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

Drug Safety Monitoring System in the Russian Federation

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.

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

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

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

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.

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)

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.

Changes in Registration of Adverse Reaction Reports in 2009/2013

2009 2010 2011 2012 20130

2000

4000

6000

8000

10000

12000

14000

16000

Forecast

Medical careinstitutions (Regionalcenters)Pharma companies

Federal MonitoringCenter

Roszdravnadzor (CA)

5,955

10,182

12,646 13,745

14,940

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)

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

Biosimilars Safety Monitoring Issues

Molecular Weight of Biologicals

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

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 Small Epoetin Aspirin

Pro

pe

rtie

s

16

Approx. a third of drugs in the pipeline are biotechnological

© V. Shilo

–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

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

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.

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

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)

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

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

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)

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

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

• 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

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.

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.)

• 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

• 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

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