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Guide Bioequivalence Studies in Drug Development: Methods and Applications (Statistics in Practice)

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Public concern and ongoing discussion about bioequivalence started in the early s with reports about digoxin intoxications. At the time, generic digoxin formulations were increasingly prescribed in the United States, and a change in the manufacturing process of a company in Great Britain led to an unintentional increase in the bioavailability of one brand of digoxin tables.

Over the years, various regulatory guidelines on the design, conduct and statistical analysis of bioequivalence studies have been published. With the publication of the FDA guidance, 6 one might have thought that agreement had been reached, finally, among researchers and regulators on the central concepts of bioequivalence. Ironically, almost exactly around that time, the new concept of individual bioequivalence 7 was formulated and sparked a new era of research and discussion, and probably more controversy than ever before.

They raised the following clinically very relevant question: does equivalence of average bio-availability, which they termed average bioequivalence, ensure that the bioavailability of two drug products is equivalent in individual patients? In other words, does average bioequivalence imply switchability of drug products in individual patients?

Following the groundbreaking article of Anderson and Hauck, numerous statistical approaches to individual bioequivalence were published Schall 8 provides a unified view of most of the approaches; see also the reviews of Hauschke, Steinijans and Pigeot 9 and Chow and Liu 2. Eventually, in , the individual bioequivalence concept was adopted in an FDA guidance. The concept of individual bioequivalence proved to be an intermezzo but it proved to be useful after all.

Critical and clinically relevant questions were asked about the traditional concept of average bioequivalence, and this concept emerged strongly. In particular, the crucial question, namely whether bioequivalence implied therapeutic equivalence, was answered in the affirmative. In a highly competitive market and litigious society such as the United States one would expect cases of therapeutic inequivalence of bioequivalent products to be publicised quickly and widely. A literature search conducted by Gould 11 10 years later to answer the question whether average bioequivalence implied switchability of drug products in practice came to the same conclusion: essentially no evidence of therapeutic failure of bioequivalent products could be found.

Encyclopedia of Biopharmaceutical Statistics

Chow and Liu 2 reported how in the United States innovator companies file citizen petitions in order to convince the regulatory agency FDA that a generic copy of a brand-name drug will not achieve therapeutic equivalence even if the generic has been shown to be bioequivalent to the brand name drug.

Those authors cite no case of a generic that has been approved as bioequivalent by the FDA but has been shown to be therapeutically inequivalent to the innovator. For example, responses to immunosuppressants, and the contrasts between different drug products can vary with time after transplantation, the target organ, ethnicity and concomitant disease conditions e. In summary, the fundamental bioequivalence assumption, namely that bioequivalent products are therapeutically equivalent and can be used interchangeably, has survived strong scrutiny; scrutiny that was inter alia a by-product of the discussion of and research on the individual bioequivalence concept.

The conventional concept of average bioequivalence seems to have served the consumers of drugs rather well.

Session I: Extreme Variability and Aberrant Data in BE Studies (Moderator: Pina D’Angelo)

What about the concerns that the producers of drugs might have with the bioequivalence concept? For such drugs, sample sizes of subjects and higher can be required to demonstrate bioequivalence. A potential solution to the problem of highly variable drugs is suggested by the observation that most highly variable drugs have a wide therapeutic index.


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If such a drug indeed has a wide therapeutic index, it should be clinically acceptable to widen the bioequivalence acceptance range for it. Therefore, the more variable the bioavailability of the reference drug product, the wider the effective acceptance range for bioequivalence. Interestingly, the basic concept of scaling the bioequivalence criterion had already been proposed early in the development of characteristics for individual bioequivalence, 8 , 19 , 20 so that the scaled average bioequivalence concept can be viewed as another by-product of the research into individual bioequivalence.

While there still are some problems with the scaled average bioequivalence concept, 17 at present it seems to be the most promising and practical approach for handling the problem of highly variable drugs in bioequivalence. The mirror image of highly variable drugs with wide therapeutic index is narrow therapeutic-index drugs whose variability typically is low.

If it is reasonable to widen the bioequivalence acceptance range for highly variable drugs with wide therapeutic index, it seems equally reasonable to narrow the bioequivalence acceptance range for drugs with low variability and narrow therapeutic index. Such a narrowing of the bioequivalence acceptance range for narrow therapeutic-index drugs could increase assurance, particularly of the safety of generics in this drug class, without imposing an undue burden, financial or otherwise, on the sponsors of bioequivalence studies for such drugs.

Medical Statistics at a Glance - Aviva Petrie, Caroline Sabin

The standard approach to bioequivalence assessment, namely conventional average bioequivalence, has proven itself under strict scrutiny over more than 20 years. Drug products that under a proper regulatory regime have been approved as bioequivalent to a reference product can generally be assumed to be therapeutically equivalent to that reference product. For highly variable drugs, scaled average bioequivalence provides an alternative, effective approach to the comparison of drug products.

National Center for Biotechnology Information , U.

Journal List Cardiovasc J Afr v. Cardiovasc J Afr. Author information Copyright and License information Disclaimer.

Bioavailability

Robert Schall: az. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. History of the bioequivalence concept Public concern and ongoing discussion about bioequivalence started in the early s with reports about digoxin intoxications.

Switchability of drug products: the individual bioequivalence intermezzo With the publication of the FDA guidance, 6 one might have thought that agreement had been reached, finally, among researchers and regulators on the central concepts of bioequivalence. Bioequivalence and therapeutic equivalence The concept of individual bioequivalence proved to be an intermezzo but it proved to be useful after all.

Highly variable drugs and widening the bioequivalence acceptance range, or scaling What about the concerns that the producers of drugs might have with the bioequivalence concept? Narrow therapeutic index drugs and narrowing the bioequivalence acceptance range The mirror image of highly variable drugs with wide therapeutic index is narrow therapeutic-index drugs whose variability typically is low.

Conclusion The standard approach to bioequivalence assessment, namely conventional average bioequivalence, has proven itself under strict scrutiny over more than 20 years. References 1. Note for Guidance on the Investigation of Bioavailability and Bioequivalence. London: Committee for Proprietary Medicinal Products, Design and Analysis of Bioavailability and Bioequivalence Studies.

Variation in biologic availability of digoxin from four preparations. N Engl J Med. Javascript is currently disabled in your browser.


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Several features of this site will not function whilst javascript is disabled. Through these positions, Dr.

Session I: Extreme Variability and Aberrant Data in BE Studies (Moderator: Pina D’Angelo)

Chow provides technical supervision and guidance to project teams on statistical issues and presentations before partners, regulatory agencies or scientific bodies, defending the appropriateness of statistical methods used in clinical trial design or data analyses or the validity of reported statistical inferences. Chow identifies the best statistical and data management practices, organizes and leads working parties for development of statistical design, analyses and presentation applications, and participated on Data Safety Monitoring Boards in clinical research and development.

Chow's professional activities include playing key roles in many professional organizations such as officer, board of directors member, advisory committee member, and executive committee member. Most recently, representing academic and scientific experts, Dr. In order to provide our website visitors and registered users with a service tailored to their individual preferences we use cookies to analyse visitor traffic and personalise content. You can learn about our use of cookies by reading our Privacy Policy. We also retain data in relation to our visitors and registered users for internal purposes and for sharing information with our business partners.