Bioequivalence Guidelines/Regulations Introduction This collection is Bioavailability / (in-vivo-) Bioequivalence, although GCP/GLP, Dissolution/BCS, Pharmacokinetics, Bioanalytics and Statistics are also covered to some minor extent. You should always consult websites of the respective regulatory body for any updated versions. Disclaimer Although this Collection contains information of a legal nature, it has been developed for informational purposes only and does not constitute legal advice or opinions as to the current operative laws, regulations, or guidelines of any jurisdiction. In addition, because new standards are issued on a continuing basis, this Collection is not an exhaustive source of all current applicable laws, regulations, and guidelines in the field. While reasonable efforts have been made to assure the accuracy and completeness of the information provided, researchers and other individuals should check with local authorities and/or research ethics committees before starting research activities. International ICH Guidelines o Development Safety Update Report; E2F: step 2, Jun 2008 o Structure and Content of Clinical Study Reports; E3: Nov 1995 o Good Clinical Practice; E6(R1): step 4, Jun 1996; including IB template o General Considerations for Clinical Trials; E8: Jul 1997 o Clinical Safety Data Management: Definitions and Standards for Expedited Reporting; E2A: step 4, Oct 1994 o Statistical Principles for Clinical Trials; E9: Feb 1998 o Validation of Analytical Procedures – Text and Methodology; Q2(R1): step 4, Nov 2005 o Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products – Chemical Substances; Q6A: Oct 1995 (Decision Trees) All documents are in step 5 (implementation state) unless noted otherwise. WHO o Guidelines for GCP for trials on pharmaceutical products (WHO Technical Report Series No. 850, Annex 3): 1995 o Handbook for GCP: 2005 o Prequalification Programme
Information for Applicants: Guidelines: Generics - Selected annex and supplement below.
o WHO Expert Committee on Specifications for Pharmaceutical Preparations, Thirty-ninth Report (WHO TRS No. 929, Annex 5); Fixed dose combinations: June 2005 o WHO Expert Committee on Specifications for Pharmaceutical Preparations, Fortieth Report (WHO TRS No. 937): May 2006 o Annexes 7–9 are available in separate documents: o Handbook Good Laboratory Practice (GLP): 2001 o Training manual for the trainer: 2001 o Training manual for the trainee: 2001 OECD-GLP Guidelines Environment Directorate: OECD Environmental Health and Safety Publications, Series on Principles of Good Laboratory Practice and Compliance Monitoring 1. OECD Principles of Good Laboratory Practice: Apr 1999 (en, fr, en/fr, de) 2. Revised Guides For Compliance Monitoring Procedures for Good Laboratory Practice: Jun 1995 (en, fr, en/fr) 3. Revised Guidance for the Conduct of Laboratory Inspections and Study Audits: Jun 1995 (en, fr, en/fr) 4. Quality Assurance and GLP: Dec 1999 (en, fr, de, es) 5. Compliance of Laboratory Suppliers with GLP Principles: Sep 2000 (en, fr, de, es) 6. The Application of the GLP Principles to Field Studies: Sep 2000 (en, fr, de, es) – not applicable for PK/BA/BE/PK, just for completeness 7. The Application of the GLP Principles to Short Term Studies: Dec 1999 (en, fr, de, es) 8. The Role and Responsibility of the Study Director in GLP Studies: Oct 1999 (en, fr, de) 9. Guidance for the Preparation of GLP Inspection Reports: Oct 1999 (en, fr, en/fr) 10. The Application of the Principles of GLP to Computerised Systems: Oct 1995 (en, fr, de, es: 4th link, also denoted as German) 11. The Role and Responsibilities of the Sponsor in the Application of the Principles of GLP: Mar 1998 (en, fr) 12. Requesting and Carrying Out Inspections and Study Audits in Another Country: Sep 2000 (en, fr) 13. The Application of the OECD Principles of GLP to the Organisation and