Enrico Marchesi Pharmacovigilance Consultant - ssfa.it _e... · the need for post-authorisation...

Enrico Marchesi – Pharmacovigilance Consultant

Milano, 17 marzo 2015

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Directive 2001/83/EC

“Requires the Applicant for a Marketing Authorisation to provide ……., where appropriate, the Risk Management System“

Directive 2010/84/EU

“The application shall be accompanied by the risk management plan describing the risk management system. The risk management system shall be proportionate to the identified risks and the potential risks of the medicinal product, and the need for post-authorisation safety data”.


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MAH shall be required to: operate a risk management system for each medicinal

product

monitor the outcome of risk minimisation measures which are contained in the risk management plan or which are laid down as conditions or requirements in the marketing authorisation …

update the risk management system and monitor pharmacovigilance data to determine whether there are new or changed risks or whether there are changes to the benefit-risk balance of medicinal products


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National Competent Authorities in collaboration with the Agency, shall take the following measures:

monitor the outcome of risk minimisation measures contained in risk management plans ….

assess updates to the risk management system


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Regulation 1235/2010

Pharmacovigilance Risk Assessment Committee (PRAC)

“The mandate of the PRAC shall cover all aspects of the risk management of the use of medicinal products including detection, assessment, minimisation and communication related to the risk”


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To improve the protection of public health

To understand the risks associated with medicinal products

To communicate identified risks more clearly

To implement measures that optimise benefit-risk of medicinal products


Risk Management System

A set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicinal products including the assessment of the effectiveness of those activities and interventions.

Risk Management Plan

A detailed description of the Risk Management System. It is a dynamic, stand alone document which should be updated throughout the life-cycle of the products.

7 Enrico Marchesi – Pharmacovigilance Consultant

Identified risk

“An untoward occurrence for which there is adequate evidence of an association with the medicinal product of interest”

Important identified risk

“An identified risk that could impact on the risk-benefit balance of the product, or have implications for public health”

Potential risk

“An untoward occurrence for which there is some basis for suspicion of an association with the medicinal product of interest but where this association has not been confirmed”

Important potential risk “A potential risk that could impact on the risk-benefit balance of the

product, or have implications for public health”


Risk minimisation activity = risk minimisation measure

“A public health intervention intended to prevent or reduce the probability of the occurrence of an adverse reaction associated with the exposure to a medicine or to reduce its severity should it occur.”


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Identify or characterise the safety profile of a product

Indicate how to characterise further the safety profile

Document measures to prevent or minimise the risks associated with the product

Document post-authorisation obligations that have been imposed as a condition of the marketing authorisation

Describe what is known and not known about the safety profile of a medicinal product

Indicate the level of certainty that efficacy shown in study populations will be seen in everyday medical practice and document the need for further studies on efficacy

Define risk minimisation measures

Plan how the effectiveness of risk minimisation measures will be assessed


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MAHs and applicants are responsible for:

“ensuring that it constantly monitors the risks of its medicinal products in compliance with relevant legislation and reports the results of this, as required, to the appropriate competent authorities”

“taking all appropriate actions to minimise the risks of the medicinal product and maximise the benefits including ensuring the accuracy of all information produced by the company in relation to its medicinal products, and actively updating and promptly communicating it when new information becomes available”


GVP V - § V.B.3.1.

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“Producing a RMP requires the input of different specialists and departments within and/or outside an organisation. The safety specification may require involvement of toxicologists, clinical pharmacologists, clinical research physicians, pharmacoepidemiologists and pharmacovigilance experts. The design of risk minimisation activities should involve people with expertise in communication and, where appropriate, patients and/or healthcare professionals. ……… Regardless of who prepares the RMP, the responsibility for the content and accuracy of the RMP remains with the marketing authorisation applicant/holder who should ensure oversight by someone with the appropriate scientific background within the company.”


GVP V - § V.B.3.1.

