, three-sequence, partial replicate crossover bioequivalence study of omeprazole enteric-coated tablet 20 mg conducted on 48 normal healthy subjects under fed conditions. The plasma concentration of omeprazole was analyzed by a validated bioanalytical method to determine the pharmacokinetic and statistical parameters to assess average bioequivalence, population bioequivalence, and individual bioequivalence. RESULTS: In this study, test formulation was shown to be bio-inequivalent to the reference formulation by average bioequivalence, population bioequivalence, and individual bioequivalence approaches. CONCLUSION: The outcome of the evaluation clearly states that the bioequivalence outcome of all these approaches are the same. Obviously, it does not mean that these three approaches provide the same outcome though the consideration of variances varies. Certainly, population bioequivalence and individual bioequivalence approach will be more accurate for the assessment of drug interchangeability.

Current Regulatory Standpoint on Evaluating the Bioequivalence of Different Classes of Generic Drugs - Is the Evaluation in the Right Direction?

BACKGROUND: The concept of evaluating bioequivalence has changed over a period of time. Currently, the Average Bioequivalence approach (ABE) is the gold standard tool for the evaluation of generics. Of late, many debates had arisen about employing ABE approach for the appraisal of all drug categories. This review aims to examine the limitations of ABE approach and the significances of Population Bioequivalence (PBE) and Individual Bioequivalence (IBE) approach, current regulatory thinking for assessing different categories of the drug, whether they are adequately assessed, and the evaluation is in the right direction. METHODS: We carried out an organized search of bibliographic databases for peer-reviewed research literatures, regulatory recommendations, guidance documents using a focused review question and eligibility criteria. The standard tools were used to appraise the quality of retrieved documents and to make sure the authenticity of the data. RESULTS: In total 73 references were used in the review, the majority of the references (guidance documents) were from the different regulatory agencies and product-specific guidance. There were 29 product-specific guidance from USFDA and EMA. The limitations of the ABE approach were discussed in detail along with the significances of Population Bioequivalence (PBE) approach and Individual Bioequivalence (IBE) approaches. CONCLUSION: It is apparent from the review that IBE approach is a precise method for evaluating the drugs as it answers drug interchangeability (prescribability and switchability). IBE approach is followed by PBE approach and ABE approach for the evaluation of different categories of drugs in terms of precision.

On assessing bioequivalence and interchangeability between generics based on indirect comparisons.

As more and more generics become available in the market place, the safety/efficacy concerns may arise as the result of interchangeably use of approved generics. However, bioequivalence assessment for regulatory approval among generics of the innovative drug product is not required. In practice, approved generics are often used interchangeably without any mechanism of safety monitoring. In this article, based on indirect comparisons, we proposed several methods to assessing bioequivalence and interchangeability between generics. The applicability of the methods and the similarity assumptions were discussed, as well as the inappropriateness of directly adopting adjusted indirect comparison to the field of generics' comparison. Besides, some extensions were given to take into consideration the important topics in clinical trials for bioequivalence assessments, for example, multiple comparisons and simultaneously testing bioequivalence among three generics. Extensive simulation studies were conducted to investigate the performances of the proposed methods. The studies of malaria generics and HIV/AIDS generics prequalified by the WHO were used as real examples to demonstrate the use of the methods. Copyright © 2017 John Wiley & Sons, Ltd.

Statistical evaluation of the scaled criterion for drug interchangeability.