Management of Multi-Site Studies: Jun 2002 (en, fr, de) 14. The Application of the Principles of GLP to in vitro Studies: Nov 2004 (en, fr) 15. Establishment and Control of Archives that Operate in Compliance with the Principles of GLP: Jun 2007 (en, fr) PIC/S: Guides and Recommendations Good Practices for Computerized Systems in Regulated “GXP” Environments: Version 3, Sep 2007 PAHO: Working Group on Bioequivalence o Good Clinical Practices - Document of the Americas: 2005 o Science Based Criteria for BE in vivo and in vitro, Bio-Waivers and Strategic Framework for Implementation: Draft 2001 o BA / BE / Biowaivers: Final Draft Aug 2004 AFRICA South Africa (MCC): Guidelines o Generic Substitution: Final, Dec 2003 o Pharmaceutical and Analytical Guideline: Jul 2007 o Medicines Controle Council Biostudies Jun 11 o Medicines Controle Council Dissolution March 11 ASIA/ASIA PACIFIC/MIDDLE EAST ASEAN States (ACCSQ): Pharmaceutical Product Working Group o BA / BE: Final Draft Jul 2004 Australia (TGA): Guidelines o BA and BE: Apr 2002 o Summary of a BA or BE Study: Dec 2002 o Australian Regulatory Guidelines for Prescription Medicines, Appendix 15: Biopharmaceutic Studies: Jun 2004 China: SFDA o Drug Administration Law: Dec 2001 o Regulations for Implementation of the Drug Administration Law: Sep 2002 o Good Clinical Practice: Aug 2003 zh o Statistical Guidelines for Clinical Trials of Drugs and Biologics: Mar 2005 zh o Hong Kong; GCP for Proprietary Chinese Medicines: Feb 2004 India (CDSCO): Central Drugs Standard Control Organization o Bioavailability / Bioequivalence: Current Draft Mar 2005 o Requirements and Guidelines for Permission to Import and / or Manufacture of New Drugs for Sale or to Undertake Clinical Trials: Schedule Y – Amended Version, Jun 2005 o GCP: 2005 o Submission of Clinical Trial Application for Evaluating Safety and Efficacy: v1.1 Dec 2008 o Ethical Guidelines for Biomedical Research on Human Participants (published by the Indian Council of Medical Research): Oct 2006 Israel: MOH: Drug Registration Section o Guidelines for Clinical Trials in Human Subjects: Jan 2006 (PDF888KB he, DOC462KB en) o SOP for Performing BE in Human Subjects: Sep 2002 he o Requirments for Registration of a Generic Product: Sep 2002 he Japan (NIHS): Division of Drugs Guidances o Clinical Pharmacokinetic Studies of Pharmaceuticals: Jun 2001 o Oral Prolonged Release Dosage Forms: Mar 1988 o Following guidelines were revised with 24 Nov 2006: - Guideline for BE Test on Oral Solid Preparation with Different Drug Strengths:Guideline ja Q&A ja
- Guideline for BE Test on Oral Solid Preparation for which the Formulation has been changed:Guideline ja Q&A ja
- Guideline for BE Studies of Generic Products for Topical Use:Guideline ja Q&A ja
- Guideline for BE Studies of Adding Dosage Form for Topical Use: new 24 Nov 2006: Guideline ja Q&A ja
Jordan: Ministry of Health Rules & Regulations o Laws and Regulations Applicable to the Conducting of Pharmaceutical Research: 2001 (Arabic) Malaysia (BPFK): Guidelines o Conduct of BA and BE Studies: Final, Sep 2000 o GCP: Second Edition, Jan 2004 o GLP: Draft Jul 2006 o Guidance Document and Guidelines for Registration of Biosimilars: Aug 2008 New Zealand (Medsafe): Guidelines o Guidance notes for applicants for consent to distribute new and changed medicines and related products (including BA/BE): Final, Oct 2001 o Biostudy Reference Products: Jul 2006 Saudia Arabia: Saudi Food & Drug Authority Singapore: HSA o Drug Registration Information and Guidelines - ASEAN Common Technical Requirements (ACTR)
