The document discusses drug safety monitoring in Russia. It outlines the legal and regulatory framework for drug safety monitoring, including key laws and orders. It then describes the drug safety monitoring system in Russia, which involves collecting adverse event reports, analyzing the data, and taking actions like modifying drug labels or suspending approval if risks are identified. For biosimilars, additional pre-clinical and clinical trials are needed to evaluate safety due to their complex nature and potential for immunogenicity. Overall, the document provides an overview of Russia's system for monitoring the safety of drugs, both traditional and biosimilar, after they reach the market.

1. S.V. Glagolev, Deputy Division Head, Head, Medical Product Efficacy and Safety
Monitoring Department, Medical Product Quality Public Control Division,
Federal Service for Surveillance in Healthcare
V.А. Polivanov, Head, Center for Drug Efficient, Safe and Reasonable Use
Monitoring at the Information and Methodical Center for Appraisal,
Accounting for and Analysis of Medical Facilities (IMCAAAMF), Federal Service
for Surveillance in Healthcare
Federal Service for Surveillance in Healthcare
Local Drug Safety
Monitoring Issues
Biosimilar Safety
Monitoring Issues

2. Drug Safety Monitoring System in
the Russian Federation

3. Legal and Regulatory Framework of the Drug Safety
Monitoring
•Federal Drug Circulation Law dated April 12, 2010, No. 61-FZ
•Resolution of the Government of the Russian Federation dated June 30, 2004, No. 323, On Approval
of the Regulations on the Federal Service for Surveillance in Healthcare and Social Development, in
the version of the Russian Government Resolution dated August 20, 2010, No. 650, On Making
Amendments to Certain Acts of the Government of the Russian Federation in connection with
Adoption of the Federal Drug Circulation Law
•Order of the Ministry of Healthcare and Social Development of the Russian Federation dated August
26, 2010, No. 757n, On Approval of the Procedure for Safety Monitoring of Medicinal Drugs,
Registration of Adverse Effects, Severe Adverse Effects, Unforeseeable Adverse Effects in Application
of Medicinal Drugs (registered by the Ministry of Justice of Russia on August 31, 2010, No. 8324)
•Order of the Ministry of Healthcare and Social Development of the Russian Federation dated August
26, 2010, No. 758n, On Approval of the Procedure for Medicinal Drug Application Suspension
(registered by the Ministry of Justice of Russia on August 31, 2010, No. 18325)
•Order of the Ministry of Healthcare and Social Development of the Russian Federation dated August
26, 2010, No. 749n, On Approval of the Format of the Document Containing the Safety Monitoring
Results for Medicinal Drugs to Confirm their State Registration (registered by the Ministry of Justice
of Russia on August 31, 2010, No. 18304)
•National Standard, Good Clinical Practice. State Standard R 52379-2005, as approved by Order of the
Federal Agency for Technical Regulation and Metrology dated September 27, 2005, no. 232-s.

4. Changes in Drug Safety Monitoring Regulation in 2010
• The duty of the pharmaceutical entities to notify the competent governmental authority of severe or
unforeseeable adverse effects or drug interactions is established
• The governmental function of drug safety monitoring is vested with the Federal Service for Surveillance in
Healthcare
• The timing for filing information on adverse drug effects to the Federal Service for Surveillance in
Healthcare is determined (15 calendar days)
• The need in and timing of filing regular drug safety reports to Federal Service for Surveillance in
Healthcare was established
• The option of drug state registration suspension or cancellation based on the safety monitoring results is
envisaged
• The new regulation on state registration cancellation, if the applicant does not provide the information
that may entail the need in making amendments to the registration file (within 30 days from occurrence of
such changes), is introduced
• The requirement to file the safety monitoring results with the Ministry of Healthcare and Social
Development of the Russian Federation in confirming drug registration is introduced

