MHRA has published
updated guidance on pharmacovigilance procedures on 01 September 2020 and new
rules will be effective from January 2021 (post-Brexit transition period comes
to an end this year).
1.
General Approach to the operation of pharmacovigilance
This document
outlines the submission requirements of pharmacovigilance data from 01 January
2021. There will be some different requirements for products placed on the
market in the UK with respect to Great Britain (England, Wales and Scotland)
and Northern Ireland. Products placed on the market in Northern Ireland will
need to be in line with EU legislation and follow EU requirements.
The Marketing
Authorization Holder (MAH) of products authorized
in Great Britain need to follow pharmacovigilance data submission requirements
as per MHRA.
- UK
and non-UK Individual Case Safety Reports (ICSRs)
- Periodic
Safety Update Reports (PSURs)
- Risk
Management Plans (RMPs)
- Post-Authorization
Safety Studies (PASS) protocols and final study report
The Good
Vigilance Practices (GVP) modules will remain in force but MHRA will publish a
guidance note on the exceptions and modifications to the EU guidance on good
vigilance practices in due course.
For medicines
authorized to be sold or supplied in Northern Ireland information will need to
be submitted according to EU requirements.
For
medicines which are the subject of a UK MA covering both Great Britain and
Northern Ireland, information will need to be submitted in accordance with
requirements for both Great Britain and the EU, as appropriate.
MHRA may ask
historical data for assessment purpose.
2.
Actions for submitting and receiving ICSRs
Submission
of all UK ICSRs (serious and non-serious) and serious ICSRs from other
countries via the new MHRA Gateway or/ICSR Submissions portal which have been
developed.
MAH can
register on the MHRA-Gateway and/or ICSR Submissions portal to enable
configuration for their systems prior to 1 January 2021.
For products
placed on the market in Northern Ireland MAH will need to submit ICSRs
according to EU requirements to the Eudravigilance database.
3. Signal
detection
MHRA will
not require MAH to conduct signal detection against MHRA database. MAH also
obliged to notify MHRA of signals arising from any data source. From 1 January
2021 this also includes standalone signal notifications submitted by MAH to the
EMA that are relevant to MAH products as well as signals raised by the EMA.
For products
placed on the NI market, MAH additionally needs to report to the EMA those
safety signals that are considered to meet the definition of an emerging safety
issue (see GVP-Module IX Signal Management).
From 1
January 2021 the MHRA will carry out assessment of signals and issue decisions
for both signals identified by the MHRA and those highlighted internationally.
Notify MHRA about
emerging safety issues within 3 working days after establishing that a signal
or a safety issue from any source meets the definition of an emerging safety
issue.
4. Risk
Management Plans (RMPs)
The MHRA
will continue to accept EU versions of the RMP. On scenario where specific request
made by MHRA then information to be included this may need to be provided in a
specific annex.
For CAPs the
current approved version of the RMP should be included in the initiating
sequence as part of the conversion process.
RMPs and
updates to RMPs for products authorized to be sold or supplied in the UK should
be submitted to the MHRA, via the appropriate variation procedure.
5.
Periodic Safety Update Reports (PSURs)
5.1 PSURs
submitted after 1 January 2021
The MHRA will continue to accept EU versions of the PSUR, but
where the MHRA has made a specific request for information or where there is
UK-specific information relevant to the benefit/ risk assessment this should be
included in a specific annex.
MHRA may develop their own submission requirements and
develop a list of UK reference dates, but until this happens the EU reference
date (EURD) list should be followed and PSURs, with submission dates after 1
January 2021, should be submitted to the UK at the same time as submission to
the EU.
All PSURs, for products which are the subject of a UK MA,
with the same active/combination, should be submitted as part of the same
procedure. The content and format will remain the same as currently required in
the EU, and the expectation is that the same PSUR will be submitted to the MHRA
as to the EU.
Unless the
marketing authorization specifies differently, PSURs for actives/combinations
not currently on the EURD list and therefore not subject to the single
assessment process should be submitted to the MHRA, at least six monthly during
the first 2 years following placing on the market, once a year for the
following 2 years and every 3 years after that.
