Template - Rapporteur variation assessment report by q4tg9N

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									Rapporteur <type II> <group of> variation<s>
assessment report



<Invented name>



International non-proprietary name: <INN>



Procedure no. EMEA/H/C/<xxx>



Marketing authorisation holder:




Rapporteur:

<Appointed rapporteur for the
WS procedure:>

Date of this report:

Deadline for comments:
ADMINISTRATIVE INFORMATION
Rapporteur’s contact person:                     Name
                                                 Tel:
                                                 Fax:
                                                 Email:

EMA Product Team Leader:                         Name
                                                 Tel:
                                                 Fax:
                                                 Email:
Names of the Rapporteur assessors:               Quality:
(Internal and external)                          Name(s)
                                                 Tel:
                                                 Fax:
                                                 Email:

                                                 Non-clinical:
                                                 Name(s)
                                                 Tel:
                                                 Fax:
                                                 Email:

                                                 Clinical:
                                                 Name(s)
                                                 Tel:
                                                 Fax:
                                                 Email:

                                                 Safety:
                                                 Name(s)
                                                 Tel:
                                                 Fax:
                                                 Email:




Rapporteur <type II> <group of> variation<s> assessment report
<Product name>                                                   Page 2/17
Rev11.11
1. Recommendation
Based on the review of the data on <quality>, <safety> <and efficacy>, the Rapporteur considers that
the <group of> variation<s> <, following a worksharing procedure according to Article 20 of
Commission Regulation (EC) No 1234/2008> for <medicinal product invented name> (<INN>), in the
treatment of <indication>, for the following proposed change <scope of variation>,

[Include for the scope the one from the CHMP ToD]

<is approvable. <could be approvable provided that satisfactory answers are given to the "other
concerns" as detailed in section 4. Failure to resolve other concerns may render the application
unapprovable>. >.

<is not approvable since "major objections" have been identified, which preclude a recommendation
for marketing authorisation at the present time. The details of these major objections are provided
below and should be addressed in writing <and in an oral explanation.> <In addition, satisfactory
answers must be given to the "other concerns" as detailed in section 4.>

<In addition, the Rapporteur has recommended <conditions for marketing authorisation> <and>
revisions to the proposed product information (see Annex I).>

<Grounds for refusal:>

[Include grounds for non-acceptance in case of negative opinion]




Rapporteur <type II> <group of> variation<s> assessment report
<Product name>                                                                                     Page 3/17
Rev11.11
2. Scientific discussion

2.1. Introduction

Introduction – Brief statement on medicinal product and
pharmacotherapeutic action
Rationale/background for the proposed change; if variation results from
previous assessment request (e.g. FUM, PSUR, Art. 46 of the paediatric
regulation) include summary of previous discussion and conclusion.
In general, the applicable section(s) and subheadings of the new MAA AR
template should be followed for the quality, nonclinical and clinical
aspects.Information on the following parts should be included with
subheadings as applicable:




Rapporteur <type II> <group of> variation<s> assessment report
<Product name>                                                   Page 4/17
Rev11.11
2.2. <Quality aspects>

2.3. <Non-clinical aspects>

2.3.1. <Methods – analysis of data submitted>

2.3.2. <Results>

2.3.3. <Discussion>

2.4. <Clinical pharmacology aspects>

2.4.1. <Methods – analysis of data submitted>

2.4.2. <Results>

2.4.3. <Discussion>

2.5. <Clinical efficacy aspects>

2.5.1. <Methods – analysis of data submitted>

2.5.2. <Results>

2.5.3. <Discussion>

2.6. <Clinical safety aspects>

2.6.1. <Methods – analysis of data submitted>

2.6.2. <Results>

2.6.3. <Discussion>

[Note: in case of composite opinion on grouping and/or worksharing, the
outcome of each variation in the group for each product should be
reflected in the scientific discussion. If a variation in the group has
been withdrawn, it should also be reflected in the discussion.]

