Conducting Trials at Russian Government Authorized Testing

and Medical Centers and Dealing with Roszdravnadzor and Rosaccreditation Authorities

Registration of MDs in Russia

Since Article 38 of the Federal Law №323-FZ came in force on 1st of January, 2013 there are 2 parts of the procedure of Medical Device Registration in Russia 1ST Part: • Technical Trials and EMS • Toxicology (Biocompatibility) • Expertise 2nd Part: •Assignment of clinical trials •Clinical Trials •Expertise

Clinical Trials in Russia

• In order to legally sell a Medical Device in Russia, the device must pass a state procedure called Registration, which is performed to release safe and high-quality medical devices on Russian Market, and receive a Registration Certificate of Roszrdavnadzor (Federal Service for Supervision of Health)

• Clinical Trials are vital part of Registration, and it is impossible to receive a Registration Certificate without conducting them.

Clinical Trials in Russia: Regulatory Basis

The decree of the Government of the Russian Federation of 27th December 2012 №1416 "On approval of rules of state registration of medical devices“

The order of the Russian Ministry of Health from 9 January 2014, №2n "On

approval of the Procedure of conformity assessment of medical devices in the form of technical tests, Toxicological research, clinical trials for the purpose of state registration of medical devices“

The order of the Russian Ministry of Health from 8th February 2013 №58n

"On approval of the Regulations on the Board of ethics in the sphere of medical products circulation"

Clinical Trials in Russia: Regulatory Basis (cont.)

The order of the Russian Ministry of Health from 1st March 2013 №108 "On approval of composition of the Board of ethics in the sphere of medical products circulation“

National standard “Guidelines for conducting clinical trials of medical

products" GOST R ISO 14155-1-2008 and GOST R ISO 14155-2-2008

National standard "Assessment of functional characteristics of medical devices for in vitro diagnostics" GOST R EN 13612-2010

Types of Clinical Trials 2 possible forms, just like in EU:

On Patients Analysis of literature sources

•Brand new type of MD •New unique/special methods of treatment and diagnostics •New complex medical technologies, in case clinical data evaluation didn’t confirm the safety and performance of MD

•All other cases

(Order of Minzdrav of Russia # 2n from 9 January 2014)

Analysis of literature sources, basis

Annex A of GOST R ISO 14155-1-2008 Recommendation on analysis of literature sources

• Aim – to create a basis for plan of clinical trials and to help with scientific justification of clinical trials.

• During this a valuable information is obtained that is used to evaluate the Risk/Benefit Ratio and to perform clinical trials according to ethical principles. • Analysis of literature sources also helps to determine if there is enough clinical data in the literature in order to demonstrate safety and clinical performance of the MD being evaluated without obtaining new data from additional clinical trials, or to conclude that there is not enough data available.

Analysis of literature sources

• Scientific activity that requires precision and objectivity; its results must be available for evaluation by the third party.

•The aim must be clearly defined, and types of research that will be used to achieve this aim must be identified, based on known data on the device.

•Criteria for selection/exclusion of data from recognized scientific publication must be defined and justified.

•To avoid systematic errors it is also recommended to take into account all available relevant unpublished data that is appropriate in the given circumstances.

•References to literature and unpublished data, as well as information about the extent of the search in databases or other sources of information must be listed.

Analysis of literature sources, evaluation of documents

It is necessary to evaluate the quality of documents and the degree of compliance of the literature data to specific characteristics and properties of the MD being evaluated, taking into account its intended use. a) the similarity of the devices in the selected documents with the MD being

evaluated from the point of view of technology, the basic characteristics, design and principles of operation to assess the applicability of these literature sources;

b) characteristics of a population of patients or test subjects, medical purpose, indications for use, as well as the severity and type of disease or pathological condition in the analyzed sources compared with those for the MD being evaluated

c) conditions of use of the MD described in the analyzed literature sources, and the intended use of the MD that is being evaluated.

Analysis of literature sources, evaluation of documents

During the the analysis of literature sources, it is necessary to evaluate the design of clinical trials and the significance of published and unpublished data. If the analysis includes unpublished data, it must be differentiated based on its significance. The following must be taken into account: a) If the author’s conclusions is supported by available data b) If the literature sources reflect contemporary medical practice and the level of

development of relevant technologies; c) If there are links to widely recognized scientific publications, and if the expert

evaluation of these publications is provided d) The degree of adherence to scientific principles in clinical trials, based on the

results of which the publication was prepared.

Analysis of literature sources, critical evaluation and report

The analysis of literature must contain its critical evaluation After the assessment of documents the criteria applied for their selection and elimination must be justified. A complete analysis should contain the data about the evaluated MD product and its intended use, and written analysis report must include: a) Brief description of the product, including its features, type, technical solution,

performance and intended use b) Analysis of all the selected literature sources and unpublished data, both favorable

and unfavorable c) A critical assessment of hazards, associated risks and necessary measures to ensure

the safety of patients, medical personnel and third parties;

Analysis of literature sources, critical evaluation and report (cont.)

a) description of approach to determining the significance of the different publications and applied statistical methods of analysis including the evaluation methods, the type and duration of the study, and the homogeneity of the population in question.

b) references to the presented list of publications. c) A justified conclusion with the evaluation of any possible health benefits from the

use of the product described by the manufacturer indications and possible risks, injuries or illness during this application, given the current level of technology development.

d) date and signature(s) of author(s) of the analysis.

