Detection of data manipulation in bioequivalence trials
In recent years regulators have documented how pharmaceutical companies or clinical research organisation can manipulate bioequivalence trial data for non-approvable formulations by performing an interim analysis followed by re-analysis of pharmacokinetic profiles under new subject aliases, with a s...
Gespeichert in:
| Veröffentlicht in: | European journal of pharmaceutical sciences Jg. 156; S. 105595 |
|---|---|
| 1. Verfasser: | |
| Format: | Journal Article |
| Sprache: | Englisch |
| Veröffentlicht: |
Elsevier B.V
01.01.2021
|
| Schlagworte: | |
| ISSN: | 0928-0987, 1879-0720, 1879-0720 |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| Abstract | In recent years regulators have documented how pharmaceutical companies or clinical research organisation can manipulate bioequivalence trial data for non-approvable formulations by performing an interim analysis followed by re-analysis of pharmacokinetic profiles under new subject aliases, with a switch of Test and Reference and/or dilutions. The net effect is that point estimates for failing products will be forced artifically towards 1 and that trials will pass the test for bioequivalence. This is not detectable by any pharmacopoeial method, and is not addressed by common assessment practices at agencies. This paper aims at demonstrating how the signals of such fraudulent study conduct can be detected. The approaches presented are called ”Buster” and ”SaToWIB” routines; these are computer programs that have been used extensively by regulators to detect signals of fraud but they have not been described in the public domain.
The Buster routines visualize trends in the form of partial statistics, residual plots, cumulative confidence intervals, cumulative mean squared errors, and more. Runs tests on the sign of the residuals may constitute a potential test for the manipulation. It is noteworthy that in 2020, regulators in the European Union have publicly begun questioning trial validity on basis of PK profile similarity. The SaToWIB routines rank profile pairs according to numerical similarity on basis of an objective function. It is shown that the rank (as determined by score) is an indicator of fraud in that the actual fraud cases will have higher rank than if there were no relationship between rank and score.
The paper also comments on the use of multivariate statistics and discusses the need for development of formal tests for manipulation in view of e.g. multiplicity.
[Display omitted] |
|---|---|
| AbstractList | In recent years regulators have documented how pharmaceutical companies or clinical research organisation can manipulate bioequivalence trial data for non-approvable formulations by performing an interim analysis followed by re-analysis of pharmacokinetic profiles under new subject aliases, with a switch of Test and Reference and/or dilutions. The net effect is that point estimates for failing products will be forced artifically towards 1 and that trials will pass the test for bioequivalence. This is not detectable by any pharmacopoeial method, and is not addressed by common assessment practices at agencies. This paper aims at demonstrating how the signals of such fraudulent study conduct can be detected. The approaches presented are called "Buster" and "SaToWIB" routines; these are computer programs that have been used extensively by regulators to detect signals of fraud but they have not been described in the public domain. The Buster routines visualize trends in the form of partial statistics, residual plots, cumulative confidence intervals, cumulative mean squared errors, and more. Runs tests on the sign of the residuals may constitute a potential test for the manipulation. It is noteworthy that in 2020, regulators in the European Union have publicly begun questioning trial validity on basis of PK profile similarity. The SaToWIB routines rank profile pairs according to numerical similarity on basis of an objective function. It is shown that the rank (as determined by score) is an indicator of fraud in that the actual fraud