2.7. <Pharmacovigilance system>

<The Rapporteur considers that the Pharmacovigilance system as described by the applicant fulfils the
requirements and provides adequate evidence that the applicant has the services of a qualified person
responsible for pharmacovigilance and has the necessary means for the notification of any adverse
reaction suspected of occurring either in the Community or in a third country.>

<The Rapporteur considers that the Pharmacovigilance system as described by the applicant has the
following deficiencies:<list the deficiencies>

<Provided that the deficiencies are rectified prior to the applicant placing the medicinal product on the
market, the CHMP may consider that the Pharmacovigilance system will fulfil the requirements. The


Rapporteur <type II> <group of> variation<s> assessment report
<Product name>                                                                                    Page 5/17
Rev11.11
applicant must ensure that the system of pharmacovigilance is in place and functioning before the
product is placed on the market>

2.8. <Risk management plan>

<The MAH submitted a<n> <updated> Risk Management Plan within this variation procedure < which
included a risk minimisation plan>.>

<Based on the safety conclusions, the CHMP requested the submission of a<n> <updated> Risk
Management Plan <which included a risk minimisation plan> within this procedure.>

Table 1. Summary of the risk management plan (including the changes related to the application
presented highlighted)

Safety issues                             Agreed pharmacovigilance    Agreed risk minimisation
                                          activities                  activities




< The Rapporteur, having considered the data submitted, was of the opinion that <routine
pharmacovigilance was adequate to monitor the safety of the product.>

Or

<no new pharmacovigilance activities in addition to those already being performed were needed to
monitor the safety of the product.>

Or
<the below pharmacovigilance activity(ies) in addition to the use of routine pharmacovigilance are
needed to investigate further some of the safety concerns:>

List all additional PhV activities that were requested by the CHMP,
such as PASS, or any other studies requested by the CHMP in the context
of an important safety issue in the RMP. Please note that such measures
could in addition be included as a condition to the MA in Annex II. In
case of an Annex II condition, please clarify/elaborate this in the B/R
discussion:

Description                                                                          Due date




< <These/this> pharmacovigilance <activity/activities> <is/are> in addition to those already
requested.>

plus either


Rapporteur <type II> <group of> variation<s> assessment report
<Product name>                                                                                 Page 6/17
Rev11.11
<No additional risk minimisation activities were required beyond those included in the product
information.>

or

<The following additional risk minimisation activities were required>

•        (list all of them).
In cases there are minor outstanding issues for the agreed RMP that
should be addressed within the next version update:

<In addition, the Rapporteur considers that the MAH should take the following minor points into
consideration when an update of the Risk management Plan is submitted :>

[In cases where the RMP was not submitted as part of the procedure and
it is deemed necessary to update it during the procedure, at least the
summary table of the RMP should be updated and the following sentence
should be included in the CHMP AR:]

<The MAH is requested to submit an updated version of the RMP by xxx in order to properly reflect the
following measures:>

[In cases where there is no RMP for a specific product and the need for
an RMP has been identified, the MAH can be requested to submit an RMP
and the following sentence should be included in the CHMP AR:]

<The MAH is requested to submit an RMP by xxx in order to properly reflect the safety profile of the
product and the following important safety concerns:>

2.9. Changes to the product information

[Changes to the Product Information should be described presented as
new text underlined and deleted text marked as strikethrough. However,
if the changes are too extensive, changes to the concerned PI sections
can be summarised and reference to the attachment can be made.

<The MAH proposed the following changes to the Product Information (PI):>

<The Rapporteur requests <for the reasons discussed in detail above.>     [refer to the
scientific discussion above]/ <the following <additional> amendments to the Product
Information:> [Include brief description of the paragraphs where further
amendments to the proposed changes are requested and the reasons for
these requests.]

<Changes were also made to the PI to bring it in line with the current Agency/QRD template, SmPC
guideline and other relevant guideline(s) [e.g. Excipients guideline, storage conditions, Braille, etc…],
which were reviewed <by QRD> and accepted by the Rapporteur.>

 [If user consultation results were submitted within this procedure,
please discuss here as well.]

<The results of the user consultation with target patient groups on the package leaflet submitted by
the MAH show that the package leaflet meets the criteria for readability as set out in the Guideline on
the readability of the label and package leaflet of medicinal products for human use.>



Rapporteur <type II> <group of> variation<s> assessment report
<Product name>                                                                                     Page 7/17
Rev11.11
<The results of the user consultation with target patient groups on the package leaflet submitted by
the MAH show that the package leaflet does not yet meet the criteria for readability as set out in the
Guideline on the readability of the label and package leaflet of medicinal products for human use. The
applicant will address the following minor issues concerning the user consultation with target patient
group population on the package leaflet.>

<No full user consultation with target patient groups on the package leaflet has been performed on the
basis of a bridging report making reference to <name(s) of product(s)>. The bridging report submitted
by the applicant has been found <acceptable> <unacceptable>.>

[Only to be included if a DHPC is agreed with this variation:]

2.10. <Direct healthcare professional communication>

<The Rapporteur considers that a Direct Healthcare Professional Communication (DHPC) is needed to
communicate on [insert brief summary of issue for communication].>

[Details of target audience of DHPC to be summarised.]

