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Topic: Bioequivalence

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	Bioequivalence and Interchangeability of Narrow Therapeutic Range Drugs
		Current bioequivalence standards for ‘uncomplicated’ drugs, as set forth by the Therapeutic Products Directorate, require that the 90% confidence interval (CI) of the relative mean log-transformed AUC of the test (T) to reference (R) formulation falls within 80-125% and the relative mean log-transformed Cmax of the T to R formulation falls within 80-125%.
		Modified bioequivalence standards for NTR drugs have been proposed by the Therapeutic Products Directorate since the prevailing opinion is that the required degree of assurance for the similarity of reference and subsequent-entry NTR drugs is greater than with ‘uncomplicated’ drugs.
		Subjects used in bioequivalence studies are young, healthy males whose activity is restricted for the duration of the study.
	www.ualberta.ca /~csps/JPPS1(1)/E.Palylyk-Colwell/bioequivalence.htm (3237 words)

	BIO \| Comments on Bioavailability and Bioequivalence
		Bioequivalence, in turn, was also defined in terms of the "rate and extent of absorption" of a test and a reference drug.
		Under MMA, an alternative definition of bioavailability and bioequivalence has been added with the explicit purpose of addressing a limited number of drug products that are not intended to be absorbed into the blood stream and for which systemic measures of absorption are not meaningful.
		While these current regulations allow for a demonstration of bioavailability and bioequivalence based on different types of evidence, the new statutory provisions of MMA require the Secretary (and, by delegation of authority, FDA) to establish drug-specific methodologies that have been fully validated.
	www.bio.org /reg/20040511BaBe.asp (724 words)

	StudySize - Software for Sample Size Calculation and Power Analysis. Example on bioequivalence.
		The new formulation is considered bioequivalent to the old one if the ratio of the true mean AUC can be concluded to be within the interval 0.80 to 1.25.
		The study is planned to have a power of 0.80 to conclude bioequivalence if the true ratio is approximately 1.05 at the significance level 0.05.
		Bioequivalence is concluded if the respective confidence interval is within the interval 0.80 to 1.25.
	www.studysize.com /example_bioequiv.htm (675 words)

	Bioequivalence (Site not responding. Last check: 2007-11-06)
		Bioequivalence studies can be used to demonstrate claims that the new product will have the same target species efficacy and safety (Part 8 Efficacy and Safety to Treated Animals) as the reference product.
		Bioequivalence studies are not compulsory, and applicants may prefer to perform clinical trials to provide data on efficacy and safety.
		Bioequivalence studies are scientific methods designed to compare two products containing the same active constituent, based on their formulation and pharmacokinetic and pharmacodynamic characteristics.
	www.apvma.gov.au /guidelines/bioequivalence.shtml (2352 words)

	FDA/ORA Compliance Program Guidance In Vivo Bioequivalence
		Bioequivalence studies usually involve administration of test and reference drug formulations to 18-36 normal healthy subjects, but patients with a target disease may also be used.
		The analytical investigator in a bioequivalence study is the scientist in the analytical facility responsible for assay development and validation, and analyses of biological specimens, e.g., Scientific Director or Laboratory Director.
		A member from the Bioequivalence Team in GBIB may participate in domestic and foreign inspections where expertise in pharmacokinetic and/or pharmacodynamic data analysis is needed, when complex scientific issues are involved, or when a field chemist/microbiologist is not participating in the analytical portion of a bioequivalence study inspection.
	www.fda.gov /ora/compliance_ref/bimo/7348_001/default.htm (7315 words)

	AMA (CSAPH) Featured Report: Generic Drugs (A-02) Full Text
		The core of the bioequivalence concept is an “absence of a significant difference.” A difference of 20% is viewed by the FDA as significant. By convention, all data are expressed as a ratio of the average response (AUC and Cmax) for test/reference, so the limit expressed in the second analysis is 125% (reciprocal of 80%).
		Also, because bioequivalence tests have been typically carried out in young, healthy male volunteers, some clinicians doubt that this approach assures bioequivalence in the actual target population in which drugs are administered, such as the elderly; individuals with gastrointestinal tract, kidney, or liver disease; and in those taking other medications.
		Recommendations have included establishing individual bioequivalence rather than average bioequivalence, establishing bioequivalence in transplant patients and in subgroups known to be poor absorbers, and requiring long-term safety and efficacy studies in transplant patients.
	www.ama-assn.org /ama/pub/category/15279.html (6704 words)

