33. Topical issues of monitoring of safety of medicines. Focus on biosimilars
S.V. Glagolev, Deputy Division Head, Head, Medical Product Efficacy and SafetyMonitoring Department, Medical Product Quality Public Control Division,Federal Service for Surveillance in HealthcareV.А. Polivanov, Head, Center for Drug Efficient, Safe and Reasonable UseMonitoring at the Information and Methodical Center for Appraisal,Accounting for and Analysis of Medical Facilities (IMCAAAMF), Federal Servicefor Surveillance in HealthcareFederal Service for Surveillance in HealthcareLocal Drug SafetyMonitoring IssuesBiosimilar SafetyMonitoring Issues
Drug Safety Monitoring System inthe Russian Federation
Legal and Regulatory Framework of the Drug SafetyMonitoring•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 Approvalof the Regulations on the Federal Service for Surveillance in Healthcare and Social Development, inthe version of the Russian Government Resolution dated August 20, 2010, No. 650, On MakingAmendments to Certain Acts of the Government of the Russian Federation in connection withAdoption of the Federal Drug Circulation Law•Order of the Ministry of Healthcare and Social Development of the Russian Federation dated August26, 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 Applicationof 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 August26, 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 August26, 2010, No. 749n, On Approval of the Format of the Document Containing the Safety MonitoringResults for Medicinal Drugs to Confirm their State Registration (registered by the Ministry of Justiceof Russia on August 31, 2010, No. 18304)•National Standard, Good Clinical Practice. State Standard R 52379-2005, as approved by Order of theFederal 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 orunforeseeable adverse effects or drug interactions is established• The governmental function of drug safety monitoring is vested with the Federal Service for Surveillance inHealthcare• The timing for filing information on adverse drug effects to the Federal Service for Surveillance inHealthcare is determined (15 calendar days)• The need in and timing of filing regular drug safety reports to Federal Service for Surveillance inHealthcare was established• The option of drug state registration suspension or cancellation based on the safety monitoring results isenvisaged• The new regulation on state registration cancellation, if the applicant does not provide the informationthat may entail the need in making amendments to the registration file (within 30 days from occurrence ofsuch changes), is introduced• The requirement to file the safety monitoring results with the Ministry of Healthcare and SocialDevelopment of the Russian Federation in confirming drug registration is introduced
Drug Safety MonitoringFSSH’s computerizedinformation systemRegional drug safetymonitoring centersDQCCIMCAAANF (FSU)at FSSH1.Input of incoming information toFSSH’s computerized informationsystem (CIS) and its analysis2.Sending of information on adversedrug reactions to drug registrationapplicants3.Arranging for information appraisalat FSSH’s IMCAAAMF FSU, includingrequest for assessment of the causalrelationship as well as the opinions onlegal cases4. Arranging for quality appraisal of thedrugs that caused adverse reaction (ifnecessary)5.Coordination of operations of theregional drug safety monitoring centersas concerns investigation into theinstances of adverse reactions.6.Review of scientific publications anddecisions of foreign regulatoryauthoritiesResolutions• to modify the drug instruction• to suspend application•to withdraw the drug•to resume the drug applicationMinistry ofHealthcare ofthe Russian FederationRecommendations based onmonitoring resultsOn 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 protocolPublication of informationon resolutions of theMinistry of Healthcareand Social Development ofRussia on the website ofthe Federal Service forSurveillance in HealthcarePublication ofinformation letterson drug safetyproblemsFederal Servicefor Surveillance inHealthcare (FSSH)MedicalProduct QualityPublic ControlDivisionMedical ProductEfficacy &Safety MonitoringDepartmentRegistered drugsReports on adverseeffects, severeadverse effects,unforeseeableadverse effects,particular features ofdrug interactionRegular safetyreportsDrugs inclinical trialsReports on severeunforeseeableadverse drugreactionsAnnual drug safetyreports
