Name of Procedure: Guidelines for Submitting Risk ... · Name of Procedure: Guidelines for...

Name of Procedure: Guidelines for Submitting Risk Management Plans to Pharmaceutical Division

Procedure Date: March 2016 Procedure Number: 142 Page 1 of 34

Risk Management and Drug Information Department Ministry of Health P.O.B 1176 Jerusalem 9101 [email protected] Tel: 02-5080234, 5080251, 5080236 Fax:02-6474858

1. General

At the time of approval for registration of a medicinal products, the information about the

safety of the medicinal product is based primarily on clinical studies. It is known that clinical

studies have several restrictions that prevent identification of the entire range of safety

problems existing in the medicinal product. Among them, the number of subjects selected

under the controlled inclusion and exclusion criteria (restrictions of age, medicinal history and

medications taken simultaneously, etc.) and duration of limited exposure. In addition, restricted

conditions of use for the medicinal product, and close monitoring that does not always exist in

"real life."

In light of the above, there is an obligation to continue monitoring adverse reactions and all

the safety information accumulated throughout the life cycle of the medicinal products

Likewise, there is a constant need for continuing to conduct a risk benefits analysis and

determine measures required to improve the – benefit –risk balance and minimize the risks

involved in the use of the product.

A most important tool for characterization, assessment and minimization of risks associated

with the use of a medicinal product is a risk management plan (RMP).

An RMP includes three main stages:

1. Characterization of the safety profile of the medicinal product, including safety

information on what is known and still not known about the product (i.e. missing

information).

2. Planning of pharmacovigilance activities intended to characterize known risks,

identifying new risks and expanding the Knowledge regarding the product's safety

profile.

3. Planning and implementation of risk minimization and mitigation as well as assessment

of the effectiveness of these activities




Risk management plans in Israel will be mostly based on an existing risk management plan

that was submitted/ approved by regulatory authorities such as EMA or FDA or another

recognized country (after receiving confirmation thereof from the risk management

department) and will be adapted to Israel in accordance with the requirements in this

procedure and the risk management and drug information department's guidelines. This

procedure does not apply to veterinary products.

The Objectives Of This Procedure Are:

1. Specifying under which circumstances submission of risk management plans are

necessary.

2. Defining the work processes pertaining to RMP's vis-à-vis the Pharmaceutical Division.

3. Defining the adjustments necessary for the risk management plan that is submitted to the

Ministry of Health in Israel.

4. Specifying the format for submission and structure of the Risk Management Plans

adapted for Israel.

5. Providing an acceptable template for submission of materials supporting the Risk

Management Plan adapted for Israel.

6. Defining the requirements for updating the Risk Management Plans adapted for Israel

and the manner they are to be updated.

This procedure will come into effect from 1.9.2016.




2. Definitions:

"The Regulations" – The Pharmacists Regulations (Products), 1986

“Marketing Authorization Holder (MAH)” – within the meaning thereof in the Regulations

"QPPV - Qualified Person Responsible for Pharmacovigilance" – within the meaning thereof

in the Regulations

“Appointed Pharmacist” – within the meaning thereof in the Regulations

Risk Management Plan - RMP – Plan for managing risks: Detailed, clear and written

description of risk management system in Europe

Risk Evaluation and Mitigation Strategies - REMS– Risk Management Plan: Detailed, clear

and written description of risk management system in USA

Risk Management Plan adapted to Israel – A Risk Management Plan that is based mostly on an

existing Risk Management Plan and adapted to Israel in accordance with the provisions of this

procedure (Section 3)

Identified Risk –An untoward occurrence for which there is adequate evidence of an association

with the medicinal product. Examples:

An adverse reaction in non – clinical studies and confirmed by the clinical information.

An adverse reaction observed in well – designed clinical trials or epidemiological studies for

which the Magnitude of the difference compared with the comparator group, on the parameter

being investigated suggests a causal relationship.

An adverse reaction appearing in a number of well – documented spontaneous reports where

causality is strongly supported by temporal relationship and biological plausibility, such as

anaphylactic reactions or application site reactions




Potential Risk – is an untoward occurrence for which there is some basis for suspicion of a

potential association with the medicinal product, but such association has not been confirmed.

Examples:

Toxicology findings from non-clinical safety studies that were not observed / confirmed in

clinical trials.

Adverse reactions observed in clinical trials or epidemiological studies for which the magnitude

of the difference, compared with the comparator group (a parameter that we will investigate)

raises a suspicion of an association, but is not large enough to indicate a causal connection.

A signal arising from the spontaneous reporting system.

An event known to be associated with other drugs within the same pharmacologic group or

which could be expected to occur based on the characteristics of the medicinal product.

Missing Information – Gaps in knowledge about a medicinal product, related to safety or use in

particular patient populations which could be clinically significant.

Examples of missing information include populations not studied or partially studied (e.g. pregnant

women or patients with severe renal impairment) or where there is a high likelihood of off-label use.

Important Identified Risk And Important Potential Risk – An identified risk or potential risk that

could have an effect on the risk-benefit balance of the medicinal product or have implications on

public health. Defining the importance of the risk will depend upon several factors: the effect of the

risk on the patient, the seriousness of the risk and the impact on public health. Normally, any risk

that is likely to be included in the contraindications or warnings and precautions section of the

product information will be considered important.

Risk Management System – A collection of risk management activities and interventions within

the framework of the pharmacovigilance activities designed to identify, characterize, prevent or

minimize risks relating to medicinal products including the assessment of the effectiveness of

those activities and interventions for minimizing risks.

