Transcript Experience from the evaluation of drug dossiers with respect to

WHO Procurement, Quality and Sourcing
Project:
Access to HIV/AIDS Drugs and Diagnostics
of Acceptable Quality
Experience from the Evaluation of
Drug Dossiers with Respect to
Bioequivalence Data
Hans Kemmler
1
Swissmedic, Switzerland
Invited Generic Products
Expressions of Interest were invited for

Nucleoside Reverse Transcriptase Inhibitors
– 7: Zidovudine, Didanosine, Lamivudine etc.

Non-nucleoside Reverse Transcriptase Inhibitors
– 3 : Nevirapine, Efavirenz, Delarvidine

Protease Inhibitors
– 6 : Amprenavir, Saquinavir, Ritonavir etc.

Other Anti-infective drugs:
Antibacterials, Antimycotics, Antiprotozoals, other
Antivirals, Anti-cancer drugs
2
Submitted Generic Products
Of the appr. 280 Expressions of Interest
were

34 files for solutions for
injection requiring no BE study

222 files for tablets/capsules/oral suspensions
requiring BE study

19 submissions for oral solutions

About 80 products up to now have been found
acceptable, in principle, for procurement by UN
agencies
(included in list available : http://mednet3.who.int/prequal/ )
3
Summary of Submissions for
HIV/AIDS-Drugs

Antibacterials
56

Antimycotics
24

Antiprotozoals
7

other Antivirals
18

Anticancer

Nucleosid RTI
86

NRTI Combi
34

Non-Nucleosid RTI
18

Prot.Inhibitors
18
6
4
Distribution of submissions
Antibacterials
Antimycotics
Antiprotozoals
18
18
other Antivirals
56
Anticancer
34
Nuclosid RTI
24
7
18
86
NRTI Combi
Non-Nucleosid RTI
Prot.I
10
5
Distribution of prequalifiedAntibacterials
Antimycotics
products (appr. 80)
Antiprotozoals
other Antivirals
8
10
Anticancer
6
Nucleosid RTI
5
2
4
4
2
NRTI Combi
Non-Nucleosid
RTI
Prot.I
32
6
NRTI prequalified
Nucleoside RTI prequalified
14
12
10
8
6
4
2
0
Abacavir
Didanosine
Lamivudine
Lam-comb
Stavudine
Zalcitabine
Zidovudine
7
id
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Innovators
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Nucleoside RTI prequalified
14
12
10
8
6
4
2
0
8
Prequalification results of
NRTI

120 submissions for NRTI and
combinations with NRTI

36 prequalified

Of 36 NRTI prequalified, only 14 are
generics

Of 98 submissions for generic NRTI,
84 not (yet) prequalified
9
Prequalification Results of
Protease Inhibitors
All prequalified PI are from
innovator companies, none
is a generic
10
WHY?
Deficiencies in BE Studies ? YES

About 50% of submissions without
bioequivalence study

Of submitted studies:
–
About 50% with inadequate method validation
– ~ 50% without verification that test product is
exactly same as applied-for-product
– ~ 35% without basic statistical evaluation
11
Other 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
12
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
13
Conclusion in Project

Some problems arise again and again,
from many applicants
More
And
advice needed !!
is possible !
14
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
15
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
16
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 .
17
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” !!!!!!
18
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]
19
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.
20
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, EU Member States,
Japan, USA, Switzerland) , and the
Product Information (or Summary of
Product Characteristics) of the
respective country should be used for
reference for future up-dates of safety
relevant informations.
21
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.

Lacking of availability on local market is
no excuse
22
„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
23
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
(individual components were, however, used as
free combinations (i.e. individual products coadministered) in comprehensive efficacy and safety
studies)
24
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. (otherwise „bio-creep“)

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 !!!
25
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®
26
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
27
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
28
Note on Choice of Comparators:
Example for FDC:

Appear in List A of Annex 11:
29
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.
30
Note on Choice of Comparators:
Schema

Wherever possible, follow:
1.
“Blue book” 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 19)
31
Note on Choice of Comparators:
Schema
However:

The “Blue book” 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
32
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
?
33
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.
34
Template: ASSESSMENT REPORT FOR
PREQUALIFICATION OF MULTISOURCE (GENERIC) FPPS

Used by assessors of BE-studies for
harmonisation of approach and
completeness of evaluation

