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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/WC500128686.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, video-conferencing 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
Food for thought: Orphan Status in the World
• USA – 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