	U.S. Pharmacist - Continuing Education - Bioavailability and Bioequivalence: Selected Issues - Default
		Bioequivalence goes beyond comparable bioavailability; it also implies that the absorption rate of the drug is similar.
		The extent of absorption is measured by the bioavailability, or fraction of dose absorbed measured by the area under the concentration-time profile (AUC), whereas the rate of absorption is roughly assessed by measuring the maximum plasma or blood level, Cmax, of a compound.
		In an open letter to healthcare practitioners in 1998, the FDA Associate Commissioner for Health Affairs indicated that any increase in symptoms or side effects that may be reported by patients receiving a generic substitute can be attributed to patients paying closer attention to their symptoms when receiving a substitute.
	www.uspharmacist.com /NewLook/CE/bioavail/lesson.htm (4589 words)

	Issues in Bioequivalence and Generic Substitution for Antiarrhythmic Drugs
		Problems are particularly apt to arise when a pharmacist substitutes a generic drug for a brand-name drug, because the antiarrhythmic properties or potential toxic effects of the two drugs may not be clinically equivalent.
		When a narrow margin for dosage is coupled with the rather limited conditions in which FDA formally tests drugs for bioequivalence and issues in patient compliance, the potential for trouble increases.
		Though they both may be considered “bioequivalent” to the innovator drug, one generic may have achieved values that lie between 80% and 100% of the innovator’s and another values that lie between 100% and 125%.
	www.americanheart.org /presenter.jhtml?identifier=3015266 (2623 words)

	21 CFR 320--BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS (Site not responding. Last check: 2007-11-06)
		(e) Bioequivalence means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.
		This approach is the least accurate, sensitive, and reproducible of the general approaches for determining bioavailability or bioequivalence.
		If a bioequivalence requirement specifies a currently available in vitro test or an in vitro bioequivalence standard comparing the drug product to a reference standard, the manufacturer shall conduct the test on a sample of each batch of the drug product to assure batch-to-batch uniformity.
	www1.va.gov /oro/apps/compendium/Files/21CFR320.htm (6772 words)

	Bioequivalence and Interchangeability: Trade-Name and Generic Drugs: Merck Manual Home Edition
		Legally, bioequivalence of different versions of a drug can vary by up to 20%, because for most drugs, such variation does not noticeably alter effectiveness or safety.
		Bioequivalence must be proved for any new form of a drug.
		For example, some generic versions cannot be determined to be bioequivalent to the original drug because no standards for comparison have been established.
	www.merck.com /mmhe/sec02/ch017/ch017d.html (353 words)

	Bioequivalence of the Co-formulation of Efavirenz/ Emtricitabine/Tenofovir (Atripla) (Site not responding. Last check: 2007-11-06)
		Efavirenz (EFV; 600 mg), emtricitabine (FTC; 200 mg) and tenofovir DF (TDF; 300 mg) are preferred agents for use in the treatment of HIV infection.
		Formulation bioequivalence was assessed by 90% confidence intervals (CI) for the ratio of geometric least square means (GMR) for Cmax, AUC0-t, and AUCinf for the Test versus Reference treatment.
		These findings show that the co-formulation of EFV/FTC/TDF is bioequivalent to administration of its individual components and represents the first one pill, once-daily complete antiretroviral regimen for the treatment of HIV 1 infection.
	www.hivandhepatitis.com /2006icr/16aids/docs/082106_h.html (243 words)

	Bioequivalence Studies for Levothyroxine
		Their contention is that the current guidance does not adequately address the endogenous background levels of the drug, and that the ratios of the PK parameters, a basis for approval of equivalence, are not assessed correctly.
		The variability of baseline measurements of levothyroxine and TSH based on baseline levels and prescreening data in a bioequivalence study (unpublished data, ANDA submission by Mova Laboratories to FDA [confidential]) is ~25% to 26% for TSH and 10% to 11% for levothyroxine.
		When evaluating bioequivalence, in addition to the PK of the drug, it is important that the formulation of the drug be considered, particularly when small changes in bioequivalence could be a significant issue.
	www.aapsj.org /view.asp?art=aapsj070106 (4948 words)