Clinical trials on Human Subjects, Rationale

• In order to select and justify the optimal design of clinical trials it is necessary to conduct and document an objective analysis of published and available unpublished medical and other scientific data and information. (GOST R ISO 14155-1-2008 Cl.4)

• The decision to conduct clinical trials of medical devices requires, among other things, the availability of favorable ratio between the expected benefits from clinical trials and residual risk. (GOST R ISO 14155-1-2008 Cl.4)

• Clinical trials can begin only when the following documents are presented: 1. developed and signed the plan of clinical trials; 2. conclusions and/or approval of the Ethics Committee(s); 3. permission or approval of the authorized bodies (if necessary).

(GOST R ISO 14155-1-2008 Cl.6.6)

Clinical Trials In order to conduct Clinical Trials the following documents are presented by

the applicant to the medical institution: a) Application for performance of clinical trials; b) A sample(s) of medical device (excluding MDs installation of which

requires permits (licenses), special conditions, buildings and additional training and in some cases – visits of specialists to MDs production site;

c) Permit for clinical trials, issued by Roszdravnadzor; d) Act of evaluation of technical test results with attached documents that

supports results of technical tests; e) Conclusion on results of toxicological (biocompatibility) tests of medical

device with attachment of documents supporting results of toxicological (biocompatibility) tests (For MDs that suggest contact with patient’s body);

Clinical Trials (cont.) f) Results of tests of measuring function (for MDs with measuring function,

contained in list of medical devices with measuring function approved by Ministry of health of Russian Federation);

g) Data on normative documentation for MD with list of national (international (Eurasian Economic Union)) standards, requirements of which the MD complies with (during its use intended by the manufacturer);

h) Technical and operational documentation of the manufacturer for MD; i) Photos (general view) of the device together with accessories needed for

its intended use (size no less than 18x24 cm); j) Documents (materials) containing data on clinical application of MD,

including outside of Russian Federation, including reviews, reports of completed scientific researches, publications, reports, risk analysis and methods of application of MD (if available)

Program of Clinical Trials

Cl.39 of The order of Ministry of health of Russia dated 09th January 2014 No. 2N

• When reviewing the documentation submitted for a Medical Device, a program and duration of clinical trials of the Medical Device is coordinated. The duration of clinical trials is dependent on the purpose and complexity of the Medical Device. The clinical trial program is composed by the applicant together with a medical company that performs clinical trials of medical devices, in accordance with the requirements specified in the technical and operational documentation of the manufacturer and the requirements of regulatory documents.

Conformity assessment of medical devices for in vitro diagnostics

Cl.47 of The order of Ministry of health of Russia dated 09th January 2014 No. 2N

• Clinical trials of Medical Devices for in vitro diagnostics are carried out in laboratory conditions with the use of biomaterial samples of patients taken during the diagnostic and treatment process (hereinafter referred clinical laboratory tests) to check the functional properties and (or) effectiveness of a Medical Device when used in accordance with the intended use specified in the manufacturer's documentation.

• Clinical laboratory tests of medical devices for in vitro diagnostics in the form of analytical systems conducted in regard to Medical Devices along with accessories, sets of reagents and calibrators required for the application of the medical product can be performed within a single test.

Clinical Trials: Organizations • Order of the Ministry of health of Russia from 16th May 2013 No. 300N

“On approving the requirements for healthcare organizations which conduct clinical trials of medical devices and procedures to establish compliance of healthcare organizations to these requirements”

• The full list of organization is located on the official Roszravnadzor’s website : http://www.roszdravnadzor.ru/services/clinicaltrials

Clinical Trials: Organizations (list)

Clinical Trials: Final Report

Cl 11. of GOST R ISO 14155-1-2008 : Presentation of results: • Drafting of the final report of clinical trials is mandatory, including in

the event of early termination of clinical trials. • The final report must be made in written form. It is signed by the

organizer and the coordinator (if one has been appointed) and the head of clinical trials at each research centre.

• Final report on clinical trials should include complete identification data of the item(s), a description of the methodology and design of clinical trials, all deviations from the plan of clinical testing, data analysis, including statistical analysis, and critical evaluation in relation to the objectives of clinical trials

Clinical Trials: Pitfalls • All of clinical trial medical facilities are located mostly in central part of

Russia, very few are scattered across the rest of the country. • Even fewer of those rest are capable of performing Clinical Trials for

your type of device. • In some clinical facilities, even though the type of your device is listed

among those that this facility can perform clinical trials for, in reality, the facility might refuse, so, at first, you need to make sure that the facility can perform trials by phone call.

• If the medical device does not have analogues in Russia, it will be difficult to perform Analysis of literature sources for it, even if analogues exist in other countries. Most likely, Clinical trials with human subjects will be required.

Group STM • Our own laboratory, accredited by Roszdravnadzor for performance of

technical trials for the purpose of Registration of MDs. • We carefully trace all changes in the Russian certification system and

keep our clients informed. • We speak your language. • We are experienced in both Russian certification requirements and

International production standards. • We are flexible and customer oriented. • We will discuss and offer the best certification schedule reflecting your

needs and capabilities. • We are friendly and like to solve your problems!

CONTACTS

Anton Dulov, Manager Coordinator E-mail: dulov@group-stm.ru

Phone/fax: +7 (495) 981-44-84 Cell ph: +7 (916) 216-45-77

www.group-stm.ru