Information on Bioequivalence (BE)
In line with the Ministry of Health objectives of ensuring quality, efficacy and safety of pharmaceutical products that are marketed, the Drug Control Authority at its 92nd Meeting has decided to review the registration of generic products to include Bioequivalence (BE) studies requirements for certain categories oral immediate release products.
Bioavailability (BA) testing of drug products in humans provides the most appropriate method available for determining bioequivalence. Two drug products are considered bioequivalent if they are pharmaceutically equivalent and their bioavailabilities after administration in the same molar dose are similar to such a degree that their effects, can be expected to be essentially the same.
The Working Committee for BE Studies which was formed in September 1999, comprising of representatives from University Malaya (UM), Universiti Sains Malaysia (USM), Universiti Kebangsaan Malaysia (UKM), International Medical University (IMU), National Pharmaceutical Control Bureau (NPCB) and the pharmaceutical industry. The members were officially appointed to undertake the task of formulating an action plan for the conduct of BE studies in Malaysia through collaborative efforts.
Publication of the 'Malaysian Guidelines for the Conduct of Bioavailability and Bioequivalence Studies' marked the first outcome of this committee's objectives. This guideline is to provide guidance to the local researchers in conducting BE Studies in accordance to established international standards. Implementation of this guideline will promote properly designed studies being carried out.
STATUS OF IMPLEMENTATION OF BIOAVAILABILITY AND BIOEQUIVALENCE (BA/BE) REQUIREMENTS IN ASEAN
The ASEAN Guideline For The Conduct of Bioavailability / Bioequivalence (BA/BE) Studies was adopted at the 8th ASEAN Consultative Committee on Standards and Quality - Pharmaceutical Product Working Group (ACCSQ - PPWG) Meeting in Bangkok. Malaysia has conducted surveys in 2004 and 2005 on BA/BE Studies and its implementation in ASEAN countries. Results of the survey showed that most ASEAN countries require BE studies on certain products based on various criteria and availability of identical innovator product on local market/ASEAN market. However, not all BE centres are being accredited and acceptance criteria of foreign BE studies varies from country to country.
The 8th ACCSQ - PPWG Meeting has also agreed on possible development of sectoral Mutual Recognition Arrangements (MRAs) for the ASEAN pharmaceutical sector and this includes BA/BE Studies. The 9th Meeting was of the view that the harmonisation of BA/BE is important as it would enable Member Countries to work towards the mutual acceptance of the BA/BE Study Report in ASEAN. ASEAN at this stage should look into harmonisation on the Definition of a Comparator Product/ASEAN Comparator Product, Decision Tree in Determining Comparator Products at ASEAN and National Level and List of ASEAN Comparator Products. In view of this, the 10th ACCSQ - PPWG has appointed a Task Force consisting of representatives from all Member Countries to follow up on the recommendations. The Taskforce is led by Indonesia and assisted by Malaysia.
The 10th meeting also encouraged Member Countries to look into the acceptance of the BE Studies conducted by recognized BE Centres in the region in order to reduce unnecessary repetition of BE Studies and transaction cost for industry. The Meeting encouraged Member Countries without adequate BE facilities at this moment to use the available BE facilities in other countries in the region. Member Countries were also requested to look into the accreditation of BA/BE Centres.
The 13th ACCSQ - PPWG held on 23rd - 27th July 2007 in Kuala Lumpur, Malaysia has endorsed the following recommendations made by the Task Force:
- To use WHO Definition for ASEAN Comparator Product i.e. 'A Pharmaceutical product with which the multi-source product is intended to be interchangeable in clinical practice.'
- The selection of comparator product is as follows:
- Innovator product and multiple manufacturing sites of the same innovator registered in the country is acceptable.
- If the innovator product used as comparator is not registered in the country, justification is required from the generic company to prove its interchangeability with the registered innovator (in vitro or in vivo).
- If the innovator product cannot be identified, the choice of comparator must be made carefully and be comprehensively justified by the applicant. The selection criteria of a comparator in order of preference are:
- Approval in ICH and associated countries
- Pre-qualified by WHO
A well selected comparator must conform to compendial quality standards, if applicable.
In view of this, the List of ASEAN Comparator Product is not necessary because the principle of comparator selection has been agreed by all member countries, in accordance with WHO Guidance in TRS 937, 2006, Annex 7.
The 14th ACCSQ-PPWG held on 18th – 22nd February 2008 in Vientiane,Lao PDR has agreed that Malaysia as Lead Country for BA/BE will continue to lead discussions on the technical guidelines on BA/BE.
The 15th ACCSQ - PPWG held on 28th – 31st July 2008 in Jerudong, Brunei Darussalam in it’s 1st technical working group (TWG) meeting on ASEAN Bioavailability/Bioequivalence (BA/BE) has deliberated the drafts on Questions & Answers (Q & A) and revision/amendment of the BA/BE Guidelines. The meeting has agreed on the proposed Q & A (version 1) and proposals on editorial corrections to the guidelines. The meeting encouraged Member States to submit proposals for Q & A and revision/amendments to the BA/BE guidelines to Malaysia in accordance with the updating and revision of the guidelines. The meeting has also discussed the Framework for Mutual Acceptance of the BA/BE Study Report in ASEAN and agreed on the following:
- ASEAN Bioequivalence Study Reporting Format
- Acceptable conformance standards on the clinical and bioanalytical aspects of BE studies as follows:
- The clinical standard is ICH GCP E6 guidelines
- The bioanalytical standard should follow applicable GLP principles
- To achieve the acceptable criteria for inspection on BA/BE studies, the following steps will be taken:
- Establishment of minimum inspection criteria for Member States including checklist
- Capacity building for inspection
- Inspection by respective Drug Regulatory Agencies (DRAs)
The 16th and 17 th ACCSQ - PPWG noted that the BA/BE Taskforce has agreed on the following:
- The acceptable minimum inspection criteria will be developed based on the EMA SOP for conducting GCP inspection and other relevant references
- The SOP for conducting inspection of BA/BE studies on clinical and bioanalytical aspects will be incorporated into one document
- Checklist as a tool for conducting inspection of BA/BE studies will be revised based on SOP developed
- To achieve the conformance standards on the clinical and bioanalytical aspects of BA/BE Studies
The next action plan is to development a framework for mutual acceptance of the BA/BE and explore the possibility of organising capacity building programmes for inspection of BA/BE among Member States.
For presentation slide on Implementation of Bioequivalence Study for Generic Medicine in Malaysia, click here.
(Updated: August, 2011)