<The MAH should agree the translations and local specificities of the DHPC with national competent
authorities. The DHPC should be sent [insert the agreed DHPC dissemination date, e.g. <upon receipt
of the Commission Decision with the revised SmPC with the changes highlighted>] to [insert target
audience]. >

[Following paediatric sections on significance and conformity only to
be included if applicable for this variation:]

2.11. <<Significance> <Non-conformity> of paediatric studies>

[ATTENTION, IF A PAEDIATRIC VALIDATION HAS OCCURRED FOR THIS VARIATION
SUBMISSION OR IF THIS SUBMISSION INCLUDES A PAEDIATRIC STUDY MENTIONED
IN THE PIP, PLEASE USE RELEVANT SECTION ON PAEDIATRIC FROM INITIAL CHMP
AR & GUIDANCE, IN CASE CHMP DENIED CONFORMITY OR SIGNIFICANCE IS
APPLICABLE]

3. Overall conclusion and impact on the benefit/risk balance
[Include here a critical review of provided data underlining the
variation request and its impact on the benefit risk balance of the
product.]
Note regarding Obligation to complete post-authorisation measures:
In a limited number of data that are considered as “key” to the benefit
risk balance may be requested as a condition of the MA. In case issues
have been identified for inclusion in Annex II as conditions, use the
following statement. Any measure identified as a condition needs to be
well motivated in the CHMP AR, notably the need for a condition should
be explained in the context of a positive benefit/risk balance.

<The Rapporteur considers the following measures necessary <to address the nonclinical issues> <to
address the issues related to pharmacology> <to address issues related to efficacy> <to address
issues related to safety>:>


Rapporteur <type II> <group of> variation<s> assessment report
<Product name>                                                                                   Page 8/17
Rev11.11
[In case of safety-related requests by the CHMP (i.e. cumulative safety
review to be submitted), please include the following sentence:]

<In addition, the Rapporteur considered that the applicant should submit the following safety data
<within X months> <the next PSUR>:>

[Note: in case of composite opinion on grouping and/or worksharing, the
outcome of each variation in the group for each product should be
reflected in the scientific discussion. If a variation in the group has
been withdrawn, it should also be reflected in the discussion.]
PSURs: Specify requirements only if different from the normal PSUR
cycle.

<The Rapporteur recommends that the MAH will continue to submit <6 monthly> / <yearly> PSURs.>

<The Rapporteur recommendation is subject to the following new condition<s>: >

<The Rapporteur is of the opinion that the following obligation has been fulfilled, and therefore
recommends its deletion from the Annex II:>

Conditions or restrictions with regard to the safe and effective use of the medicinal product

Additional (beyond product literature) risk minimisation activities to
be fulfilled by the MAH should be listed here.
In case of additional risk minimisation activities (e.g. controlled
distribution, educational material, pregnancy prevention programmes)
are proposed beyond those addressed in the product information, these
should be listed here and, as required to ensure correct implementation
by the Member States, also in an Annex IV addressed to the Member
States. Any exception to this rule (e.g. set up of surveillance
programmes in only a few MS) should be discussed and reflected in the
CHMP AR.

<Obligation to complete post-authorisation measures>

The MAH shall complete, within the stated timeframe, the following measures:

Description                                                                            Due date




Conditions or restrictions with regard to the safe and effective use of the medicinal product
to be implemented by the member states.

Actual risk minimisation activities to be implemented by the Member
States should be listed here. These should mirror the information under
the section above, unless there are risk minimisation activities
specific to single Member States.



Rapporteur <type II> <group of> variation<s> assessment report
<Product name>                                                                                      Page 9/17
Rev11.11
This annex should be provided for whenever there are ‘Conditions or
restrictions with regard to the safe and effective use of the medicinal
product’ specified in Annex IIB (e.g. controlled distribution,
educational material, pregnancy prevention programmes) that require
Member States to ensure their correct implementation. Any exception to
this rule (e.g. set up of surveillance programmes in only a few MS)
should be discussed and reflected in the CHMP AR but not mentioned
here.