Safety Concern – An important known and identified risk, important potential risk or missing

information




Target Population – The patients who might be treated with the medicinal product in accordance with the

indications and contraindications of the medicinal product

3. General Guidelines for Submitting a Risk Management Plan

3.1 Situations In Which Submission Of An RMP Is Required, How To Submit It And

The Handling Thereof

3.1.1 In general, a risk management plan should be submitted at the time of the

submission of a new application for, during the dossier evaluation and post-

authorization of the medicine inasmuch as this is required in accordance with the

risk assessment of the product by the Marketing Authorization Holder (MAH) or

Pharmaceutical Division according to the specification below.

3.1.2 When Submitting An Application For Registration Of A product Or An

Additional Indication:

3.1.2. 1 At the point of submission of an application for a new medicinal product

or for an additional indication, the appointed pharmacist must submit the

full Risk Management Plan for the medicinal product as it was submitted

by the Marketing Authorization Holder (MAH) / manufacturer outside

Israel and / or was approved by regulatory authorities such as EMA or

FDA or another recognized country as specified below. The Risk

Management Plan shall be submitted in accordance with the instructions

as communicated by the medicinal product registration department.

3.1.2.1.1 This procedure is based on the European procedure and there is

a preference for submitting a Risk Management Plan approved

in Europe (RMP).

3.1.2.1.2 In case the medicinal product has no Risk Management Plan

approved in Europe (RMP), but there is a Risk Management Plan

approved in the USA (REMS) or one country only (non –

centralized) – then the existing plan may be submitted and

adjustments for Israel shall be implemented upon demand by the

Pharmacovigilance and Drug Information Department.




3.1.2.1.3 When submitting medicinal products for registration of an

additional indication for which there is a Risk Management

adapted to Israel, the updated plan will be submitted as detailed

in Section 6.1.1.

3.1.2.2 When submitting an application for registration of a product for which there is

no Risk Management Plan that was submitted and / or approved by another

regulatory authority, the Drug Registration Department and Pharmacovigilance

and Drug Information Department shall be updated accordingly. Individual

guidelines shall be provided by the Pharmacovigilance and Drug Information

Department.

3.1.2.3 Regarding generic products for which there is a registered reference product in

Israel, the aforementioned guidelines will be based on the risk management plan

determined for the reference product. See reference in Section 3.3.11.

3.1.2.4 In cases of applications for authorization of medicinal products not belonging to

a category mentioned above the Marketing authorization holder should contact

Risk Management Department in order to obtain individual guidance.

3.1.3 Registered And Marketed Drugs 3.1.3. 1 A Risk Management Plan adapted to Israel shall be submitted as required

by the Pharmacovigilance and Drug Information Department in

accordance with the risk assessment and the safety information received

at the Pharmacovigilance and Drug Information Department and the

possible actions to minimize them for a pharmacological group /

medicinal product. An adapted plan may be required in accordance with

an internal plan of the Department for high risk medicinal products such

as: narrow range therapeutic drugs, biological drugs, teratogenic drugs,

drugs with a unique risk requiring suitable products will be required etc.

In the event of a decision that a minimization of existing risks is needed

by means of applying a Risk Management Plan adapted for Israel, the

Pharmacovigilance and Drug Information Department shall notify the

marketing authorization holder (MAH) of the considerations leading to

the decision to implement the plan and will send a demand to the

marketing authorization holder (MAH) to submit a risk management plan

adapted to Israel for the medicinal product. Marketing authorization




holder (MAH) Submission dates shall be determined by the department in

accordance with the urgency in implementing the plans.

3.1.3. 2 Formulation (Type 2) Changes or New Manufacturing Process (Type

2) – In these cases the risk assessment will be performed by the marketing

authorization holder (MAH)and in the event it is decided that the change

may affect the safety or efficacy of the product, the Risk Management

Department is to be advised thereof. The Risk Management Department

will decide whether the submission of a Risk Management Plan is

required, and will send written notice thereof to the marketing authorization

holder (MAH). This guideline does not nullify the requirement to notify

the Institute for Standardization and Control of any Pharmaceuticals

revision nor the duty to report new safety information in accordance with

Procedure 6 Revision 5 (October 2013). Marketing authorization holder

(MAH).

3.2 Following receipt of guidance from the Ministry of Health regarding the submission of a

Risk Management Plan adapted to Israel, the plan shall be submitted for approval by the

Risk Management and Drug Information Department.

3.3 Guidelines For Submitting A Risk Management Plan Adapted For Israel

3.3.1 The plan shall be submitted in Hebrew or English.

3.3.2 A risk management plan in Israel will generally be based on the existing Risk

Management Plan as submitted by the Marketing Authorization Holder (MAH)

Marketing Authorization Holder (MAH) / manufacturer outside Israel and / or approved

by regulatory bodies such as the EMA or FDA or another recognized country as detailed

above and will be adapted to Israel in accordance with the requirements in this

procedure and the guidelines of the Risk Management and Drug Information

Department.

3.3.3 When submitting the Risk Management Plan adapted to Israel, the full plan that served

as a reference for formulation of the plan shall be attached thereto.




3.3.4 Submission of a plan for a product that has no Risk Management Plan approved by

another regulatory authority, will be conducted according to the principles and format

specified in this procedure without attaching the reference mentioned above.

