SR-PIN GUIDELINE

Cluster: Food Control and Pharmaceutical Products Regulation and Management

Directorate: Clinical Evaluations and Trials

Ms Hellen MoropyaneDeputy-Director: Clinical Post-registration Evaluations

12 September 2014

CLINICAL EVALUATIONS AND TRIALS DIRECTORATE

OVERVIEW OF THE GUIDELINEObjectives of this presentation:• To give an overview of the SR-PIN

guideline and its implementation• To clarify/explain what is regarded as

an acceptable SR-PIN amendment application or non-acceptable SR-PIN amendment application

INTRODUCTION

PACKAGE INSERT– A legal document which needs approval by the

Medicines Control Council (MCC) to be valid– It ensures the safe and effective use of the medicine

under most circumstances– Any amendment including safety –related amendment

to this document needs prior approval by the MCC

Regulation 9 of Act 101 of 1965 as amended, each package of a medicine shall be accompanied by a package insert.

The Medicines Control Council is the medicines regulatory authority of South Africa.

INTRODUCTION cont…

What is an SR-PIN?

• A notification of safety-related change (s) to the package insert(s) not necessarily requiring prior review.

Why an SR-PIN process?• To enable rapid implementation of certain safety-related

changes to package Inserts (PIs) than the current system for routine review o f PI amendments allows.

GENERAL REQUIREMENTS Proposed SR-PIN amendment application must:– have a cover letter stating: the code CCC-SRN,

the type of safety-related amendment, as specified in 3.1 to 3.5 of the guideline and that the SR-PIN submission is in line with the requirements of an SR-PIN

– include all supporting documentation, as required by the current system

GENERAL REQUIREMENTS cont…

Changes to the approved PI that significantly change the balance of the clinical benefit to risk ratio of a medicine are not acceptable as an SR-PIN.

– Any SR-PIN change to the medicine package insert should simultaneously be applied to the patient information leaflet.

– Changes made to the package inserts and /or PILs without prior review which are not in line with the defined requirements of an SR-PIN will be regarded as unapproved

GENERAL REQUIREMENTS cont…

• If the submission is not compliant with the requirements for an SR-PIN it will be rejected within 60 working days of receipt at the MCC.

• If there is no rejection from the MCC after 60 working days, the SR-PIN submission can be regarded as accepted.

• The amended SR-PIN PI and PIL must be printed and included in the pack within 120 days of acceptance at the MCC

GENERAL REQUIREMENTS cont…

• The applicant must submit an annual report to the MCC by the end of the first quarter (31 March of every year) in a form of a line listing of the accepted SR-PIN submissions and the type of the SR-PIN amendment they met

• Any data generated to validate the SR-PIN change must be retained by the applicant and readily available on request.

• The SR-PIN amendment must meet the specified requirements for qualification as an SR-PIN.

GENERAL REQUIREMENTS cont…

• No deviation from the guideline will be allowed. Inclusion of any information/statement in addition to that which qualifies the submission as an SR-PIN will render the submission invalid as an SR-PIN.

• A list of SR-PINs submissions received in the period between the last and the next Central Clinical Committee (CCC) meeting must be presented as an agenda item every CCC meeting

ACCEPTABLE SR-PIN AMMENDMENT(S)

1. Information relating to safety, as determined by Council from time to time for inclusion in the package inserts, which is applicable to all products containing a specific substance or applicable to a class of medicines, may be implemented without delay

• a submission for the proposed PI together with all supporting documentation, is still required to inform the MCC that the change to the package insert is being made

• the wording as determined by Council must be used.

ACCEPTABLE SR-PIN AMMENDMENT(S) cont…

• 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.

2. Amendment that concern the addition of adverse reaction terms only under the heading Side Effects or of interaction data under the heading Interactions, in line with the ‘global’ company core data sheet (CCDS) update.

An amendment which indicates an increase in frequency of an existing side effect, as per the CCDS may be included

ACCEPTABLE SR-PIN AMMENDMENT(S) cont…

• The submission must include the reference CCDS

together with the information on which the CCDS

update based.

• 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. Amendments which concern the addition of adverse

reaction terms only under the heading Side Effects

ACCEPTABLE SR-PIN AMMENDMENT(S) cont…

or of an interaction with another medicine or substance under the heading Interactions from sources other than the CCDS.

An amendment which indicates an increase in frequency of an existing side effect, as per these sources may be included.

• The source(s) of such data as well as the information on which the data is based must be included in the submission of the PI amendment.

• 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.

