Bioequivalence Dossier Requirements

Tanzania, 21-25 August 2006 Dr. Barbara Sterzik, BfArM, Bonn 1

Bioequivalence dossier Bioequivalence dossier requirements for the requirements for the

prequalification projectprequalification projectWHO Training Workshop on WHO Training Workshop on

Pharmaceutical Quality, Good Pharmaceutical Quality, Good Manufacturing Practice and Manufacturing Practice and

Bioequivalence with a Focus on Bioequivalence with a Focus on ArtemisininesArtemisinines

Tanzania, 21-25 August 2006 2Dr. Barbara Sterzik, BfArM, Bonn

Dossier requirementsDossier requirementsgeneralgeneral

The product dossier should The product dossier should include information on:include information on:

1. Details of the product 1. Details of the product 2. Regulatory situation in other 2. Regulatory situation in other

countries countries 3. Active pharmaceutical 3. Active pharmaceutical

ingredient(s)- ingredient(s)- API API



((3. API continue3. API continue))

3.1 Properties of the API(s)3.1 Properties of the API(s)3.2 Sites of manufacture 3.2 Sites of manufacture 3.3 Route of synthesis 3.3 Route of synthesis 3.4 Specification3.4 Specification

API described in a pharmacopoeia API described in a pharmacopoeia API not described in a API not described in a

pharmacopoeia pharmacopoeia 3.5 Stability testing 3.5 Stability testing



4. Finished product4. Finished product4.1 Formulation4.1 Formulation 4.2 Sites of manufacture 4.2 Sites of manufacture 4.3 Manufacturing procedure 4.3 Manufacturing procedure 4.4 Specifications for excipients 4.4 Specifications for excipients 4.5 Specifications for finished 4.5 Specifications for finished

product product 4.6 Container/closure system(s) and 4.6 Container/closure system(s) and

other other packaging packaging



((4. Finished product continue )4. Finished product continue )

4.7 Stability testing 4.7 Stability testing

4.8 Container labelling 4.8 Container labelling

4.9 Product information 4.9 Product information

4.10 Patient information and package 4.10 Patient information and package insertsinserts

4.11 Justification for any differences to the 4.11 Justification for any differences to the product in the country or countries issuing product in the country or countries issuing the submitted WHO-type certificate(s) the submitted WHO-type certificate(s)



55. Interchangeability. Interchangeability

5.1 Bioequivalence study5.1 Bioequivalence study

5.2 Summary of 5.2 Summary of pharmacology, pharmacology, toxicology toxicology** and efficacy of the and efficacy of the product (expert reports)product (expert reports)

* not required anymore for * not required anymore for artemisinines but for combinationsartemisinines but for combinations


Basic guidelinesBasic guidelines

In vivo In vivo Bioequivalence Bioequivalence studies studies areare clinical trials: clinical trials:

in accordance with the guidelines in accordance with the guidelines onon

Good Clinical Practice Good Clinical Practice Good Manufacturing PracticeGood Manufacturing Practice Good Laboratory PracticeGood Laboratory Practice


Basic guidelinesBasic guidelines

Additional guidanceAdditional guidance

WHO TRS No. 937, 2006, Annex 9WHO TRS No. 937, 2006, Annex 9

Guidelines for organizations Guidelines for organizations performing in vivo bioequivalence performing in vivo bioequivalence studiesstudies. In: WHO Expert Committee . In: WHO Expert Committee on Specifications for Pharmaceutical on Specifications for Pharmaceutical Preparations. Fortieth report. Preparations. Fortieth report. Geneva, World Health OrganizationGeneva, World Health Organization


Bioequivalence study reportBioequivalence study report

The The BioequivalenceBioequivalence study reportstudy report should should include information on:include information on:

Ethics, Investigators and Ethics, Investigators and administrative structureadministrative structure

Clinical phase of a studyClinical phase of a study Bioanalytical method of studyBioanalytical method of study Pharmacokinetic and statistical Pharmacokinetic and statistical

analysisanalysis Study protocolStudy protocol



1. Ethical principles1. Ethical principles : : current version of the Declaration of current version of the Declaration of HelsinkiHelsinki

Ethic Committee (EC) should be Ethic Committee (EC) should be independentindependentInformation about the EC e.g.Information about the EC e.g.

membersmembersconstitution of meetingsconstitution of meetings

discussions, recommendations, decisions discussions, recommendations, decisions of the EC should be documentedof the EC should be documented



All All clinical trial protocols, clinical trial protocols, screeningscreening consentconsent and and informed informed consent formsconsent forms (ICFs) should be (ICFs) should be reviewed, amended and reviewed, amended and approved by the EC approved by the EC

beforebefore the start any trial-related the start any trial-related activities.activities.



