EU - Regulatory Evaluation Process

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This ppt provides a brief overview of the regulatory evaluationprocess for New Applications under various types - Mutual recognition process, Decentralized procedure along with an overview of Grouping variations & Worksharing procedures.

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EU - Regulatory Evaluation Process

  1. 1. MARKETING AUTHORIZATION PROCEDUREGangavaram Pradeep
  2. 2. MARKETING AUTHORIZATION PROCEDURE• Applicant must obtain a MA either under the centralized procedure, the mutual recognitionprocedure or the decentralized procedure to market a medicinal product in more than oneMember State .CENTRALIZED PROCEDURE• The centralized procedure is compulsory for medicinal products derived from biotechnology,advanced therapy medicinal products, new active substances for certain therapeutic areas andfor orphan medicinal products.• Applicants should notify the EMA of their intention to submit a marketing authorization (MA)by submitting a letter of intent to submit and the Pre-submission request form.• The applications are validated and during validation the project team leader will, besidesreviewing the completeness of the application, consider whether any related actions arerequired e.g., in connection with GMP or GCP inspections and/ or analysis of samples.LEGAL BASIS: Regulation (EC) No 726/2004 (for centralized procedure),Regulation (EC) No 658/2007 (for imposing financial penalties for any infringement),Regulation (EC) No 507/2006 (for conditional marketing authorisations).
  3. 3. CENTRALIZED PROCEDUREApplication to EMAApplication to EMAScientific Evaluation(CHMP)Scientific Evaluation(CHMP)CHMP OpinionCHMP OpinionCompany AppealCompany AppealCHMP Second OpinionCHMP Second OpinionTransmission of CHMPOpinion to CommissionTransmission of CHMPOpinion to CommissionFinal CommissionDecisionFinal CommissionDecisionValidation10 DaysEvaluationby CHMP210 Days (+ possible “clock stop” for further information)Unfavourable Favourable60 Days60 Days15 Days15 Days52 Days
  4. 4. MUTUAL RECOGNITION PROCEDUREUnder this procedure the applicant seeks to have an existing national authorisation recognized byone or more Member States.The mutual recognition procedure involves the following stages:If agreement cannot be reached then the following stages occur:LEGAL BASIS: Directive 2001/83/EC provides the legal basis for the mutual recognition procedure.
  5. 5. DECENTRALIZED PROCEDUREUnder this procedure the RMS prepares, in consultation with CMSs, a draft assessment report. The CMSsand RMS then agree on the terms of the authorisation.If agreement can not be reached by the Member States, on the grounds of “a potential serious risk topublic health”, then a reconciliation phase occurs by CMD(h). If the matter can’t be resolved then CHMPwill arbitrate & deliver an opinion (binding opinion) that lead to a binding Commission decision.Important principles relating to the decentralised procedure are:·Assessment in a maximum of 210 days·More opportunities (compared to the mutual recognition procedure) for discussion·Opportunity to reach consensus and to close the procedure any time, if consensus is reached;and as for the mutual recognition procedure:·Harmonized labeling and package leaflets agreed during the procedure·Referral to the CMD(h) of points of disagreement between Member States·Compulsory referral (even if an application is withdrawn, a claim of serious risk to public health mustbe investigated by the CMD(h) and if necessary the CHMP).LEGAL BASIS: Directive 2001/83/EC provides the legal basis for the mutual recognition procedure.
  6. 6. PROCEDURE FOR VARIATIONS / CHANGES / SUPPLEMENTSA variation application is an application to amend the contents of the documentation used to supportan existing marketing authorization.Variations are classified into minor variations (Type IA, Type IB) and Major variations (Type II) orextensions.REGULATIONS & GUIDELINESCommission Regulation (EC) 726/2012 This EC regulation applies from 06-Aug-2012 except for theprovisions relating to unforeseen variations.Guideline (2010/C 17/01) gives a detailed information on the classification of variations.Guideline (2009/C 323/04) covers the procedures and documentation requirements .Note: Regulation (EC) No 1234/2008 replaces the former Regulations covering variations: Regulation (EC) No1084/2003 [mutual recognition/ decentralized procedures] and Regulation (EC) No 1085/2003 [centralizedprocedure].
  7. 7. CLASSIFICATION OF VARIATIONSType IA: It is a Minor variation which “has only a minimal impact or no impact at all, on thequality, safety or efficacy of the medicinal product”.Type IA – variation should be notified within 12 months following implementation ofType IAIN – variation should be notified immediately after implementation.Type II : Major variation “which is not an extension and which may have a significant impact onthe quality, safety or efficacy of the medicinal product concerned”.Type IB: Minor variation which is “neither a minor variation of type IA nor a major variation oftype II nor an extension”.Note: Type IA changes are fully defined in terms of conditions and documentation requirements. If one or moreof the conditions for a Type IA change are not met and the change is not a Type II then the variation becomes aType IB.UNFORESEEN VARIATIONS: When the proposed variation is not considered a minor variation ofType IB following the Commission classification Guideline, or has not been classified as a Type IBvariation in an Article 5 recommendation.
  8. 8. VARIATION PROCEDUREThe Marketing authorization (MA) holder needs to submit variation notification to all relevantauthorities.TYPE IA VARIATIONA Type IA variation must be submitted within the 12 month period following variationimplementation.This may be by periodic reporting (“Annual report”) which allows a MA holder to submit a single application forseveral minor Type IA variations which have been implemented during the previous 12 months.However, for some changes an immediate notification (“submitted immediately after theimplementation of the variation”) is required (Type IAIN).Type IA variations are handled according to a 30 day procedure. The HA will not perform a fullassessment but will only check for the presence of the required documentation and compliancewith conditions.
