OCT Practical Aspects of Conducting Clinical Trials for Russian Innovative Companies Innovative Drug Research and Development in Russia 2012
OCT: CRO in Russia, Central and Eastern Europe
Russian Innovative Company: A New Client Positive results from Russia s Pharma 2020 plan Since 2010, ¼ OCT revenue comes from Russian innovative companies: Russian startups invested by state funds, venture companies Russian biopharmaceutical companies involved in R&D
Problems Facing Russian Companies Developing New Drugs 1. Pre-clinical studies 2. Phase I in healthy volunteers 3. Definition of registration and multinational study 4. Drug dossier 5. No relevant/ambiguous regulations 6. No scientific advice 7. No orphan drug status 8. Lack of infrastructure for R&D
Problem # 1: Limited possibilities to study efficacy in pre-clinic locally Many animal models are not developed in Russia Much time for development No guarantee that the model will be developed even if the site agrees to develop the model It is not possible to predict human response/justify start of clinical study without good animal models Outsourcing of pre-clinical studies to certified European or US laboratories
Problem # 2: Phase I in Healthy Volunteers in Russia Phase I in healthy volunteers studies of medications produced outside of Russia are forbidden in accordance with FZ-61 1) to establish safety and/or tolerance of medicinal products for healthy volunteers, except for the trials of medicinal products manufactured outside the Russian Federation; Drug dossier preparation or initiation of the trial in another country Phase I unit identification
Problem # 3: Definition of Registration and Multinational Studies According to FZ-61 there are 3 types of studies: Clinical trials for registration Multicenter multinational trials Multicenter trials Post-registration trials Multinational clinical trials Postregistration clinical trials
Definition of Registration and Multinational Studies Federal law on changes in part two of Tax Code of the Russian Federation, Article 333.32.1. determines the following state fees: Expertise of documents for clinical trial approval and state drug registration- 75 000 Rub (clause 1) Approval of multinational multicenter clinical trial- 200 000 Rub (clause 12) Approval of post-registration clinical trial- 50 000 Rub (clause 13)
Problem # 4: Drug Dossier Preparation in Russia Study initiation delay due to big amount of documents Two stage approval process Disclosure of confidential information on drug manufacturing
A Way to Avoid Dossier Collection in Russia Initiation of another country: Feasibility Additional costs associated with CTA (state fee, insurance, site initiation, monitoring) Additional documents needed for CTA in some countries (IMPD or its parts)
Problem # 5: No relevant/ambiguous regulations Risk comes from not knowing what you re doing! Warren Buffett
Example. No Regulation on Biosimilars (1) No definition for biosimilar drugs No official documents describing regulatory requirements for the quality, pre-clinical and clinical studies for biosimilars But: Biosimilar and biobetter drugs are under development in Russia
Example. No Regulation on Biosimilars (2) Reference to European guidelines: In vitro studies Characterization of the chemical structure of biosimilar drug Comparative studies of pharmacodynamic effects In vivo studies Comparative studies of efficacy Comparative safety and toxicology studies in animals
Example. No Regulation on Biosimilars (3) Study to show comparable pharmacokinetics and pharmacodynamic (PD) effects: Study population: patients vs. healthy volunteers PK parameters of interest Availability of relevant PD markers Number of study subjects Overall cost of the study Study to show comparable safety and efficacy : If dose comparative and highly sensitive PD studies cannot be performed convincingly showing comparability in a clinically relevant manner, similar clinical efficacy between the similar and the reference product should be demonstrated in adequately powered, randomised, parallel group comparative clinical trial(s), preferably double-blind, normally equivalence trials. http://www.ema.europa.eu/docs/en_gb/document_library/scientific_guideline/2012/06/wc50012 8686.pdf
Problem # 6. No Scientific Advice in Russia Unofficial expert recommendations No guarantees Quick Official comments after CTA decline Official and legal Time consuming New comments can be issued after second file review
Food for thought: Scientific Advice in Europe (1) The MHRA has for many years provided scientific and regulatory advice to Sponsors Sci advice can be requested during any stage of the initial development of the drug The MHRA prefers to meet face to face with companies, but in exceptional circumstances, videoconferencing may be arranged TCs are generally considered satisfactory to discuss complex issues
Food for thought: Scientific Advice in Europe (2) The MHRA Licensing Division held about 275 Sci Advice meeting in 2011 The MHRA Clinical Unit has held almost 80 meetings over the last 10 months The CTU s e-mail helpline fields 250 queries
Food for thought: Scientific Advice in Europe (3) Sci advice can be obtained from the CHMP SAWP has been established as a standing party with the sole permit of providing Sci Advice and Protocol Assistance to applicants It is SAWP/CHMP responsibility to give Sci Advice to industry by answering questions based on the documentation provided by the company in the light of the current scientific knowledge
Food for thought: Scientific Advice in Europe (4) An immune therapy developed by Immunocore Ltd won approval from the MHRA to start clinical trials on the basis of in vitro safety studies only, without conducting animal studies After intense consultations with the regulators, Immunocore conducted test on human cells
Problem # 7: No Orphan Status in Russia Definition of orphan disease and orphan drug in Federal Law of the Russian Federation dd. 21 November 2011 # 323-FZ On the Fundamentals of Public Health Protection in the Russian Federation But: No incentives for companies developing orphan drugs
USA Food for thought: Orphan Status in the World tax credits on clinical research; technical assistance during the elaboration of the application file necessary for marketing approval as well as simplification of administrative procedures (reduction of the waiting period and reduction of the amount of registration fees); marketing exclusivity of 7 years after the marketing approval is granted. Europe protocol assistance access to the centralised authorization procedure ten years of market exclusivity Fee reductions grants
Problem # 8: Lack of infrastructure for R&D Commercial pre-clinical laboratories Commercial phase I units Bioanalytical laboratories Central laboratories Data Management companies Statisticians (SPSS, SAS) Medical writers
Questions