3.3.5 In the event that a Marketing authorization holder was instructed to submit a Risk

Management Plan adapted to Israel during the medicinal product authorization process,

the plan adapted to Israel shall constitute a condition in the terms of authorization of the

medicinal product and an integral part of the medicinal product's authorization

certificate. Likewise, it will not be possible to receive first batch approval without prior

approval of the RMP by the Risk Management Department. The timetables for

submitting for approval thereof shall be adapted to those required for approval of the

medicinal product's authorization. Approval of the plan and the supporting materials will

be received in writing from the Risk Management Department (Appendix 3).

3.3.6

In the event that a Marketing authorization holder was instructed to submit a Risk

Management Plan adapted to Israel for a registered drug, the requirement for a plan

adapted to Israel will be noted in the product's registration certificate and will constitute

an integral part of the product's registration conditions.

3.3.7 The adapted plan shall include the possible risks arising from use of the product and a

proposal for contending with them in Israel, including reference to specific risk factors

and ways of minimizing the risks. For individual guidelines in respect of possible

supporting materials see Section 7 of this procedure.

3.3.8 The Marketing Authorization Holder (MAH) will receive written notification of the

plan implementation date.

3.3.9 The prescribing information and PIL are to include a reference to the risk management

plan and supporting materials (patient card, patient booklet etc.) (Guidelines in Section

7). The supporting materials will be uploaded to the drug registry on the Ministry of

Health's website (together with the approved prescribing information and PIL) and will

also be posted on the website of the Risk Management and Drug Information Dept. \

The company is given 6 months from the approval date to implement the changes in the

Prescribing information and the PIL attached to the medicinal product packaging from

their approval date. The risk management plan can be initiated (for example: the




patient's safety information card, doctor's booklet, letter to doctor etc.) before the

implementation of the changes to the prescribing information and PIL relating to the risk

management plan for medicinal product packaging.

Marketing Authorization Holder (MAH)

3.3.10 At the same time, upon the beginning of distribution of the RMP materials, the

Marketing Authorization Holder (MAH) must issue a communication to the media in

agreement with the Risk Management and Drug Information Department. The notice

shall include, inter alia, the important safety updates, distribution method and the

distribution dates of the risk management plan materials and contact details for ordering

the materials in addition to the accompanying materials. The notice will state, if

necessary, that the updated prescribing information and PIL and the components of the

plan have been posted on the Ministry of Health's website, and that the update of the

prescribing information and PIL will be performed within six months from the date of

approval.

3.3.11 In General, a Risk Management Plan adapted to Israel that was required for a medicinal

product, shall be implemented "across the board" for all the registered / about to be

registered products belonging to that pharmacological group, including generic products.

Accordingly, the Risk Management Department will notify the relevant Marketing

Authorization Holder (MAH)s of the need for a risk management plan and its

requirements . In the event that the product belonging to the said pharmacological group

has a known and fundamentally different safety profile than that of the other products in

that pharmacologic group, the Marketing Authorization Holder (MAH) will be allowed to

submit an application for a Risk Management Plan that is different from the original plan

or be exempt from implementation of a plan adapted for Israel, subject to prior approval

on an individual basis by the Risk Management Department.

3.3.12 Concurrent with receiving the risk management plan approval, ensure the receipt of

written approval from the Risk Management Department regarding the final graphics

and the manner of distribution of the supporting materials.

3.3.13 In the event of ongoing post – marketing studies as part of the Risk Management Plan

around the world, the Marketing Authorization Holder (MAH) must update the Risk

Management Department regarding their existence and submit timetables for providing

findings from these studies. In the event that post – marketing studies are being




performed in Israel, the Risk Management Department shall be notified about their

location (or planned location) (If centers have yet to be determined, the Department shall

be updated after the locations have been determined).

When submitting / updating a Risk Management Plan adapted for Israel, a statement by

the QPPV shall be attached including Appendix 1

3.3.14 The Marketing Authorization Holder (MAH) is responsible for monitoring the product's

safety profile and for submitting updates of the risk management plan adapted to Israel

in accordance with the provisions in Section 6.

3.3.15 The email address for submitting a risk management plan adapted to Israel and

supporting materials for the plan is [email protected]

mailto:[email protected]




4. The Structure of a Risk Management Plan Adapted To Israel:

Risk Management Plans consists of the following 6 principal parts:

4.1 Part One: An Overview Of The medicinal product, Including Details Regarding the

Indications and Target Population.

4.1.1 General Information:

4.1.1. 1 Details of the medicinal products to which the RMP relates.

4.1.1. 2 Name of Marketing Authorization Holder (MAH).

4.1.1. 3 Date of submission and version number. If an update to the RMP is

involved, indicate the update number and the differences from previous

versions (including details of previous version dates).

4.1.1. 4 Date and country of first marketing authorization (if applicable).

4.1.2 Brief Description Of product, Including:

4.1.2. 1 The active substance(s)

4.1.2. 2 The pharmacological group (ATC code)

4.1.2. 3 Summary of mode of action

4.1.2. 4 Important information about the composition of the medicinal product

(origin of active substances of biologicals, relevant adjuvants /

residues in vaccines).

4.1.3 Indications And Target Population For Treatment:

4.1.3. 1 Approved indications

4.1.3. 2 Proposed indications -

In this section, the epidemiology of the indications should be discussed, including

occurrence, prevalence, mortality and comorbidity (including reference to age and

gender)




4.1.4 Dosage:

4.1.4. 1 Dosages approved

4.1.4. 2 Proposed dosages

4.1.5 Forms Of Administration And Strengths:

4.1.5. 1 Forms of administration approved

4.1.5. 2 Proposed forms of administration

4.2 Part Two – Important Safety Specifications

In this part, the safety specifications for the product shall be listed and divided into known

risk, potential risk and missing information. The relevant information shall be presented,

including planned activities for risk minimization as well as a summarizing table that will

include timelines for implementation in Israel.

