RMP and PSUR: a comprehensive article

In this comprehensive article, I write about RMP and PSUR, the drug safety brothers in arms! Though my intended primary focus for this article is RMP, you’ll find a lot of aggregate report relevance as well since both reports have many similarities and analogies.

-         It contains relevant information from many documents such as GVP modules 5, 7, XVI, ICHE2E, ICHE2C, GVP definitions module and 10+ presentations by TGA and SCOPE WP8 document on regulatory assessment of RMP.

-         The article uses some pictures from TGA presentation as they are compact and massively useful, all credit to them!

-         This article contains data/information from over 200 pages plus my original inputs!

-         Also, I have discussed how to derive safety concerns for RMP and PSUR both.

-         In the end, various special scenarios are discussed such as RMP requirements in the US and in Australia.

-         Also tried to cover an interesting topic: How RMP and PSUR go hand in hand together!

-         The difference between these terms: Regulations vs directives

-         Key similarities and differences in these two documents.

-         Public health impact as per PSUR and RMP.

-         Working in aggregate reports for such a long time, RMP becomes an integral part of life and RMP people become your best friends and knowledge sharing partners!

-         DSRM would involve both RMP and PSUR anyway.

-         It always helps to know and understand RMP better while working in aggregate teams!

-         While the article tells an awful lot about RMP, PSUR always shows up everywhere in the article since I’m basically the creature of PSUR ??

Pls do read and share your thoughts too!

 RMP is a prospective dynamic lifecycle document, here’s why;

As knowledge regarding a medicinal product’s safety profile increases over time, so will the risk management plan change.

Overview of RMP and what RMPs contain:

The aim of a risk management plan (RMP) is to document the risk management system considered necessary to identify, characterize and minimize a medicinal product’s important risks.

To this end, the RMP contains:

1.      The identification or characterization of the safety profile of the medicinal product, with emphasis on important identified and important potential risks and missing information, and also on which safety concerns need to be managed proactively or further studied (the ‘safety specification’);

2.      The planning of pharmacovigilance activities to characterize and quantify clinically relevant risks, and to identify new adverse reactions (the ‘pharmacovigilance plan’);

3.      The planning and implementation of risk minimization measures, including the evaluation of the effectiveness of these activities (the ‘risk minimization plan’).

 Most important overall principle of RMP is to ensure benefit of a product exceeds risk by the greatest achievable margin as possible for:

1.      Individual patients

2.      Population as a whole.

Principle of RMP stays same regardless of stakeholders and across territories.

Objectives of RMP

As per IR 520/2012, elements of RMP include:

·        Identify and characterize safety profile of a product

·        Indicate how to further characterize the safety profile

·        Document measurements to prevent or minimize the risks associated with use of the product

·        Document post-authorization measurements which are obligations as per approval at the time of granting marketing authorization.

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

·        Indicate level of certainty to which the efficacy shown in clinical trial populations will also be seen when product is used in the general population

·        Indicate how the effectiveness of the Risk Minimization Measures (RMMs) will be ascertained

RMP is a legally binding document (just like PSUR)

Legal basis of RMP (also same as PSUR):

·        Regulation (EC) No 726/2004

·        Directive 2001/83/EC

·        Commission Implementing Regulation (EU) No IR 520/2012

Additionally, relevant ICH document for RMP is ICHE2E.

RMP document = written agreement applied as a condition of registration

An applicant/marketing authorisation holder is responsible for: having an appropriate risk management system in place.

Important to understand the difference between these terms: Regulations vs directives

Regulations:

Regulations have binding legal force throughout every Member State and enter into force on a set date in all the Member States.

·        Immediately applicable and enforceable by law in all Member States

·        As good practice, Member States issue national legislation that defines the competent national authorities, inspection and sanctions on the subject matter

·        Individual states get no choice, results are defined and so are means to reach there.

·        Example: Regulation (EC) No 726/2004 (useful for both PSUR and RMP)

Directives:

Directives lay down certain results that must be achieved but each Member State is free to decide how to transpose directives into national laws.

