MARKETING AUTHORIZATION PROCEDURE

Gangavaram Pradeep

MARKETING AUTHORIZATION PROCEDURE

• Applicant must obtain a MA either under the centralized procedure, the mutual recognition procedure or the decentralized procedure to market a medicinal product in more than one Member 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 and for 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, besides reviewing the completeness of the application, consider whether any related actions are required 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).

CENTRALIZED PROCEDURE

Application to EMAApplication to EMA

Scientific Evaluation (CHMP)

Scientific Evaluation (CHMP)

CHMP OpinionCHMP Opinion

Company AppealCompany Appeal

CHMP Second OpinionCHMP Second OpinionTransmission of CHMP Opinion to CommissionTransmission of CHMP Opinion to Commission

Final Commission Decision

Final Commission Decision

Validation

10 Days

Evaluation by CHMP

210 Days (+ possible “clock stop” for further information)

Unfavourable Favourable

60 Days

60 Days

15 Days

15 Days

52 Days

MUTUAL RECOGNITION PROCEDURE

Under this procedure the applicant seeks to have an existing national authorisation recognized by one 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.

DECENTRALIZED PROCEDURE

Under this procedure the RMS prepares, in consultation with CMSs, a draft assessment report. The CMSs and 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 to public health”, then a reconciliation phase occurs by CMD(h). If the matter can’t be resolved then CHMP will 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 must be 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.

PROCEDURE FOR VARIATIONS / CHANGES / SUPPLEMENTS

A variation application is an application to amend the contents of the documentation used to support an existing marketing authorization.

Variations are classified into minor variations (Type IA, Type IB) and Major variations (Type II) or extensions.

REGULATIONS & GUIDELINES

Commission Regulation (EC) 726/2012 This EC regulation applies from 06-Aug-2012 except for the provisions 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) No 1084/2003 [mutual recognition/ decentralized procedures] and Regulation (EC) No 1085/2003 [centralized procedure].

CLASSIFICATION OF VARIATIONS

Type IA: It is a Minor variation which “has only a minimal impact or no impact at all, on the quality, safety or efficacy of the medicinal product”.

Type IA – variation should be notified within 12 months following implementation of Type IAIN – variation should be notified immediately after implementation.

Type II : Major variation “which is not an extension and which may have a significant impact on the 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 of type II nor an extension”.

Note: Type IA changes are fully defined in terms of conditions and documentation requirements. If one or more of the conditions for a Type IA change are not met and the change is not a Type II then the variation becomes a Type IB.

UNFORESEEN VARIATIONS: When the proposed variation is not considered a minor variation of Type IB following the Commission classification Guideline, or has not been classified as a Type IB variation in an Article 5 recommendation.

VARIATION PROCEDURE

The Marketing authorization (MA) holder needs to submit variation notification to all relevant authorities.

TYPE IA VARIATIONA Type IA variation must be submitted within the 12 month period following variation implementation. This may be by periodic reporting (“Annual report”) which allows a MA holder to submit a single application for several minor Type IA variations which have been implemented during the previous 12 months.

However, for some changes an immediate notification (“submitted immediately after the implementation of the variation”) is required (Type IA IN).

Type IA variations are handled according to a 30 day procedure. The HA will not perform a full assessment but will only check for the presence of the required documentation and compliance with conditions.

TYPE IB VARIATION

MUTUAL RECOGNITION PROCEDURE ( 0 - 30 Days)

CENTRALIZED PROCEDURE ( 0 - 30 Days)

TYPE IB VARIATION

MUTUAL RECOGNITION PROCEDURE ( 0 - 30 Days)

1.Notification to RMS & CMSs (Receipt Day 0) (CMSs may only comment if notification / fee not

received)

2.Validation: The RMS validates the notification. If necessary the validation period may be

extended 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 upgraded

to 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 the

name, 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.

TYPE IB VARIATION

CENTRALIZED 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 be

extended by an extra five days to deal with an “unforeseen” variation). Confirmation of Type IB

status 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 MA

holder 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 holder

may implement the variation after acceptance (or deemed acceptance).

TYPE II VARIATIONS

Type II variations are major variations which require approval before implementation.

The normal assessment time is 60 days (overall procedure time: 90 days). This may be reduced to a 30 day procedure (overall procedure: 30 days) for urgent variations concerning safety issues or, may be increased to 90 days procedure (overall procedure time of 120 days) for variations like a change to or addition of therapeutic indications

MUTUAL RECOGNITION PROCEDURE

Key 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

CENTRALIZED PROCEDURE

Key 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.

EXTENSION

Extension 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 applied to the granting of the initial marketing authorisation to which it relates (Article 19 of the Variations Regulation).

Extension applications are therefore subject to the 210 day assessment period provided for in Directive 2001/83/EC (IDRAC 37421) (mutual recognition/ decentralised procedures) 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 granting the authorisation and notified the MA holder

GROUPING VARIATIONS

The applicant has the option in certain circumstances to combine and submit as a single application 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. If Type IB or Type II variations are grouped across more than one authorisation, then the worksharing procedure must be followed.

Grouping of variations not covered by the Annex may be agreed with the RMS or, for centralized authorisations, the Agency (the MA holder is requested to give at least two months advance notice of a request for group considerations).

The group variation is handled in the same way as the respective application type for a single variation of the highest type. For instance, a group consisting of an extension and a major variation of Type II will be handled as an extension application, while a group consisting of a minor variations of Type IB and Type IA will be handled as a Type IB notification

WORKSHARING

Under the worksharing procedure, one authority (Reference Authority) examines the variation on behalf of the other concerned authorities (Article 20 of the Variations Regulation).

This optional procedure is initiated at the request of the MA holder. A single worksharing application may be submitted in cases where the same Type IB or the same Type II variation, or the same group of variations, affects more than one marketing authorisation owned by the same MA holder.

A group of variations, included in a worksharing application, may not contain an extension application. However a group may contain Type IA changes if these are included in a group containing also Type IB or Type II variations.

The MA holder is requested to give at least three months advance notice of their intention to 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 usually based on a 60 day assessment period.

The 60 day period may be reduced for urgent situations, or may be extended to 90 days where a variation concerning a change to or addition of therapeutic indications forms part of the worksharing procedure.