SAFETY-RELATED PACKAGE INSERT NOTIFICATIONS. (SR-PINs). This guideline is intended to provide recommendations to applica
Registration of Medicines
SR-PINs
MEDICINES CONTROL COUNCIL
SAFETY-RELATED PACKAGE INSERT NOTIFICATIONS (SR-PINs) This guideline is intended to provide recommendations to applicants wishing applications for amendment of a registration dossier of a medicine. It represents the Medicines Control Council’s current thinking on the safety, quality and efficacy of medicines. It is not intended as an exclusive approach. Council reserves the right to request any additional information to establish the safety, quality and efficacy of a medicine in keeping with the knowledge current at the time of evaluation. Alternative approaches may be used but these should be scientifically and technically justified. The MCC is committed to ensure that all registered medicines will be of the required quality, safety and efficacy. It is important that applicants adhere to the administrative requirements to avoid delays in the processing and evaluation of applications.
First publication released for comment
October 2008
Deadline for comment
15 December 2008
Version 1
July 2012 12 Nov 2012 – 10 May 2013
Pilot phase Version 2
March 2014
Implementation
With immediate effect
Version 3, published for comment
November 2016
Due date for comment
05 December 2016
DR JC GOUWS REGISTRAR OF MEDICINES MS M HELA
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Registration of Medicines
SR-PINs
Table of Contents Page 1
Introduction.........................................................................................................................................3
2
General Requirements .......................................................................................................................3
3
Acceptable Safety-related package insert notifications (SR-PINs) ...............................................4
4
Amendments requiring full review and approval by MCC .............................................................5
5
Update History ....................................................................................................................................5
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1
SR-PINs
Introduction The package insert is a legal document and requires Medicines Control Council (MCC) approval to be valid. The purpose of this document is to provide a process whereby certain safety-related changes to package inserts could be implemented more rapidly than the system for routine review of package insert amendments allows. without full review by MCC but by structured notification process. This process is intended for the implementation of safety-related changes to package inserts after notification to the MCC within a defined time period if no response is received from the MCC,. and not necessarily requiring prior review. The process is referred to as Safety-Related Package Insert Notifications (SR-PINs).
2
General Requirements
2.1
All proposed SR-PINs must be submitted as a proposed amendment, and include all supporting documentation, as is required by the current system in place. All proposed SR-PINs submitted should contain a declaration signed by the Chief Executive Officer (CEO) and the Responsible Pharmacist that the submission is compliant with the requirements of the SR-PIN guideline. The code CCC-SRN is used for SR-PIN submissions.
2.2
Any change to an approved package insert which significantly changes the balance of the clinical benefit to risk ratio of a medicine is not acceptable as an SR-PIN.
2.3
Any SR-PIN change to a medicine’s package insert must simultaneously be applied to the medicine’s patient information leaflet (PIL) and to the package insert for any medicine registered, but currently not marketed, and included in the submission.
2.4
Changes made to package inserts and/or patient information leaflets without prior review which are not in line with the defined criteria of an SR-PIN will be regarded as unapproved.
2.5
An accompanying letter should state - the type of safety-related amendment, as specified in 3.1 to 3.5 - that the submission is in line with the requirements for an SR-PIN.
2.6
If the application (submission) does not comply with the requirements, it must be rejected by the MCC within 60 working days of receipt at the MCC. If there is no rejection from MCC after 60 working days, the SR-PIN submission can be regarded as accepted. The time period for the response starts on the day of receipt at the MCC (not necessarily the date recorded on the cover letter of the applicant).
2.7
A package insert amended according to this process must be printed and included in the pack within of the first batch produced after 120 days of acceptance at the MCC.
2.8
An applicant must submit all final printed package inserts and/or PILs that were submitted for SR-PINs in an annual report to the MCC by the end of the first quarter (31 March) of every year. The annual report should take the format of a line-listing, which includes the date of the SR-PIN submission, and the type of safety-related amendment (i.e. specify which of 3.1 – 3.5).
2.9
The specified requirements for qualification as an SR-PIN must be met and any data generated to validate the change must be retained by the applicant and readily available on request.
2.10
Inclusion of any statement/information in addition to that which qualifies the submission as an SR-PIN, will render the submission invalid as an SR-PIN.