BA / BE: Final Draft Jul 2004 Validation of Analytical Procedures: Final, Jan 2005 South Korea: KFDA o Minimum Requirements for BE Test: Dec 2005 Taiwan: CDE Regulations in zh Thailand (FDA): DCD o BE Study Protocol / Report: 2003 th o BA / BE: Aug 2004, adopted 2005 o BA / BE: Current th o Instruction for the In Vivo BE Study Protocol Development: Oct 2006 th EUROPE European Union (EMEA) EudraLex – The Rules Governing Medicinal Products in the European Union o Procedure for European Union Guidelines and Related Documents within the Pharmaceutical Legislative Framework: Jan 2009 o Guidelines: Clinical Efficacy and Safety o Guidelines: Multidisciplinary o Legislation o Bioavailability / Bioequivalence - Note for Guidance and associated documents
Bioavailability / Bioequivalence: Jul 2001 Bioequivalence: Draft Jul 2008 Questions & Answers on the BA and BE Guideline: Jul 2006 Recommendation on the Need for Revision of NfG on BA/BE: May 2007 Concept Paper on BCS-based Biowaiver: May 2007 Advice to Applicants/Sponsors/CROs of BE Studies: Sep 2008 o Pharmacokinetics o Statistical Issues o Miscellaneous Definition and Terminology: Jun 1994 Methodology: Jun 1997 All pages refer to current documents (PDF). General Information Application for Marketing Authorisation (MA) Generics in MRP and DCP Applicants response Renewal Procedure Variation Procedure Urgent Safety Restriction Art. 61.3 Procedure Post Referral Phase EDQM: Quality Assurance Activities Guidelines o Validation of Analytical Procedures: Jun 2005 o Uncertainty of Measurements o Qualification of Equipment (core document): Sep 2008 Denmark DKMA: Guidelines and Forms o Bioequivalence and labelling of medicinal products with regard to generic substitution: Jan 2006 Netherlands (GBG-MEB): Legislation & Guidelines o Exemptions from BE-testing (positive list): for strict national registration only: Jan 2008 Switzerland: Swissmedic o Instructions for Generics: Dec 2002 o Reference Formulations for BE / CTDs for Generics: Apr 2004 o Biosimilars: Feb 2008 de Federal Office of Public Health, AGIT : Guidelines on computerized systems o Guidelines for the archiving of Electronic Raw Data in a GLP Environment: May 2003 o Guidelines for the management of electronic SOPs in GLP: Sep 2006 o Guidelines for the acquisition and processing of electronic raw data in a GLP environment: Sep 2006 o Guidelines for the validation of computerised Systems in GLP Environment: Dec 2007 Turkey: Ministry of Health o Good Laboratory Practice Principles: Jun 2002 tr o Licensing Regulation for Pharmaceutical Products: 2003 o Submission of BA/BE Dossiers: Jan 2006 LATIN AMERICA Argentina: Administración Nacional de Medicamentos, Alimentos y Tecnología Médica o GCP Guideline for studies in human subjects: Nov 2007 es o Good Practices in Clinical Pharmacology Research: Feb 2008 es o BA / BE: Final Sep 2006, amended Mar 2007 es o Bioanalytical Method Validation: Final, Sep 2005 es Brazil (ANVISA): Legislation o Implementation of Relative BA and BE Studies: Apr 2006 o Pharmaceutical Equivalence / Dissolution: Sep 2004 o BA / BE: May 2003 o Exemption and Substitution of BE Studies: May 2003 o Bioanalytical Method Validation: May 2003 o Explanation of the Implementation of Re No. 899/2003 – Validation of Bioanalytical Methods: Jun 2008 o Statistics for BA/BE Studies: May 2003 o Protocol of BE Studies: May 2003 o Report of BE Studies: May 2003 o List of Reference Products: Current o Rules / Technical Regulations for CROs: May 2003 Annex I: Certification for BA/BE Centers: Application Form Renewal Form Annex II: Guidelines for Inspection at Centers of BA/BE of Medicines Annex III: Certificate of Good Practices of BA/BE of Medicines Annex IV: Form for Outsourcing of Phase for Assays of BA/BE of Medicines Annex V: Form for Monthly Report of Assays of BA/BE of Medicines o Guidance for Pharmaceutical Equivalence and Bioequivalence of Nasal Sprays and Aerosols: Jun 2008 o BA BE Good Practices Manual Mexico: Secretaría de Salud o BA / BE: Final, May 1999 o BA / BE Update, Biowaivers: Mar 2000 es o Comisión Permanente de la Farmacopea de los Estados Unidos Mexicanos: Legislación santitaria relacionada con la industria farmacéutica es NORTH AMERICA USA (FDA): CDER Guidances OGD Homepage o Legislation (excerpts from Code of Federal Regulations, CFR) - Title 21, Vol. 1, Ch. I, Part 11 [21CFR11]): Electronic records; electronic signatures (overview containing links to Subparts/Sections)