·        Sets a process for it to be implemented by Member States

·        National authorities must create or adapt their legislation to meet these aims by the date specified in each given Directive

·        However, it is up to the individual countries to devise their own laws on how to reach these goals.

·        In short defined results can be achieved with some autonomy to member states on how to reach there.

·        Example: Directive 2001/83/EC (relevant for both PSUR and RMP)

Decisions are EU laws relating to specific cases and directed to individual or several Member States, companies or private individuals. They are binding upon those to whom they are directed.

·        Decisions are targeted and not generalized.

·        For example: Commission Implementing Regulation (EU) No IR 520/2012

Recommendations:

·        These are non-binding.

·        Not legally enforceable.

·        Ideal if followed with no legal consequences if not followed.

·        PVG example would be GVP modules

·        Also if you read FDA documents, they write ‘contains non-binding recommendations/ guidelines’ at the top of all such documents on each page, no hiding stuff there!

·        A recommendation allows the institutions to make their views known and to suggest a line of action without imposing any legal obligation on those to whom it is addressed.

Opinions:

·        An "opinion" is an instrument that allows the institutions to make a statement in a non-binding fashion, in other words without imposing any legal obligation on those to whom it is addressed. An opinion is not binding.

·        While laws are being made, the committees give opinions from their specific regional or economic and social viewpoint.

Structure of the RMP:

-         The RMP consists of seven parts.

-         Part II of the RMP contains eight modules.

Level of information to be included in RMP:

The amount of information, particularly in RMP part II, should be proportionate to the identified risk and the potential risk, and will depend on:

·        The type of medicinal product

·        Its risks

·        Where it is situated in its life cycle

The most famous picture in RMP vertical: The risk management cycle (from TGA):

RMP and PSUR: Drug safety brothers in arms ??

Similarities between RMP and PSUR:

·        RMP and PSUR both are legally binding documents.

·        Post-authorization pharmacovigilance/ safety documents.

·        Both are lifecycle documents.

·        Both RMP and PSUR share same legal basis namely: Regulation (EC) No 726/2004, Directive 2001/83/EC and Commission Implementing Regulation (EU) No IR 520/2012.

·        The RMP document includes all relevant medicinal products from the same applicant/marketing authorisation holder containing the same active substance, same for PSUR.

·        Sections are analogues in RMP and PSUR such as summary of safety concerns, risk characterization, patient exposure, worldwide actions taken by the regulatory, Risk minimization measures and effectiveness of RMM and clinical trials exposure.

RMP and PSUR key differences:

·        Relevant ICH document for PSUR is ICHE2C and for RMP it is ICH E2E.

·        PSUR is based on GVP module 7 whereas for RMP, relevant GVP is module 5.

·        PSUR is a global retrospective review document which identifies and clarifies what happened in report period (what happened in the past), whereas RMP is a prospective proactive planning document that includes plan to deal with identified risks (What are we gonna do about it?). As a consequence, the lists of safety concerns in the RMP and PSUR might differ and that is okay!

·        Focus of PSUR is retrospective review of integrated risk benefit analysis whereas RMP is proactive prospective plan to deal with known risks and identify and further characterize little known risks.

·        As per revised module 5: PSUR and RMP modules may contain similar information, however, may not be in identical format and may not be interchangeable.

 GVP Module VII is applicable for the purpose of risk classification in the PSUR. Therefore, the definitions in GVP Module V should generally not be used for the purpose of risk reclassification in the PSUR.

 When RMP/ update to RMP is required?

A Risk Management Plan (RMP) may be submitted at any time of a product’s life-cycle, that is: during both the pre-authorisation and post-authorisation phases.

·        Since July 2012, all new marketing authorisations (MAs) applications should include an RMP.

·        Update is required when new safety concerns are identified.

·        When significant changes to the MA occurs.

·        Whenever new data are provided as part of a regulatory application in the post-authorisation setting, the MAH should consider whether consequential significant changes to the RMP are needed.

·        New or a significant change in the existing additional pharmacovigilance or additional risk minimisation activities.

·        When an emerging safety issue is still under assessment (as defined in GVP Module VI), in particular in the context of a signal or potential risk that could be an important identified risk, an RMP update may be required if the emerging safety issue is confirmed and the important identified or potential risk requires to be added to the list of safety concerns in the RMP.