5. Drug Safety Monitoring
FSSH’s computerized
information system
Regional drug safety
monitoring centers
DQCC
IMCAAANF (FSU)
at FSSH
1.Input of incoming information to
FSSH’s computerized information
system (CIS) and its analysis
2.Sending of information on adverse
drug reactions to drug registration
applicants
3.Arranging for information appraisal
at FSSH’s IMCAAAMF FSU, including
request for assessment of the causal
relationship as well as the opinions on
legal cases
4. Arranging for quality appraisal of the
drugs that caused adverse reaction (if
necessary)
5.Coordination of operations of the
regional drug safety monitoring centers
as concerns investigation into the
instances of adverse reactions.
6.Review of scientific publications and
decisions of foreign regulatory
authorities
Resolutions
• to modify the drug instruction
• to suspend application
•to withdraw the drug
•to resume the drug application
Ministry of
Healthcare of
the Russian Federation
Recommendations based on
monitoring results
On making amendments to the instruction
•On drug application suspension
•On drug withdrawal from circulation
•On resumption of drug application
•On termination of verification tests
•On making amendments to VT protocol
Publication of information
on resolutions of the
Ministry of Healthcare
and Social Development of
Russia on the website of
the Federal Service for
Surveillance in Healthcare
Publication of
information letters
on drug safety
problems
Federal Service
for Surveillance in
Healthcare (FSSH)
Medical
Product Quality
Public Control
Division
Medical Product
Efficacy &
Safety Monitoring
Department
Registered drugs
Reports on adverse
effects, severe
adverse effects,
unforeseeable
adverse effects,
particular features of
drug interaction
Regular safety
reports
Drugs in
clinical trials
Reports on severe
unforeseeable
adverse drug
reactions
Annual drug safety
reports

6. Federal Drug Circulation Law dated April 12, 2010, No. 61-FZ
Article 64
Section 3. Pharmaceutical entities shall be obliged to notify of all instances of
side effects not specified in the drug application instructions (leaflet), оf
severe adverse drug reactions, unforeseeable adverse reactions resulting
from application of medicinal drugs, of particular features of drug
interaction with other drugs, which have been found in clinical trials and drug
application, in such manner as established by the competent federal executive
authority.
6

7. Federal Drug Circulation Law dated April 12, 2010, No. 61-FZ
Article 64
Clause 4. For non-disclosure or concealment of the information
envisaged in Part 3 of this Article, the persons who become aware
of such information by the nature of their professional activities
shall be liable according to Russian law.
Article 19.7, Russian Administrative Procedural Code, envisages liability for non-disclosure or delay with disclosure
of information (data) – the penalty for officials of RUB 300-500; for legal entities, RUB 3,000-5,000
Article 32
Cancellation of drug state registration
The resolution to cancel drug state registration is made in the following case:
Section 1. Presentation by FSSN of the opinion on the risk or threat to human health or life posed by drug application,
which surpass its efficacy, based on the results of its drug safety monitoring.
Section 4. Non-presentation by the applicant of the information that may entail the need in making amendments to
documents contained in the registration file for the registered drug within thirty business days from these changes.

8. Periodical Safety Update Reports (PSUR)
PSUR (or) by the drug manufacturer [… ] on electronic or paper media, within
the periods of time calculated from the date when the drug is registered in the
country where it is first permitted for medical application:
• during the first two years from the drug registration: once in 6 months;
• during the subsequent two years, the third and the fourth years from the drug
registration: annually;
• starting from the fifth year from the drug registration: once in three years.
Periodical reports shall be provided within 30 days from the counting period
expiry date.
(order by the Ministry of Health and Social Development of the Russian
Federation dated August 26, 2010, No. 757n)

9. Main Formats of PSUR Submitted to FSSH
• ICHE2C (R1), Clinical Safety Data Management: Periodical Safety Reports for
Drugs Available on the Market (PSUR)
• ICH E2C (R2), Periodical Report on Drug Risk and Benefits Ratio (PBER)
• The format described in the Methodical Recommendations, Guidelines on
Establishing the Drug Safety Monitoring System at Drug Manufacturers or
Registration Certificate Holders, as approved by FSSH’s Head on October 5, 2009
NB! At present, FSSN finishes working on the Methodical Recommendations on
drafting of periodical drug safety reports by developers and manufacturers of
the drugs circulating in the Russian Federation.