- Title 21, Vol. 1, Ch. I, Part 50 (21CFR50): Protection of human subjects (Overview+links)
- Title 21, Vol. 1, Ch. I, Part 56 (21CFR56): Institutional review boards (Overview+links)
- Title 21, Vol. 1, Ch. I, Part 58 (21CFR58): GLP for Nonclinical Laboratory Studies (Overview+links)
- Title 21, Vol. 5, Ch. I, Part 312 (21CFR312): Investigational NDA (Overview+links)
- Title 21, Vol. 5, Ch. I, Part 320 (21CFR320): BA and BE Requirements (Overview+links)
o CDER’s Manual of Policies and Procedures o Bioavailability / Bioequivalence Cumulative supplement [published monthly] Electronic ‘Orange Book’: Current version [including online search] Statistical Information 1997 Questions and Answers Individual Product BE Recommendations by API o Miscellaneous - Bioanalytical Method Validation: May 2001
- Reviewer Guidance – Validation of Chromatographic Methods: Nov 1994
- Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products: May 1998
- Pharmacokinetics in Patients with Impaired Renal Function — Study Design, Data Analysis, and Impact on Dosing and Labeling: May 1998
- General Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biological Products: Nov 1998
- Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling: May 2003
- Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers: Jul 2005
- Current GMP for Phase 1 Investigational Drugs: Jul 2008
- Population PK: Feb 1999
- Safety Testing of Drug Metabolites: Feb 2008
- Drug Metabolism/Interactions: Nov 1999
- Drug Interaction Studies—Study Design, Data Analysis, and Implications for Dosing and Labeling: Draft Sep 2006
- Exposure-Response Relationships—Study Design, Data Analysis, and Regulatory Applications: Apr 2003
- Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors: 1998—2008
- International Compilation of Human Research Protections: Nov 2008
- General Principles of Software Validation; Final Guidance for Industry and FDA Staff: Jan 2002
- Part 11, Electronic Records; Electronic Signatures — Scope and Application: Aug 2003
- Computerized Systems Used in Clinical Investigations: May 2007
ORA Bioresearch Monitoring Information Page o GLP (Non-Clinical Laboratories) Compliance Program Guidance Manual: Feb 2001 Final Rule: Sep 1987 Questions and Answers: Jun 1981, Dec 1999, Jul 2007 Remark: In the USA two sets of GLP regulations are in force; the other one is issued by the Environmental Protection Agency (EPA).
For a comparison between FDA’s, EPA’s, and OECD’s GLPs see the comparison charts o Sponsors, Contract Research Organizations and Monitors: Feb 2001 o Clinical Investigators: Dec 2008 o Guideline for the Monitoring of Clinical Investigations: Jan 1988 o Institutional Review Boards: Oct 1994 Canada: HPFB Guidances o BA / BE - Part A [IR]: 1992 o BA / BE - Part B [MR]: Nov 1996 o BA / BE - Part C [IR, complicated or highly variable PK]: Dec 1992 o Inclusion of Women in Clinical Trials: Apr 1997 o Drug Interactions: Sep 2000 o CTAs for Comparative BA Studies: Draft Oct 2001; updated Feb 2008 o Records Related to Clinical Trials: May 2006 o Draft Policy: BE Requirements: Drugs Exhibiting Non-linear Pharmacokinetics, Jun 2003 o BE of HVDs/HVDPs: Discussion Paper, Jun 2003 o Removal of Requirement for 15% Random Replicate Samples: Notice, Sep 2003 o BE of Combination Drug Products: Notice, Jun 2004 o Metabolites in Comparative BA Studies: Draft May 2004 o Preparation of Comparative BA Information for Drug Submissions in the CTD Format: Draft May 2004 o BE in Fed State: Jun 2005 o BE for Long Half-life Drugs: Notice, Jun 2005 o BE for Rapid Onset Drugs: Notice, Jun 2005 o BE for Critical Dose Drugs: May 2006 |