2. Justification2. Justification of the study designof the study design Specific aim, problems, risk, and Specific aim, problems, risk, and

benefit should be consideredbenefit should be considered based on the knowledge of the based on the knowledge of the

pharmacokinetics, pharmacokinetics, pharmacodynamics, therapeutics of pharmacodynamics, therapeutics of the API.the API.

Information on the manufacturing Information on the manufacturing procedure and used batchprocedure and used batch



3. Selection of Investigators3. Selection of Investigators Expertise, qualifications, competenceExpertise, qualifications, competence Before starting: agreement between Before starting: agreement between

investigator(s) and sponsor oninvestigator(s) and sponsor onprotocolprotocolmonitoringmonitoringauditingauditingSOPSOPresponsibilities (study responsibilities (study

related)related)



Complete structure is presented:Complete structure is presented:

Table of Contents (see example on Table of Contents (see example on Cd Rom 2)Cd Rom 2)

Bioequivalence Trial Information Bioequivalence Trial Information Form (BTIF)Form (BTIF)


Bioequivalence dossier Bioequivalence dossier requirementsrequirements

particularsparticularsGeneral study design:General study design:

A two-period, single-dose, cross-over A two-period, single-dose, cross-over study in healthy volunteers.study in healthy volunteers.

AlternativesAlternatives Using the API at a lower strength in Using the API at a lower strength in

case of toxicity (PK should be case of toxicity (PK should be proportional, no solubility problems)proportional, no solubility problems)



particularsparticulars single-dose, cross-over study in single-dose, cross-over study in

case of drugs with long elimination case of drugs with long elimination half-life half-life (wash-out about 5 times terminal (wash-out about 5 times terminal tt1/21/2, not more than 3-4 weeks), not more than 3-4 weeks)

oror parallel design (example: parallel design (example:

amodiaquine)amodiaquine)



particularsparticulars

Multiple dose, cross-over study Multiple dose, cross-over study in in patientspatients in case of an too toxic and/or too in case of an too toxic and/or too potent drug without interrupting potent drug without interrupting the therapy. the therapy.



particularsparticularsFixed-dose combination products:Fixed-dose combination products:

Comparison withComparison with

a)a) an existing combinationan existing combination

b)b) separate active APIs (drug)separate active APIs (drug)



particularsparticulars► ► Problem: no existing combination Problem: no existing combination

and no established therapeutic use and no established therapeutic use of the individual APIs (Example: of the individual APIs (Example: Artesunate/amodiaquine)Artesunate/amodiaquine)

►►Consequence: Consequence: as there is no as there is no acceptable reference available, acceptable reference available, additionally clinical studies on additionally clinical studies on efficacy and safety are necessary.efficacy and safety are necessary.


Bioequivalence dossier requirementsBioequivalence dossier requirementsSPC and PILSPC and PIL

EU – GuidelinesEU – Guidelines- A guideline on Summary of Product A guideline on Summary of Product

CharacteristicsCharacteristics- Notice to applicants; Rev0, December 1999)- Notice to applicants; Rev0, December 1999)

- Guideline on the readability of the label and Guideline on the readability of the label and package leaflet of medicinal products for human package leaflet of medicinal products for human use – Notice to applicants; use – Notice to applicants; Vol. IIAVol. IIA Rev3, September 1999Rev3, September 1999

WHO – GuidelineWHO – Guideline- SPC: according to the EU guideline- SPC: according to the EU guideline http://mednet3.who.int/prequal/


Bioequivalence dossier Bioequivalence dossier requirementsrequirementsSPC and PILSPC and PIL

The The “generic” “generic” SPC + PILSPC + PIL

= =

innovatorinnovator SPC + PIL SPC + PIL



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Bioequivalence Dossier Requirements