·        The frequency of RMP updates should be proportionate to the risks of the product.

·        In general, the focus of RMP updates should be on the risk minimisation measures and in providing updates on the implementation of risk minimisation measures where applicable. If there is a consequential change to the summary RMP, this should also be highlighted in the cover letter.

·        Changes to the product information should not be proposed via a standalone RMP update, but rather a variation application should be submitted.

·        A PSUR can also result directly in an update to product information (if PSURs are being submitted by the marketing authorisation holder for a given generic product), however, this was countered in EMA explanatory note later.

Examples of situations warranting RMP updates:

·        A change in study objectives

·        Population

·        Due date of final results

·        A due date for protocol submission for an imposed study

·        Addition of a new safety concern in the key messages of the educational materials would be expected to be reflected in an updated RMP.

Experience with PSUSAs shows that very old products authorized through old regulatory routes may include safety profiles which are not fully defined, hence RMP may be required.

MAH responsibilities for RMP:

Who is responsible for the RMP?

The MAH is responsible for the RMP and their responsibilities includes the following:

·        Developing a RMP

·        Updating the RMP as new safety information emerges

·        Implementing the activities and interventions outlined in the RMP

·        Collecting information and performing an analysis regarding the efficacy of these activities and interventions

·        Communicating this information to the regulatory authorities in a timely manner.

Lifecycle of an event in PVG:

-         This is a very interesting topic to understand.

-         What is the ultimate goal of whole DSRM activity: appropriate inclusion of an event in the RSI/SmPC/PI

-         When regulators or MAH become aware of potential association of an event with a drug --> Event under monitoring in section 15 of PBRER --> Signal --> Risk (safety concern) --> Variation --> Inclusion in the PI/SmPC in an appropriate section.

-         Inclusion of any event in section 4.8 Undesirable events of the RSI/SmPC is the highest degree of PVG by all means!

Use of RMP while drafting PSUR:

·        For all reports, ask client and internal RMP team if RMP is available for PSUR/PBRER molecule you’re drafting report.

·        Procure the same using official emails if available!

·        Confirm from client if RMP is approved, and can be used in our report.

·        Check the RMP sections esp. risk characterization, if same safety concerns are mentioned and RMP is approved for use by client, check for safety concerns section.

·        Also check if used RSI is same for both RMP and PSUR.

·        Look into level of details in risk characterization, if it is sufficient then thank god profusely and bless your RMP team because it’ll save a lot of time @ PSUR team end; and the prepared document will always get good quality score and fly through audit and inspections ??

Medical review section 16.4 and use of RMP information:

·        Background incidence/prevalence

·        Risk factors

·        Prevention

·        Impact on individual patients

·        Potential public health impact sections can be used from RMP if available in 16.4.

·        Additionally, information from RMP part II module SVI epidemiology of indications, can be used to draft section 18.1 of PSUR Medical need and alternative treatments!

RMP updates with PSUR:

·        When PSUR and RMP are submitted together: The RMP should reflect the conclusions of the accompanying PSUR.

·        In a situation, when preparing a PSUR, if there is a need for changes to the RMP as a result of new safety concerns, or other data presented in the PSUR, then an updated RMP should be submitted at the same time. In this case no stand-alone RMP variation is necessary.

·        Timing for submission of both documents may coincide, but if the changes are not related to each other, then the RMP submission should be handled as a stand-alone variation. 

·        In the context of a PSUSA, submission of RMP updates cannot be accepted together with the PSURs of medicinal products (centrally and/or nationally authorised).

·        Marketing authorisation holders should take the opportunity of another upcoming procedure to update their RMP. Alternatively, marketing authorisation holders should submit a separate variation to update their RMP. 

·        For nationally authorised medicinal products, RMP updates should be submitted to the competent authorities in the Member States for assessment.

Pharmacovigilance Plan:

Pharmacovigilance objectives:

-         Monitor the occurrence of known risks post-approval

-         Identify new and unknown risks that were not apparent in clinical development

-         Gain an understanding of ‘real world use’ vs clinical study use

-         Further inform and characterise the safety profile of the medicine.