cases will have higher rank than if there were no relationship between rank and score. The paper also comments on the use of multivariate statistics and discusses the need for development of formal tests for manipulation in view of e.g. multiplicity.In recent years regulators have documented how pharmaceutical companies or clinical research organisation can manipulate bioequivalence trial data for non-approvable formulations by performing an interim analysis followed by re-analysis of pharmacokinetic profiles under new subject aliases, with a switch of Test and Reference and/or dilutions. The net effect is that point estimates for failing products will be forced artifically towards 1 and that trials will pass the test for bioequivalence. This is not detectable by any pharmacopoeial method, and is not addressed by common assessment practices at agencies. This paper aims at demonstrating how the signals of such fraudulent study conduct can be detected. The approaches presented are called "Buster" and "SaToWIB" routines; these are computer programs that have been used extensively by regulators to detect signals of fraud but they have not been described in the public domain. The Buster routines visualize trends in the form of partial statistics, residual plots, cumulative confidence intervals, cumulative mean squared errors, and more. Runs tests on the sign of the residuals may constitute a potential test for the manipulation. It is noteworthy that in 2020, regulators in the European Union have publicly begun questioning trial validity on basis of PK profile similarity. The SaToWIB routines rank profile pairs according to numerical similarity on basis of an objective function. It is shown that the rank (as determined by score) is an indicator of fraud in that the actual fraud cases will have higher rank than if there were no relationship between rank and score. The paper also comments on the use of multivariate statistics and discusses the need for development of formal tests for manipulation in view of e.g. multiplicity. In recent years regulators have documented how pharmaceutical companies or clinical research organisation can manipulate bioequivalence trial data for non-approvable formulations by performing an interim analysis followed by re-analysis of pharmacokinetic profiles under new subject aliases, with a switch of Test and Reference and/or dilutions. The net effect is that point estimates for failing products will be forced artifically towards 1 and that trials will pass the test for bioequivalence. This is not detectable by any pharmacopoeial method, and is not addressed by common assessment practices at agencies. This paper aims at demonstrating how the signals of such fraudulent study conduct can be detected. The approaches presented are called ”Buster” and ”SaToWIB” routines; these are computer programs that have been used extensively by regulators to detect signals of fraud but they have not been described in the public domain. The Buster routines visualize trends in the form of partial statistics, residual plots, cumulative confidence intervals, cumulative mean squared errors, and more. Runs tests on the sign of the residuals may constitute a potential test for the manipulation. It is noteworthy that in 2020, regulators in the European Union have publicly begun questioning trial validity on basis of PK profile similarity. The SaToWIB routines rank profile pairs according to numerical similarity on basis of an objective function. It is shown that the rank (as determined by score) is an indicator of fraud in that the actual fraud cases will have higher rank than if there were no relationship between rank and score. The paper also comments on the use of multivariate statistics and discusses the need for development of formal tests for manipulation in view of e.g. multiplicity. [Display omitted] |
| ArticleNumber | 105595 |
| Author | Fuglsang, Anders |
| Author_xml | – sequence: 1 givenname: Anders orcidid: 0000-0002-6733-2187 surname: Fuglsang fullname: Fuglsang, Anders organization: Hiort Lorenzens Vej 6c, DK6100 Haderslev, Denmark |
