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