	Bioequivalence of Thyroid Preparations: The Final Word?
		The ability to declare the bioequivalence of natural products, because of the large number and variable amounts of constituents, continues to be a challenge.
		While the FDA has treated the bioequivalence of levothyroxine products as a special case, the potency of levothyroxine products is no longer an issue and there is no evidence that it has an NTI.
		There is now consensus that the impact of endogenous thyroxine levels on the estimation of bioavailability and bioequivalence can be substantially reduced in 2 ways: (1) by using a large dose of thyroxine in bioequivalency studies, rather than clinical doses; and (2) by applying an individual baseline adjustment.
	www.aapsj.org /view.asp?art=aapsj070108 (1433 words)

	INSIDE AAPS: Focus Groups - Bioequivalence Focus Group
		Bioequivalence is established if the bioavailability, i.e., rate and extent of drug absorption from a test drug product does not differ significantly from the rate and extent absorption from a Reference drug product.
		Bioequivalence applies not only to generic drug product development in an Abbreviated New Drug Application (ANDA) but also applies to bridging studies comparing the bioavailability of a drug product used in clinical studies as part of a New Drug Application (NDA) to the to-be-marketed brand product.
		Some of the topics for discussion include the proper statistical design and metrics for bioequivalence, the determination of bioequivalence from locally acting drug products such as topical and inhalation drug products, highly variable drugs, drugs with long elimination half-lives, drugs given orally that are not systemically absorbed, and biotechnology derived drugs.
	www.aapspharmaceutica.com /inside/focus_groups/Bioequiv/index.asp (343 words)

	Statistical Approaches to Establishing Bioequivalence
		Requirements for submitting bioavailability (BA) and BE data in NDAs, ANDAs, and supplements, the definitions of BA and BE, and the types of in vivo studies that are appropriate to measure BA and establish BE are set forth in 21 CFR part 320.
		The 1992 guidance further recommended that statistical analysis for pharmacokinetic measures, such as area under the curve (AUC) and peak concentration (Cmax), be based on the two one-sided tests procedure to determine whether the average values for the pharmacokinetic measures determined after administration of the T and R products were comparable.
		This approach is termed average bioequivalence and involves the calculation of a 90% confidence interval for the ratio of the averages (population geometric means) of the measures for the T and R products.
	www.fda.gov /cder/guidance/3616fnl.htm (8030 words)

	Results of a randomized, open-label, crossover study of the bioequivalence of subcutaneous versus intramuscular ...
		For each of these parameters, the 90 percent confidence intervals for the least squares mean ratios of alefacept SC to alefacept IM were well within the conventional bioequivalence range of 80 percent to 125 percent.
		The standard 80 percent to 125 percent bioequivalence criterion for log-transformed data was used.
		The CIs were constructed by the classical (shortest) CI approach, which is equivalent to Schuirmann's two one-sided tests procedure for bioequivalence [8].
	dermatology.cdlib.org /123/original/Alefacept/sweetser.html (2057 words)

	21 CFR PART 320 (Site not responding. Last check: 2007-11-06)
		Bioequivalence means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.
		Bioequivalence requirement means a requirement imposed by the Food and Drug Administration for in vitro and/or in vivo testing of specified drug products which must be satisfied as a condition of marketing.
		(b) FDA shall include in a proposed rule to establish a bioequivalence requirement the evidence and criteria set forth in §320.33 that are to be considered in determining whether to issue the proposal.
	www.washingtonwatchdog.org /documents/cfr/title21/part320.html (6540 words)

	Bioequivalence of generic and brand-name levothyroxine
		Although bioequivalence studies are not required by the FDA for levothyroxine, standardization of tablet potency has been enhanced by US Pharmacopeia regulations since 1984.
		The biggest concern is with drugs that have a narrow therapeutic index which need to be carefully titrated to blood levels and/or to therapeutic effect (such as digoxin, coumadin, anti-convulsants, anti-arrhythmics).
		In my opinion, this study is reassuring concerning the bioequivalence of brand and generic l-thyroxine preparations, but there are a few caveats.
	www.journalclub.org /vol2/a47.html (1469 words)