| BookMark | eNp9kDtrwzAUhUVJoUnaP9DJYxenekSWBF1K-oRAl3YWsnQNMo7lSHag_7523KlDpwOH-1043wot2tACQrcEbwgmxX29gbpLG4rpVHCu-AVaEilUjgXFC7TEisocKymu0CqlGmNcSIGXSDxBD7b3oc1ClTnTm-xgWt8NjTmXvs1KH-A4-JNpoLWQ9dGbJl2jy2oMuPnNNfp6ef7cveX7j9f33eM-t4yxPneCCMedVNaUjsoCsKkchm3luALGiSu4U4a5UhFWOE4VVhaAMFUybkvC2RrdzX-7GI4DpF4ffLLQNKaFMCRNt5wwiYUQ46mcT20MKUWotPX9eUUfjW80wXpypWs9udKTKz27GlH6B-2iP5j4_T_0MEMw7j95iDpZPylyPo5KtQv-P_wHaduFLA |
| CitedBy_id | crossref_primary_10_1208_s12248_024_01000_x crossref_primary_10_4155_bio_2023_0248 |
| Cites_doi | 10.1534/genetics.105.049643 10.1080/01621459.1968.10480934 10.7754/Clin.Lab.2015.150414 |
| ContentType | Journal Article |
| Copyright | 2020 Elsevier B.V. Copyright © 2020 Elsevier B.V. All rights reserved. |
| Copyright_xml | – notice: 2020 Elsevier B.V. – notice: Copyright © 2020 Elsevier B.V. All rights reserved. |
| DBID | AAYXX CITATION 7X8 |
| DOI | 10.1016/j.ejps.2020.105595 |
| DatabaseName | CrossRef MEDLINE - Academic |
| DatabaseTitle | CrossRef MEDLINE - Academic |
| DatabaseTitleList | MEDLINE - Academic |
| Database_xml | – sequence: 1 dbid: 7X8 name: MEDLINE - Academic url: https://search.proquest.com/medline sourceTypes: Aggregation Database |
| DeliveryMethod | fulltext_linktorsrc |
| Discipline | Pharmacy, Therapeutics, & Pharmacology |
| EISSN | 1879-0720 |
| ExternalDocumentID | 10_1016_j_ejps_2020_105595 S0928098720303833 |
| GroupedDBID | --- --K --M .~1 0R~ 1B1 1RT 1~. 1~5 4.4 457 4G. 53G 5GY 7-5 71M 8P~ 9JM AABNK AACTN AAEDT AAEDW AAIAV AAIKJ AAKOC AALRI AAOAW AATCM AAXUO ABFRF ABJNI ABLJU ABMAC ABYKQ ABZDS ACDAQ ACGFO ACGFS ACIUM ACRLP ADBBV ADEZE AEBSH AEFWE AEKER AENEX AFKWA AFTJW AFXIZ AGHFR AGUBO AGYEJ AHHHB AIEXJ AIKHN AITUG AJOXV ALCLG ALMA_UNASSIGNED_HOLDINGS AMFUW AMRAJ AXJTR BKOJK BLXMC C45 CS3 DU5 EBS EFJIC EFLBG EO8 EO9 EP2 EP3 F5P FDB FIRID FNPLU FYGXN G-Q GBLVA GROUPED_DOAJ IHE J1W KOM M34 M41 MO0 N9A O-L O9- OAUVE OGGZJ OVD OZT P-8 P-9 P2P PC. Q38 ROL RPZ SCC SDF SDG SDP SES SPCBC SSP SSZ T5K TEORI ~G- 29G 5VS 9DU AAQFI AAQXK AATTM AAXKI AAYWO AAYXX ABFNM ABWVN ABXDB ACLOT ACRPL ACVFH ADCNI ADMUD ADNMO ADVLN AEIPS AEUPX AFJKZ AFPUW AGQPQ AIGII AIIUN AKBMS AKRWK AKYEP ANKPU APXCP ASPBG AVWKF AZFZN CITATION EFKBS EJD FEDTE FGOYB G-2 HMT HVGLF HZ~ OK1 R2- SEW SPT WUQ ~HD 7X8 ADPDF |
| ID | FETCH-LOGICAL-c333t-d717d5d89cabd286e0afd0e4fd59e351d65d9a3db9136d52909cee139b35cb153 |
| ISICitedReferencesCount | 3 |
| ISICitedReferencesURI | http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000597380300012&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| ISSN | 0928-0987 1879-0720 |
| IngestDate | Sun Sep 28 15:18:38 EDT 2025 Sat Nov 29 07:08:14 EST 2025 Tue Nov 18 22:02:57 EST 2025 Fri Feb 23 02:46:13 EST 2024 |
| IsPeerReviewed | true |
| IsScholarly | true |
| Keywords | Fraud Bioequivalence Similarity Re-analysis Residuals |
| Language | English |
| LinkModel | OpenURL |
| MergedId | FETCHMERGED-LOGICAL-c333t-d717d5d89cabd286e0afd0e4fd59e351d65d9a3db9136d52909cee139b35cb153 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ORCID | 0000-0002-6733-2187 |
| PQID | 2451380777 |
| PQPubID | 23479 |
| ParticipantIDs | proquest_miscellaneous_2451380777 crossref_citationtrail_10_1016_j_ejps_2020_105595 crossref_primary_10_1016_j_ejps_2020_105595 elsevier_sciencedirect_doi_10_1016_j_ejps_2020_105595 |
| PublicationCentury | 2000 |
| PublicationDate | 2021-01-01 2021-01-00 20210101 |
| PublicationDateYYYYMMDD | 2021-01-01 |
| PublicationDate_xml | – month: 01 year: 2021 text: 2021-01-01 day: 01 |
| PublicationDecade | 2020 |
| PublicationTitle | European journal of pharmaceutical sciences |
| PublicationYear | 2021 |
| Publisher | Elsevier B.V |
| Publisher_xml | – name: Elsevier B.V |