Summary of Risk Management Plan by Safety Concern

Risk Risk minimization measures + Time for

implementation

Important identified risk:

Important potential risk:

Missing information:




4.2.1 This Part Will Include, If Necessary, Additional Safety Issues relevant to the

product For example:

4.2.1. 1 Quality aspects, if relevant, in the context of the safety and efficacy of

the product.

4.2.1. 2 Disposal of the medicinal product where it might pose a particular risk

because of a residue of the active substance (e.g. disposal of cytotoxic

products, disposal of patches containing an active substance to ensure

that children cannot reach them).

4.2.1. 3 Innovative pharmaceutical forms or combined use of a medicinal

device.

4.2.1. 4 If a particular medicinal product intended for use in women of

childbearing age, the information on reproductive toxicity/teratogenicity

or lack of information regarding pregnancy should be expressly stated,

and there should also be a discussion of the implications of use in this

population, the potential risks and about the missing information

respectively.

4.2.1. 5 In the event that additional studies are required as part of the terms and

conditions for registration of the product or the original RMP, they

should be stated in this section. If the product is subject to additional

monitoring in Europe USA / another recognized country in which it was

approved, this should be stated in this section

4.3 Part Three: Specification of risk management activities that were indicated in Section 4.2 and

planned for implementation in Israel and around the world (in accordance with an attached

reference). In this section, specify the activity plan for each risk (e.g. safety information card for




the patient, physician's guide, patient's guide, letter to physician, educational material, studies to

be conducted as required by the Risk Management Department etc.). Timelines for

implementation in Israel should be specified.

4.4 Part Four: Measuring the efficacy of risk minimization measures. This part will include a

reference to actions taken to measure efficacy of risk minimization measures around the world.

While specifying the activity and updating the department regarding the findings once received.

Additionally, it will include details of the activities planned in the future to measure efficiency of

risk minimization measures to be conducted in Israel as needed and pursuant to the Ministry of

Health's demand, as coordinated vis-à-vis the Marketing Authorization Holder (MAH).

4.5 Part Five: A brief summary of the RMP

When the RMP applies to more than one medicinal product, a summary of the RMP shall be

submitted for each product separately. An RMP may be submitted for several products together

when it involves the same active substance and indications, and provided that there is separate

reference to the unique potential risks to the various formulations and forms of the product's

administration.

4.6 Part Six: Appendices (e.g. safety information card for patient, physician's guide, patient's

guide, letters to the medical staff, training materials for medical staff etc.).

5. Timetables For Submission Of A Risk Management Plan Adapted To Israel

5.1 Upon Submission Of The Application For Registration Of A New Medicinal product :

5.1.1 The Appointed Pharmacist must attach to the registration portfolio the RMP as it

was submitted by the Marketing Authorization Holder (MAH) / manufacturer

outside Israel and / or approved by regulatory authorities such as the EMA or FDA

or another recognized country as specified above, as a hardcopy in a separate binder

and on a CD, at the time the registration file is submitted, in accordance with the

Memo of 27.8.2015 (65188015). The Registration Department shall forward the

RMP's to the Risk Management Department. For Medicinal products that do not

have an existing risk management plan see Section 3.1.2.2.




5.1.2 The Appointed Pharmacist will be notified if there is a need for a risk management

plan adapted to Israel upon receiving the Medicinal products Registration

Department’s approval for the submission of the registration file. The Appointed

Pharmacist will update the QPPV.

5.1.3 If it is decided that there is a need to submit a plan adapted to Israel, the Marketing

Authorization Holder (MAH) through the QPPV will submit a plan adapted to Israel

including all the adjuvant materials f to the Risk Management Department in

accordance with the details in this procedure within 45 days of receiving the notice

from the Pharmaceutical Division, unless another instruction is received from the

Ministry of Health. If there is a need to deviate from this time limit, the Risk

Management Department should be contacted.

5.1.4 The Risk Management Department shall update the Marketing Authorization Holder

(MAH) through the QPPV of its decision in respect of the submitted risk

management plan adapted to Israel within 30 days from receipt of the plan and

adjuvant materials. The Risk Management Department's decision regarding the plan

that was submitted shall include approval of the plan submitted or change therein,

removal or addition of risk management actions as it sees fit

5.1.5 In the event that the Risk Management Department's decision relates to a change to

the submitted plan, the Marketing Authorization Holder (MAH) shall submit the

changes required within 15 days from receipt of the notice. Nonetheless, the

Marketing Authorization Holder (MAH) may request a longer period of time to make

the changes. After submitting the changes, the Risk Management Department shall

review these changes within 15 days after receiving them.

5.1.6 It is important to note that in the event that the Marketing Authorization Holder

(MAH) receives an instruction to submit a risk management plan adapted to Israel

approval of the release of first batch shall be contingent upon approval of the RMP,

including all adjuvant materials ( e.g.: patient card, prescriber's guide etc.). Approval

of the plan and the adjuvant material will be sent in writing from the Risk

Management Department (Appendix 3).




5.1.7 Timetables for products that undergo a shortened registration track (70 or 180 days)

shall be shortened accordingly.

5.1.8 Timetables for products for which there is no risk management plan that was

submitted and/or approved by another regulatory authority will be determined by the

risk management department in co-operation with the Marketing Authorization

Holder (MAH).

5.1.9 Timetables for submitting a risk management plan adapted to Israel for generic

products will be determined by the risk management department in co-operation

with the Marketing Authorization Holder (MAH).

