GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE SEPTEMBER 2010 – GUIDELINE ON SUBMISSION FOR INDIAN GENERIC PRODUCTS UNDER THE CECA SCHEME

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APPENDIX 16 GUIDELINE ON SUBMISSION FOR INDIAN GENERIC PRODUCTS UNDER THE CECA SCHEME

Pursuant to Chapter 5 of the India-Singapore Comprehensive Economic Cooperation Agreement (CECA), a special scheme (hereinafter referred to as ‘CECA scheme’) for the registration of generic products manufactured in India was introduced to facilitate the market authorization of these products in Singapore. Registration of Indian generic products may be possible through the CECA scheme provided that the application meets the eligibility and documentary requirements. This document is intended to provide assistance in the submission of applications under the CECA scheme. A generic product is essentially similar to a currently registered product in Singapore (known as the ‘Singapore reference product’). Essentially similar1

is defined as having the same qualitative and quantitative composition in terms of active substances, having the same pharmaceutical form and being bioequivalent. Thus, the generic product to be registered should demonstrate pharmaceutical and bio-equivalency with the Singapore reference product – i.e. to demonstrate interchangeability with the Singapore reference product.

1 Eligibility for application under the CECA scheme For eligibility of registration under the CECA scheme, the following criteria must be satisfied: a) The generic product is manufactured by licensed manufacturer(s) located onlyb) The generic product has been evaluated and approved by at least one of the following

regulatory agencies: EMA, UK MHRA, US FDA, Australia TGA and Health Canada;

in India;

c) The approval by the reference agency is within two (2) years from the date of submission to HSA; and,

d) All aspects of the generic product’s quality, including the formulation, manufacturing site(s), release and shelf life specifications and primary packaging, must be identical

to that currently approved by the reference agency.

Approval from EMA must be from the Centralised Procedure. Approval from UK MHRA must be from the national route or with UK MHRA acting as a Reference Member State for the Decentralised or Mutual Recognition Procedure. Applicants should note that approval by these reference regulatory agencies does not obligate HSA to approve the application. Generic products excluded

from this scheme include:

a) Products that infringe upon valid patents in Singapore, b) Products that do not have a Singapore Reference Product, c) Biological or biotechnological products; d) Products that have been rejected, withdrawn from, approved via appeal process or

pending deferral by a national drug regulatory authority; and, e) Products that have been approved by one of the reference agencies via an

accelerated/fast-track approval, approval under exceptional circumstances or an equivalent approval process.

1 Note for Guidance on the Investigation of Bioavailability and Bioequivalence. CPMP/EWP/QWP/1401/98.

GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE SEPTEMBER 2010 – GUIDELINE ON SUBMISSION FOR INDIAN GENERIC PRODUCTS UNDER THE CECA SCHEME

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2 Registration process Applications for registration of Indian generic products shall undergo the same process as other medicinal products as described in the Guidance of Medicinal Product Registration in Singapore (hereinafter referred to as ‘Guidance’). Figure 3 on page 12 of the Guidance is a flowchart of the registration process. It is highly recommended

for applicants wishing to submit applications under the CECA scheme to undergo a pre-submission consultation. This consultation is to determine the eligibility of the dossier and suitability of the dataset for registration under this scheme. In turn, this should facilitate the registration process as it may help to minimize/reduce potential delays – i.e. the need for Input Requests – in the registration process.

Applicants who wish to arrange for a pre-submission consultation should request an appointment, stating the purpose and proposed date(s) & time(s), via email to HSA_MedProd_Registration@hsa.gov.sg. 3 Documentary requirements Dossiers submitted under the CECA scheme must be in the ICH CTD or ACTD format. Dossiers submitted should also be in electronic format, either as a CD/DVD or uploaded into PRISM. See section 6.3.1 in the Guidance for more information. Administrative documents (ICH CTD Module 1 or ACTD Part 1) Administrative documents must be submitted in both

hard copy and soft copy. All official documents must be original or certified true copies.

The administrative documentary requirements for the CECA scheme is the same the GDA abridged evaluation route. See section 6.4.2 in the Guidance for more information. However, applicants should note that the requirements listed in table below are specific to the CECA scheme: Administrative document CECA scheme 1.4 – PI or PIL The PI/PIL should be aligned to the currently-registered

Singapore Reference Product. 1.5 – SmPC/PI/PIL The SmPC/PI/PIL should be that approved by the

reference agency. 1.6 – Assessment report The unedited assessment report from the reference

agency shall include details of imposed licensing conditions, final product labelling, chemistry review and other relevant documents in relation to the product’s approval. Refer to pages 33 & 34 in the Guidance.

1.9 – Approval letter from reference agency

Approval letter issued by the reference agency.