The purpose of the safety specification is to provide a synopsis of the safety profile that includes:

Description of what is known and not known

A summary of

– important identified risks

– important potential risks

– important missing information

Populations potentially at risk

Outstanding safety questions which warrant further investigation


Safety specification will form the basis of the pharmacovigilance plan and the risk minimisation plan.


The purpose of the pharmacovigilance plan is:

the identification of new safety concerns

further characterisation of known safety concerns

the investigation of whether a potential safety concern is real or not

how important missing information will be sought


It does NOT include actions intended to reduce, prevent or mitigate risks.

Pharmacovigilance activities can be:

Routine

Additional


Routine PV activities are:

the summary of product characteristics

the labelling

the package leaflet

the pack size(s)

the legal status of the product


Additional PV activities are based on: o The guideline for Good Pharmacoepidemiology Practices (GPP)

o ENCePP* guide on Methodological Standards in Pharmacoepidemiology

o The guideline on conduct of PV for medicines use by the paediatric population

o Efficacy in legislation for paediatric medicines and ATMP

“If additional risk minimisation activities are proposed, these should be detailed and a justification of why they are needed provided.”

“..... the burden of imposing additional risk minimisation should be balanced with the benefit for patients.”


* ENCePP: European Network of Centres for Pharmacoepidemiology and Pharmacovigilance

Additional PV activities

“Many additional risk minimisation tools are based on communication which aims to augment the information in the summary of product characteristics (SmPC) and the package leaflet. Any communication material should be clearly focused on the risk minimisation goals, and should not be confused or combined with promotional material for marketing campaigns.”

Enrico Marchesi – Pharmacovigilance Consultant 19

Objectives of the risk minimisation plan are:

routine risk minimisation activities

additional risk minimisation activities, individual objectives and justification

how the effectiveness of each (or all) risk minimisation activities will be evaluated

what are the criteria for judging success of risk minimisation

milestones for evaluation and reporting

Enrico Marchesi – Pharmacovigilance Consultant 20

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The description of risk minimisation measures should cover: Rationale

Objectives

Description

Implementation

Evaluation

“The success of risk minimisation activities in delivering these objectives needs to be evaluated throughout the lifecycle of a product to ensure that the burden of adverse reactions is minimised and hence the overall benefit-risk profile is optimised.”


GVP V - V.B.11.4.

To evaluate:

What risk minimisation activities are needed for each safety concern

The effectiveness of risk minimisation activities



SmPC and PIL

“The summary of product characteristics (SmPC) and the package leaflet are important tools for risk minimisation as they constitute a controlled and standardised format for informing healthcare practitioners and patients about the medicinal product.”


SmPC and PIL variations

Regulation IR 520/2012 Art. 2 (4)

“e) procedures for communicating safety concerns and safety variations to the summary of product characteristics and package leaflet to healthcare professionals and the general public”


SmPC and PIL variations

The need for communicating safety information should be considered throughout the pharmacovigilance and risk management process

To facilitate changes to healthcare practices (including self-medication practices)


Pack size

“Planning the number of “dosage units” within each pack, and the range of pack sizes available can be considered a form of routine risk management activity.”

“A small pack size can also be useful, especially if overdose is thought to be a major risk or if the potential for drugs to get into the general population needs to be controlled.”


Legal status

Restricted medical prescription

treatments that can only be followed in hospital conditions that must be diagnosed in hospital

environment or institutions with adequate diagnostic facilities

intended for outpatients but may produce very serious ADRs requiring specialist prescription and special supervision throughout the treatment


Legal status

Special medical prescription

narcotic or psychotropic substance substantial risk of medicinal abuse leading to

addiction or misuse substance which, due to its novelty or properties,

could be considered as belonging to above groups (precautionary measure)

Categorisation at Member State level

Member States can tailor the classifications described above to their national situation

Educational programme

Educational tools – targeting healthcare professionals

– targeting patients and/or carers

Controlled access programme

Other risk minimisation measures Pregnancy prevention programme

Controlled distribution systems

Direct health care professional communication (DHPC)


Educational programme “Ideally, educational materials should be available in a range of formats so as to ensure that access is not limited by disability or access to the internet”

“Any educational programme should be completely separated from promotional activities and contact information of physicians or patients gathered through educational programmes should not be used for promotional activities.”


