An update to the procedure of reporting side effects and new safety information

STATE OF ISRAEL

Ministry of Health Pharmaceutical Administration

1. General

The control of the use of drugs requires the gathering of field data on side effects that result from the use of the medication.

Regulation 7(B)(2) of the Pharmacists Regulations (Medicinal Products) 5746-1986 (hereinafter: the Regulations) requires a registration holder to inform the Director immediately via the appointed pharmacist of any new information that is related to a registered medicinal product.

Update number 1, August 2012 to this procedure specifies the types of information that must be reported by the registration holder and allows, as per the common practice in the world, the registration holder to appoint a pharmacist to serve as a qualified person for pharmacovigilance concerning reports that are included in this procedure.

The aim of update no: 2 February 2013 are:

1. Clarify the work processes related to the reporting of side effects and new safety information.

2. Update the definitions of the procedure.

3. Update the types of information whose reporting is required by the registration holder as set forth in Section 3.1 of this procedure.

4. Update the address for forwarding side effect reports and safety information [email protected]

5. This update applies from May 1^st, 2013.

Update no: 3 of this procedure’s objective is to adapt the procedure to the Pharmacist Regulations (products)(amendment) � 2013. The contents of the update will be effective from 1.12.13 with the exception of sections 3.1 and 3.2.2.10 that their implementation will commence with the implementation of the directives for medicinal follow up and items 3.2.2.1 and 3.2.2.2 that their reporting time will change with the commencement of the directive of the medical follow up.

2. Definitions

“The Regulations” – Pharmacist Regulations (products) (amendments) � 2013

“QPPV” � Qualified Person for Pharmacovigilance � A pharmacist or physician that has an Israeli license and at least 2 years’ experience in their profession registered to act as qualified person for pharmacovigilance according to this procedure. Relating to a pharmaceutical product that is a medical gas, an engineer may be appointed, that is defined by the law of Engineers and Technicians, 2012 with relevant training; appointed pharmacist or engineer as said, will consult with the physician according to necessity regarding new clinical questions relating to his responsibilities. A person that is not a pharmacist but works in the field of pharmacovigilance for the registration holder on the date of issue of this procedure may serve as QPPV on condition that he holds a BA in life sciences or natural sciences and has 3 years’ experience working as a QPPV.

“Registration Holder” � As defined by the regulations.

“Signal” � as defined by the World Health Organization (WHO) and Uppsala Monitoring Center.

“New Safety Information” � All safety information that can affect the safety of the product according to detailed directives in section 3.2.2 of this procedure.

“Appointed Pharmacist” � as defined by the regulations.

“Adverse Event” � an undesirable, unintended effect of a medicinal product.

“Serious Adverse Event” � side effects that are reversible or irreversible that caused one of the following: death; life threatening; caused disability, or severe or persistent morbidity; required hospitalization or extension of an existing hospitalization; a congenital defect as a result of treatment with the medicinal product during pregnancy; or any other serious medical events that can put the patient at risk or that requires medical intervention to prevent the above events.

“Unusually Frequent Side Effects” � a side effect whose frequency is suspected to have increased beyond the level known (in the physician’s leaflet or known to the monitoring system of the company of the product) or found in literature reports.

“Medicinal Product” � as defined by the Pharmacists Ordinance (new version) -1981.

3. Contents of Procedure

3.1 Qualified Person for Pharmacovigilance (QPPV)

The registration holder will complete in appendix 2 of this procedure all details regarding the QPPV and will forward them to the director together with a CV and

contact details of the QPPV to [email protected]. The director will approve by letter the appointed person according to appendix 3 of this procedure.

3.2 Tracking and Reporting by the Registration Holder

3.2.1. The registration holder must maintain a system for tracking side effects and new safety information for a medicinal product that is has registered.

3.2.2. The registration holder, through the QPPV (or appointed pharmacist till implementation of regulations) will report to the Risk Management and Drug Information Department at the Ministry of Health in the following incidents:

3.2.2.1 Prohibition, restriction or warning that is related to safety issues (existing or potential) determined by a health authority in a recognized country regarding marketing and use of the product. Immediately and not later than 3 working days from the day of receipt of information from the registration holder in Israel. This section will become valid with this amendment and until then reporting will be immediate and not later than 15 calendar days from the day of receipt of information by the registration holder in Israel.

3.2.2.2 Notification to the medical staff or the public that was published by the manufacturer, registration holder or medical authorities in a recognized country regarding marketing or use of the product, that it is connected to the side effect, except for updates of the product leaflet; immediately and not later than 3 working days from receipt of information by the registration holder in Israel. The directive will become valid with the applicability of the regulations and until then reporting will be immediate and not more than 15 calendar days from day of receipt of information by the registration holder in Israel.

