Transcript Experience from the evaluation of drug dossiers with respect to

WHO Procurement, Quality and Sourcing Project:
Access to Tuberculosis Drugs of Acceptable Quality
Experience from the Evaluation of
Drug Dossiers with Respect to
Bioequivalence Data
Hans Kemmler
1
Swissmedic, Switzerland
Invited Generic Products 1
Expressions of Interest were invited for
First line drugs

Ethambutol Hydrochloride 400mg tablets

Pyrazinamide 400mg tablets

Isoniazid 300mg tablets

Rifampicin 150/300/450/600 mg tablets
2
Invited Generic Products 2
Second line drugs

Cycloserine 250mg tablets

Ethionamide125 mg or 250mg tablets

Ofloxacin 200 mg tablets

Prothionamide 125 mg or 250mg tablets

Para-Aminosalicylic Acid 100 g or 4 g
granules or powder

Moxifloxacin 400 mg tablets
3
Invited Generic Products 3
Fixed-Dose-Combinations (FDC)

2FDC: Rifampicin 150 mg /Isoniazid 75mg
tablets

2FDC: Rifampicin 150 mg /Isoniazid
150mg tablets

2FDC: Ethambutol Hydrochloride 400 mg
/Isoniazid 150mg tablets
4
Invited Generic Products 4
Fixed-Dose-Combinations (FDC)

3FDC: Rifampicin 150 mg / Isoniazid 75
mg / Ethambutol Hydrochloride 275 mg
tablets

4FDC: Rifampicin 150mg /Isoniazid 75mg
/Pyrazinamide 400mg /Ethambutol
Hydrochloride 275mg tablets
5
Invited Generic Products 5
FDC’s for children:
1) Rifampicin 60 mg /Isoniazid 60mg/
Pyrazinamide 150 mg (R60/H30/Z150)
2) Rifampicin 60 mg /Isoniazid 30mg
(R60/H30)
3) Rifampicin 60 mg/ Isoniazid 60 mg
(R60/H60)
6
Invited Generic Products 6
Preparations for injection
(no bioequivalence study needed)

Streptomycin Sulfate 1g vial (injection)

Water for injection 5ml vial (injection)

Amikacin 500mg/2 ml vial (injection)

Kanamycin 1g powder for injection, vial

Capreomycin 1g powder for injection, vial
7
Submitted Generic Products
Of the 153 files submitted

7 files for solutions for
injection requiring no BE study

146 files for tablets/capsules/oral
suspensions requiring BE study

Only 8 products up to now have been found
acceptable, in principle, for procurement by
UN agencies
(included in list available : http://mednet3.who.int/prequal/ )
8
Summary of Submissions for
Tuberculosis-Drugs

2-FDC (R, H)
29

Pyrazinamide (Z)
19

Ethambutol (E)
18

Isoniazid (H)
16

4-FDC (R,H,Z,E)
13

Rifampicin (R)
12

3-FDC
8
9
Current Status
S C PQ
A

2-FDC (R, H)
29
8
3
18

Pyrazinamide (Z)
19
12
1
6

Ethambutol (E)
18
5
1
13

Isoniazid (H)
16
6
0
10

4-FDC (R,H,Z,E)
13
4
3
6

Rifampicin (R)
12
5
0
7

3-FDC
8
3
0
5
10
Deficiencies in BE Studies
Selected examples:
Pyrazinamide: (19 submissions, 1 prequalified, 12 cancelled)

For 13 products no BE study submitted

For 3 , BES were submitted, but major
deficiencies in all aspects (reporting, reference
product)

Only 2 BE studies (for three products)
acceptable -> one product prequalified

18 of 19 submissions with quality
documentation deficits
11
Deficiencies in BE Studies
Selected examples:
Pyrazinamide:
“Bioequivalence study report
The report and protocol is not paged and is
submitted completely randomised. “
12
Identified Deficiencies in Applications
Requiring BE Studies
Selected examples:
4-FDC (R,H,Z,E): (13 submitted, 3 prequalified, 4
cancelled, 6 with deficits)

For 3 products, no BES

For 7, major deficits, 6 studies with
unacceptable reference products

9 products with quality deficits
13
Identified Deficiencies in
Applications Requiring BE
Studies
Major deficiencies

No bioequivalence study performed and no
adequate justification for not performing a
study

Unacceptable reference product

Inadequate validation data of bioanalytical
method
14
Identified Deficiencies in BE
studies
Major deficiencies (cont.)