Educational tools

“The information should focus on clearly defined actions related to specific safety concerns described in the RMP and should not be unnecessarily diluted by including information that is not immediately relevant to the safety concern and that is adequately presented in the SmPC or package leaflet.”


Educational tools (Patient alert card)

“The aim of this tool should be to ensure that special information regarding the patient’s current therapy and its important risks (e.g. potential life-threatening interactions with other therapies) is held by the patient at all times and reaches the relevant healthcare professional as appropriate.

The information should be kept to the minimum necessary to convey the key minimisation message(s) and the required mitigating action, in any circumstances, including emergency. Ability to carry with ease (e.g. can be fitted in a wallet) should be a key feature of this tool.”


Educational tools (Patient alert card)

information on current therapy and important risks to be held by the patient at all times

relevant healthcare professional is made aware of

minimum information to convey the key message and the mitigating action, including emergency situations.

easy to carry (e.g. can be fitted in a wallet)”


Controlled access programme should be guided by:

a clear therapeutic need based on its demonstrated benefit, to treat: – serious disease without alternative therapies – patients who have failed on existing therapies

the nature of the associated risk (e.g. life-threatening)

minimising an important risk with significant public health or individual patient impact


Controlled distribution systems

“A controlled distribution system refers to the set of measures implemented to ensure that the stages of the distribution chain of a medicinal product are tracked up to the prescription and/or pharmacy dispensing the product. Orders and shipments of product from a single or multiple identified distribution points in the EU facilitate traceability of the product.”


Pregnancy prevention programme scope:

to ensure that female patients are not pregnant when starting therapy

to prevent to become pregnant during the course and/or soon after stopping the therapy

It combines the use of educational tools with interventions to control access to the medicine.


DHCP

“..... important information delivered directly to individual HCPs to inform of the need to take certain actions or adapt their practices in relation to a medicinal product. “

Delivered by a marketing authorisation holder or by a competent authority

DHPC dissemination described in GVP Module XV


Efficacy

Time points of particular relevance are as follows:

after initial implementation of a risk minimisation programme (e.g. within 12-18 months), in order to allow the possibility of amendments, should they be necessary

in time for the evaluation of the renewal of a marketing authorisation

careful consideration of the need for continuing with the additional risk minimisation measure


Process indicators Measures of the extent of implementation of the

original plan, and/or variations in its delivery.

Outcome indicators Measures of success of a risk minimisation

programme.

Process indicators complement the assessment of the outcome indicators.


Process indicators

Reaching the target population

Assessing clinical knowledge

Assessing clinical actions


Outcome indicators

An example is: – incidence rate or cumulative incidence of an

adverse reaction, obtained for example in the context of post-authorisation safety studies

Spontaneous reporting should be considered with caution

“Scientific rigour and recognised principles of epidemiologic research should always guide the assessment of the final outcome indicator of interest.”


Quality system

“Although many experts may be involved in developing and implementing risk minimisation measures, the final responsibility for the quality, accuracy and scientific integrity of those measures and the plan describing them lies with the marketing authorisation holder and its qualified person responsible for pharmacovigilance in the EU (QPPV).”


MAH responsibilities

implement measures at national level after agreement with NCAs

provide information on their implementation status

keep NCAs informed of any changes, challenges or issues encountered in their implementation

agree with NCAs any relevant changes to the implementation

report in PSUR the results of the assessment of the effectiveness of risk minimisation measures

ensure timely communication with the CAs for relevant regulatory evaluation and actions


MAH responsibilities For generic products:

develop risk minimisation in line with the reference medicinal product

schedule and plan interventions, carefully coordinated with other MAHs, in order to minimise the burden on the healthcare systems

assess the effectiveness of risk minimisation measures in close cooperation with CAs


Post-Authorisation Studies:

PASS

Post-Authorisation Safety Studies

PAES Post-Authorisation Efficacy Studies

DUS Drug Utilization Studies*


*WHO (1977) «Marketing, distribution, prescription, and use of drugs in a society, with special emphasis on the resulting medical, social and economic consequences».