Federal Drug Circulation Law dated April 12, 2010, No. 61-FZArticle 64Section 3. Pharmaceutical entities shall be obliged to notify of all instances ofside effects not specified in the drug application instructions (leaflet), оfsevere adverse drug reactions, unforeseeable adverse reactions resultingfrom application of medicinal drugs, of particular features of druginteraction with other drugs, which have been found in clinical trials and drugapplication, in such manner as established by the competent federal executiveauthority.6
Federal Drug Circulation Law dated April 12, 2010, No. 61-FZArticle 64Clause 4. For non-disclosure or concealment of the informationenvisaged in Part 3 of this Article, the persons who become awareof such information by the nature of their professional activitiesshall be liable according to Russian law.Article 19.7, Russian Administrative Procedural Code, envisages liability for non-disclosure or delay with disclosureof information (data) – the penalty for officials of RUB 300-500; for legal entities, RUB 3,000-5,000Article 32Cancellation of drug state registrationThe 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 todocuments 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, withinthe periods of time calculated from the date when the drug is registered in thecountry 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 drugregistration: 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 periodexpiry date.(order by the Ministry of Health and Social Development of the RussianFederation dated August 26, 2010, No. 757n)
Main Formats of PSUR Submitted to FSSH• ICHE2C (R1), Clinical Safety Data Management: Periodical Safety Reports forDrugs 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 onEstablishing the Drug Safety Monitoring System at Drug Manufacturers orRegistration Certificate Holders, as approved by FSSH’s Head on October 5, 2009NB! At present, FSSN finishes working on the Methodical Recommendations ondrafting of periodical drug safety reports by developers and manufacturers ofthe drugs circulating in the Russian Federation.
Changes in Registration of Adverse Reaction Reports in2009/20132009 2010 2011 2012 20130200040006000800010000120001400016000ForecastMedical careinstitutions (Regionalcenters)Pharma companiesFederal MonitoringCenterRoszdravnadzor (CA)5,95510,18212,64613,74514,940
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 formalapproach to work (reports on minor and foreseeable adverse reactions,same-type data etc.)• Incorrect assessment of severity and predictability of the reactions as wellas the causal relationship• Low quality of the significant number of reports: there is no information onthe patient’s co-morbidities, the treatment mode, the adverse reactionoutcome, and the results of instrumental tests (ideally, the scope ofinformation should approximate to the hospital discharge summary)
Spontaneous Reports: Method Limitations and Problems• Low reportability (1%-10% of detected reactions in the countries withthe 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 lengthyapplication and in the period long after the drug application onset
Post-Translation ModificationCOOHVariability in N-linked carbohydrateside chainsO-GlycosylationProteolysis at Arg-XN-terminal sequence lengthvariationNH2t-PA (Alteplase): a relatively small protein!Deamidation of Asn residuesOxidation of Cys or MetresiduesSingle-chain and two-chainforms1.09 x 109 options are possible!15
–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 betweenbiopharmaceutical 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 humanbody.– 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 separatelyAccessory substances andimpuritiesSchellekens H. Nat Rev Drug Discov. 2002;1:457-62.ImmunogenicityBiological 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 ofreactions 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 Dtype 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 dynamicsIn addition, it is difficult to assess how efficient the spontaneous report method is inidentifying ‘production’ problems in long-applied drugs•A comprehensive biosimilar safety description is possible, if the entire range ofpharmacovigilance methods is used (post-registration surveys, registers, activemonitoring etc.)•Efficient and safe application of biosimilars necessitates planning of the effortsaimed at detecting and mitigating the risks of their use at the development stage.