5.1.10 In cases of registering a medicinal product for which no reference has been made in

the sections above, contact the risk management department to receive individual

guidance.

5.1.11 For questions about method and date of submission, please contact the Risk

Management Department.

5.2 Authorised and Marketed Drugs – The QPPV will submit a Risk Management Plan

adapted to Israel upon demand by the Risk Management Department in accordance with

timetables determined in co-operation with the Marketing Authorization Holder (MAH).

Request for approval of an additional indication for an authorised medicinal product - In the

event it is decided that submission of a Risk Management Plan adapted to Israel is required,

the timetables to submit these products will be determined by the risk management

department in co-operation with the Marketing Authorization Holder (MAH). The

provisions above do not refer to updating medicinal products plans in respect of which a risk

management plan adapted to Israel is implemented.

6. Updating the Risk Management Plan

Pursuant to Regulation 26(b) of the Regulations, the Marketing Authorization Holder (MAH)

shall be responsible for monitoring the safety profile of the product. As a consequence the RMP

adapted to Israel must be updated if new relevant safety information arises. In the event of new

safety information that requires updating the plan, the Marketing Authorization Holder (MAH)

shall specify the nature of the update. The details will include inter alia the change in activities

to minimize the risks that were identified after marketing and timetables for implementation.




The email address to submit the updated risk management plan adapted to Israel is

[email protected].

Approval by the department must be received for the proposed timetables.

6.1 Updates Of A Risk Management Plan For A medicinal product For Which There Is A

Reference Approved by another regulatory authority

6.1.1 An update to an RMP for a product for which an RMP adapted to Israel that was

submitted with a reference as specified in Article 3.1.2.1 shall be submitted by the

QPPV upon receipt of new wording by the Marketing Authorization Holder (MAH) /

manufacturer outside Israel together with the reference or upon demand by the

Ministry of Health. This does not nullify the need for submitting an update to the plan

in the following cases:

6.1.1. 1 New information that is liable to affect the risk / benefit balance in a

significant manner, such as detection of a new signal / new safety

information, including detection of a signal arising from submission of a

periodic safety report or submission of final study results which is likely to

affect the RMP.

6.1.1. 2 A change in formulation (type 2) or new manufacturing process (Type 2) –

in these cases the risk assessment will be conducted by the Marketing

Authorization Holder (MAH)/ manufacturer. In the event it is decided on a

change likely to affect the safety or efficacy of a product, the Risk

Management Department shall be informed. The Risk Management

Department will decide whether there is a need to update the risk

management plan adapted to Israel and will submit written notice to the

Marketing Authorization Holder (MAH) thereof. This guideline does not

nullify the requirement to update the Institute for Standardization and

Control of Pharmaceuticals nor the duty to report the new safety

information in accordance with Procedure 6 Update 3 (October 2013).

6.1.1. 3 In the case of other changes which require approval by the Registration

Advisory Committee such as an additional dosage form and/or route of

administration, update of an indication including: treatment of new

category of disease or condition , change of target population such as new





age groups (e.g. children) or treatment of a milder form of indicated

disease (or vice versa) transition from second line to first line (or vice versa)

or a change in the dosage or treatment regimen , , the update to the risk

management plan adapted to Israel will be submitted to the risk management

department by the QPPV after approval of the change by the Registration

Advisory Committee

6.1.2 There is no need to submit an RMP update for which the RMP was not adapted to

Israel except in the following cases:

6.1.2.1 Update of a reference outside Israel that was submitted in the past to the

Pharmaceutical Division – in the event that the reference led to risk

minimization activity beyond routine pharmacovigilance activity, the update

to be submitted should include risk minimization activity decided upon and the

information on which it is based to the Pharmacovigilance and Drug

Information Department as it was submitted by the Marketing Authorization

Holder (MAH) and / or approved by regulatory authorities as stated above. The

Risk Management Department shall inform the Marketing Authorization

Holder (MAH) whether submission of an RMP adapted to Israel is needed.

6.1.2.1.1 In the event of updating a reference outside Israel that was not

submitted in the past to the Pharmaceutical Division, a report on the

update will be submitted in accordance with the guidelines on reporting

pursuant to Procedure 6 (Update 3, October 2013).

6.1.2.2 Submission of an application for approval of an additional indication –act in

accordance with Section 3.1.2.




6.2 Updating An RMP For A medicinal product For Which There Is No RMP Approved

By Another Regulatory Authority As Specified In Section 3.3.5

6.2.1 An update of the RMP adapted to Israel is necessary in these cases

6.2.1. 1 New information that is liable to affect the risk / benefit balance in a

significant manner, such as detection of a new signal or new safety

information, including a signal/information arising from submission of a

periodic safety report or submission of final study results which is likely to

affect the RMP.

6.2.1. 2

In the case of changes which require approval by the Registration Advisory

Committee such as an additional dosage form and/or route of administration,

update of an indication including: treatment of new category of disease

condition , change of target population such as new age groups (e.g.

children) or . treatment of milder form of indicated disease (or vice versa)

transition from second line to first line (or vice versa) or a change in the

dosage or treatment regimen , , the update to the risk management plan

adapted to Israel will be submitted to the risk management department by the

QPPV after approval of the change by the Registration Advisory Committee

6.2.1. 3 A change in formulation (type 2) or new manufacturing process (type 2)– in

such cases the risk assessment will be conducted by the Marketing

Authorization Holder (MAH) / manufacturer and if it is decided that the

change is likely to affect the safety or efficacy of the product, the

Pharmacovigilance and Drug Information Department shall be informed

thereof. The Pharmacovigilance and Drug Information Department will

decide if it is necessary to update the risk management plan adapted to Israel

and will submit written notice on this to the Marketing Authorization Holder

(MAH). This guideline does not nullify the requirement to update the the

Institute for Standardization and Control of Pharmaceuticals revision nor the

duty to report new safety information in accordance with Procedure 6

Revision 3 (October 2013).