10. Changes in Registration of Adverse Reaction Reports in
2009/2013
2009 2010 2011 2012 2013
0
2000
4000
6000
8000
10000
12000
14000
16000
Forecast
Medical care
institutions (Regional
centers)
Pharma companies
Federal Monitoring
Center
Roszdravnadzor (CA)
5,955
10,182
12,646
13,745
14,940

11. Existing Challenges in Collection and Review of
‘Spontaneous’ Adverse Reaction Reports
• Frequency of reporting is lower than in the European Community or U.S.A.
• Pressure on physicians leads to deterioration of the reports or formal
approach to work (reports on minor and foreseeable adverse reactions,
same-type data etc.)
• Incorrect assessment of severity and predictability of the reactions as well
as the causal relationship
• Low quality of the significant number of reports: there is no information on
the patient’s co-morbidities, the treatment mode, the adverse reaction
outcome, and the results of instrumental tests (ideally, the scope of
information should approximate to the hospital discharge summary)

12. Spontaneous Reports: Method Limitations and Problems
• Low reportability (1%-10% of detected reactions in the countries with
the well-developed pharmacovigilance system)
• The number of reports depends on the length of stay on the market,
the mass media focus, and biased attitude of healthcare specialists
• It is impossible to assess the frequency of adverse reactions
• It is impossible to identify the reactions that develop in case of lengthy
application and in the period long after the drug application onset

13. Biosimilars Safety Monitoring
Issues

14. Molecular Weight of Biologicals

15. Post-Translation Modification
COOH
Variability in N-linked carbohydrate
side chains
O-Glycosylation
Proteolysis at Arg-X
N-terminal sequence length
variation
NH2
t-PA (Alteplase): a relatively small protein!
Deamidation of Asn residues
Oxidation of Cys or Met
residues
Single-chain and two-chain
forms
1.09 x 109 options are possible!
15

16. Differences between Generics and Biosimilars
1Sharma BG. EJHP Practice. 2007;13:54-56; 2Prugnaud JL. Br J Clin Pharmacol. 2007;65:619-620;
3Roger SD. Nephrology. 2006;11:341-346; 4Power DA, et al. J Pharm Pract Res. 2008;38:137-139.
Production
Unique line of live cells; it is impossible to
guarantee the identity of copies
Predictable chemical process
Identical copies are possible
Drug description
Complete description is impossible
due to the mixture of similar molecules
Full description is easy and possible
Stability
Sensitive to storage and application
conditions
More stable
Immunogenicity High potential Low potential
Structure Complicated Simple
Stability Unstable Stable
Modifications Many options Definite
Biosimilars Generics
Size Large SmallEpoetin Aspirin
Properties
16
Approx. a third of drugs in the pipeline are biotechnological
© V. Shilo

17. –Most of biologicals are capable of inducing the immune response, during which
–The antibodies to the active agent may neutralize the molecule effect
–The cross-response to own biological molecules cannot be eliminated (Schellekens H. Relationship between
biopharmaceutical immunogenicity of epoetin alfa and pure red cell aplasia. Curr Med Res Opin. 2003;19(5):433-4.)
–Clinical trials are mandatory because animal tests cannot predict the immune response in the human
body.
– Besides, it is impossible to predict the risk of neutralizing antibodies in the long-term
–The immunogenicity risk for different indications should be estimated independently and separately
Accessory substances and
impurities
Schellekens H. Nat Rev Drug Discov. 2002;1:457-62.
Immunogenicity
Biological molecule

18. Biological Safety Problems
• Different safety profiles for the original drug and biosimilar
• Possible differences in frequency of C and D type reactions
• Impact of the production process on safety
• Different safety indicators when applied for different indications
• Immunogenicity
• Significant individual variability of effects

19. Safety Monitoring Problems of Biotheraupeutics
•Each biological necessitates de novo post-marketing safety study (the analysis of
reactions under the international non-proprietary name is not permitted)
•But: the originator’s safety problems may be identified for biosimilars, too.
•Separate review of spontaneous reports does not allow
–Detecting reactions that develop in case of long use and in the remote drug application period (C and D
type reactions)
–Detecting the responses that are similar to the main disease symptoms
–Carrying out comparative assessment of the originator and the biosimilar efficacy
–Assessing change in the frequency of adverse reactions is some particular patients in dynamics
In addition, it is difficult to assess how efficient the spontaneous report method is in
identifying ‘production’ problems in long-applied drugs
•A comprehensive biosimilar safety description is possible, if the entire range of
pharmacovigilance methods is used (post-registration surveys, registers, active
monitoring etc.)
•Efficient and safe application of biosimilars necessitates planning of the efforts
aimed at detecting and mitigating the risks of their use at the development stage.