Pre-Registration Pre-Clinical and Clinical Trials ofBiosimilars 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 studymay 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 fordemyelinization 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 Guidelinesbiotechnologically obtained proteinshtpp://www.emea.europa.eu/htsm/human/humanguidelines/multidiscipline.htmGuideline (CHMP/437/04)“Guideline on Biosimilar Medicinal Products”QualityPre-clinicalClinicalInsulinsGrowthhormonesEpoetin InterferonsGranulocyte-macrophagecolony-stimulatingfactorFunda-mentalprinciplesGeneralrequire-mentsRequirementsfor certaindrugsMonoclonalantibodies (draft)
Registration Stage in EC• Insufficiency of information on immunogenicity and the impact ofantibodies 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 ExperienceRisk management – the set ofpharmacovigilance operations and eventsaimed at detection, determination, preventionor mitigation of drug-related risks, includingassessment of the efficiency of these effortsObjectives•Post-registration assessment of the risk andbenefits ratio•Development and implementation of riskmitigation efforts, with benefits preservation•Risk mitigation effort efficiency assessment•Corrective effortsDrug risk management planPart I•− Safety Specification•− Pharmacovigilance PlanPart II− Evaluation of the Need for Risk Minimization Activities− Risk Minimization PlanEMEA Guideline on Risk Management Systems for Medicinal Productsfor Human Use (EMEA/CHMP/96268/2005The risk management plan is part ofthe biosimilar registration file
Observation Studies• The possibility of safety assessment in clinical practice• The studies are planned based on the pre-registration study data andthe originator safety information• The number of participants depends on the anticipated frequency ofadverse reactions– If the reaction risk is over 1%, approx. 300 participants may be sufficient to detectat least one reaction• To assess differences in frequency of the extremely rare reactions, itmay be necessary to maintain global registers with dozens ofthousands of patients (e.g. to detect a 4-fold increase in frequency offractional red-cell aplasia, it was necessary to review 20,000 patientyears of drug application, PRIMS register)
• Drug information dissemination• Application instructions• Specialized educational programs• Audio and visual information• Drug guidelines for physicians pharmacists and patients (Patient Infobooklets)• 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, limitationon the prescription validity period (observation frequency increase)• Patients’ informed consent (in some countries, it is applied with respect toregistered drugs)• Maintenance of patient registers• Cards of drug recipientsRisk 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 – holdersof 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 legalpharmacovigilance requirements are not complied with.
Future Ways to Improve the Drug Safety Monitoring System• Increased attention of registration applicants and drug developers topharmacovigilance– Improvement of law and law enforcement practice in indemnification againstdamage 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 certaindrug groups into the registration file (by analogy with the risk management planin EC)– Introduction of special conditions of the permit to use certain drug classes witha high safety risk profile in the post-registration period (statutory post-registration intervention or observation studies, active monitoring, informationsupport to physicians and consumers etc.)
• Promotion of the drug safety monitoring system development atpharmaceutical enterprises– Development of the national standard on establishing the corporatepharmacovigilance system – drug registration applicants (the requirements toresponsible persons, adverse reaction information collection, processing andsystematization system, standard operating procedures)– Drawing attention to the problem of proper and reasonable drug use (requirementsto comprehensible presentment of information in the instruction, enabling todisseminate patient-oriented flyers, recommendations on approaches to providingimportant information on drug safety and relations with physicians)– Establishment of the uniform schedule for filing periodical statements on genericdrugs (enabling generic manufacturers with one international non-proprietary nameto draft one joint report)– Improvement of the electronic drug safety information processing and collectionsystems - to ensure transition to the electronic receipt of PDSR and spontaneousreports, development of adverse reaction information statistical analysis toolsFuture Ways to Improve the Drug Safety Monitoring System
• Ensuring sufficient personnel potential of business units of healthcaremanagement bodies, regional centers and treatment institutions involved indrug safety monitoring• Development of WHO-recommended network tools for the drug safetymonitoring. Legal establishment to the status of regional monitoring centers asexpert organizations that promote adverse reaction detection, improvement ofthe quality of information on them as provided to FSSH, advice to physicians ondrug safety problems• Development of relations with WHO on early detection of drug safety problems,improvement of pharmacovigilance information support and professionaltraining. Use of international data arrays on adverse reactions tо detect safetyalarms (VigiBase)• Development of scientific and practical cooperation with foreign regulatoryauthorities (including ЕМА), in particular, discussion of the opportunities to gainaccess to spontaneous report bases (Eudravigilance)Future Ways to Improve the Drug Safety Monitoring System
Thank you!FEDERAL SERVICE FOR SURVEILLANCE IN HEALTHCAREMedical Product Quality Public Control DivisionMedical Product Efficacy & Safety Monitoring Department4, Bldg 1, Slavyanskaya Square, Moscow 109074Tel. (499)578-02-73Facsimile: (495)698-17-73Email: email@example.com