analysis of the organization and conducting of clinical trials in healthy volunteers in the russian...
TRANSCRIPT
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
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
Development of expertise ofEthic 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
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
The volume of clinical trials in Russia (1 and 2 quarters of 2015)
Orange Paper, 2015
Distribution of clinical trials: international and Russian sponsors (1-2 quarters of 2015)
The structure of clinical trials in Russia depending on the phase (1 and 2 quarters of
2015)
АОКИ, 2015
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)
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)
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.
PHARMACO-GENOMICS IN CLINICAL TRIALS : ATTITUDE OF FDA
PHARMACO-GENOMICS IN CLINICAL TRIALS : ATTITUDE OF EMEA
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
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
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.
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
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
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
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
Adherence to the study protocol
Smoking control
Vehicle 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
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%).
Sufficient level of compliancePsychological 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.
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
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
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
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.
Thank you for attention!