MHRA will issue the outcomes of assessments shortly after
publication of the EU assessment, at the latest, in order to maintain harmonization
with the submission requirements on the EURD list. submission requirements,
where appropriate.
MHRA has developed their own submission portal for PSURs
which will be ready for use from 1 January 2021. More detailed requirements for
submission will be issued but PSURs can be submitted to the portal in PDF or
Word or as part of a zip file format. PSUR submissions will not be
required as part of the CTD lifecycle in the UK and should not be submitted as
part of the initiating sequence in the conversion process for centrally authorized
to Great Britain MAs.
A fee of
£890 will be payable for the assessment of PSURs for actives/ combinations
currently listed on the EURD (or future UK reference date list) which are
submitted to the MHRA. There will be a reduction to £445 for each PSUR where
more than one PSUR is involved in the procedure.
Following
assessment, MHRA will publish the outcome of PSUR assessment procedures
including any amendments to the SPC and PL wording. No further fee will be
payable for the amendment of the product information as a result of the UK
assessment which will generally be made by a Type IA variation.
For Great
Britain-only MAs the PSUR should be submitted to the MHRA system.
For products authorized to be sold or supplied in Northern
Ireland, PSURs should be submitted in line with EU requirements and submitted
to the EMA via the EU PSUR repository. The outcomes from the EU procedure
should be implemented.
PSURs for UK
MAs covering both Great Britain and Northern Ireland will need to be submitted
to both the MHRA and EMA.
5.2 PSURs
submitted before 1 January 2021
For Great
Britain-only MAs where a PSUR has been submitted before 1 January 2021 but the
EU single-assessment procedure has not been concluded, MHRA will assess the
PSUR considering any relevant information, including any EU decision and may
request further information, where appropriate, in order to conclude the
assessment.
Where the
PSUR is for a product authorized by a UK MA, in respect to both Great Britain
and Northern Ireland the procedure will continue in line with the
single-assessment procedure.
Where the
assessment has been concluded but the outcome not implemented before 1 January
2021, the MHRA will take the necessary steps to implement the outcome.
6. Post
Authorisation Safety Studies (PASS)
6.1 PASS
protocols and results submitted after 1 January 2021
For PASS where the study is a condition of the UK MA, prior
to the start of the study the draft protocol should be submitted to the MHRA
and will be assessed in line with usual practices. Where the MA extends to
Northern Ireland or is an Northern Ireland only MA the draft study protocol
should also be submitted to the Pharmacovigilance Risk Assessment Committee
(unless the study is only to be conducted in the UK at the request of the
MHRA).
For all
PASSs that are non-interventional, that are either voluntary or a condition of
the MA and that involve collection of safety data from patients/healthcare
professionals MAH should send the final study reports to the MHRA for
assessment
MAH should
submit the final study report (and abstract of study results) to the MHRA.
Where the MA extends to Northern Ireland or is a Northern Ireland only MA the
study report should also be submitted to the Pharmacovigilance Risk Assessment
Committee (unless the study was only conducted in the UK at the request of the
MHRA).
The final
study report should be submitted within 12 months of the end of data
collection. The fee for assessment of PASS protocols or final study reports is
£8,309. Both
protocols and final study reports should be submitted to us using the Type II
complex variation route (classification C.I.13) with the corresponding fee.
6.2
Ongoing issues regarding PASS protocols after 1 January 2021
For products authorized in the UK where the EU PRAC
(Pharmacovigilance Risk Assessment Committee) has either endorsed a draft study
protocol or made a substantial amendment to a draft protocol before 1 January
2021, MHRA will accept the draft or the amended draft study protocol but may
request that further information is submitted to us within a specified time.
Where a non-interventional PASS has been proposed or imposed
but the draft protocol has not been endorsed prior to 1 January 2021, any
information required by the PRAC, together with any information required by the
MHRA regarding the protocol must be submitted directly to the MHRA. This must
happen even if the information was submitted via the EU procedure prior to 1
January 2021. The MHRA will then assess the information in line with the usual
procedures.
