Editing Bioequivalence (section)

== Regulatory definition ==

=== The World Health Organization ===

The World Health Organization considers two formulation bioequivalent if the 90% confidence interval for the ratio multisource (generic) product/comparator lie within 80.00–125.00% acceptance range for AUC<sub>0–t</sub> and C<sub>max</sub>. For high variable finished pharmaceutical products, the applicable acceptance range for C<sub>max</sub> can be expanded (up to 69.84–143.19%).<ref>[https://www.who.int/medicines/areas/quality_safety/quality_assurance/trs1003_annex6.pdf?ua=1 WHO guidelines on Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability WHO Technical Report Series, No. 1003, 2017, Annex 6]</ref>

=== Australia ===

In [[Australia]], the [[Therapeutics Goods Administration]] (TGA) considers preparations to be bioequivalent if the 90% [[confidence interval]]s (90% CI) of the rate ratios, between the two preparations, of ''C''<sub>max</sub> and AUC lie in the range 0.80–1.25. ''T''<sub>max</sub> should also be similar between the products.<ref name="Birkett_2003"/>

There are tighter requirements for drugs with a narrow [[therapeutic index]] and/or saturable metabolism &ndash; thus no generic products exist on the Australian market for [[digoxin]] or [[phenytoin]] for instance.

=== Europe ===

According to regulations applicable in the [[European Economic Area]]<ref name="urlwww.emea.europa.eu">{{cite web | url = http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf | title = Guideline on the Investigation of Bioequivalence | author = Committee for Medicinal Products for Human Use |date=20 January 2010 | publisher = [[European Medicines Agency]] | access-date = 21 April 2011}}</ref> two medicinal products are bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and if their bioavailabilities after administration in the same molar dose are similar to such a degree that their effects, with respect to both efficacy and safety, will be essentially the same. This is considered demonstrated if the 90% [[confidence interval]]s (90% CI) of the ratios for AUC<sub>0–t</sub> and ''C''<sub>max</sub> between the two preparations lie in the range 80–125%.

=== United States ===

The FDA considers two products bioequivalent if the 90% CI of the relative mean C<sub>max</sub>, AUC<sub>(0–t)</sub> and AUC<sub>(0–∞)</sub> of the test (e.g. generic formulation) to reference (e.g. innovator brand formulation) should be within 80% to 125% in the fasting state. Although there are a few exceptions, generally a bioequivalent comparison of Test to Reference formulations also requires administration after an appropriate meal at a specified time before taking the drug, a so-called "fed" or "food-effect" study. A food-effect study requires the same statistical evaluation as the fasting study, described above.<ref name="url_www.fda.gov"/>

=== China ===
[[File:仿制药一致性评价LOGO.svg|thumb|right| Passing drugs may display this blue checkmark sign with the text {{lang|zh|仿制药一致性评价}} (Generic Drug Consistency Evaluation).<ref>{{cite web |trans-title=Announcement from the General Administration on Matters Related to the Consistency Evaluation of the Quality and Efficacy of Generic Drugs (No. 100 of 2017)|script-title=zh:总局关于仿制药质量和疗效一致性评价工作有关事项的公告（2017年第100号） |url=https://www.nmpa.gov.cn/xxgk/ggtg/ypggtg/ypqtggtg/20170825205601306.html?type=pc&m= |website=nmpa.gov.cn |access-date=18 September 2024}}</ref>]]
There were no requirements for bioequivalence in generic medications in China until the 2016 ''Opinion on Conducting Consistent Evaluation of the Quality and Efficacy of Generic Drugs'' ({{lang|zh|关于开展仿制药质量和疗效一致性评价的意见}}), which established basic rules for future bioequivalence work. Since July 2020, all newly-approved generics must pass bioequivalence checks; previous drugs may apply to be checked. Since 2019, National Centralized Volume-Based Procurement uses "passes generic-consistency evalulation" as one of the bidding criteria.<ref name="Su">{{cite journal |author1=苏华 |author2=郭瑞臣 |script-title=zh:仿制药一致性评价的背景、实施及结局|trans-title=The background, implementation and outcome of the consistency evaluation of generic drugs |journal=中国医院药学杂志 [Chinese Journal of Hospital Pharmacy] |date=2022 |volume=42 |issue=14 |doi=10.13286/j.1001-5213.2022.14.21 |url=http://journal18.magtechjournal.com/Jwk_zgyyyx/CN/10.13286/j.1001-5213.2022.14.21}}</ref>

The Chinese definition of "bioequivalence" entails having the test drug's geometric mean C<sub>max</sub>, AUC<sub>(0–t)</sub>, and AUC<sub>(0–∞)</sub> fall into 80%&ndash;125% of the reference drug in both fasting and fed states. The reference drug should be preferably the original brand-name drug, then (if not available) an internationally-recognized generic approved by a developed country, then (if still not available) an internationally-recognized generic approved domestically &ndash; this is to avoid deviation from the original drug by serial use of generics as reference. If pharmacokinetic values such as C<sub>max</sub> do not apply to the type of drug (e.g. if the drug is not absorbed orally), comparisons can be made using other means such as [[dose-response curve]]s.<ref name=Su/>

According to Wei et al. (2022), the Consistency Evaluation Policy increased R&D spending for Chinese pharmaceutical companies, especially among private and high-yielding ones.<ref>{{cite journal |last1=Wei |first1=Y |last2=Zhu |first2=J |last3=Qiao |first3=J |last4=Zhang |first4=D |last5=Chen |first5=Y |last6=Suchecki |first6=S |title=The Impact of the Consistency Evaluation Policy of Generic Drugs on R&D Investment Intensity of Pharmaceutical Companies-An Empirical Study Based on the Difference-in-Differences Model. |journal=Frontiers in Public Health |date=2022 |volume=10 |pages=902025 |doi=10.3389/fpubh.2022.902025 |doi-access=free |pmid=35757628 |pmc=9218526}}</ref> Liu et al. (2023) argues that the Policy increased the innovation quality of the Chinese pharmaceutical industry.<ref>{{cite journal |last1=Liu |first1=Q |last2=Huang |first2=Z |last3=Mao |first3=Z |title=Has the consistency evaluation policy of generic drugs promoted the innovation quality of Chinese pharmaceutical manufacturing industry? An empirical study based on the difference-in-differences model. |journal=Frontiers in Public Health |date=2023 |volume=11 |pages=1265756 |doi=10.3389/fpubh.2023.1265756 |doi-access=free |pmid=38106910 |pmc=10722264}}</ref>