of November 26, 2019 No. 202
About approval of the Management on preclinical trials of safety for the purpose of conduct of clinical trials and registration of medicines
According to article 30 of the Agreement on the Eurasian Economic Union of May 29, 2014, article 6 of the Agreement on the single principles and rules of drug circulation within the Eurasian Economic Union of December 23, 2014 and Item 15 of the list of acts of the Eurasian economic commission on questions of regulation of the total markets of medicines and medical products within the Eurasian Economic Union for 2017 - 2019 ("About acts of the Eurasian economic commission on questions of regulation of the total markets of medicines and medical products within the Eurasian Economic Union" of May 17, 2017 No. 15) the Board of the Eurasian economic commission solved appendix to the order of Council of the Eurasian economic commission:
1. Approve the enclosed Management on preclinical trials of safety for the purpose of conduct of clinical trials and registration of medicines.
2. This Decision becomes effective after 6 months from the date of its official publication.
At the same time to recognize that if the realization of provisions of the specified Management is enabled according to acts of the Eurasian economic commission, use of such provisions is performed from the effective date (from start date of use) the relevant acts.
Chairman of Board of the Eurasian economic commission
Approved by the Decision of Board of the Eurasian economic commission of November 26, 2019 No. 202
1. The purpose of the present manual is establishment of single procedure for carrying out preclinical trials of safety of medicines (further - preclinical trials) for their subsequent registration within the Eurasian Economic Union. The interrelation between need of carrying out preclinical trials and conduct of clinical trials with participation of the person is reflected in the present manual.
2. The present manual is aimed at providing:
safe, ethic development and deployment of new medicines;
timely conduct of clinical trials;
reducings use in researches of laboratory animals according to the principles 3R (replacement, improvement, reducing) (replacement, refinement, reduction);
reducings use of other resources in case of development of medicines.
It is necessary to consider possibility of use of new alternative invitro of evaluation methods of safety which in case of their proper validation and approval by authorized bodies (the expert organizations) of state members of the Eurasian Economic Union (further respectively - state members, the Union) can replace the existing standard methods.
3. The present manual is constituted for the purpose of harmonization of the preclinical trials directed to reasons for carrying out clinical development of medicines at its different stages.
4. The present manual contains instructions concerning type, duration and terms of carrying out preclinical trials as reasons for conduct of clinical trials and registration of medicines.
5. Preclinical assessment of safety of medicines for the purpose of their registration provides carrying out:
a) pharmacological researches;
b) researches of all-toxic properties;
c) toksikokinetichesky and preclinical pharmacokinetic trials;
d) researches of reproductive toxicity;
e) genotoxicity researches;
e) estimates of cancerogenic potential concerning the medicines causing special concerns or intended for prolonged use.
6. Need of carrying out preclinical trials for the purpose of assessment of phototoxicity, immunotoxicity, toxicity on immature animals and tendency to emergence of medicinal dependence is determined in individual procedure.
7. The present manual is applied at development stage of medicines and contains general requirements to process of preclinical development of medicines. Planning and design of preclinical trials and clinical trials with participation of the person are based on the way, satisfactory from the scientific and ethical points of view.
8. Researches of safety of biotechnological medicines need to be conducted according to requirements of Chapters 5.3 and 5.4 of Rules of carrying out researches of the biological medicines of the Eurasian Economic Union approved by the Decision of Council of the Eurasian economic commission of November 3, 2016 No. 89. When carrying out research of safety of biotechnological medicines the present manual is applied only to terms of carrying out preclinical trials depending on phase of clinical development of biotechnological medicines.
Results of researches of safety of medicines, it is long applied in medical practice and containing active ingredients, data on which preclinical trial are limited or are absent, it is allowed to represent as a part of the mixed registration files of medicines. Creation of documents on preclinical trials for the mixed registration files of medicines is performed according to requirements, according to appendix No. 1.
9. For the purpose of optimization and acceleration of development of medicines for treatment of the zhizneugrozhayushchy and serious illness (for example, widespread cancer, resistant HIV infection, the condition caused by inborn enzymatic insufficiency) which does not have effective therapy we will allow individual approach to toxicological assessment and clinical development. In these cases, and also concerning the medicines created on the basis of innovative therapeutic methods (for example, small interfering RNA (siRNA) and adjuvant vaccines), in the program of preclinical trial reducing, refusal of carrying out or addition of certain researches is admissible. For the solution of question of amount of changes of the program of preclinical trial it is necessary to be guided by provisions of acts of bodies of the Union in the field of drug circulation or the legislation of state members.
10. Preclinical trials need to be conducted taking into account requirements of Items 34 and 35 of Rules of registration and examination of the medicines for medical application approved by the Decision of Council of the Eurasian economic commission of November 3, 2016 No. 78 (further - Rules of registration and examination).
11. The preclinical trials conducted outside customs area of the Union shall be executed taking into account instructions of Item 35 of Rules of registration and examination, and also to correspond to the present manual and other acts of bodies of the Union in the field of drug circulation.
12. On the questions which are not settled in the present manual, applicants have the right to address for scientific consultation in authorized bodies (the expert organizations) of state members according to Item 26 of Rules of registration and examination.
13. Medicine development - the step-by-step process providing assessment of data on its efficiency and safety for animals and the person. Establishment belongs to the purposes of preclinical assessment of safety:
characteristics of toxic action concerning target organs;
dependences of toxic action on dose;
dependences of toxic action on exposure;
potential reversibility of toxic action (in appropriate cases).
The received data use for assessment of initial safe dose and the range of doses in researches with participation of the person, and also for determination of ratio "advantage - risk" and parameters of clinical monitoring of potential undesirable effects.
14. Preclinical trials, despite limited nature at the initial stage of clinical development, shall be sufficient for the description of potential undesirable reactions which can arise in the conditions of reasonable clinical trial.
15. Clinical trials are conducted for the purpose of studying of efficiency and safety of medicine, since rather low system exposure at small number of subjects. They are followed by clinical trials in which exposure of medicine increases, as a rule, at the expense of duration of use and (or) the size of population of patients.
16. Clinical trials need to be expanded if the results confirming sufficient safety of medicine in earlier conducted clinical trial (researches) and also in the presence of additional these preclinical trials of safety which become available in process of accomplishment of clinical development are received.
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