20. Pre-Registration Pre-Clinical and Clinical Trials of
Biosimilars in the European Community
• Pre-clinical trials:
– Comparative nature (identification of possible differences in the safety profile)
– The animal type selection is determined by pharmacological activity of a drug
– Pharmacodynamics study and, at least, one subacute toxicity study
• Clinical trials:
– In certain cases, a comparative pharmacodynamics and pharmacokinetics study
may be sufficient to prove ‘similarity’; however, comparative clinical trials
(normally for the main indication) are often required
– Clinical trials may be conducted using surrogate end points (e.g. dynamics for
demyelinization foci at MRI in multiple sclerosis patients in interferon clinical trials)
– Extrapolation of clinical trial findings to other indications is limited
– Remote immunogenicity study findings (during 1 year) are required for long-
applied drugs

21. European Community Biosimilar Guidelines
biotechnologically obtained proteins
htpp://www.emea.europa.eu/htsm/human/humanguidelines/multidiscipline.htm
Guideline (CHMP/437/04)
“Guideline on Biosimilar Medicinal Products”
Quality
Pre-clinical
Clinical
Insulins
Growth
hormones
Epoetin Interferons
Granulocyte-
macrophage
colony-
stimulating
factor
Funda-
mental
principles
General
require-
ments
Requirements
for certain
drugs
Monoclonal
antibodies (draft)

22. Registration Stage in EC
• Insufficiency of information on immunogenicity and the impact of
antibodies on the drug efficacy
• Lack of data on long-term application
• No data on application for the originator’s other indications
• The need in prompt detection of quality defects
• Intercheangibility problem

23. Biosimilars Risk Management – EC Experience
Risk management – the set of
pharmacovigilance operations and events
aimed at detection, determination, prevention
or mitigation of drug-related risks, including
assessment of the efficiency of these efforts
Objectives
•Post-registration assessment of the risk and
benefits ratio
•Development and implementation of risk
mitigation efforts, with benefits preservation
•Risk mitigation effort efficiency assessment
•Corrective efforts
Drug risk management plan
Part I
•− Safety Specification
•− Pharmacovigilance Plan
Part II
− Evaluation of the Need for Risk Minimization Activities
− Risk Minimization Plan
EMEA Guideline on Risk Management Systems for Medicinal Products
for Human Use (EMEA/CHMP/96268/2005
The risk management plan is part of
the biosimilar registration file

24. Observation Studies
• The possibility of safety assessment in clinical practice
• The studies are planned based on the pre-registration study data and
the originator safety information
• The number of participants depends on the anticipated frequency of
adverse reactions
– If the reaction risk is over 1%, approx. 300 participants may be sufficient to detect
at least one reaction
• To assess differences in frequency of the extremely rare reactions, it
may be necessary to maintain global registers with dozens of
thousands of patients (e.g. to detect a 4-fold increase in frequency of
fractional red-cell aplasia, it was necessary to review 20,000 patient
years of drug application, PRIMS register)

25. Adverse Drug Reaction (ADR) Detection Methods
ADR frequency
Method: %
> 10 1-10 0.1-1 0.02-0,1 0.01-0.02 0.002-0.01 < 0.002
Clinical trials ++ ++ - - - - -
Induced reporting method (in early
post-registration period)
- - - - - - -
Spontaneous report method
(locally)
- + ++ ++ ++ ++ +
WHO level spontaneous reports (72
countries)
- - + ++ ++ ++ ++
Intensive monitoring in the in-
patient’s department
- - ++ ++ + - -
Prescription monitoring - + ++ ++ + - -
Method of accounting for patient
medical records
- - ++ ++ + + -
Case/control type supervision - - + ++ ++ - -
- The method is not applied or its efficiency is low;
+ the method may be useful;
++ the method is highly suitable
© B.К. Romanov