As more and more generic drug products become available in the marketplace, it is a concern whether these generic drug products can be used interchangeably in terms of their quality, safety, and efficacy. The United States Food and Drug Administration (FDA) indicates that an approved generic drug product can serve as a substitute for the innovative drug product. The FDA, however, does not indicate that approved generic drug products can be used interchangeably even if they are bioequivalent to the same innovative drug product. In the past decade, several criteria for assessing interchangeability were proposed in regulatory guidances and/or literature. Chow, Xu, and Endrenyi proposed a scaled criterion for drug interchangeability (SCDI), which takes both intra-subject variability and subject-by-drug variability into consideration. In this paper, the performance of this criterion is statistically evaluated by deriving the upper confidence limit of the test statistic and extrapolating expression of the power to facilitate sample size calculation. The performance of SCDI is also compared with that of the criterion for assessment of individual bioequivalence (IBE) for addressing drug switchability recommended by the FDA, which also takes into account the subject-by-drug variability, under various parameter specifications.

Assessing bioequivalence and drug interchangeability.

As indicated by the US Food and Drug Administration (FDA), approved generic drug products can be used as substitutes for their respective innovative drug products. The FDA, however, does not indicate that two generic copies of the same innovative drug can be used interchangeably, even though they have been shown to be bioequivalent to the same innovative drug product. As more and more generic drug products become available in the market place, it is a concern whether these approved generic drug products have the same quality and safety/efficacy and hence can be used interchangeably. To address the issue of drug interchangeability, several criteria such as individual bioequivalence criterion, a criterion based on the variability due to subject-by-drug interaction, and a scaled criterion for drug interchangeability (SCDI) have been proposed in the literature. In this article, the performances of these criteria, including a newly proposed reversed average bioequivalence criterion, are studied under a 2x4 replicated crossover design in terms of the percentage of passing at the best and worst possible scenarios of similarity. The goal of this paper is to investigate the interchangeability in terms of switchability between a generic (test) drug product and an originator (reference) drug product.

Some thoughts on drug interchangeability.

Current regulation for generic approval is based on the assessment of average bioequivalence. As indicated by the United States Food and Drug Administration (FDA), an approved generic drug can be used as a substitute for the innovative drug. FDA does not indicate that two generic copies of the same innovative drug can be used interchangeably even though they are bioequivalent to the same brand-name drug. In practice, bioequivalence between generic copies of an innovative drug is not required. However, as more generic drug products become available, it is a concern whether the approved generic drug products have the same quality and therapeutic effect as the brand-name drug product and whether they can be used safely and interchangeably. In this article, several criteria including a newly proposed criterion for assessing drug interchangeability are studied. In addition, comments on possible study designs and power calculation for sample size under a specific design are also discussed.

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

Bioavailability and Bioequivalence in Drug Development.

Bioavailability is referred to as the extent and rate to which the active drug ingredient or active moiety from the drug product is absorbed and becomes available at the site of drug action. The relative bioavailability in terms of the rate and extent of drug absorption is considered predictive of clinical outcomes. In 1984, the United States Food and Drug Administration (FDA) was authorized to approve generic drug products under the Drug Price Competition and Patent Term Restoration Act based on evidence of average bioequivalence in drug absorption through the conduct of bioavailability and bioequivalence studies. This article provides an overview (from an American point of view) of definition of bioavailability and bioequivalence, Fundamental Bioequivalence Assumption, regulatory requirements, and process for bioequivalence assessment of generic drug products. Basic considerations including criteria, study design, power analysis for sample size determination, and the conduct of bioequivalence trial, and statistical methods are provided. Practical issues such as one size-fits-all criterion, drug interchangeability and scaled average criteria for assessment of highly variable drug products are also discussed.

Nanotechnology in Dermatology

The scientific community and general public have been exposed to a series of achievements attributed to a new area of knowledge: Nanotechnology. Both abroad and in Brazil, funding agencies have launched programs aimed at encouraging this type of research. Indeed, for many who come into contact with this subject it will be clear the key role that chemical knowledge will play in the evolution of this subject. And even more, will see that it is a science in which the basic structure is formed by distilling different areas of inter-and multidisciplinary knowledge along the lines of new paradigms. In this article, we attempt to clarify the foundations of nanotechnology, and demonstrate their contribution to new advances in dermatology as well as medicine in general. Nanotechnology is clearly the future. .