1. ANALYSIS OF THE ORGANIZATION AND CONDUCTING OF CLINICAL TRIALS IN HEALTHY VOLUNTEERS IN THE RUSSIAN FEDERATION Alexander Khokhlov Professor, Head of the Department of Clinical Pharmacology YMSU

2. Article №21 of the Constitution of the Russian Federation, Federal law «On circulation of medicines» from 12.04.2010 No.61-FL, National standard of the Russian Federation «Good clinical practice», Helsinki Declaration of the world medical Association, amended and supplemented in accordance with the latest edition of Guidelines for bioequivalence study in the countries of the European Union. Clinical Studies in Russia

3. Development of expertise of Ethic Council of Russia New SOPs are working out, harmonized with international requirements The patient attention to phase I studies Collaboration with Ethic Committees from different countries Chair Alexander Chuchalin

4. High-qualified specialists (PI, SC, SI) of Russia conduct daily medical and consultative help to patients using modern medical and diagnostic equipment Clinical trials in Russia today

5. The volume of clinical trials in Russia (1 and 2 quarters of 2015) Orange Paper, 2015

6. Distribution of clinical trials: international and Russian sponsors (1-2 quarters of 2015)

7. The structure of clinical trials in Russia depending on the phase (1 and 2 quarters of 2015)

8. АОКИ, 2015

10. Planning of the sample size 1.3 Quantity of patients Sample size. Author of the protocol should provide a number of subjects is required to prove the initial hypothesis (the value of the sample size is calculated on the basis of mathematical laws of statistics). The sample size is affected by the disease to be studied, the purpose of research and study endpoints. Statistical evaluation of the typical sample size should be based on the estimated result of the treatment, the variability of the data specified (small) probability of error (ICH E9) and the expected information about subgroups and secondary endpoints. Some studies may need a large database to establish the safety of the drug. In clinical studies of the drug for new indications may be used a minimum sample size for a registration database to evaluate the safety (ICH E1 and ICH E7 ). These numbers should not be construed as absolute and may be insufficient in some cases (such as when to expect the delayed effects of the drug)

11. How to plan the sample size in clinical trials? ICH E9 STATISTICAL PRINCIPLES FOR CLINICAL TRIALS 3.5 SAMPLE SIZE «The number of subjects in a clinical trial should always be large enough to provide a reliable answer to the questions addressed.» Note for Guidance on Statistical Principles for Clinical Trials (CPMP/ICH/363/96)

12. The risks of wrong planning of bioequivalence studies For the manufacturer: the production of defective products. For patients: receiving a generic drug with a risk of a lack of effect (worsening of the disease), or side effects. For society as a whole: reducing the effectiveness of drug therapy and public health, loss of confidence in generics, Increasing the cost of drug therapy.

13. PHARMACO- GENOMICS IN CLINICAL TRIALS : ATTITUDE OF FDA

14. PHARMACO- GENOMICS IN CLINICAL TRIALS : ATTITUDE OF EMEA

15. Example: lornoxicam (exception genotypes CYP2C9*2, CYP2C9*3) 3.7 Screening of volunteers before beginning of the studies After signing the informed consent is conducted clinical and paraclinical examinations of volunteers, including a medical examination in view of the expected pattern of action of the drug being studied, and the following laboratory tests: If it is known that the test drug biotransformation is controlled genetically by polymorphic cytochrome isoenzymes, in order to reduce the variability of pharmacokinetic parameters genotyping volunteers advisable to avoid participation in the study patients with genotypes of "slow" and "fast" metabolism

16. Patients who are not able for various reasons to fully exercise their right to voluntary informed consent to participate in a clinical trial Vulnerable groups of patients

17. Clinical trials involving children These trails are carrying out after completion of the similar studies of efficacy and safety in adults (with a few exceptions especially pediatric drugs) in phase III clinical trials.

18. Legal representatives of minors: Parents Adopters Guardians (children under 14) Trustees (children from 14 to 18 years) Only parents and adoptive parents, under current legislation, may sign the informed consent

19. How to plan the number and participation of volunteers in bioequivalence studies? When studies have a complex design (long- term, multi-day hospitalization, drugs with poor tolerance, hormonal treatments for women), as well as during the flu epidemic the number of doublers shall be sufficient to provide 80% of the power of the statistical test (about 25% of the total number of volunteers) Doublers have to go through all the stages of study

20. Difficulties with compliance Careful monitoring of drug receiving (the drug from the beaker, using a spatula, a flashlight) Although all methods of control in 0.4% of cases occur sample with zero concentration of the test drug

21. BASIS OF COMPLIANCE - CORRECT LINE OF PHYSICIAN BEHAVIOR COMPLIANCE- IS THE DEGREE OF APPROPRIATE OF BEHAVIOR OF THE PATIENT TO RECOMMENDATIONS RECEIVED FROM DOCTOR my recommendations You must perform voluntarily COMPLIENCE In the narrow medical sense

22. Adherence to the study protocol Smoking controlVehicle conducting control In 35% of cases registered attempts to bring and pass the forbidden foods and drinks in the clinic Creating the necessary conditions for the volunteers to stay in hospital Regular training sessions for medical staff to work with volunteers

23. The problems associated with multi- day hospitalization (2-7 days) Procuring of conveniences and good quality of life to volunteers while they are staying in hospital (WiFi, books, newspapers, television, games, shower) 24-hour monitoring by clinic staff is needed Additional complexity of design are an additional factor withdrawal of informed consent (failure rate of 0 to 3.7%).

24. Sufficient level of compliance Psychological portrait of the patient. The search of new manners of treatment, the thirst for more information about the disease, methods treatment, search for "authorities". Overly expressed interest in the objective data about the disease (results of analyzes, opinions of experts). Imaginary dangers excite more than real.

25. All the bioequivalence studies in Yaroslavl Clinical hospital №2 are carried out on the basis of Standard operating procedures In clinic is constantly working team of professionals, consisting of 9 doctors and 25 nurses, 4 SC. Department of bioequivalence consists of a wardrobe, 8 wards for volunteers, 2 offices of physicians, 2 bathrooms, the laboratory room and the dining room. It is possible to hospitalize 45 patients. Department is equipped with electronic clock, fire sensors and alarm system

26. For the study highlighted staff with professional experience in the field of bioequivalence and pharmacokinetics. In our clinic is constantly working team of professionals, consisting of 9 doctors and 25 nurses, 4 SC. Department of bioequivalence consists of a wardrobe, 8 wards for volunteers, 2 treatment rooms, 2 offices of physicians, 2 bathrooms, room of the laboratory and the dining room. It is possible to hospitalize 45 patients. Department is equipped with electronic clock, fire sensors and alarm system

27. State membership in solving the problems of developing Russian pharmaceutical and medical industry The federal goal-oriented program “Development of the pharmaceutical and medical industry in Russian Federation up to the year 2020 and following perspective” was worked out for development realization of pharmaceutical and medical industry

28. Development of market of Russian drugs According to the expert's opinion to the year 2020 the market's volume of drugs in Russian Federation should extend up to 3 times and should be 300 milliards of roubles per year, and Russian medicines' market should be 1,5 trillions of roubles per year.

29. Thank you for attention!