07 December 2022

Ollen Pharma Trading Inc.

Km. 18 No. 5 Maywood Ave.
Maywood II Subdivision, Marcelo Green
Parafiaque City, Metro Manila

Subject Gliclazide + Metformin Hydrochloride 80 mg/ 500 mg Film-Coated

Tablet [Saphzimetl

Dear Sir/Madam:

This has reference to your application for Initial registration of the above subject
product.

Please be informed that upon evaluation of the supporting documents, it was

found that your submission is unsatisfactory. Specifically, we have noted that
two Bioequivalence (BE) Study Protocols were separately developed for the
fixed-dose combination product [i.e., 1 each to pharmacokinetically measure the
Gliclazide and Metformin Hydrochloride components involving different set of
study subjects, and at different periods of time, as detailed below] without
scientific justification, which we find inappropriate to satisfy the product
interchangeability/equivalence evidence requirements of this Office.
Furthermore, the submitted BE Study for Metformin Hydrochloride is for
another drug product - Irbesartan:
BE study of SAPHCLAZIDE versus BE study of IRBESAPH versus
Gliclazide DIAMICRON MR Irbesartan APROVEL
Study Protocol OS/GLIC/12- Study Protocol
19/23 TAB/SAP/IRBE- 1021
BE Testing Site BE Testing Site
0m Sai Clinical Research Pvt. Ltd. TAAB Biostudy Services
C.S.T. No. 379/1-6, Kamal Chowki, Peth 77/2/1 B/I, Bade Raipur Road, Jadavpur,
Bhag, Sangli — 416 416, Maharashtra, Kolkata-700032, India
India
Study Dates Study Dates
Clinical Phase: 24 January 2020 to 1 1 Clinical Phase: 08 November 2021 to 19
February 2020 November 2021
Analytical Phase: 14 February 2020 to Analytical Phase: 22 November to 30
21 November 2021
Februa 2020
Number of Subiects 24 Number of Subiects 24
health adults health adults

Based from the above inefficient study design where the fixed-dose combination test
product (SAPHZIMET) was not compared to the concurrently or
simultaneouslyadministered individual comparator products (DIAMICRON MR and
GLUCOPHAGE), there appears to be a lack of appropriate planning or foresight on
the part of the study sponsor/manufacturer to have conducted two BE studies
separately (instead of one), unnecessarily exposing a different set of healthy subjects
to the risks of a clinical study, which could have been avoided in the first place.

Moreover, the inherent variabilities between the two separate BE studies in terms of
the BE testing centers' clinical and analytical proficiency, sampling periods and
testing conditions during the study, set of study subjects involved, and actual study
dates make the demonstration of the interchangeability of the drug product as a
fixeddose combination questionable, notwithstanding the satisfactory
pharmacokinetic results presented in both studies based AUC0-t, AUC0-∞, on Cmax.

Please take note that for a fixed-dose combination product with systemic action
containing at least one component requiring an in vivo study, a single BE Study
Protocol should have been designed to cover both the pharmacologically active
components/drug substances. In the selection of the comparator product, in case no
fixed-dose combination product is available in the market, the comparator product of
the individual components administered in loose combination should be used. Also,
you have failed to submit the pertinent attachments (raw data sheets) of P 5.4
(3.2.P.5.4) Batch Analyses to support the test results obtained in the analysis.

Previously, an email was sent to the company (reg.ollenpharma@gmail.com and

ollenpharmatrading@gmail.com) on 14 November 2022. However, certain
deficiencies were still found despite our request to comply by 29 November 2022.

In view of the above, your application for registration is hereby DISAPPROVED.

A disapproved application may be resubmitted within six (6) months from the
date of the Letter of Disapproval (LOD) to be assigned a new Document
Tracking Number (DTN) and charged with a corresponding fee of Php 1,010,
inclusive of the Legal Research Fee (LRF). A resubmitted application shall
only include documents in fulfillment of the deficiencies cited in this letter.

If resubmission is filed beyond this period, the application shall be treated as initial
registration with new DTN, complete documentary requirements and corresponding
initial fee.