Safety specifications section:

Source: ICHE2E

The purpose of the safety specification is to provide an adequate discussion on the safety profile of the medicinal product(s), with focus on those aspects that need further risk management activities.

The heart of the RMP: Safety concerns

RMP part II, module SVII Identified and potential risks

The single most important part of RMP as this module provides a focussed discussion on the identification of important identified and important potential risks, and missing information (i.e. safety concerns).

Points to consider for deriving safety concerns:

·        One of the most intellectually rigorous task if you are working in DSRM (Drug Safety and Risk Management) verticals (E.g. PSUR and RMP).

·        Mostly it is a medical reviewer activity/ duty.

·        This is relevant for both RMP and PSUR medics.

·        Consultation with manager or even QPPV may be required.

·        Clients may at times become ‘protective’ of their molecule, but this is counter-productive big time.

·        If a theme of ‘hiding stuff’ is noticed, this would cause major perception deficit when it comes to how methodology and rigour for report are received by regulators.

·        The more thorough and evidence-based approach, the better reports are (RMP and PSUR both).

 Safety concerns:

What changed with reference to safety concerns in GVP module 5 Rev 2?

Important identified risks:

·        Identified risk is an untoward occurrence for which there is adequate evidence of an association with the medicinal product of interest.

·        An identified risk that could have an impact on the risk-benefit balance of the product or have implications for public health is considered important identified risk.

·        From all the identified risks of the medicinal product, the RMP should address only the risks that are undesirable clinical outcomes and for which there is sufficient scientific evidence that they are caused by the medicinal product.

·        Risk may not be “important” if it is infrequent, non-serious, reversible, and readily managed with no significant impact on the individual patients or public health.

·        A common ADR may not constitute an important risk if it is not linked to clinically significant adverse sequelae.

·        An adverse reaction adequately demonstrated in non-clinical studies and confirmed by clinical data;

·        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 a parameter of interest suggests a causal relationship;

·        An adverse reaction suggested by 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

·        Non-clinical findings confirmed by clinical data, clinical trials, epidemiological studies, and spontaneous data sources, including published literature.

·        They may be linked to situations such as off label use, medication errors or drug interactions.

·        Not all reported adverse reactions are necessarily considered a relevant risk of the product in a given therapeutic context.

·        To be considered as important identified risk, adequate causal association should be indicated in RSI section 4.4 (warning and precautions), 4.5 (drug interactions)/ 4.6 (pregnancy and lactation) AND the event should also be mentioned in section 4.8 (Adverse reactions/undesirable events) of the RSI.

·        This is important to understand, inclusion of any event in section 4.8 of the RSI itself is indicative of the fact that cases of the event are already identified.

·        If event is not mentioned in 4.8 but just in 4.4/4.5/4.6, we should refrain from considering it as an important identified risk.

·        Important: Adverse reactions included in section 4.8 of the summary of product characteristics (SmPC) are also considered identified risks (but not all of them are important identified risks).

Regulatory thinking on safety concerns:

·        As per SCOPE WP8 document, this is what regulators look for while reviewing proposed safety concerns: Ask yourself if the risk is potentially so serious and so frequent that it could impact on the B/R of the product, or that specific guidance/tools are needed to ensure correct use of the medicine.

·        A risk may not be “important” if it is infrequent, non-serious, reversible and readily managed with no significant impact on the individual patients or public health.

·        A common ADR may not constitute an important risk if it is not linked to clinically significant adverse sequelae.

Important potential risks:

·        Any potential risk that could have an impact on the risk-benefit balance of the product or have implications for public health is important potential risk.

·        Difference here is there is suspicion of association of the product and an adverse event which is not proven yet for potential risks.

·        Identified risk means evidence of association between the drug and event (such as cases/ section 4.8 of RSI), whereas potential risk means suspicion of association between drug and event which is yet to be proven.

