Global New Drug Development – Opportunities for Brazil Jurij Petrin, M.D. ENIFarMed19 Sep 2014

ENIFarMed2 Agenda Global New Drug Development - Background Where is Brazil? Preclinical and Clinical Aspects Opportunities 9 Sep 2014

ENIFarMed3 Pharmaceutical Business Environment - Innovative Products Globalization Speed-to-market Increased competition Advances in science New therapeutic classes Need for strong intellectual property protection 9 Sep 2014

ENIFarMed4 Global Regulatory Environment – Innovative Products Different tiers of regulatory agency sophistication Need for sequential approvals Harmonized regulations vs local regulatory independence & authority –Local acceptance of foreign data –Climatic zones –Ethnic differences –International Conference on Harmonization (ICH) –Regional initiatives (EU, Andean Pact, ASEAN, Mercosul….) 9 Sep 2014

ENIFarMed5 Companies Face Global Dilemmas Concentrate on major markets first? If yes, for how long? Utilize research capabilities of the international markets? If yes, should they launch the product in these markets and when? Available in-house expertise and resources If not – can we outsource? What? 9 Sep 2014

ENIFarMed6 Decision to Go Global What kind of a molecule? Disease target: unmet medical need? Life saving or recreational? Investment, timing, resource needs IP protection issues Business interest Competitive environment Risk of early generic competition 9 Sep 2014

ENIFarMed Main scientific development of new drugs done in major countries around the world, with less experienced countries providing clinical sites Normally, new drug submissions are done sequentially - US, Europe, smaller markets - usually in this order Main reason – only selected regulatory agencies willing/able to review a dossier before other countries! When approved in major markets, follow with submissions in smaller markets In global environment, this is becoming unacceptable Ultimate goal - to be able to develop and launch a new product worldwide as simultaneously as possible in key markets Global Regulatory Development of Innovative Products 7 9 Sep 2014

ENIFarMed8 Regulatory Development Experience 9 Sep 2014

ENIFarMed Goal? 99 Sep 2014

ENIFarMed10 Regulatory Development Experience 9 Sep 2014

ENIFarMed Is this possible? 119 Sep 2014

Current Status with New Drug Development in Brazil Strong and well developed generic industry Sporadic local development of improved or novel products, often based on rich biodiversity sources of Brazil Many development activities performed abroad (preclinical, clinical) No organized new chemical/biotechnology discovery efforts ongoing (for example, high-throughput screening methodology) ENIFarMed129 Sep 2014

Current Status with New Drug Development in Brazil GMP, GLP, GCP standards not closely followed in Brazil Regulatory environment not very supportive of new drug development –Appropriate regulations do not exist –No formal regulatory or scientific advice meetings available –Data reviews primarily bureaucratic –Extremely long and non-transparent review timelines US – 30 days (IND) EU – 60 days (CTA) Brazil – several months (improvements being discussed) –Data developed under such circumstances would not be acceptable in most developed countries ENIFarMed139 Sep 2014

Benefits of Local Innovative, R&D Driven Pharmaceutical Industry Advancement of local science and expertise: better connection of academia and industry Faster availability of new drugs to treat unmet medical needs in Brazil and elsewhere Decreased dependence on imported innovative drugs Growth of the domestic pharmaceutical sector Transition to export oriented industry Very positive results for the Brazilian economy ENIFarMed149 Sep 2014

Can a Consensus on How to Get There Be Reached? Education and training of all stakeholders: –Regulators –Local industry personnel –Academia –Medical practice personnel (doctors, nurses…) –Patients/public Establish a regulatory environment that will be supportive of new drug discovery and development Financial incentives: research grants, tax benefits, intellectual property protection Help local researchers and industry, and attract foreign investment Consider concentration of R&D activities ENIFarMed159 Sep 2014

Singapore Biopolis Biopolis is an international research and development center for biomedical sciences located in Singapore Almost 40 corporations with research and manufacturing activities Within a decade, Biopolis has established a reputation as a world- class biomedical research hub and put Singapore on the scientific world map The biomedical sciences industry has also generated economic wealth for Singapore, created well paid jobs and improved human health and quality of life Since 2000, biomedical science manufacturing output has increased by nearly five-fold from $6 billion in 2000 to $29.4 billion in 2012 NOTE: Singapore population-5.3 million (2012) ENIFarMed169 Sep 2014

How To Improve the Regulatory Environment for New Drug Development in Brazil? Consider an Investigational New Drug (IND) approach ENIFarMed179 Sep 2014

