Download Bioequivalence dossier requirements for the prequalification project

Bioequivalence dossier
requirements for the
prequalification project
WHO Training Workshop on Pharmaceutical
Quality, Good Manufacturing Practice and
Bioequivalence with a Focus on Artemisinines
Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
1
Dossier requirements
general
The product dossier should include
information on:
1. Details of the product
 2. Regulatory situation in other countries
 3. Active pharmaceutical ingredient(s)API

Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
2
Dossier requirements
general
(3. API continue)
3.1 Properties of the API(s)
3.2 Sites of manufacture
3.3 Route of synthesis
3.4 Specification
API described in a pharmacopoeia
API not described in a pharmacopoeia
3.5 Stability testing

Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
3
Dossier requirements
general

4. Finished product
4.1 Formulation
4.2 Sites of manufacture
4.3 Manufacturing procedure
4.4 Specifications for excipients
4.5 Specifications for finished product
4.6 Container/closure system(s) and other
packaging
Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
4
Dossier requirements
general
(4. Finished product continue )
4.7 Stability testing
4.8 Container labeling
4.9 Product information
4.10 Patient information and package inserts
4.11 Justification for any differences to the
product in the country or countries issuing the
submitted WHO-type certificate(s)
Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
5
Dossier requirements
general
5. Interchangeability
5.1 Bioequivalence study
5.2 Summary of pharmacology,
toxicology* and efficacy of the
product (expert reports)
* not required anymore for artemisinines but
for combinations
Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
6
Basic guidelines
In vivo Bioequivalence studies are clinical
trials:
in accordance with the guidelines on
 Good Clinical Practice
 Good Manufacturing Practice
 Good Laboratory Practice
Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
7
Basic guidelines

Additional guidance

WHO TRS No. 937, 2006, Annex 9
Guidelines for organizations performing in vivo
bioequivalence studies. In: WHO Expert Committee on
Specifications for Pharmaceutical Preparations. Fortieth
report. Geneva, World Health Organization
Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
8
Bioequivalence study report





The Bioequivalence study report should include
information on:
Ethics, Investigators and administrative structure
Clinical phase of a study
Bioanalytical method of study
Pharmacokinetic and statistical analysis
Study protocol
Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
9
Bioequivalence study report
1. Ethical principles :
current version of the Declaration of Helsinki
 Ethic Committee (EC) should be independent
Information about the EC e.g.
members
constitution of meetings
discussions, recommendations, decisions of the
EC should be documented
Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
10
Bioequivalence study report
All clinical trial protocols, screening
consent and informed consent forms
(ICFs) should be reviewed, amended and
approved by the EC
before the start any trial-related activities.
Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
11
Bioequivalence study report
2. Justification of the study design
 Specific aim, problems, risk, and benefit should
be considered
 based on the knowledge of the
pharmacokinetics, pharmacodynamics,
therapeutics of the API.
 Information on the manufacturing
procedure and used batch
Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
12
Bioequivalence study report
3. Selection of Investigators
 Expertise, qualifications, competence
 Before starting: agreement between investigator(s) and
sponsor on
protocol
monitoring
auditing
SOP
responsibilities (study related)
Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
13
Bioequivalence study report
Complete structure is presented:


Table of Contents (see example on Cd Rom 2)
Bioequivalence Trial Information Form (BTIF)
Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
14
Bioequivalence dossier requirements
particulars
General study design:
A two-period, single-dose, cross-over study in
healthy volunteers.
Alternatives
 Using the API at a lower strength in case of
toxicity (PK should be proportional, no
solubility problems)
Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
15
Bioequivalence dossier requirements
particulars
single-dose, cross-over study in case of
drugs with long elimination half-life
(wash-out about 5 times terminal t1/2, not
more than 3-4 weeks)
or
 parallel design (example: amodiaquine)

Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
16
Bioequivalence dossier requirements
particulars

Multiple dose, cross-over study in patients
in case of an too toxic and/or too potent
drug without interrupting the therapy.
Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
17
Bioequivalence dossier requirements
particulars
Fixed-dose combination products:
Comparison with
a) an existing combination
b) separate active APIs (drug)
Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
18
Bioequivalence dossier requirements
particulars
► Problem: no existing combination and no
established therapeutic use of the individual
APIs (Example: Artesunate/amodiaquine)
►Consequence: as there is no acceptable
reference available, additionally clinical studies
on efficacy and safety are necessary.
Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
19
Bioequivalence dossier requirements
SPC and PIL
EU – Guidelines
-
A guideline on Summary of Product Characteristics
- Notice to applicants; Rev0, December 1999)
-
Guideline on the readability of the label and package leaflet of
medicinal products for human use – Notice to applicants;
Vol. IIA Rev3, September 1999
WHO – Guideline
- SPC: according to the EU guideline
http://mednet3.who.int/prequal/
Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
20
Bioequivalence dossier requirements
SPC and PIL
The “generic” SPC + PIL
=
innovator SPC + PIL
Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
21
Bioequivalence dossier requirements
Thank you for your
attention
Tanzania, 21-25 August
2006
Dr. Barbara Sterzik, BfArM, Bonn
22