Examples of important potential risks:

·        Non-clinical evidence of an AE that is not yet proven in clinical trials

·        Drug class effects

·        ‘Use in risks’ (such as use in special population for example, use in elderly, use in paediatric patients, use in patients with liver impairment, use in patients with renal impairment etc)

·        Events mentioned in SmPC/RSI sections 4.4,4.5 or 4.6 but not in 4.8

·        Events can occur but cases of them are not yet identified

Missing information:

Not all unknown particulars can be considered as missing information.

Missing information relevant to the risk management planning refers to:

-         Gaps in knowledge about the safety of a medicinal product for certain anticipated utilisation (e.g. long-term use) or for

-         Use in particular patient populations, for which there is insufficient knowledge to determine whether the safety profile differs from that characterised so far.

-         To be considered a missing information, sufficient reason should be provided on why safety profile may differ in population (e.g. hepatic/renal impairment, children/elderly or pregnant women).

The absence of data itself (e.g. exclusion of a population from clinical studies) does not automatically constitute a safety concern.

Regulatory thinking on missing information as per SCOPE WP8 document:

• Usually we only want to specify something as missing information if we want to study exposure in those patient groups further.
• Subgroups of the targeted populations that are expected to frequently use the product and are not included in the clinical development program can be considered as missing information, e.g. patients with impaired renal and hepatic function, children, elderly, pregnant and lactating women, off-label use.
• Exclusion criteria should not automatically translate into missing information.
• The assessor should rather consider clinical relevance and likely real-world use to be of importance for the missing information.
• If the indication implies chronic use, long-term use should be considered as missing information if not studied.
• If studies of relevant drug-drug interaction have not been done, this should be considered as possible missing information.

 Key sources for proposing safety concerns:

·        CmDH (as available from https://www.hma.eu/464.html )

·        EPAR

·        Previous report (PSUR/RMP)

When safety concerns are required to be proposed?

• If none of the above is available or CCDS is recently updated and RMP is not as per current safety information, medical reviewer may need to propose safety concerns.
• Safety sections of the RSI provide the basis for safety concerns in such situations.

RSI is the single most important key routine risk minimization tool!

Safety sections of the RSI (4.3 to 4.8) include:

·        4.3 Contraindications

·        4.4 Warnings and precautions

·        4.5 Drug interactions

·        4.6 Pregnancy, lactation and fertility

·        4.7 Effects on ability to drive and use machines

·        4.8 Undesirable effects/ Adverse events

Based on inclusion of relevant information in RSI, safety concerns can be proposed accordingly.

Proposing/deriving safety concerns based on RSI/SmPC:

We can simplify the formula:

·        Section 4.4 + Section 4.8= Important identified risk

·        Just section 4.4/ 4.5/ 4.6 or if mentioned as a drug class effect= Important potential risk

·        Impact on individual patient is one parameter we need to consider when proposing risk characterization as well.

Safety topics (Identified and potential risks) of interest:

Safety topics derived from specific situations/data sources are thought to be of particular interest for the risk identification discussion in module SVII, and should be discussed such as:

·        Overdose: Potential harm from overdose, whether intentional or accidental, for example in cases where there is a narrow therapeutic margin or potential for major dose-related toxicity, and/or where there is a high risk of intentional overdose in the treated population (e.g. in depression).

·        Medication error: Potential for risks resulting from medication errors, defined as an unintended failure in the drug treatment process that leads to, or has the potential to lead to, harm to the patient. Medication errors leading to important risks, identified during product development including clinical trials, should be discussed and information on the errors, their potential cause(s) and possible remedies given.

·        Infection spread: Scenario in which due to the nature of the manufacturing process or the materials involved, inherent chance of infection spread is identified.

·        Off-label use: potential for off-label use, when differences in safety concerns between the target and the off-label population are anticipated, the potential risks arising from the off-label use

·        Drug class effect risks: If an important identified or potential risk common to other members of the pharmacological class is not thought to be an important identified or important potential risk with the concerned medicinal product, the evidence to support this should be provided and discussed.

·        Risks in pregnant and lactating women, e.g. teratogenic risk: Direct or through exposure to semen.

·        Effect on fertility - appropriate risk minimisation measures should be considered.