IND Data necessary to establish that the product will not expose human subjects to unreasonable risks in early studies: –Animal pharmacology and toxicology studies –Manufacturing (CMC) information –Clinical protocols and investigator information IND is a “living document” – initial submission is supplemented with new data as research continues Rapid regulatory review of new data (30-60 days max) Allow scientific and procedural questions to be discussed at formal meetings or via /teleconferences Result: Brazilian regulators actively involved with the development ENIFarMed189 Sep 2014

Main Components of IND 1.Administrative Part (country specific) 2.Table of Contents 3.General Investigational Plan 4.Investigator’s Brochure 5.Clinical Protocols (s) 6.CMC Information 7.Pharmacology and Toxicology 8.Previous Human Experience (if any) 9.Additional Information ENIFarMed199 Sep 2014

New Drug Development Cascade Target Discovery (identification, validation)  Lead Discovery (High Throughput Screening)  Medicinal Chemistry (library development, structure based design)  Cellular & Molecular Pharmacology (in vitro, mechanism of action)  Preclinical Development (PK/PD, toxicology)  Drug Candidate ENIFarMed209 Sep 2014

New Drug Development Cascade Target Discovery (identification, validation)  Lead Discovery (High Throughput Screening)  Medicinal Chemistry (library development, structure based design)  Cellular & Molecular Pharmacology (in vitro, mechanism of action)  Preclinical Development (PK/PD, toxicology)  Drug Candidate ENIFarMed21 10,000 compounds 9 Sep 2014

New Drug Development Cascade Target Discovery (identification, validation)  Lead Discovery (High Throughput Screening)  Medicinal Chemistry (library development, structure based design)  Cellular & Molecular Pharmacology (in vitro, mechanism of action)  Preclinical Development (PK/PD, toxicology)  Drug Candidate ENIFarMed22 10,000 compounds 250 compounds 9 Sep 2014

New Drug Development Cascade Target Discovery (identification, validation)  Lead Discovery (High Throughput Screening)  Medicinal Chemistry (library development, structure based design)  Cellular & Molecular Pharmacology (in vitro, mechanism of action)  Preclinical Development (PK/PD, toxicology)  Drug Candidate ENIFarMed23 10,000 compounds 250 compounds 5 compounds 9 Sep 2014

Early Development Preclinical development needs to identify the most promising drug candidate to take into the clinical phase Modern global preclinical development needs to: –Follow ICH guidelines –Good Laboratory Practice (GLP) standards –Be of highest quality –Best possible speed (not to waste resources if the drug candidate has problems) –Acceptable cost Overseeing regulatory agency must enable and assist good quality preclinical development ENIFarMed249 Sep 2014

Preclinical Drug Development ENIFarMed25 Purpose of preclinical development is to: –Define potential toxicities in humans and the likely target organs –Provide data from which the potential dose range in humans can be calculated –Provide basic information regarding the potential ADME of the drug –Reduce potential for harm to subjects Consider establishing Centers of Excellence – research, education, training. Good example: CIEnP in Florianopolis! 9 Sep 2014

ENIFarMed26 Clinical Drug Development Protection of clinical trial subjects Scientific approach in design and analysis Strict adherence to GCP 9 Sep 2014

ENIFarMed27 Classification of Clinical Studies According to Objective Human Pharmacology (Phase I) Therapeutic Exploratory (Phase II) Therapeutic Confirmatory (Phase III) Therapeutic Use (Phase IV) 9 Sep 2014

Possible Goals for Brazil in Clinical Trial Development Participation in multicenter multinational trials of new products –Offer existing and further improve local expertise –Experience with new drugs –Earlier access of Brazilian patients to new therapies –Financial benefits Improve quality of local clinical trials ENIFarMed289 Sep 2014

Marketing Application Submissions Consider changes to improve Brazil’s standing in global drug development: –Closer harmonization of local guidelines with ICH guidelines –Implementation of Good Review Practices –Faster regulatory reviews and decisions ENIFarMed299 Sep 2014

Principles of Good Review Practices Quality (expertise, training) Efficiency (keeping targeted timelines) Clarity (accurate review + effective communication) Transparency (applicants’ awareness of each review step) Consistency (across departments, drug types, therapeutic areas) Results: More scientific and less bureaucratic procedures Efficient and transparent regulatory processes Faster availability of needed drugs in Brazil ENIFarMed309 Sep 2014

Summary Brazil can and should play a bigger role in global drug development This is true for both preclinical as well as clinical phases Mandatory prerequisites are: –High quality of scientific and procedural work at all levels –Compliance with ICH –Strict GLP-GMP-GCP control –Transparent local guidelines –Adherence to Good Review Practices performed in line with globally competitive timelines ENIFarMed319 Sep 2014