6.3 submission of an update pursuant to a request by risk management and drug

information department

6.4 method of submission of an update for a risk management plan adapted to Israel

In the event that an RMP adapted to Israel was submitted in the past by the

Marketing Authorization Holder (MAH) of a product, any repeat submission thereby

shall be in the format of an update, unless requested otherwise by the Ministry of

Health.

6.4.1 The version number and date shall be indicated for every submission of an

RMP update adapted to Israel.

6.4.2 The updated RMP shall be submitted in a clean and "Track Changes" format

6.4.3 Appendix 2, which specifies the changes effected since submission of the

previous version and reference, shall be attached to the update.

7. Details of the Guidelines Pertaining to Supporting Materials for the RMP:

The supporting materials for a plan will include the approval date by the Ministry of Health /

update date and version number of the plan. There is no need to request approval for the

publication of supporting materials pursuant to the guidelines in Procedure 137.

7.1 Training of Medical Staff Plan

Specify the training subjects to be learnt, target audience and estimation of the number of

training sessions per year. Additionally, attach slides/ designated training material

concerning the safety of use of the drug.

7.2 Safety Information Card For The Patient:

7.2.1 The patient's safety information card is intended to minimize risks by supplying

important medical and safety information to the patient.

7.2.2 The patient's card adapted to Israel can be based on an existing

patient's card. If there is no such patient's card, you may use the




template below or in accordance with the guidelines of the Risk

Management and Drug Information Department.

7.2.3 The card will be submitted in Hebrew. After approval, it will also be

translated into Arabic and English pursuant to the emphases in this

procedure. It is also recommended to provide it in Russian and

Amharic.

7.2.4 After approval of the version, the risk management department's

approval is to be obtained for the card's graphic design.

7.2.5 Upon submitting the final supporting materials, the QPPV will

declare that the materials correspond with the final version approved

by the Ministry of Health.

7.2.6 Information about the availability of a patient's safety information

card shall also appear in prescribing information and PIL and the

prescribing information and PIL.

7.2.6.1 The following statement shall appear in the PIL:

In addition to this leaflet, there is also a safety information card concerning Product X for

the patient.

This card contains important safety information that you need to know before commencing

treatment with X and thereafter. The safety information card and PIL should be read before

beginning use of the product. The card should be kept for further review if necessary.

7.2.6.2 The following statement shall appear in the prescribing information:

Patient safety information Card

The marketing of X is subject to a risk management plan (RMP) including a 'Patient safety

information card'. The 'Patient safety information card', emphasizes important safety

information that the patient should be aware of before and during treatment. Please explain to

the patient the need to review the card before starting treatment.




7.2.7 Template for patient's safety information card:

The safety information card shall include the following clauses (as applicable):

7.2.7.1 General information:

7.2.7.1.1. Patient's particulars: Name, date of birth, address, phone and

additional relevant information in accordance with the drug, such as: Weight,

blood type and renal function.

7.2.7.1.2. Treating physician's particulars: Name, clinic or private phone no.

7.2.7.1.3. Family relative's particulars: Name, relation, phone no.

7.2.7.1.4. Emergency phone number (clinic / first aid).

7.2.7.2 Use of medication:

7.2.7.2.1 Date on which treatment was begun.

7.2.7.2.2 Indication

7.2.7.2.3 Dosage and times for taking medication. Including forgotten dose.

72.7.2.4 Special instructions in regard to discontinuation of treatment.

7.2.7.2.5 Instruction not to take medication including over – the – counter

medications or food additives without notifying the treating physician or consulting

with the pharmacist.

7.2.7.2.6 Information on possible adverse reactions, how to identify and deal with

them.

7.2.7.2.7 Indicate risk factors for these adverse reactions.

7.2.7.2.8 Guidelines for monitoring if necessary.

7.2.7.2.9 Referral on reporting adverse reactions to – Pharmacovigilance and Drug

Information Department with the following wording: Adverse reactions may be

reported to the Ministry of Health by means of the online form for reporting adverse

reactions located on the homepage of the Ministry of Health's website:




www.health.gov.il or by logging in to:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=

[email protected]

You may also add, the particulars of the manufacturer of medicinal product

to the report.

7.2.7.2.10 Referral to the PIL – study the PIL before beginning use of the product.

7.3 Prescriber's Guide:

The prescriber's guide is intended to minimize risks due to the medicinal product by

making important medical and safety information accessible to the treating medical

staff.

The guide shall be submitted in Hebrew (preferred) and / or English. The

information in the guide shall not contradict or differ from the information

contained in the approved prescribing information. In the event of a need to add

information not included in prescribing information, approval shall be received

from the Risk Management Department.

The guide adapted to Israel can be based on an existing guide. If a prescriber's guide

does not exist then use the template appearing below or in accordance with the

instructions of the risk management and drug information department.

The following wording will appear in the prescriber's leaflet:

Prescriber guide

This product is marketed with a prescriber guide providing important safety information.

Please ensure you are familiar with this material as it contains important safety information.

http://www.health.gov.il/

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType





The guide will include the following sections as applicable:

7.3.1 the most important safety information for the Physician prescribing the

drug:

7.3.1.1This part shall appear at the beginning of the guide in bold lettering.