6.3
Ongoing issues with PASS final study reports after 1 January 2021
For products
authorized in the UK, where a final study report was submitted to the EMA
before 1 January 2021 but no recommendation was made before that date, it may
be required that the study report and abstract of the study report are submitted
to the MHRA together with any further information relating to the study. In any
event MAH should evaluate the impact of the results on the authorization and
submit a variation application as necessary.
Where PRAC
made a recommendation prior to 1 January 2021, the MHRA will implement the
agreed measures in line with the agreed timetable. MAH should submit any
variation to us (for converted CAPs please refer to the guidance on our website
and MHRA will determine the application within the usual timeframes).
7. Safety
Referrals
For
procedures started but not concluded before 1 January 2021, such as where a
CHMP/CMDh opinion had not been reached the MHRA will complete the assessment,
where appropriate, and make a decision on the procedure based upon the information,
including any decision made at EU level prior to 1 January 2021. MHRA may
request further information regarding the procedure on a case-by-case basis
where deemed appropriate and take the necessary steps to implement the
decision.
Where the the referral has been concluded but the decision not implemented before 1 January
2021, the MHRA will take the necessary steps to implement the final decision.
8. Major
Safety Reviews
From 1 January 2021, where there are concerns regarding a
medicine or class of medicines that are authorized in the UK, the MHRA may
conduct a major safety review to review the available data and consider what
regulatory action may be needed.
In these circumstances, MHRA will publicly announce the
initiation of the review, outlining the reasons for the review, the list of
affected active substances and products, and the timescales for the review.
Where MAH holds a MA for an affected product, MAH will be
notified of the start of and reasons for the review. List of questions will be provided
that should be addressed by all MAHs along with the deadline by which the
requested information should be submitted.
In the first instance, this correspondence will be done via
the Qualified Person for Pharmacovigilance (QPPV) but a different or additional
contact for future correspondence can be nominated.
The outcome of the review will be published. Where the
recommendations include proposals for regulatory action the details of the
measures to be taken including any changes to the product information will be
published.
A major safety review will incur the following fees for
assessment:
- £51,286
where one or two active ingredients or combinations of active ingredients are
included
- £59,595,
where three active ingredients, or combinations of active ingredients, are
included
- £67,904,
where four active ingredients, or combinations of active ingredients, are
included
- £76,213,
where five or more active ingredients, or combinations of active ingredients,
are included
Where the review relates to 2 or more authorizations, the fee
will be divided by the number of authorizations forming part of the review and MAH
will pay that reduced fee for each relevant authorization it holds.
9. Post-authorization
Measures (PAMs)
Post-authorization obligations, including specific
obligations, Annex II conditions, additional pharmacovigilance activities in
the RMP (MEA), legally binding measures (LEG) or recommendations, in place on 1
January 2021 will remain in place.
For converted EU MAs MHRA recommends that MAH need to use the
current application forms for PAMs and submits the information to us as a post-authorization
commitment, following the same principles for submission as for variations in
the CAPs conversion guidance.
Where data relating to a PAM has been submitted before 1
January 2021, but the assessment has not been concluded MHRA will conclude the
assessment where appropriate. For converted EU MAs a copy of the application
should be included in the data submission package.
Where MAH
evaluation of data supporting a MEA or LEG suggests that an update to the
product information is required this should be submitted via a Type II
variation application.
10.
Implementation of outcomes of referrals and procedures concerning PSURs, PASS,
signal assessments and PAMs
Where an
amendment to the product information is required as a result of the above
procedures, this will be implemented via a variation procedure. Where the the procedure has been concluded before 1 January 2021, but the variation has not
been submitted, the outcome will be implemented by the same procedure as for
the EU (Type IA, Type IB or Type II).
Where the
variation has been submitted, but not finally processed before 1 January 2021,
the variation will be concluded in line with the outcome of the procedure.
Where there has been no EU decision before 1 January 2021, MHRA
will carry out assessment where appropriate and the outcomes of assessments
will be published together with advice on implementation
Source: MHRA Updated guidance on pharmacovigilance procedures, Published 01 September
2020