ACCEPTABLE SR-PIN AMMENDMENT(S) cont…

4. If an adverse reaction terms mentioned 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

 

ACCEPTABLE SR-PIN AMMENDMENT(S) cont…

5. Warning or Special Precautions,

• which lead to more restrictive use of the medicine, which are in line with a CCDS and without significantly changing the benefit-risk balance, will be

acceptable as an SR-PIN.• Information in support of the amendment must

accompany the submission.

CHANGES ARE NOT ALLOWED AS SR-PIN APPLICATIONS

• Addition of new indication or change to the approved indication

• Changes to dosage information• Inclusion of a contraindication • Changes to the composition • Changes which may relax or change the way in which

the medicine is used.

CHANGES ARE NOT ALLOWED AS SR-PIN APPLICATIONS

• An amendment which indicates a decrease in the frequency of an existing side effect may not be included.

• 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.

CHANGES ARE NOT ALLOWED AS SR-PIN APPLICATIONS CONT

• Comparative statements

• Class statements, e.g. “as with other beta-blockers” or “ as with all antihistamines”

• Additional information on the lack of interaction with other substances.

• Additional information on the treatment of overdose

 

CHANGES ARE NOT ALLOWED AS SR-PIN APPLICATIONS CONT

• Any safety issues that have given rise to Dear Healthcare Professional (DHCP) letters, public health advisories, press releases or similar safety alerts, or other significant communications to the public or HCPs in any other countries

DO NOT:

• Send a new PIL with an SR-PIN application. This needs to be fully reviewed.

• Include information on the results of a clinical study as this will need full review.

• Do not include information on a pending safety update so that it can be reviewed together with the SR-PIN information as this disqualifies the application as an SR-PIN and needs full review

DO NOT: CONT...

• Do not put any other information under the sections that are not regarded as acceptable SR-PINs

FREQUENTLY ASKED QUESTIONS

1. Point 2.7: PI must be printed and included in pack within 120 days of MCC acceptance

Response: This is 120 working days2. Bringing a PI in line with Regulation 9 (Act 101/1965): If a

product is being updated in terms of the Interactions, Pregnancy and Lactation etc, headings, as well as standard statements/information that need to be included e.g. drowsiness & use of machinery, lactose intolerance, list of excipients under Composition, can this be done together with a SR-PINs notification?

Response:

FREQUENTLY ASKED QUESTIONS CONT….

3. Similarly, bringing a PI in line with Regulation 9 (Act 101 of 1965) as amended in Government Gazette No. 37032 of 15 Nov 2013 with respect to Warnings, Special Precautions and Side Effects: Would it be possible to do this together with an SR-PINs application as this too would possibly be seen as a notification as it is just a re-arrangement/formatting of information.

Response:

FREQUENTLY ASKED QUESTIONS CONT….

4. Point 4.6: Decrease in frequency of an existing side effect: does this apply to post-marketing adverse events too?

Response: 

5.On implementing SR-PINs to printed Pis, after no response following 60 working days, should we use SR-PINs submission date as the new ‘date of publication’?

Response:

FREQUENTLY ASKED QUESTIONS CONT….

6. From the guideline, assumption is implementation after 120 working days?

Response: 

7. Is it possible to provide a template for annual line-listing?Response:

8. To whom must the annual listing be submitted? Do applicant wait for their prompt or just submit?

Response:

FREQUENTLY ASKED QUESTIONS CONT….

9. The SR-PIN guideline lacks clarity in terms of the criteria and conditions whereby safety related changes would be considered as notifiable changes, e.g .: “adverse reaction term(s) only”

Any safety related statement/phrase clarification of the adverse reaction term is not regarded as an SR-PIN. For example, the terms such as :

• “cough is exacerbated by….”• “ Most reports of coughing were reported in patients with

predisposing risk factors including pneumonia…”have not been accepted as SR-PINs.

Response:  This is not allowed as such statements may dilute the message.

FREQUENTLY ASKED QUESTIONS CONT

10. Any wording or information to further qualify or elaborate on new safety related information such as “occurs rarely” is not allowed.

This contradicts the PI for Human medicines guideline (2.16), section 3.12.3, which requires the frequency of Adverse Drug Reaction (ADR) where known to be stated.

Response: This is not true for post-marketing data. No frequency categories can be allocated to individual reports from spontaneous reporting.

IN CONCLUSION

PLEASE NOTE:• In the case where there is further elaboration or

qualification of the adverse drug reaction term, the Clinical committee will determine whether such qualification as an SR-PIN is justifiable.