<Paediatric data>

[ATTENTION, IF A PAEDIATRIC VALIDATION HAS OCCURRED FOR THIS VARIATION
SUBMISSION OR IF THIS SUBMISSION INCLUDES A PAEDIATRIC STUDY MENTIONED
IN THE PIP, PLEASE USE RELEVANT SECTION ON PAEDIATRIC RECOMMENDATION
FROM INITIAL CHMP AR & GUIDANCE]

4. Request for supplementary information

4.1. <Major objections>

Definitions of questions
“Major objections”, preclude a recommendation to the variation to the
term of the marketing authorisation. In principle, one major objection
may entail more than one question and the use of bullet points or
subheadings is encouraged. It is vital that the structure and content
of a major objection are clear and understandable to the reader.
Detailed comments may be necessary along with a reference to guidance
documents
Ideally, the objection should include a clarification as to what kind
of response/action by the applicant could be considered to solve the
problem.
“Other concerns”, may affect the proposed conditions to the variation
to the term of the marketing authorisation and product information.
The wording of the objections and concerns should clearly provide the
scientific rationale for the issues raised.

<Quality aspects>

<Deficiencies arising from concerns over the confidential (ASM - Active
Substance Manufacturer restricted) part of the DMF are mentioned in
annex II (this annex is not supplied to the MAH). These concerns will
be conveyed in confidence to the holder of the DMF.>

<Non-clinical aspects>

<Clinical aspects>



Rapporteur <type II> <group of> variation<s> assessment report
<Product name>                                                   Page 10/17
Rev11.11
4.2. <Other concerns>

<Quality aspects>

<Non-clinical aspects>

<Clinical aspects>

5. <Rapporteur’s assessment of MAH responses to RSI>

6. <Updated overall conclusion and impact on the benefit-
risk balance>
[Include here an updated/consolidated critical review of provided data
(initial submission and responses to RSI(s)) underlining the variation
request and its impact on the benefit risk balance of the product.]
Please also updated section 1 Recommendation.
Note regarding Obligation to complete post-authorisation measures:
In a limited number of data that are considered as “key” to the benefit
risk balance may be requested as a condition of the MA. In case issues
have been identified for inclusion in Annex II as conditions, use the
following statement. Any measure identified as a condition needs to be
well motivated in the CHMP AR, notably the need for a condition should
be explained in the context of a positive benefit/risk balance.
<The Rapporteur considers the following measures necessary <to address the nonclinical issues> <to
address the issues related to pharmacology> <to address issues related to efficacy> <to address
issues related to safety>:>

[In case of safety-related requests by the CHMP (i.e. cumulative safety
review to be submitted), please include the following sentence:]

<In addition, the Rapporteur considered that the applicant should submit the following safety data
<within X months> <the next PSUR>:>

[Note: in case of composite opinion on grouping and/or worksharing, the
outcome of each variation in the group for each product should be
reflected in the scientific discussion. If a variation in the group has
been withdrawn, it should also be reflected in the discussion.]
PSURs: Specify requirements only if different from the normal PSUR
cycle.

<The Rapporteur recommends that the MAH will continue to submit <6 monthly> / <yearly> PSURs.>

<The Rapporteur recommendation is subject to the following new condition<s>: >

<The Rapporteur is of the opinion that the following obligation has been fulfilled, and therefore
recommends its deletion from the Annex II:>




Rapporteur <type II> <group of> variation<s> assessment report
<Product name>                                                                                  Page 11/17
Rev11.11
Conditions or restrictions with regard to the safe and effective use of the medicinal product

Additional (beyond product literature) risk minimisation activities to
be fulfilled by the MAH should be listed here.
In case of additional risk minimisation activities (e.g. controlled
distribution, educational material, pregnancy prevention programmes)
are proposed beyond those addressed in the product information, these
should be listed here and, as required to ensure correct implementation
by the Member States, also in an Annex IV addressed to the Member
States. Any exception to this rule (e.g. set up of surveillance
programmes in only a few MS) should be discussed and reflected in the
CHMP AR.

<Obligation to complete post-authorisation measures>

The MAH shall complete, within the stated timeframe, the following measures:

Description                                                                    Due date




Conditions or restrictions with regard to the safe and effective use of the medicinal product
to be implemented by the member states.

Actual risk minimisation activities to be implemented by the Member
States should be listed here. These should mirror the information under
the section above, unless there are risk minimisation activities
specific to single Member States.
This annex should be provided for whenever there are ‘Conditions or
restrictions with regard to the safe and effective use of the medicinal
product’ specified in Annex IIB (e.g. controlled distribution,
educational material, pregnancy prevention programmes) that require
Member States to ensure their correct implementation. Any exception to
this rule (e.g. set up of surveillance programmes in only a few MS)
should be discussed and reflected in the CHMP AR but not mentioned
here.