1.11 – GMP certification Valid GMP certificate and latest inspection report as issued by the reference agency.

1.14 – Declaration Declaration letter stating that the Singapore product to be registered and the information submitted are exactly the same as those submitted to the reference agency.

The assessment reports must be unredacted or unedited. Reports obtained from the public domain are deemed unacceptable. To facilitate the retrieval of unredacted reports

GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE SEPTEMBER 2010 – GUIDELINE ON SUBMISSION FOR INDIAN GENERIC PRODUCTS UNDER THE CECA SCHEME

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from US FDA, applicant may request for a US FDA Sponsor Authorisation Form from HSA and, upon completion of the form, submit it to HSA to allow for the release of the unredacted report by US FDA to HSA. Applicants should note that, with effect from 1st April 2004, all overseas drug product manufacturing sites previously not registered with HSA will be subjected to a GMP Conformity Assessment by HSA. Refer to GUIDE-20 on the HSA2

website for more information.

Summaries (ICH CTD Module 2 or ACTD Part 2/3/4) The documentary requirements for the CECA scheme is the same as the GDA abridged evaluation route, which includes the Quality Overall Summary, Singapore Quality Overall Summary and the Clinical Overview. Quality documents (ICH CTD Module 3 or ACTD Part 2) The CMC quality documents required for the CECA scheme is as follow: i. The initial dossier submitted to the reference agency that had approved the generic

product; ii. The initial open and closed parts of the Drug Master File submitted to the reference

agency, along with an original Letter of Access, if applicable; iii. All Questions and

iv. All Questions and Answers between the primary reference agency and DMF Holder, if applicable – the Answers should include supporting documents used in response to the Questions;

Answers between the reference agency and Sponsor during the evaluation which led to market authorization of the generic product – the Answers should include all supporting documents in response to the Questions; and,

v. If applicable, all post-approval variations approved by the primary reference agency up to the time of submission to HSA, including a. application letters for the variations; b. supporting documents for the variations; c. all Questions & Answers between the Agency and Sponsor and/or DMF Holder,

with supporting documents; and, d. the approval letters for the variations from the primary reference agency;

Applicants should refer to section 6.4 of the Guidance for more detailed information. Furthermore, with the implementation of the ASEAN Guideline for Drug Product Stability Study from 1 January 2009, dossiers are expected to contain drug product stability data in compliance to the ASEAN Guideline. Non-clinical & Clinical documents Non-clinical documents (ICH CTD Module 4 or ACTD Part 3) are not required. The clinical documents (ICH CTD Module 5 or ACTD Part 4) required for the CECA scheme is as follow: i. All clinical documents submitted to the reference agency that had approved the

generic product. Examples of clinical documents include bioequivalence (BE) studies, justification for biowaiver of BE studies and other relevant documents; and,

2 http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/GMP/guidelines.html

GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE SEPTEMBER 2010 – GUIDELINE ON SUBMISSION FOR INDIAN GENERIC PRODUCTS UNDER THE CECA SCHEME

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ii. All Questions and

Answers between the reference agency and Sponsor during the evaluation which led to market authorization of the generic product – the Answers should include all supporting documents in response to the Questions.

Applicants are to note that generic products applied through the CECA scheme must also

demonstrate essential similarity to the Singapore reference product. As such, applicants should refer to Appendix 12 of the Guidance for more information.

4 Regulatory Decision A regulatory decision is made based on the evaluation of the submitted data package. Applicants should refer to section 9 of the Guidance for more information. Upon issuance of a Product Licence, applicants are responsible fulfilling all

post-approval licensing conditions attached to the Licence. Applicants should view the licensing conditions online for specific details.

5 Timeline Because this scheme was established to facilitate market entry of Indian generic products, the table below describes the target processing timeline, in working days and excluding any stop-clocks: CECA scheme GDA Abridged Screening of the dossier before the 1st query 14 25 Evaluation of the dossier to regulatory decision 90 240

6 Fees The fee structure and quanta are subject to on-going review. For updated information, please visit the HSA website. The screening fee is payable at the time of PRISM submission. The evaluation fee is payable upon acceptance of the dossier for evaluation. The screening and evaluation fees are non-refundable, regardless of the final decision by HSA. Thus, applicants are advised to ensure that the dossier is compiled according to the required format and complete prior to submission. With effect from 15 April 2009, a progressive payment scheme was implemented to allow payment of evaluation fees by instalments. The evaluation fees of the CECA scheme can be paid by instalments via the progressive payment scheme.

NOTE: the screening timeline begins from the date of submission of the complete dossier. Applicants are advised to refer to Appendix 1 of the Guidance for more information. As such, HSA reserves the right to amend the application date when all documents have been submitted.