  9. 9. TYPE IB VARIATIONMUTUAL RECOGNITION PROCEDURE ( 0 - 30 Days)CENTRALIZED PROCEDURE ( 0 - 30 Days)
  10. 10. TYPE IB VARIATIONMUTUAL RECOGNITION PROCEDURE ( 0 - 30 Days)1.Notification to RMS & CMSs (Receipt Day 0) (CMSs may only comment if notification / fee notreceived)2.Validation: The RMS validates the notification. If necessary the validation period may beextended by an extra seven days to deal with an “unforeseen” variation).This may result in confirmation of Type IB status or a decision that the variation should be upgradedto a Type II Variation (MA holder then has 21 days to upgrade the application).3.Notification Evaluation: RMSs may seek an opinion from the CMSs with respect to Change in thename, pack size, introduction of DDPS, deletion of Pharmaceutical form or indication.4.Communication from RMS:If no communication, the changes may be deemed acceptable.Unfavorable Opinion: MA holder has a 30 day period to submit amended notification /deficient documents. The evaluation procedure is then repeated (Days 0-30)5.Post Acceptance Update MA within 6M from the end of the procedure.
  11. 11. TYPE IB VARIATIONCENTRALIZED PROCEDURE ( 0 - 30 Days)1.Notification to Agency and to the Rapporteur/Co-Rapporteur/CHMP members (Receipt Day 0)2.Validation: The Agency validates the notification. If necessary the validation period may beextended by an extra five days to deal with an “unforeseen” variation). Confirmation of Type IBstatus or a decision that the variation should be upgraded to a Type II variation.3.Notification Evaluation: The Agency (Rapporteur) evaluates the notification and informs the MAholder of the outcome of the procedure.4.Communication from Agency:If no communication, the changes may be deemed acceptable.Unfavorable Opinion: MA holder has a 30 day period to submit amended notification /deficient documents. The evaluation procedure is then repeated (Days 0-30)5.Post Acceptance Update MA within 6M from the end of the procedure. However, the MA holdermay implement the variation after acceptance (or deemed acceptance).
  12. 12. TYPE II VARIATIONSType II variations are major variations which require approval before implementation.The normal assessment time is 60 days (overall procedure time: 90 days). This may bereduced to a 30 day procedure (overall procedure: 30 days) for urgent variationsconcerning safety issues or, may be increased to 90 days procedure (overall proceduretime of 120 days) for variations like a change to or addition of therapeutic indicationsMUTUAL RECOGNITION PROCEDUREKey stages for the 60 day procedure include submission, Validation (within 14 days),Evaluation (upto 30 / 60 days), Outcome (60-90 days), and Post acceptance actionsCENTRALIZED PROCEDUREKey stages for the 60 day procedure include submission, Validation (within 14 days),Evaluation (upto 30 / 60 days), Outcome (60-90 days), and Post acceptance actions.
  13. 13. EXTENSIONExtension applications apply to the following types of applicationschange to the active substance;new strength;new pharmaceutical form;new route of administration.An extension application is evaluated in accordance with the same procedure appliedto the granting of the initial marketing authorisation to which it relates (Article 19 ofthe Variations Regulation).Extension applications are therefore subject to the 210 day assessment periodprovided for in Directive 2001/83/EC (IDRAC 37421) (mutual recognition/ decentralisedprocedures) or Regulation (EC) No 726/2004 (centralised procedure).An extension may only be implemented after the relevant Member State authority or,for centralised authorisations, the Commission, has amended the decision grantingthe authorisation and notified the MA holder
  14. 14. GROUPING VARIATIONSThe applicant has the option in certain circumstances to combine and submit as a singleapplication several variations relating to one or more marketing authorisations.The “Highest” type of variation in the group determines how it must be submitted.Grouping across different marketing authorisations is only allowed for Type IA variations. IfType IB or Type II variations are grouped across more than one authorisation, then theworksharing procedure must be followed.Grouping of variations not covered by the Annex may be agreed with the RMS or, forcentralized authorisations, the Agency (the MA holder is requested to give at least twomonths advance notice of a request for group considerations).The group variation is handled in the same way as the respective application type for asingle variation of the highest type. For instance, a group consisting of an extension and amajor variation of Type II will be handled as an extension application, while a groupconsisting of a minor variations of Type IB and Type IA will be handled as a Type IBnotification
  15. 15. WORKSHARINGUnder the worksharing procedure, one authority (Reference Authority) examines thevariation on behalf of the other concerned authorities (Article 20 of the VariationsRegulation).This optional procedure is initiated at the request of the MA holder. A single worksharingapplication may be submitted in cases where the same Type IB or the same Type IIvariation, or the same group of variations, affects more than one marketing authorisationowned by the same MA holder.A group of variations, included in a worksharing application, may not contain an extensionapplication. However a group may contain Type IA changes if these are included in a groupcontaining also Type IB or Type II variations.The MA holder is requested to give at least three months advance notice of their intentionto submit a variation or group of variations to be subject to a worksharing procedure.The procedure follows the same timelines as applied for Type II variations and is usuallybased on a 60 day assessment period.The 60 day period may be reduced for urgent situations, or may be extended to 90 dayswhere a variation concerning a change to or addition of therapeutic indications forms partof the worksharing procedure.

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