<Paediatric data>

[Attention, if a paediatric validation has occurred for this variation
submission or if this submission includes a paediatric study mentioned
in the PIP, please use relevant section on Paediatric REcommendation
from initial CHMP AR & Guidance]




Rapporteur <type II> <group of> variation<s> assessment report
<Product name>                                                                        Page 12/17
Rev11.11
<Annex I: Proposed changes to the <SmPC>, <PL>,
Labelling> annoted with the Rapporteur’s comments after
each section>




Rapporteur <type II> <group of> variation<s> assessment report
<Product name>                                                   Page 13/17
Rev11.11
<Annex II>:

APPENDIX - QRD CHECKLIST FOR THE REVIEW OF USER
TESTING RESULTS

PRODUCT INFORMATION

Name of the medicinal product:

Name and address of the applicant:

Name of company which has performed
the user testing:

Type of Marketing Authorisation
Application:

Active substance:

Pharmaco-therapeutic group

(ATC Code):

Therapeutic indication(s):

Orphan designation                                          yes   no

Rapporteur/CoRapporteur




- Full user testing report provided                                    yes       no

- Bridging report provided                                             yes       no

- Grounds for bridging based on a sound justification:

            extensions for the same route of administration
            ref to test on same class of medicinal product
            ref to test with same safety issues
           other (specify):

- Is the justification for bridging acceptable?                        yes       no

- Is the justification for not submitting a report acceptable?         yes       no

Reasons ___________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________




Rapporteur <type II> <group of> variation<s> assessment report
<Product name>                                                               Page 14/17
Rev11.11
1.         TECHNICAL ASSESSMENT

1.1        Recruitment


           Is the interviewed population acceptable?                           yes            no
                                                                                no information
Comments/further details:



1.2        Questionnaire


           Is the number of questions _______ sufficient?                      yes            no
                                                                                no information

           Questions cover significant (safety) issues for the PL concerned?    yes           no
                                                                                no information
Comments/further details:




1.3        Time aspects


           Is the time given to answer acceptable?                             yes            no
                                                                                no information

           Is the length of interview acceptable?                              yes            no
                                                                                no information
Comments/further details:




1.4        Procedural aspects


           Rounds of testing including pilot _______                           yes            no
                                                                                no information
Comments/further details:




1.5        Interview aspects


           Was the interview conducted in well structured/organised manner?    yes            no
                                                                                no information
Comments/further details:




Rapporteur <type II> <group of> variation<s> assessment report
<Product name>                                                                             Page 15/17
Rev11.11
2.         EVALUATION OF RESPONSES

2.1        Evaluation system


           Is the qualitative evaluation of responses acceptable?               yes            no
                                                                                 no information


           Does the evaluation methodology satisfy the minimum prerequisites?   yes            no
                                                                                 no information
Comments/further details:



2.2        Question rating system


           Is the quantitative evaluation of responses acceptable?              yes            no
                                                                                 no information
Comments/further details:




3.         DATA PROCESSING

           Are data well recorded and documented?                               yes            no
                                                                                 no information
Comments/further details:




4.         QUALITY ASPECTS

4.1        Evaluation of diagnostic questions


           Does the methodology follow Readability guideline Annex?             yes            no
                                                                                 no information

       Overall, each and every question meets criterion of 81% correct answers (e.g. 16 out of 20
        participants)                                                        yes               no
                                                                              no information
Comments/further details:



4.2        Evaluation of layout and design


           Follows general design principles of Readability guideline           yes           no

           Language includes patient friendly descriptions                      yes           no

           Layout navigable                                                     yes           no

           Use of diagrams acceptable                                           yes           no


Rapporteur <type II> <group of> variation<s> assessment report
<Product name>                                                                              Page 16/17
Rev11.11
Comments/further details:




5.         DIAGNOSTIC QUALITY/EVALUATION

           Have any weaknesses of the PL been identified?                           yes           no

           Have these weaknesses been addressed in the appropriate way?             yes           no

Comments/further details:




6.         CONCLUSIONS

           Have the main objectives of the user testing been achieved?   yes              no

           Is the conclusion of applicant accurate?                      yes              no

           Overall impression of methodology                             positive         negative

           Overall impressions of leaflet structure                      positive         negative

CONCLUSION/OVERVIEW




Rapporteur <type II> <group of> variation<s> assessment report
<Product name>                                                                                  Page 17/17
Rev11.11

								
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