| References | (bib0010) 2001 European Medicines Agency, Committee for human medicinal products. guideline on bionanalytical method validation. EMEA/CHMP/EWP/192217/2009 Rev.1. United States Food and Drug Administration. Untitled letter issued on April 19, 2016, to a company in Bangalore, India. Dumache, Ciocan, Muresan, Enache (bib0001) 2016; 62 (bib0009) 2013 European Medicines Agency, Referral Notification, February 19, 2020. European Medicines Agency, Committee for Human Medicinal Products. Investigation of bioequivalence. CHMP CPMP/EWP/QWP/1401/98 Rev. 1. 2010. World Health Organization. Notice of Concern, issued on February 12, 2016, to a company in Bangalore, India.The Notice of Concern is in the public domain but no copy could be found on WHO's website as of the date of this submission. A copy is available from the author upon request. O'Driscoll (bib0007) 2007; 27 Sen (bib0008) 1968; 63 World Health Organization. Annex 7, Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. WHO Technical Report Series No. 992, 2015. United States Food and Drug Administration. Form 483 issued on October 9, 2015, to a company in Bangalore, India. MacQueen (bib0006) 1967 Accessed June 20, 2020. Fuglsang (bib0005) 2006; 172 Fuglsang (10.1016/j.ejps.2020.105595_bib0005) 2006; 172 (10.1016/j.ejps.2020.105595_bib0009) 2013 MacQueen (10.1016/j.ejps.2020.105595_bib0006) 1967 Dumache (10.1016/j.ejps.2020.105595_bib0001) 2016; 62 O'Driscoll (10.1016/j.ejps.2020.105595_bib0007) 2007; 27 Sen (10.1016/j.ejps.2020.105595_bib0008) 1968; 63 (10.1016/j.ejps.2020.105595_bib0010) 2001 10.1016/j.ejps.2020.105595_bib0016 10.1016/j.ejps.2020.105595_bib0003 10.1016/j.ejps.2020.105595_bib0004 10.1016/j.ejps.2020.105595_bib0015 10.1016/j.ejps.2020.105595_bib0002 10.1016/j.ejps.2020.105595_bib0013 10.1016/j.ejps.2020.105595_bib0011 |
| References_xml | – volume: 172 start-page: 1301 year: 2006 end-page: 1307 ident: bib0005 article-title: Estimating the “effective number of codons”: the Wright way of determining codon homozygosity leads to superior estimates publication-title: Genetics – year: 2013 ident: bib0009 article-title: Center for Drug Evaluation and Research. Bioequivalence publication-title: Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an Abbreviated New Drug Application – volume: 62 start-page: 245 year: 2016 end-page: 248 ident: bib0001 article-title: Molecular DNA analysis in forensic identification publication-title: Clin. Lab. – reference: European Medicines Agency, Committee for human medicinal products. guideline on bionanalytical method validation. EMEA/CHMP/EWP/192217/2009 Rev.1. – reference: World Health Organization. Annex 7, Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. WHO Technical Report Series No. 992, 2015. – year: 1967 ident: bib0006 article-title: Some Methods for classification and Analysis of Multivariate Observations publication-title: Proceedings of 5th Berkeley Symposium on Mathematical Statistics and Probability – reference: . Accessed June 20, 2020. – volume: 63 start-page: 1379 year: 1968 end-page: 1389 ident: bib0008 article-title: "Estimates of the regression coefficient based on Kendall’s tau publication-title: J. Am. Stat. Assoc. – reference: World Health Organization. Notice of Concern, issued on February 12, 2016, to a company in Bangalore, India.The Notice of Concern is in the public domain but no copy could be found on WHO's website as of the date of this submission. A copy is available from the author upon request. – volume: 27 start-page: 1257 year: 2007 end-page: 1265 ident: bib0007 article-title: Extracellular nucleic acids and their potential as diagnostic, prognostic and predictive biomarkers publication-title: Anticancer Res. – year: 2001 ident: bib0010 article-title: Center for Drug Evaluation and Research publication-title: Statistical Approaches to Establishing Bioequivalence. Guidance for Industry: Statistical Approaches to Establishing Bioequivalence – reference: European Medicines Agency, Committee for Human Medicinal Products. Investigation of bioequivalence. CHMP CPMP/EWP/QWP/1401/98 Rev. 1. 