3.2.2.3 All serious side effects originating in Israel. Reporting should be immediate and not later than 15 calendar days from day of receipt of information by the registration holder in Israel.

3.2.2.4 Side effects or lack of efficacy that has been discovered during the first 12 months of marketing of the medicinal product with a new formulation in Israel; change of formulation will be regarded as change of formulation type II in accordance to the definitions set by the European Directive. In addition, a report must be made on a cluster of 5 or more non-serious adverse events in a medicinal product after a change in formulation that is not a type II change. Report will be immediate and not more than 15 calendar days from day of receipt of report by the registration holder in Israel.

3.2.2.5 Side effects outside of Israel that may have implications on the safety of the medicinal product and requires attention (signal) should be reported once every 30 days.

3.2.2.6 New information that has been published in medical literature regarding the safety of the medicinal product should be reported immediately and not later than 15 calendar days from the day of receipt of information from the registration holder in Israel.

3.2.2.7 New information that was publicized as a valid Case Report (according to the criteria detailed in section 3.2.5.2) in professional literature that has safety implications on the medicinal product; report should be immediate and not later than 15 calendar days from the day of receipt of information from the registration holder in Israel.

3.2.2.8 Adverse events with unusual frequency compared to frequency that appears in the physician’s leaflet approved in Israel or in accordance with monitoring data from the company or literature reports.

Initiated evaluation of unusual frequency of adverse events in Israel will be carried out by the registration holder once every 3 months in relation to the number of reports in Israel, unless the registration holder receives information of unusual frequency through signals by marketing authorization holder/manufacturer abroad. Reports should be immediate and not later than 15 calendar days from day of receipt of information by the registration holder in Israel.

For medicinal products where the marketing authorization holder/manufacturer is abroad, reporting of sections 3.2.2.5 � 3.2.2.8 can be carried out through signals as they were received or recognized by the marketing authorization holder or manufacturer abroad after they have been assessed by the company and were evaluated with possible connection to the medicinal product (details of what the assessment was based on should be included).

3.2.2.9 DSUR for prescription drugs that are undergoing Post marketing trials

In Israel should be submitted once a year.

3.2.2.10 Reports on non-serious side effects (expected and unexpected) from Israel.

Should be submitted within 90 days from date of receipt of information from the

registration holder in Israel. This section will become valid upon implementation of

regulations.

3.2.2.11 The PSUR reports or PBRER of the medicinal product; in accordance to time

frame dictated by the GVP of the European Union and published in the website of

the European Union (EURD list) as updated from time to time. Where relevant it is

possible to forward the report together

with a signed declaration within 7 working days from the date of submission of the PSUR according to the European timeframe.

In the event that the medicinal product was not published in the timeframe by the GVP of the European Union or if the medicinal product is generic and therefore the GVP of the European Union does not require a report, contact should be made to the Risk Management and Drug Information Department in order to receive an exemption for submission or receipt for timetable and method of submission. When relevant the Risk Management and Drug Information Department are authorized to request from the registration holder a PSUR not according to the set timeframe.

3.2.2.12 All information collected by the registration holder in Israel which have safety implications of the medicinal product that are not included in sections 3.2.2.1 � 3.2.2.11 should immediately and not later than 15 calendar days from the date of receipt of information by the registration holder in Israel.

For the benefit of doubt, the reports in section 3.2.2.1 � 3.2.2.12 that refer to the use of the drug not according to the instructions or safety instructions (warnings/contraindication) or the physician’s leaflet/patient information leaflet or usage not according to the indication. (off label). For veterinary products – sections 3.2.2.4 � 3.2.2.10 and 3.2.2.12 should be excluded. Despite the above, the Risk Management and Drug Information Department maintain the right to change the date of the report for all the above sections if necessary.

3.2.3. Reporting Method:

(a). Reports for sections 3.2.2.3, 3.2.2.4 and 3.2.2.10 will be forwarded via an online form that can be found on the website of the Ministry of Health after the QPPV has ensured that the report is valid and contains all the information required according to the GVP principles of the European Union.

(b) Reports for sections 3.2.2.1, 3.2.2.2, 3.2.2.5 � 3.2.2.9, 3.2.2.11 and 3.2.2.12 will be forwarded by email to [email protected]

(c) Despite the instructions in point b, report of Case reports (3.2.2.7) will be executed when possible as an individual report via the online form.

(d) Registration holder that reports sections 3.2.2.5 � 3.2.2.8 by signals should forward them to email [email protected] separately for each individual medicinal product once a month if received.