No verification that test product used in
bioequivalence study is identical to
product intended for marketing

90 % Confidence Intervals for
pharmacokinetic parameters not
presented (or more generally, no
adequate statistical analysis)
15
Identified Deficiencies in BE
studies
Minor deficiencies (information not presented,
but easily accessible)

Individual pharmacokinetic parameters not
submitted

Pharmacokinetic and statistical calculations not
submitted

Detailed description of study design not
submitted
16
Identified Deficiencies in BE
studies
Minor deficiencies (cont.)

No information on batch size of test product

Certificate of Analysis of test batch not
submitted

In-vitro dissolution profiles not submitted
– for test product
– for reference product
– for different strengths of the same product
17
Conclusion in Project

Some problems arise again and again,
from many applicants
More
advice needed !!
And
is possible and
here!
18
Two New Documents
soon available
1.
Note to Applicants on Choice of
Comparator Products in the
Prequalification Project
2.
Template: ASSESSMENT REPORT FOR
PREQUALIFICATION OF MULTISOURCE (GENERIC) FINISHED
PHARMACEUTICAL PRODUCTS (FPPS)
NOT REGISTRED IN ICH REGIONS OR
RELATED COUNTRIES
19
Note on Choice of
Comparator Products:
Current status

Note to Applicants on Choice of
Comparator Products in the
Prequalification Project:
– First draft (Jan. 2005) was circulated
among experienced assessors from
several countries
– After receiving and evaluating
comments, few changes to be expected
20
Note on Choice of Comparators

Objective:

This note is intended to provide to
applicants some additional guidance
and clarification on existing guidance
documents how to select an
appropriate comparator product for a
bioequivalence study necessary for
generic products submitted into the
WHO prequalification project .
21
Note on Choice of Comparators

Background 1:

The following information is already
provided on the web site, see (http://mednet3.
who.int/prequal/ , Documents and Materials, Bio-equivalence)

“What data and information needs to be
submitted in a dossier for a generic
product?”

“A set of bio-equivalence study data is
required for all oral preparations” !!!!!!
22
Note on Choice of Comparators

Background 2:

With regard to the choice of comparator
products reference is made on the website to
“International comparator products for bioequivalence testing"

Annex 11 of Thirty-sixth Report of the WHO Expert
Committee on Specifications for Pharmaceutical
Preparations. WHO Technical Report Series, No. 902,
2002: 161-180: Guidance on the selection of
comparator pharmaceutical products for
equivalence assessment of interchangeable
multisource (generic) products. [Annex 11]
23
Note on Choice of Comparators:
General comments:

The innovator pharmaceutical product
is usually the most logical comparator
product for a multisource
pharmaceutical product because its
quality, safety and efficacy should have
been well assessed and documented in
premarketing studies and postmarketing monitoring schemes.
24
Note on Choice of Comparators:
General comments:

Whenever possible the innovator
products should be obtained from a
well regulated market with stringent
regulatory authority (countries such as
Australia, Canada, European Union
Member States, Japan, USA,
Switzerland) , and the Product
Information (or Summary of Product
Characteristics) of the respective
country should be used for reference.
25
Note on Choice of Comparators:
General comments:

Never should a generic drug be used as
comparator as long as an innovator
drug is available, because this could
lead to a “bio-creep” phenomenon,
resulting in progressively less reliable
similarity of future multisource
products and to lack of
interchangeability with the innovator.
26
„Bio-Creep“
Relative BA
Interchangeable
Not Interchangeable
120
100
80
% 60
Relative BA
40
20
0
Generic 1
Innovator
Generic 2
Generic 3
Generic 4
27
Note on Choice of Comparators:
General comments, FDC:

Similar considerations apply to the use
of fixed-dose-combinations, which were
approved exclusively on the basis of
bioequivalence studies comparing with
the individual components, which were
used as free combinations (i.e.
individual products co-administered) in
efficacy and safety studies.
28
Note on Choice of Comparators:
General comments, FDC:

Such FDC’s should normally not be
used as comparators – even if approved
by ICH countries – instead again the
individual components should be used
as comparators.

However, there are also some fixeddose-combinations which were used as
such extensively in clinical trials, thus
direct, “own” evidence for their efficacy
and safety is available.
These can be used !!!
29
Note on Choice of Comparators:
Example for 4-FDC:

Bioequivalence study, 1999,
accepted in EU, Switzerland and
by WHO:

Rimstar 4-FDC®

versus

Rimactane ® + Isozid ® + Rolab
Pyrazinamide ® + Myambutol®
30
Note on Choice of Comparators:
Example for 4-FDC:

Rimstar 4-FDC® (Rifampicin 150, Isoniazid 75,
Pyrazinamide 400, Ethambutol 275mg) 4 tablets given
in a single dose

versus

Rimactane ® (Novartis, Switzerland*) 4 capsules each
containing 150mg rifampicin

Isozid ® (Fatol, Germany) 3 tablets each containing
100 mg isoniazid

Rolab Pyrazinamide ® (Rolab, South Africa) 3 tablets
each containing 500 mg Pyrazinamide

Myambutol® (Lederle Arzneimittel GmbH & Co) 2
tablets containing 400mg and 3 tablets containing
100mg ethambutol
31
Note on Choice of Comparators:
Example for FDC:

However, even if approved in
many countries, Rimstar ® is still
not an acceptable reference,
because approval was based
exclusively on BE-studies

In contrast, with Rifater ® (3FDC)
and Rifinah ® (2FDC) extensive
clinical studies have been done,
these would be acceptable
32
Note on Choice of Comparators:
Example for FDC:

Appear in List A of Annex 11:
33
Note on Choice of Comparators:
General comments, Principle:

General principle for selection of
an appropriate comparator:

As near as possible in the
chain of evidence to the
product for which efficacy
and safety has been directly
shown.
34
Note on Choice of Comparators:
Schema

Wherever possible, follow:
1.
Marketing Authorization of
Pharmaceutical Products with special
Reference to Multisource (Generic)
Products : a Manual for a Drug
Regulatory Authority,
WHO/DMP/RGS/98.5
2.
Annex 11 (see above, slide 23)
35
Note on Choice of Comparators:
Schema
However:

The “Manual” and the “Annex 11” were
developed for national regulatory
agencies regulating single national
markets

Not all recommendations applicable to
international markets

The concept of a “national market
leader” cannot be used for
prequalification project
36
Note on Choice
How to choose
1.
Innovator
a)
b)
2.
Easily identifiable for new drugs (only two
for TB)
Consult Annex 11, List A, also for Tb several
drugs listed
Pharmaceutical products approved in the WHO
prequalification project for which a full dossier
for quality, safety and efficacy was submitted
and evaluated. (currently only anti-malarials)
3.
Try to find accepted comparator in “Note”
4.
If no innovator and no product listed in Annex11
?
37
Note on Choice
How to choose
4.
No innovator, no List A product, nothing in
„Note“:
Difficult, extensive justification is necessary:
The most important selection criterion will be
based on extensive – documented – use in
clinical trials reported in peer-reviewed
scientific journals, and after this, approval in
ICH- and associated countries.
38