7.3.1.2 This part will include the main safety information important for

preventing serious adverse reactions during treatment with the drug and for

wise use of the drug (e.g.: drug- interactions, emergencies requiring

discontinuation of the treatment, situations where close monitoring of the

medical treatment is needed, adapting dosages in different illness situations

etc.).

7.3.2 Indications

7.3.3 Contraindications

7.3.4 Medical Information

7.3.4.1 Manner and duration of use for each indications (if more than

one), adjusting dosages, forgotten dose.

7.3.4.2 Drug reactions (there is no need to specify all the reactions that

appear in the PIL, and it is preferable to emphasize especially severe

reactions or interactions with common drugs. Refer to additional

information in the consumer's leaflet.

7.3.4.3 Special populations – cautionary rules, adjusting dosage and

monitoring.

7.3.4.4 Overdose and relevant courses of treatment.

7.3.4.5 Referral to additional sources of information (prescribing

information, company website, phone numbers).




7.3.4.6 Notification about the patient's safety information card (if exists),

its significance and the importance of distributing it to the patient

accompanied by an appropriate explanation.

7.3.4.7 Referral to reporting of adverse reactions (according to the

following wording: Adverse reactions may be reported to the Ministry of

Health by means of the online form for reporting adverse reactions located

on the homepage of the Ministry of Health's website:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=

[email protected]

You may also add, particulars of the manufacturer to the

report.

7.4 Method of distribution of supporting materials to the plan (patient's safety

information card, prescriber's guide):

7.4.1 The patient's safety information card shall be distributed to the patient in the

Hebrew, English and Arabic languages (in accordance with the requirement

regarding i the PIL.) It is possible and recommended to also provide it in Russian

and Amharic. The prescriber guide will be distributed in the Hebrew and/or

English languages.

7.4.2 An electronic version of the patient's safety information card and

prescriber's guide shall be sent for posting on the Ministry of Health's

website.

7.4.3 The file must be in in PDF format. The file name should be called Patient safety

information card or Prescriber guide for XXXX medicinal product, and include

only English letters and numbers. To separate between words use the punctuation

marks: dash (-) or underline (_) only. Do not use letters in Hebrew, spaces,

punctuation marks such as: inverted comas, apostrophe, percentage, brackets, and

full stop.

7.4.4 The approved patient safety information card will be distributed to patients through

any means guaranteeing its receipt by the patient. The risk management and drug

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType





information department's approval is to be obtained regarding the distribution

method.

7.4.5 The distribution dates and medical institutions to whom the supporting materials

were distributed are to be documented.

7.4.6 Before beginning distribution of the supporting materials, the Marketing

Authorization Holder (MAH)'s representatives are to be instructed to mention the

existence of the patient safety information card and the prescriber guide in meetings

with doctors and pharmacists.

7.4.7 The medical staff shall receive the option to order supporting materials (patient's

safety information card and prescriber's guide).

7.4.8 When beginning distribution of the Risk Management Plan, the companies must

publish an announcement in the medical media about the important safety matters

and distribution of RMP materials, together with the adjuvant materials as detailed in

Section 3.3.10. This announcement must receive prior agreement from the Ministry

of Health

7.4.9 . The Marketing Authorization Holder (MAH) is responsible for the patient's welfare

and therefore it must act to ensure this in co-operation with the institutions to which

the product is supplied inter alia health funds and medical hospitals.

7.4.10 Copies of all versions of the approved supporting materials are to be saved for audit

and inspection.




Responsibility for Implementation:

Marketing Authorization Holder (MAH)s of the products

QPPV, Marketing Authorization Holder (MAH)s

Qualified pharmacists, Marketing Authorization Holder (MAH)s

Pharmaceutical Division – Ministry of Health

8 Applicable Documents:

Pharmacists Regulations (Products) 5746 1986

Guideline 6 – Reporting Adverse Reactions and New Safety Information Guideline 9 – First

Batch Procedure

Guideline on Good Pharmacovigilance Practice (GVP), Module V – Risk Management

Systems

9 Distribution:

CEO

Deputy CEO

Head of Administration for Medical Technologies and Infrastructures, Head of Public Head

of Medical Administration

Head of Quality of Service and Safety Administration




Head of Public Health Services

National Health Insurance Law Ombudsman

The Pharmaceutical Division

Office of the Legal Consultant

District Pharmacists – Jerusalem, Tel Aviv, Haifa, Center, North, South

The Institute for Standardization and Control of Pharmaceuticals

Manufacturers / Importers – Marketing Authorization Holder (MAH)s of Medicinal products,

The Manufacturers Association of Israel – Pharmaceutical Industry

Federation of Israeli Chambers of Commerce – Pharmaceutical Industry

Pharma Israel

Pharmacists Association – New Histadrut, Federation of Pharmacists – Pharmacy Dept.

Pharma Chains

Head of Pharmaceutical Services at Hospitals

Head of Pharmaceutical Services at Health Funds

Director of risk management at hospitals

Director of risk management at health funds

Director of drug surveillance at health funds

Director of drug surveillance Medical follow-up drugs in hospitals




Protocol Authors:

Dr. Dorit Diehl Nachlieli

Signature and Date:

Magister Einat Goralik

Michal Hirsch Vexberg

Dr. Denise Einbinder

Dr. Yael Zanziper Streichman

Protocol approved by:

Dr. Eyal Schwarzberg

Signature and Date:

We would like to thank Reuven Miller for his significant assistance with the translation

of this Procedure




Appendix 1

Declaration of QPPV regarding a Risk Management Plan (RMP) adapted to

Israel:

To: Pharmaceutical Division / Risk Management and Drug Information Department –

Product registration number ______ / ______ / __________ / ____

I, _________________, am responsible for pharmaceutical monitoring of Marketing Authorization Holder

(MAH) ________________________.