26. Best ADR Detection Methods
Type А Type В Type С Type D
Clinical trials
(Phase III-IV)
Spontaneous report
method
Case-control type tests Case-control type tests
Cohort tests Prescription monitoring
Cohort tests with long-
term supervision
Patient record accounting
method
Prescription monitoring Case-control type tests
Morbidity and drug
consumption analysis
Spontaneous report
method
Disease register data
Patient record accounting
method
Experimental animal
trials
Patient record accounting
method
Long-term prescription
monitoring
© B.К. Romanov

27. • Drug information dissemination
• Application instructions
• Specialized educational programs
• Audio and visual information
• Drug guidelines for physicians pharmacists and patients (Patient Info
booklets)
• II. Drug application control
• Drug prescription status determination
• Designation of the persons entitled to prescribe/ dispense drugs
• Prescription/ dispensing control
• Control over the maximum quantity dispensed per prescription, limitation
on the prescription validity period (observation frequency increase)
• Patients’ informed consent (in some countries, it is applied with respect to
registered drugs)
• Maintenance of patient registers
• Cards of drug recipients
Risk Prevention Efforts

28. Amendments to the Federal Drug Circulation Law
•Harmonization of basic pharmacovigilance definitions with ICH documents;
•An option for expert companies to take part in drug safety monitoring;
•Liability of registration certificate holders for drug safety:
–Possibility to establish legal monitoring system requirements in the companies – holders
of registration certificates and sponsors of clinical trials;
–Duties to study the detected safety problems;
–Duties to reduce and prevent risks related to new safety (risk management) problems.
•Possibility to suspend application of a drug or to hold a clinical trial, if legal
pharmacovigilance requirements are not complied with.

29. Future Ways to Improve the Drug Safety Monitoring System
• Increased attention of registration applicants and drug developers to
pharmacovigilance
– Improvement of law and law enforcement practice in indemnification against
damage to life and health and emotional distress (ensuring “investment appeal”
of establishing corporate pharmacovigilance systems)
– Inclusion of requirements to provision of information on safety tools for certain
drug groups into the registration file (by analogy with the risk management plan
in EC)
– Introduction of special conditions of the permit to use certain drug classes with
a high safety risk profile in the post-registration period (statutory post-
registration intervention or observation studies, active monitoring, information
support to physicians and consumers etc.)

30. • Promotion of the drug safety monitoring system development at
pharmaceutical enterprises
– Development of the national standard on establishing the corporate
pharmacovigilance system – drug registration applicants (the requirements to
responsible persons, adverse reaction information collection, processing and
systematization system, standard operating procedures)
– Drawing attention to the problem of proper and reasonable drug use (requirements
to comprehensible presentment of information in the instruction, enabling to
disseminate patient-oriented flyers, recommendations on approaches to providing
important information on drug safety and relations with physicians)
– Establishment of the uniform schedule for filing periodical statements on generic
drugs (enabling generic manufacturers with one international non-proprietary name
to draft one joint report)
– Improvement of the electronic drug safety information processing and collection
systems - to ensure transition to the electronic receipt of PDSR and spontaneous
reports, development of adverse reaction information statistical analysis tools
Future Ways to Improve the Drug Safety Monitoring System

31. • Ensuring sufficient personnel potential of business units of healthcare
management bodies, regional centers and treatment institutions involved in
drug safety monitoring
• Development of WHO-recommended network tools for the drug safety
monitoring. Legal establishment to the status of regional monitoring centers as
expert organizations that promote adverse reaction detection, improvement of
the quality of information on them as provided to FSSH, advice to physicians on
drug safety problems
• Development of relations with WHO on early detection of drug safety problems,
improvement of pharmacovigilance information support and professional
training. Use of international data arrays on adverse reactions tо detect safety
alarms (VigiBase)
• Development of scientific and practical cooperation with foreign regulatory
authorities (including ЕМА), in particular, discussion of the opportunities to gain
access to spontaneous report bases (Eudravigilance)
Future Ways to Improve the Drug Safety Monitoring System

32. Thank you!
FEDERAL SERVICE FOR SURVEILLANCE IN HEALTHCARE
Medical Product Quality Public Control Division
Medical Product Efficacy & Safety Monitoring Department
4, Bldg 1, Slavyanskaya Square, Moscow 109074
Tel. (499)578-02-73
Facsimile: (495)698-17-73
Email: pharm@roszdravnadzor.ru