PASS

Directive 2001/83/EC art.1(15) defines PASS as a study:

to identify a safety hazard to characterise a known safety hazard to quantify a safety hazard to confirm the safety profile to measure the effectiveness of risk

management measures


PAES are studies requested by the CAs

where there are concerns about efficacy which can be resolved only after the product is marketed

when knowledge about the disease or the clinical methodology used to investigate efficacy indicate that previous efficacy evaluation may need significant revision


DUS are studies requested by the CAs or the Rapporteur/RMS

to monitor drug usage (prescribing behaviour) in their country, often in relation to reimbursement discussions

to provide useful information on: – effectiveness of risk minimisation activities

– demographics of target populations



Market survey

To assess clinical knowledge achieved by educational interventions and/or information provision (e.g. preventing drug exposure during

pregnancy)

Most appropriate data collection instruments

Standard questions can be administered through: – telephone contact – person interview – self-administered (postal/electronic communication)

Scientifically rigorous survey methods to be used


Market survey

Repeated over time Use of appropriate(*)

– research objectives – study design – sample size – representativeness

Surveys to be considered only for prescribing behaviour when no pre-existing data available

statistical analysis

(*) GVP XVI. Appendix 1. Key elements of survey methodology


PSUR frequency change

Directive 2010/84/EU Preamble Recital 23

“The periodicity is defined on the basis of a risk-based approach in order to prioritise the periodic re-evaluation of the risk-benefit balance of active substances in a way that best protects public health.”


Directive 2010/84/EU Art. 107c: ”The frequency with which the periodic safety update reports are to be submitted shall be specified in the marketing authorisation.”

Directive 2010/84/EU Art. 107e “A single assessment of periodic safety update reports shall be performed for medicinal products authorised in more than one Member State … for which a Union reference date and frequency of periodic safety update reports has been established.”



Directive 2010/84/EU Art. 107f: “Following the assessment of periodic safety update reports, the national competent authorities shall consider whether any action concerning the marketing authorisation for the medicinal product concerned is necessary. They shall maintain, vary, suspend or revoke the marketing authorisation as appropriate.”

Directive 2010/84/EU Art. 107g: “In the case of a single assessment … Pharmacovigilance Risk Assessment Committee, consider … maintenance, variation, suspension or revocation of the marketing authorisations…”



Additional monitoring

Legal requirement as per: – Regulation (EC) 726/2004 Art. 23 – Directive 2001/83/EC Art. 11 – GVP Module X

Enhancement of ADR reporting for – newly authorised products – products with newly emerging safety concerns


Additional monitoring

Collection of additional information as early as possible to further elucidate the risk profile

Quick identification of new safety information EMA to set up, maintain and make public a list

of such products Black inverted equilateral triangle

The summary of the RMP should contain

For each indication: Overview of disease epidemiology Summary of existing efficacy data

For the medicinal product Summary of safety concerns

– Important identified risks – Important potential risks – Important missing information

Summary of risk minimisation activities Planned post authorisation development plan Studies which are a condition of the marketing

authorisation Major changes to the Risk Management Plan over time


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RMP takes time, people and money

Make sure that stakeholders in your company understand the need for RMPs and what implications are for some departments (e.g. Senior Management, Clinical, Regulatory, Marketing, ….)

Does the company have the necessary expertise for each element of the RMP (e.g. Toxicologist, Pharmacologist, Pharmacoepidemiologist)?


To be considered

Some questions that need an answer

Who is the team? Who leads it?

What data are needed?

Who will provide what data? By when?

Who will provide expert content?

Who will write each section?

Who need to review and approve?

Budget for commitments

Who will pay for PASS or educational tools?

Who will pay for risk minimisation programmes?


To be considered

Enrico Marchesi Pharmacovigilance Consultant - ssfa.it _e... · the need for post-authorisation...

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