2010. – reference: European Medicines Agency, Referral Notification, February 19, 2020. – reference: , Accessed June 20, 2020. – reference: United States Food and Drug Administration. Form 483 issued on October 9, 2015, to a company in Bangalore, India. – reference: United States Food and Drug Administration. Untitled letter issued on April 19, 2016, to a company in Bangalore, India. – ident: 10.1016/j.ejps.2020.105595_bib0002 – year: 1967 ident: 10.1016/j.ejps.2020.105595_bib0006 article-title: Some Methods for classification and Analysis of Multivariate Observations – volume: 172 start-page: 1301 issue: 2 year: 2006 ident: 10.1016/j.ejps.2020.105595_bib0005 article-title: Estimating the “effective number of codons”: the Wright way of determining codon homozygosity leads to superior estimates publication-title: Genetics doi: 10.1534/genetics.105.049643 – volume: 63 start-page: 1379 issue: 1968 year: 1968 ident: 10.1016/j.ejps.2020.105595_bib0008 article-title: "Estimates of the regression coefficient based on Kendall’s tau publication-title: J. Am. Stat. Assoc. doi: 10.1080/01621459.1968.10480934 – volume: 27 start-page: 1257 year: 2007 ident: 10.1016/j.ejps.2020.105595_bib0007 article-title: Extracellular nucleic acids and their potential as diagnostic, prognostic and predictive biomarkers publication-title: Anticancer Res. – ident: 10.1016/j.ejps.2020.105595_bib0004 – year: 2001 ident: 10.1016/j.ejps.2020.105595_bib0010 article-title: Center for Drug Evaluation and Research – ident: 10.1016/j.ejps.2020.105595_bib0013 – ident: 10.1016/j.ejps.2020.105595_bib0003 – ident: 10.1016/j.ejps.2020.105595_bib0011 – ident: 10.1016/j.ejps.2020.105595_bib0015 – ident: 10.1016/j.ejps.2020.105595_bib0016 – volume: 62 start-page: 245 year: 2016 ident: 10.1016/j.ejps.2020.105595_bib0001 article-title: Molecular DNA analysis in forensic identification publication-title: Clin. Lab. doi: 10.7754/Clin.Lab.2015.150414 – year: 2013 ident: 10.1016/j.ejps.2020.105595_bib0009 article-title: Center for Drug Evaluation and Research. Bioequivalence |
| SSID | ssj0006870 |
| Score | 2.3337398 |
| Snippet | In recent years regulators have documented how pharmaceutical companies or clinical research organisation can manipulate bioequivalence trial data for... |
| SourceID | proquest crossref elsevier |
| SourceType | Aggregation Database Enrichment Source Index Database Publisher |
| StartPage | 105595 |
| SubjectTerms | Bioequivalence Fraud Re-analysis Residuals Similarity |
| Title | Detection of data manipulation in bioequivalence trials |
| URI | https://dx.doi.org/10.1016/j.ejps.2020.105595 https://www.proquest.com/docview/2451380777 |
| Volume | 156 |
| WOSCitedRecordID | wos000597380300012&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| hasFullText | 1 |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| journalDatabaseRights | – providerCode: PRVESC databaseName: Elsevier SD Freedom Collection Journals 2021 customDbUrl: eissn: 1879-0720 dateEnd: 99991231 omitProxy: false ssIdentifier: ssj0006870 issn: 0928-0987 databaseCode: AIEXJ dateStart: 19950201 isFulltext: true titleUrlDefault: https://www.sciencedirect.com providerName: Elsevier |
| link | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwtV1LS8QwEA6-Dl7EJ64vIogXrfSVtjkuPlAR2cMKeytJk8Uu0l3trui_d_Jo9yErevBSSkmnIV8yM5lm5kPohIeMgpXkjgeaUEerHMaFdKKQJYKFDHZkumT-Q_z4mHQ6tGUZBUtNJxAXRfLxQQf_CjU8A7BV6uwf4K6FwgO4B9DhCrDD9VfAX8mhzCo_UB0AVSdU84qmS8U3eN6Xr6McPqqXtSbuKOeG6K27OnieCn5byznOHgE_vLSx56ZOmJmMJ_jeRDzBBgZVzWpqzWClI8mkllOkmoYa85sCNrGA3oXsDVQxdF8TCdvG09WuZ6xQfTawOnbWS5WMVMlIjYxFtOzHhILuWm7eXXfua4sbJZoUsO65TY4y5_hmezLPAZkxxdq_aK-jNbsxwE0D6AZakMUmOm2ZUf88x-1xolx5jk9xa1xz_HMLxTXquN_FCnU8iTrOCzyNOjaob6Onm-v25a1jOTGcLAiCoSNg-y2ISGgGS8pPIumyrnBl2BWEyoB4IiKCskBw6gWRID51KbhB4ObzgGQczNsOWir6hdxFmLoupy6DLan6HexxxnXxfRAliMuToIG8aqDSzBaMV7wlL-l8iBrorH5nYMql_NiaVOOf2mlrHLkUptOP7x1XYKWgDdUvLlbI_ggahcRTFApxvPennuyj1fFaOEBLw7eRPEQr2fswL9-O0GLcSY7srPsCIl6Dzg |
| linkProvider | Elsevier |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Detection+of+data+manipulation+in+bioequivalence+trials&rft.jtitle=European+journal+of+pharmaceutical+sciences&rft.au=Fuglsang%2C+Anders&rft.date=2021-01-01&rft.issn=0928-0987&rft.volume=156&rft.spage=105595&rft_id=info:doi/10.1016%2Fj.ejps.2020.105595&rft.externalDBID=n%2Fa&rft.externalDocID=10_1016_j_ejps_2020_105595 |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0928-0987&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0928-0987&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0928-0987&client=summon |