I am forwarding the Risk Management Plan adapted to Israel for product ___________

Report number _________________ for period from ____________ to _____________

I have read the plan and ensured that the following terms and conditions are fulfilled for the Risk

Management Plan adapted to Israel (please mark the appropriate box)

I apprised the Qualified Pharmacist of the main features of the plan and its components:

The risk management plan adapted to Israel is based on a reference approved by another regulatory

authority

____ The plan is based on the full risk management plan that served as a reference for this submission excluding

cases where other guidelines were given by the Ministry of Health.

_____The plan conforms to the Ministry of Health guidelines for a Risk Management Plan adapted to Israel.

_____ A comprehensive review was conducted of the relevant information pertaining to the safety chapter in the

RMP that was submitted.

____ For activities under the Risk Management Plan, defined timetables were set out for the activities

proposed.




The risk management plan adapted to Israel not based on a reference approved by another regulatory

authority

_____The plan conforms to Ministry of Health guidelines for a Risk Management Plan adapted to Israel.

_____A comprehensive review was conducted of the relevant information pertaining to the safety chapter in

the RMP that was submitted.

_____For activities under the Risk Management Plan, defined timetables were set out for the activities

proposed

Overall Risk Management Plan Adapted to Israel (Mark in appropriate place and attach as an appendix to the

Risk Management Plan):

□ Patient's safety information card

□ Patient's Guide

□ Prescriber's Guide

□ Training / educational sessions for healthcare professionals

□ Educational material

□ Restriction on marketing

□ Other (specify):

______________________________________________________________________________

______________________________________________________________________________

______________________________________________________________________________

Stamp and signature: __________________________ Date: _____________________________

Please briefly state the main actions to be taken in Israel to minimize risks, timetables and manner of

implementation:

Please indicate whether the Prescribing Information and PIL need to be updated in respect of the

relevant risks? Yes/ No

If yes – please specify the format and timetable for the update: ____________

If no – which risks are not included and why? ___________________

Stamp and signature: __________________________ Date: _____________________________




Appendix 2

Declaration of QPPV regarding Updating a Risk Management Plan (RMP)

Adapted to Israel: (Fill out this part only if an update of the plan is implemented)

To: Pharmaceutical Division / Risk Management and Drug Information Department –

Product registration number ______ / ______ / __________ / ____

I, _________________, am responsible for pharmaceutical monitoring of Marketing Authorization Holder

(MAH) ________________________.

I am forwarding the updated Risk Management Plan adapted to Israel for product ____________________

This includes the updated plan in a clean and "track change" version

Version number _______________ Update no. _______________ Submission date: _____________

Previous version no. and submission date:

___________________________________________________________________________

_____________________________________________________________

Nature of update (mark in appropriate space)

□ New information that is likely to affect risk balance / efficacy in a significant manner

□ Addition of new dosing form and / or new route of administration

□ Change and / or addition of indication including:

□ Treatment of new category of disease, change of target population such as new age groups (e.g.

children) or . treatment of milder form of indicated disease (or vice versa) illness, transition

from second line to first line (or vice versa) or a change in the dosage or treatment regimen ,

□ Change in formulation (type 2) or new manufacturing process (type 2)




□ Change in one or more of the components in the Risk Management Plan (such as patient's safety

information card / Prescribers Guide). Please specify: __________________________________

Other: ________________________________________________

Please specify briefly the nature of the update:

_____________________________________________________________________________

_____________________________________________________________________________

Please specify briefly the risk minimization activities that were added to this update, including timetables

and method of implementation in Israel. If, due to the update, changes are proposed in one or more of the

existing components of the plan (such as patient's safety information card, Prescribers Guide et al), they

should be attached as an appendix for approval by the Risk Management Department.

_____________________________________________________________________________

_____________________________________________________________________________

_____________________________________________________________________________

Please note whether the prescribing information and PIL require an update following an update of the

Risk Management Plan? Yes / No

If yes – please specify the wording and timetable for the update: _________________________

If no – please specify the reason(s): ________________________________________________

I declare that I apprised the Qualified Pharmacist of the update.

I am responsible for pharmaceutical monitoring

Stamp and signature: _______________________________ Date: _______________________




Appendix 3 Risk Management Department Approval for a Risk Management Plan

Adapted to Israel

To:

Person responsible for pharmaceutical monitoring, Marketing Authorization Holder (MAH):

_______________________

The Risk Management and Drug Information Department hereby approves the Risk Management Plan for

product _________________________ that was submitted on (date): ________________

The Risk Management Plan that was approved includes:

Patient's safety information card

Patient's Guide

Prescribers Guide

Training program

Letter to medical staff

Restriction on conditions of marketing

Other (specify):

This plan shall be implemented by (date): ____________________________________________

(If there are several target dates in accordance with the various actions required, please state them

separately):____________________________________________________________

Special remarks: ____________________________________________________________

This Risk Management Plan constitutes an integral part of the conditions for registration of a

product, and its approval is necessary for Approval of First Batch.

Approval: Date: _________________________ Signature: ________________________

Sincerely,

The Risk Management and Drug Information Department

Copies:

Director of Risk Management and Drug Information Department – Pharmaceutical Division

Director of Registration Department – Pharmaceutical Division

Department of Pharmaceutical Control

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