(e) In addition to the points noted in b and d above, in the event of an unusual change of frequency (section 3.2.2.8), reports should be sent via email to [email protected] and individual reports via online form.

3.2.4 Periodic Safety Update Report (PSUR or PBRER)

3.2.4.1 The registration holder will forward through the appointed QPPV to the Risk Management and Drug Information Department the PSUR or PBRER for the medicinal product completely filled out according to the timeframe dictated by the GVP of the European Union. The report to the Risk Management and Drug Information Department will be forwarded as determined by the GVP or according to the department’s request.

In the event that the medicinal product does not appear on the timeframe list of the GVP of the European Union, the Risk Management and Drug Information Department should be contacted in order to either receive exemption of submission or a timeframe for submission.

3.2.4.2 The QPPV will review the PSUR and will submit a report that contains the following sections noted below together with the executive summary and conclusions and declaration according to annex 1 of the procedure complete and signed. As necessary, the report can be forward (Annex 1) together with the signed declaration with 7 working days from the date of submission of the PSUR according to the timeframe dictated by the European Union.

The declaration refers to the following sections in the PSUR

� Actions taken in the reporting interval for safety reasons

� Changes to reference safety information

� Data in summary tabulations

� Overall safety evaluation

Or the following sections for the PBRER or the new PSUR

� Actions taken in the reporting interval for safety reasons

� Changes to reference safety information

� Cumulative summary tabulations for serious adverse events from clinical trials

� Cumulative and interval summary tabulations from post-marketing data sources

� Long-term follow up

� Overview of signals: new, ongoing or closed

� Signal and risk evaluation

� Integrated benefit-risk analysis for approved indications

� Conclusions and actions.

3.2.4.3. Information that has safety implications on the medicinal product which appear in the executive summary and additional information which exists in sections above and does not exist in the executive summary of the PSUR or PBRER will be forwarded to the Risk Management and Drug Information Department together with the declaration.

3.2.4.4. In the event that during the time of reporting, action was taken or is planned to be taken based on conclusions of report to change marketing conditions of the medicinal product for safety reasons by the manufacturer or the EMA , FDA authorities or other authorities that appear in the report that have taken measures or intend to and the reasons and note whether the registration holder submitted a request for update or his intention to update the leaflets in Israel accordingly.

3.2.5 Postmarketing Spontaneous reporting of individual case safety report (ICSRs)

3.2.5.1 Postmarketing ICSRs are of great importance in the tracking of drug safety.

3.2.5.2. There are 4 minimal criteria for a valid report;

1. Identifying details of the patient � at least one of the following details: age, gender, initials or name etc.

2. Identifying details of the reporter � (name of the company reporting or head of medical affairs or patient reported independently) � to obtain contact details so further details can be obtained.

3. Name of the medicinal product/suspicious drug

4. Adverse Event.

3.2.5.3. The registration holder assumes the responsibility for submitting an adverse event report (via the online form available in the website of the Ministry of Health) with complete information to the extent available from the reporter and in accordance to the requirements of the Risk Management and Drug Information Department. It is clarified that complete information does not refer to identifying details of the patient but information that is required in accordance to the report form.

3.2.5.4 The registration holder, through the QPPV must take all action to collect all details that are required for investigating the adverse event as shown in the relevant report forms in the Ministry of Health website and to document these efforts. If requested, the documentation will be presented to the Ministry of Health.

3.2.5.5 The registration holder must direct its employees who are in charge of collecting this information to make all efforts to receive this information and to request consent of the reporter to follow up if necessary (particularly in the case of a serious side effect). If the information has reached the registration holder from a patient, an attempt is to be made to get the details of the attending physician and the consent of the patient to receive additional information from the physician as necessary.

3.2.6 Follow Up Reports

3.2.6.1. Follow up reports are to be submitted for any serious adverse events in general and for additional reports by the registration holder should the Risk Management and Drug Information Department request via the online form with the original report. In the event that this is not possible, it is possible to submit follow up report via email to [email protected]. The email should be titled as “Follow Up” with reference number of first report. It is advisable to fill in full details as much as possible but without jeopardizing the patient’s privacy in order to prevent double reporting in the system.

3.2.6.2. Follow up reports for serious adverse events are to be submitted within 15 calendar days from date of receipt of new information or according to the request of the Risk Management and Drug Information Department.

3.2.6.3. In the event that it is not possible to obtain new information within 2 months, from the submission date of the first report to the Ministry of Health, the unsuccessful attempts to receive this information should be documented and kept with the registration holder. This information will be submitted to the Risk Management and Drug Information Department upon request.