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Registration of Medicines
2.11
3
SR-PINs
A list of all submissions of SR-PINs made in the period between the last and next Central Clinical Committee (CCC) meeting must be presented as an agenda item at every CCC meeting. Acceptable Safety-related package insert notifications (SR-PINs)
3.1
Information relating to safety including alignment with regulations as well as package inserts standardised text (wording), as determined by Council from time to time for inclusion in the package insert, which is applicable to all products containing a specific substance or applicable to a class of medicines, may be implemented without review. A submission for a proposed package insert amendment together with all supporting documentation, however, is still required from the applicant to inform the MCC that the change to the package insert is being made. The wording of standardised text as determined by Council must be used. If the applicant makes any changes to the wording that may alter the meaning or intensity of the information, a submission with information in support of the deviations must be made.
3.2
Amendments that concern the addition of inclusion of safety related information and adverse reactions terms only under the headings Warnings and Special Precautions, Interactions, Side Effects, and Known Symptoms of Overdosage or of interaction data under the heading Interactions, in line with a the most recent ‘global’ company core data sheet (CCDS) update and other reputable sources, provided they do not affect the risk:benefit balance of the medicine. In cases where the risk:benefit balance is affected, amendment will require full review and approval by MCC prior to implementation. An amendment which indicates an increase in frequency of an existing side effect, as per the CCDS, may be included. The submission must include the reference CCDS together with the information on which the CCDS update is based and information from other reputable sources. Such amendments may be implemented if the applicant has had no response from the secretariat within 60 working days of the date of submission to the MCC offices.
3.3
Amendments which concern the addition of adverse reaction terms only under the heading Side Effects or of an interaction with another medicine or substance under the heading Interactions from sources other than the CCDS. The source(s) of such data as well as the information on which the data is based must be included in the submission for the package insert amendment. Such amendments may be implemented if the applicant has had no response from the secretariat within 60 working days of the date of arrival at the MCC offices.
3.4
If an Adverse Drug Reaction (ADR) term according to 3.2 or 3.3 above requires a special precaution or warning, this will be allowed as long as it does not negatively affect the risk-benefit balance of the medicine for the approved indications. In such cases where the risk benefit balance is significantly affected the amendment will require full review.
3.5
Warnings or Special Precautions, which lead to more restrictive use of the medicine, are in line with a CCDS and without significantly changing the benefit-risk ratio, will be acceptable as an SR-PIN. Information in support of the amendment must accompany the submission.
3.63
All other safety-related amendments or amendments which do not comply with the above will be subject to the current process in place, whereby submissions will be reviewed in turn as received.
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Registration of Medicines
SR-PINs
4
CHANGES NOT ALLOWED AS SAFETY-RELATED PACKAGE INSERT NOTIFICATIONS (SR-PINs)
4
Amendments requiring full review and approval by MCC
4.1
Addition of a new indication(s) or change to the approved indication(s).
4.2
Changes to the dosage information and directions for use.
4.3
Inclusion of a contraindication.
4.4
Changes to the composition. (These will be dealt with by the Post-Registration Amendments unit of the Directorate: Medicines Evaluation & Research.)
4.5
Any change or amendment to the package insert that changes the risk:benefit profile of the medicine. Changes which in any way may relax or change the way in which the medicine is used.
4.6
An amendment which indicates a decrease in frequency of an existing side effect may not be included.
4.7
Any wording or information to further qualify (“soften”) or elaborate on the new safety-related information, such as “unknown clinical significance”, “only occurs at higher dose”, “occurs rarely”, etc.
4.8
Comparative statements.
4.9
Class statements, e.g. “as with other beta-blockers” or “as with all antihistamines”.
4.10
Additional information on lack of interaction with other substances.
4.11
Additional information on treatment of overdose.
4.126 Any safety issues that have given rise to significant correspondence/interaction between the applicant and the Regulatory authorities with which the MCC aligns itself, Dear Healthcare Professional (DHCP) letters, public health advisories, press releases or similar safety alerts, or other significant communications to the public or health care professionals in any other countries (see USRN guideline). 5
Update History
Date
Reason for update
Version & publication
2008
Published for comment
October 2008
July 2012
Released for piloting
v1, November 2012
March 2014
Guideline name changed. Amendment to sections 1, 2.6, 3.2, 3.3 Addition of new 2.10, 4.6
v2
Published for implementation
v2, March 2014
Version 3 published for comment
v3, November 2016
September 2016
Amendment to sections 1, 2.1, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 4, 4.2, 4.4, 4.5, 4.6, 4.12 Deletion of sections 3.3, 3.4, 3.5, 4.5, 4.6, 4.7, 4.8, 4.9, 4.10, 4.11 05 December 2016
Due date for comment
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