1. Ivana Knezevic | 1 |1 | PANDRH meeting, BTP session WHO Survey on Biotherapeutic Products (focus on clinical issues) Ottawa, 6 th September 2013 Dr Ivana Knezevic, WHO/HIS/EMP

2. Ivana Knezevic | 2 |2 | WHO survey on BTP To understand the situation in American Region with respect to the following: – Obstacles in developing and regulating BTP – Required clinical data for already licensed products – Definitions used for "originator" product and "copy product" – Diversity of national regulatory requirements in the region WHO Questionnaire was sent to 20 NRAs in American Region and 2 associations of manufacturers: ALIFAR and FIFARMA Feedback received from: – 16 NRAs but 1 set of answers (USA) was not included in the analysis. – No response from Guatemala, Paraguay, and Barbados. – 1 manufacturers' association (FIFARMA) Analysis of the results – Responses from NRAs from 14 countries (Bolivia, Brazil, Canada, Chile, Colombia, Costa Rica, Cuba, Ecuador, El Salvador, Honduras, Mexico, Panama, Peru, Uruguay, Venezuela) and FIFARMA were included in the preliminary analysis. – Preliminary analysis at end August 2013, final by end September 2013.

3. Ivana Knezevic | 3 |3 | Main outcomes (1) Q1. Main obstacles in developing/ regulating SBPs: – Use of originators licensed in one country as RBP in another country – Access to information on RBP – Design of pivotal clinical trial Q2. Required clinical data for BTP already licensed in your country – Ph I-III: 11 out of 15 countries – Only review protocol for CT approval: Bolivia – No requirement: Peru (before 2009) and Uruguay – Only Phase III: Brazil (before 2010), Panama – Only safety data: El Salvador – A separate trial required for each indication or clinical use: Chile, Cuba, Canada and Mexico Q3. Definition of originator product: Licensed with full data package in a country in question / or by well-recognized jurisdictions (FDA, EMA, etc)

4. Ivana Knezevic | 4 |4 | Main outcomes (2) Q4. Definition of copy product – Proven similar structure and comparable safety and efficacy in clinical studies: 8 out of 15 countries. In terms of quality, similar structure is the only requirement while none of other quality aspects were mentioned. – Bioequivalence should be demonstrated: 5 out of 15 countries. – Indirect comparison in clinical aspects: Chile – Indirect comparison in quality part: Uruguay – SBPs are categorized as one of copy products: Cuba a.Proven comparable structure, safety and efficacy profile to originator product. Direct comparison vs originator always needed for quality, non clinical and clinical. b.Similar Mabs could be an exceptional case (case by case analysis), direct comparison in clinical is not always required.

5. Ivana Knezevic | 5 |5 | Copy products in Chile Q4. Copy products in Chile: New law from Dec 2011: all biologicals should be licensed as new pharmaceuticals Before the new law, BTPs were approved in 3 ways: –Treated as generics (no clinical data on safety and efficacy, incomplete quality dossier) but assigned as innovator –Not considered as generic: incomplete quality and clinical data –Innovators: complete quality, non-clinical and clinical data Before implementation of new law, copy products were licensed

6. Ivana Knezevic | 6 |6 | Next steps Outcomes of the survey will be: – Discussed at PANDRH meeting in Ottawa on 6 th Sep 2013 – If participants of the survey agree, the outcomes will be used for a review article and maybe published in one of scientific journals or as a meeting report on WHO web site – Considered in the preparation of the e-learning tools for improving expertise for regulatory review of BTP in general and SBP in particular – Discussed in the context of Regulatory Risk Assessment for the purpose of: developing WHO Guidelines Sharing experience with other regional regulatory networks, manufacturers and other relevant parties

7. Ivana Knezevic | 7 |7 | Panel discussion All panelists are invited to comment on the following: 1. Rationale for different requirements, for instance, clinical data requirements: should they be the same in all countries? 2. Way forward: how regulatory convergence can be achieved or how current situation could be improved?

8. Ivana Knezevic | 8 |8 | Many thanks to All participants of the survey for valuable feedback HyeNa Kang and Maria Luz Pombo for help with the preparation of the Questionnaire, distribution and analysis of results Agnes Klein and Catherine Njue from HC for useful suggestions regarding the Questionnaire