3.2.7 The QPPV must maintain all records and information and make them available for inspection should the Risk Management and Drug Information Department request.

3.2.8 The QPPV should make all records available for inspection to the director upon request.

4. Responsible for Implementation

The registration holders of the medicinal products

The Pharmaceutical Administration, Ministry of Health

5. Applicable Documents

Pharmacists Ordinance (New version) � 1981

Pharmacists Regulations (Medicinal Products) – 1986

Pharmacists Regulations (Good Manufacturing Practice for Medicinal Products) – 2008.

Notice of defect or medicinal product recall procedure (procedure 3)

Information forwarding and medicinal product related crisis management procedure (procedure 84).

Guideline on good pharmacovigilance practices (GVP)

6. Distribution

Director General

Deputy Director General

Director of the Medical Administration

Director of the Medical Technology and Infrastructure Administration

Director of Public Health Services

Pharmaceutical Administration

District Pharmacists � Jerusalem, Tel Aviv, Haifa Central, Northern, Southern

The Institute for Standardization and Control of Pharmaceuticals

Office of the Legal Adviser

Manufacturers / Importers � registration holders of medicinal products

Drug Stores

The Manufacturer’s Association � The Pharmaceutical Industry

Federation of chambers of Commerce � the Pharmaceutical Industry

Pharma Israel

The Association of Pharmacists � The New Histadrut

The Pharmaceutical Society of Israel

The Federation of Pharmacists � the Pharmacy Industry

Pharma chains

Hospital Pharmaceutical Services

Kupat Holim Pharmaceutical Services

Re-distribution Medical Administration

Annex 1

Declaration of report of PSUR or PBRER

To: The Pharmaceutical Administration � The Risk Management and Drug Information Department.

Medicinal Product Registration Number____/_______/______/______

I, __________________the QPPV (or appointed Pharmacist until the application of this amendment) of the registration holder _______________________________________

Am forwarding to you the PSUR, it conclusions and executive summary for the medicinal product ______________________________.

Report number_____________for the period of____________until_________________

After having read the conclusions and executive summary of the report and of the following

Sections of the PSUR:

Actions Taken in the Reporting Interval for Safety Reasons

Changes to Reference Safety Information

Date in Summary Tabulations

Overall Safety Evaluation

Or sections in the PBRER and the new PSUR:

Actions Taken in the Reporting Interval for Safety Reasons

Changes to Reference Safety Information

Cumulative Summary Tabulations of Serious Adverse Events from Clinical Trials

Cumulative and Interval Tabulations from Post-marketing Data Sources

Long-term Follow-up

Overview of Signals: New, Ongoing or Closed

Signal and Risk Evaluation

Integrated Benefit-risk Analysis for Approved Indications

Conclusions and Actions

I, the QPPV am forwarding the appointed Pharmacist a copy of this appendix.

In the timeframe of the report steps have / have not been taken to change the marketing conditions of the medicinal product for safety reasons by the manufacturer or the EMA, FDA authorities or other authorities that appear in the report (including updates in the Company Core Data Sheet (CCDS) of the medicinal product.

If measures have been taken, as set forth in the paragraph above, please elaborate briefly the measures that were taken, the safety information that led to taking these steps and has or will be done in view of these measures in Israel.

Signed:__________________

Stamp:__________________

Date:___________________

Annex 2

Form Request for Appointment of QPPV

Date:

Attn:

The Director

Risk Management and Drug Information Department

Pharmaceutical Administration

Ministry of Health

Subject: Request for approval to appoint a QPPV

I hereby request your approval for appointment _________________ID no:____________that will be responsible for drug monitoring (QPPV) of (name of company/institute):__________________________to perform all necessary actions in accordance to this procedure and any procedures published from time to time by the Ministry of Health.

I am fully aware that the appointed QPPV has been given full professional certification to carry out drug monitoring by the registration holder according to this procedure of reporting adverse events and new drug safety information and according to the Pharmacist Regulations (medicinal products) (update) � 2013.

I undertake responsibility to forward to the QPPV all relevant information in order for the responsibilities of this position to be carried out thoroughly.

Enclosed:

Curriculum Vitae (including contact details and details of experience and professional training).

With respect,

Name of Nominator:______________

Position:________________________

Signature:_______________________

Annex 3

Approval of Appointing QPPV

Name: ___________________

ID Number: _______________

Approved as QPPV for company: ________________________________

Address: ____________________________________________________________

The QPPV is the professional authority for the drug monitoring on behalf of the registration holder according to this procedure for management of drug monitoring and new safety information.

Approval valid from day: _______________

Copy: Nominator

Director of Pharmaceutical Administration

Director of Risk Management and Drug Information Department __________________________