	Bioequivalence Studies
		One motivation for individual bioequivalence is to identify a subject-by-formulation interaction.
		The data sets included herein were from replicate and non-replicate in vivo bioequivalence studies submitted to the FDA, which were re-analyzed by the Agency to detect this type of interaction.
		These are bioequivalence studies with non-replicated treatment design conducted in both males and females.
	www.fda.gov /cder/bioequivdata/index.htm (398 words)

	Kinematic analysis for determination of bioequivalence of a modified Hybrid III test dummy and a wheelchair user (Site not responding. Last check: 2007-11-06)
		Assessments of average, individual, and population bioequivalence were conducted after data were subjected to natural logarithmic transforms.
		This is common during pharmaceutical testing to show that a generic drug is as effective as the name brand, to show that a drug is as effective after scaling up production from its clinical counterpart, or to validate changes to a drug already approved [13-14].
		Geometric means, ratios, and 90% confidence intervals (CIs) associated with determining average bioequivalence of Cmax and AUC of trunk angular displacement (TAD), trunk angular velocity (TAV), and trunk angular acceleration (TAA) curves.
	www.vard.org /jour/05/42/3/dvorznak.html (3920 words)

	[Ip-health] Combined Pills
		The clinical trials I were speaking of, in case you were unable to gather from the context, were bioequivalence trials.
		It was the lack of bioequivalence trials that I was concerned about, and also which Mr.
		There is a serious ethical question in activists urging that Africans use generic antiretrovirals which have not undergone bioequivalence testing, when we would NEVER use these in the United States or Europe.
	lists.essential.org /pipermail/ip-health/2001-October/002014.html (751 words)

	2005 FDA Science Forum Poster Abstract: C-27 (Site not responding. Last check: 2007-11-06)
		Data from the two failed bioequivalence studies were used to fit pharmacokinetic parameters and to determine variabilities and covariances for pharmacokinetic parameters.
		Results: Virtual bioequivalence trials showed that the newest formulation was less likely to demonstrate bioequivalence than the first two.
		Conclusions: (1) Virtual bioequivalence trials can provide understanding of the complex interactions that exist among physicochemical properties, physiological variables, pharmacokinetics, and formulation variables, and with that understanding, contribute to reducing the risk of failure.
	vm.cfsan.fda.gov /~frf/forum05/C-27.htm (318 words)

	FDA Standards For Levothyroxine Bioequivalence, Substitution May Lead To Adverse Effects
		FDA bioequivalence standards for levothyroxine product comparisons and directions to pharmacists for product substitution may result in some patients no longer receiving the proper amount of levothyroxine.
		The most susceptible patients, children, the elderly, thyroid cancer patients, and pregnant women with hypothyroidism, are especially vulnerable to the adverse effects of receiving too much or not enough levothyroxine.
		Yet, the FDA has directed pharmaceutical companies to delete the "fl box" warning indicating that dose adjustments may be required after switching patients from one preparation to another-leaving patients and physicians unaware of whether or not thyroid hormone levels have been affected by the change.
	www.medicalnewstoday.com /medicalnews.php?newsid=53692 (768 words)

	A Comparative Single-Dose Bioequivalence Study of Two Enteric Coated Aspirin Brands Among Healthy Volunteers
		For this reason, this investigation was carried out to evaluate the in vitro dissolution as well as the bioavailability and pharmacokinetic properties of 2 tablet oral dosage forms of enteric-coated aspirin, Aspirin protect® and Aspicot®, in a single dose of 200 mg among healthy volunteers.
		These findings suggest that the 2 products are bioequivalent in terms of bioavailability and pharmacokinetic effects on healthy volunteers.
		Such formulations include solution (by using either rapidly water-soluble salt such as lysine ASA or amino acid l-ornithine) and buffered ASA using effervescent carbonated-buffered formulations.6 Other formulations were formulated in an attempt to decrease side effects, mainly gastrointestinal toxicity, such as enteric-coated tablets, sustained-release, and topical formulations (such as suppositories).
	www.jrnlappliedresearch.com /articles/Vol3Iss3/Dib.htm (2968 words)

	2003 CFR Title 21, Volume 5
		Criteria for waiver of evidence of in vivo bioavailability or bioequivalence.
		Basis for measuring in vivo bioavailability or demonstrating bioequivalence.
		Analytical methods for an in vivo bioavailability or bioequivalence study.
	www.access.gpo.gov /nara/cfr/waisidx_03/21cfr320_03.html (176 words)

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