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1 Copenhagen, Denmark 24 – 27 September 2018
Prequalification Team – Medicines
(PQTm)
Bioequivalence Assessment
Update
Dr. John Gordon
Bioequivalence on the PQTm website
Notes on bioequivalence study design Product specific guidance
Bioequivalence Trial Information Form (BTIF)
Additional supporting data requirements
Comparator products
Biowaivers
Zinc
Overview
Copenhagen, Denmark 24 – 27 September 2018 2
3 Copenhagen, Denmark 24-27 September 2018
4 Copenhagen, Denmark 24-27 September 2018
WHO Expert Committee on Specifications for
Pharmaceutical Preparations (ECSPP)
Multisource (generic) pharmaceutical products:
guidelines on registration requirements to establish
interchangeability
WHO Technical Report Series (TRS) 992, Annex 7 (2015)
Now re-published in WHO TRS 1003, Annex 6 (2017) with
additional appendix
Appendix 2: Equilibrium solubility experiments for the purpose of
classification of active pharmaceutical ingredients according to
the Biopharmaceutics Classification System (BCS)
Principal Bioequivalence
Guideline
5 Copenhagen, Denmark 24-27 September 2018
Product specific guidance
Based on best information available to PQTm
Maybe revised if more information becomes
available
New guidances being added regularly
50 guidances + RH guidance currently posted
28 guidances added since last meeting!
Most recent additions include advice on the design
of studies for:
Lopinavir/ritonavir
Primaquine
Notes on bioequivalence study design
6 Copenhagen, Denmark 24 – 27 September 2018
7 Copenhagen, Denmark 18-21 September 2017
Must be completed in Word format for every
bioequivalence study submitted to PQTm
New version of BTIF posted in 20 September 2018
Clarification to Section 2.4.3.2 c
Information on Purchase, shipment, storage of the comparator
Revision to Section 8.4 a
Intra-day precision and accuracy summary not required
Addition of Section 10
Appendix 1: Individual pharmacokinetic results (AUC and
Cmax) for each subject
List of all bioequivalence studies conducted
Bioequivalence Trial Information Form
(BTIF)
8 Copenhagen, Denmark 24-27 September 2018
Purchase, shipment, storage of the comparator product (Indicate from which company/pharmaceutical distributor the
comparator product has been obtained. Clearly indicate in
chronological order the steps and dates of shipment/transport from
company of purchase to the study site. In addition, the storage
conditions should be given. This information should be cross-
referenced to location in submission of documents (e.g. receipts)
proving conditions.
BTIF Section 2.4.3.2
9 Copenhagen, Denmark 24-27 September 2018
For example:
A = Name and location of Pharmaceutical Distributor (date of purchase);
location in dossier of purchase invoice;
Shipped from A to B (date shipped, method of shipment); location in dossier of
bill of lading and shipping temperature record;
B = Sponsor’s site (date received, storage conditions at site); location in dossier
of record of storage conditions over period stored at site
Shipped from B to C (date shipped, method of shipment); location in dossier of
bill of lading and shipping temperature record;
C = CRO site (date received, storage conditions at site); location in dossier of
record of storage conditions over period stored at site)
BTIF Section 2.4.3.2
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10.1 Electronic copy of Study AUC and Cmax data in
Appendix 1 to BTIF (A MS Excel file containing the AUC and Cmax data from the study
should be included in Module 1.4.1 of the CTD identified as Appendix 1
to the BTIF. The Excel file template provided on the PQTm website
should be used and its format should not be modified except to add
extra columns for studies larger than a two-way design.
Confirm below that the requested Excel spreadsheet has been provided
in the dossier.)
BTIF Section 10
Additional supporting data
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10.2 List of all bioequivalence studies conducted with
proposed product and studies conducted during
product development
Confirm below that the list of studies is provided as required. If no
additional studies (beyond the study summarized in this BTIF) have
been conducted, please so indicate here.)
BTIF Section 10
Additional supporting data
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1. A list of all bioequivalence studies, including pilot studies, conducted with the
proposed product i.e., same formulation and manufacturing process as that
submitted for prequalification, regardless of the comparator (reference)
product employed and regardless of the study outcome. Complete study
synopses should be provided for all listed studies, in accordance with Annex
I of ICH Guideline E3: Structure and Content of Clinical Study Reports.
2. A list of all bioequivalence or comparative bioavailability studies, including
pilot studies, conducted during pharmaceutical development (development
of formulation and/or manufacturing processes) of the product, regardless of
the comparator (reference) product employed and regardless of the study
outcome. Complete study synopses should be provided for all listed studies,
in accordance with Annex I of ICH Guideline E3: Structure and Content of
Clinical Study Reports.
Full study reports for all listed studies should be available upon request.
Module 2.7
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Lists for comparator products for each treatment area
available on PQTm website
All lists updated regularly
Not all products listed in PQ Expressions of Interest
(EOIs) will have comparators indicated on these lists
For example, some dispersible products do not have
comparable references so conventional product may have
to be used as comparator
If a comparator is not listed, consult PQTm
Comparator products
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A regulatory authority that is
a member of ICH prior to 23 October 2015, namely: the US
Food and Drug Administration, the European Commission
and the Ministry of Health, Labour and Welfare of Japan also
represented by the Pharmaceuticals and Medical Devices
Agency; or
an ICH observer prior to 23 October 2015, namely: the
European Free Trade Association, as represented by
Swissmedic and Health Canada; or
a regulatory authority associated with an ICH member
through a legally-binding, mutual recognitionagreement prior
to 23 October 2015, namely: Australia, Iceland, Liechtenstein
and Norway.
Comparator products:
Where can they be purchased?
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If WHO comparator product cannot be located in those
markets, consult PQTm
Identification of alternate markets for sourcing
particular products
Assistance identifying pharmaceutical distributors
If a comparator is not indicated on our PQTm list then
contact PQTm
Comparator Products
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Biowaivers
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In vitro approaches for demonstrating safety and efficacy of products in lieu of conducting in vivo bioequivalence studies
Biopharmaceutics Classification System (BCS) –
based biowaivers Suitable for products containing eligible APIs
Abbreviated submission if API is on the eligibility list
Additional strengths biowaivers Suitable for additional strengths in a product line when
one of the strengths has shown in vivo bioequivalence
to the comparator
BCS-based Biowaivers
eligible APIs
20
Medicines for HIV/AIDS and
related diseases Abacavir sulfate (Class III)
Emtricitabine (Class I)
Fluconazole Polymorphs II & III (Class I)
Lamivudine (Class III)
Stavudine (Class I)
Zidovudine (Class I)
Neglected Tropical Disease
medicines
Diethylcarbamazine (Class III)*
Anti-tuberculosis medicines Ethambutol (Class III)
Isoniazid (Class III)
Levofloxacin (Class I)
Linezolid (Class I)
Moxifloxacin HCl (Class I)
Ofloxacin (Class I)
Pyrazinamide (Class III)
Copenhagen, Denmark 24-27 September 2018
BCS-based Biowaivers
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Do not use classifications provided in 2006 WHO TRS 937, Annex 8
ECSPP overseeing the development of a new
biowaiver classification list Living document
Information on equilibrium solubility experiments Appendix 2 of WHO TRS 1003, Annex 6 (2017)
Document with more technical detail under
development by ECSPP
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ZINC PRODUCTS UPDATED DOCUMENTS
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ZINC PRODUCTS UPDATED DOCUMENTS
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Safe quality
medicines
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