In project used since appr. July 2004

Derived with small adjustments from
template of Canadian drug regulatory
authority (there used since many
years)
35
Template
BIOEQUIVALENCE TRIAL INFORMATION
1 SUMMARY OF BIOAVAILABILITY/BIOEQUIVALENCE STUDIES PERFORMED
(Provide a brief description of each comparative bioavailability study included in the submission)
2 Has comparative bioavailability data been submitted for all strengths?
(If comparative bioavailability data has not been submitted for all strengths, provide a scientific justification for not
submitting such data)
Sections 3.0 – 9.0 below should be copied and completed separately for each
bioequivalence study performed.
3.0 CLINICAL STUDY REPORT
36
Template
3.0 CLINICAL STUDY REPORT
Study #:
Study Title:
Location of Study Protocol:
Start and stop dates for each phase of the clinical study:
3.1 ETHICS
(a) Name of review committee, date of approval of protocol and consent form, location of
approval letter in the submission
(b) State location of a reference copy of the informed consent form
37
Template Section 3.2
3.2 INVESTIGATORS AND STUDY ADMINISTRATIVE
STRUCTURE
(a) Name of principal investigator(s) (State location of C.V. in the
submission)
(b) Clinical Facility (Name and full mailing address)
(c) Clinical Laboratories (Name and full mailing address)
(d) Analytical Laboratories (Name and full mailing address)
(e) Company performing pharmacokinetic/statistical analysis (Name and
full mailing address)
38
Template Section 3.4
3.4 INVESTIGATIONAL PLAN
3.4.1 Overall Study Design and Plan – Description
(Describe the type of study design employed in 1-2 sentences)
3.4.2 Selection of Study Population
3.4.2.1 Inclusion Criteria
3.4.2.2 Exclusion Criteria
(List the exclusion criteria applied to subjects)
3.4.2.3 Removal of Patients from Therapy or Assessment
(a)
Number of subjects enrolled in the study
(All subjects including alternates, withdrawals, and dropouts)
(b)
Withdrawals
(Identify each withdrawal by subject and provide the reason for withdrawal and at
what point in the study the withdrawal occurred)
39
Template Section 3.4
3.4.2
Treatments Administered
3.4.3.1 Test Product
(a) Batch number and date of manufacture for the test product
(b) Potency (measured content) of test formulation as a
percentage of label claim
(This information should be cross-referenced to the
location of the certificate of analysis in the submission)
40
Template Section 3.4.3.2
Reference Product
(a) Name and manufacturer of the reference product
(b) Batch number and expiry date for the reference product
(c) Potency (measured content) of the reference formulation as a
percentage of label claim (This information should be crossreferenced to the location of the certificate of analysis in the
submission)
(d) Justification of choice of reference product
(Provide short summary here and cross-reference to location of
comprehensive justification in study protocol)
41
Template Section 3.4.6
Blinding
3.4.6.1 Identify which of the following were blinded. If
any of the groups were not blinded, provide a justification for
not doing so
(a)
(b)
(c)
study monitors
subjects
analysts
3.4.6.2 Identify who held the study code and when the
code was broken
42
Template Section 3.4.7
3.4.7 Drug Concentration Measurements
3.4.7.1 Biological fluid(s) sampled
3.4.7.2 Sampling Protocol
(a) Number of samples collected per subject
(b) Volume of fluid collected per sample
(c) Total volume of fluid collected per subject per phase of the
study
(d) List the study sampling times
(e) Identify any deviations from the sampling protocol
(State location of summary in the submission)
(Describe and explain reasons for deviations from sampling
protocol. Comment on impact on study. Indicate whether the
deviations were accounted for in the pharmacokinetic analyses)
43
Template Section 3.5
3.5 Comments from review of Section 3.0 – WHO
use only
44
Template Section 5
5.0 PROTOCOL DEVIATIONS
5.1 Protocol deviations during the clinical study
(Describe any such deviations and discuss their
implications with respect to bioequivalence)
5.2 Comments from review of Section 5.0 – WHO use
only
45
Template Section 7
7.0 EFFICACY EVALUATION –
Efficacy Results and Tabulations of Individual Patient Data
7.1 Presentation of Data
(a) State location in submission of tables of mean and individual
subject concentrations
(b) State location in submission of (mean and individual) linear
and semi-logarithmic subject drug concentration vs. time plots
46
Template Section 7.1
7.2 PHARMACOKINETIC (PK) PARAMETERS
Parameter
Test
Reference
% Ratio of
Geometric Means
90 % Confidence Interval
AUCT (units)
AUCI (units)
Cmax (units)
47
Template Section 8
Must always be provided !!
8.0 ANALYTICAL STUDY REPORT
8.1 ANALYTICAL TECHNIQUE
8.1.1 Analytical protocol
(State the location of the analytical protocol)
8.1.2 Identify analyte(s) monitored
8.1.3 Identify analytical technique employed
48
Template Section 8.6
Must always be provided !!
8.6 Chromatograms
(State the location in the submission where the sample chromatograms
can be found. The chromatograms should be obtained from a minimum
of two analytical batches and include at least 20% of the subjects, up to
a maximum of five. A complete set includes standards, QC samples,
pre-dose and post-dose subject samples for both phases. Each
chromatogram should be clearly labelled with respect to the following:
date of analysis; subject ID number; study period; sampling time;
analyte; standard or QC, with concentration; analyte and internal
standard peaks; peak heights and/or areas)
49
Template Section 9
Must always be provided !!
9.0 ANALYTICAL VALIDATION REPORT
9.1 Precision and Accuracy
(a) Summarize inter-day and intra-day accuracy and
precision during assay validation
(b) Summarize inter-day and intra-day accuracy and
precision during assay re-validation
(If applicable)
50
Template Section 10
10.0 QUALITY ASSURANCE
10.1
Internal quality assurance methods
(State locations in the submission where internal
quality assurance methods and results are
described for each of study sites (see 3.2 b-d)
10.2
Monitoring, Auditing, Inspections
(Provide a list of all monitoring and auditing reports
of the study, and of recent inspections of study sites
by regulatory agencies. State locations in the
submission of the respective reports for each of
study sites (see 3.2 b-d)
51
Wanted !
52