·        Risks associated with the disposal of the used product (e.g. transdermal patches)

·        Risks related to the administration procedure (e.g. risks related to the use of a medical device (malfunction which impacts on the dose administered, risk of variability in complex administrations)

·        Paediatric safety issues that are particular causes of concern in paediatric population.

·        Drug interactions: important risks related to identified and potential pharmacokinetic and pharmacodynamic interactions should be discussed in relation to the treatments for the condition, but also in relation to commonly used medications in the target population.

Sections “Risk considered important for inclusion in the list of safety concerns” and “Risk not considered important for inclusion in the list of safety concerns:

Whether to consider a risk important or no depends on various factors, such as:

-         Risk seriousness

-         Risk frequency

-         The risk-benefit impact of the risks.

For risks not taken forward as safety concerns, the information can be grouped by reasons for not including them as safety concerns.

RMP Presentation of important identified risks and important potential risks data:

-         Name of the risk (using MedDRA terms when appropriate)

-         Potential mechanism

-         Evidence source(s) and strength of the evidence (i.e. the scientific basis for suspecting the association);

-         Characterisation of the risk: e.g. frequency, absolute risk, relative risk, severity, reversibility, long-term outcomes, impact on quality of life;

-         Risk factors and risk groups (including patient factors, dose, at risk period, additive or synergistic factors);

-         Preventability (i.e. predictability of a risk; whether risk factors have been identified that can be minimised by routine or additional risk minimisation activities other than general awareness using the PI; possibility of detection at an early stage which could mitigate seriousness);

-         Impact on the risk-benefit balance of the product;

-         Public health impact (e.g. absolute risk in relation to the size of the target population and consequently actual number of individuals affected, or overall outcome at population level).

The recurrent theme of RMP: Susceptible population

·        If you notice, there’s an underlying theme in the topics above namely, the affected susceptible population.

·        This topic is of utmost importance in particular for RMPs: the potential susceptible population.

·        To measure and estimate this population, sound medical judgment is required.

·        There are no defined rules or guidelines or formulas available to define and measure susceptible population.

·        However, there are some common-sense truisms: like susceptible population to any genetic disorder would simply be less compared to susceptible population for a medical condition like diabetes!

·        This concept leads to another most important topic, relevant for both RMP and PSUR section 16.4: Potential public health impact:

Potential public health impact (RMP and PSUR) :

EMA Q and A PSUR document question 13.5 provides insight on how to write public health impact.

In RMP, public health impact is considered based on:

-         Absolute risk in relation to the size of the target population

-         Consequently, actual number of individuals affected

-         Overall outcome at population level

Public health impact in PSUR:

Q: In Section 3.16.4 (Characterization of Risks) of the ICH E2C(R2) Guideline, “public health impact” is listed as one of the points that can be included in characterizing an important risk. What factors should the MAH consider in providing this information for the purposes of Section 16.4 of the PBRER?

Answer:

·        This is a complex undertaking that takes into account multiple factors and considerations.

·        In Section 16.4 of the PBRER, the MAH should present its evaluation of the public health impact of the risk as part of the characterization of important risk(s) for the purposes of the PBRER.

In assessing the public health impact of individual risks, the MAH should consider the following points that are intended to be illustrative rather than comprehensive:

?            Extent of product use (size of treated population)

?            Frequency

?            Health consequences (including consideration of seriousness, preventability, and reversibility).

?            Characterization of risk should include consideration of the impact on the individual patient, as well as on the overall population.

Important point to consider is information from the MAH database.

·        While susceptible population may remain same based on underlying indications, details of cases from MAH database adds value and provides context for public health impact in PSUR.

·        In PSURs, cumulative case count would be one factor that needs to be taken into account invariably while proposing potential public health impact.

·        However, proposing potential public health impact just on the basis of MAH case count is never sufficient as there is no clear scope for generalization based on this case count alone.

·        Hence, rationale for public health impact should always include cumulative case count plus formula!

·        Public health impact= Cumu case count/reporting frequency from MAH database + Health consequences for individual patients + Susceptible population (incidence/prevalence)

·        While there is noting set in stone about rules of proposing public health impact and no fixed guideline is available for the same, the above formula can provide some criteria ??

·        Public health impact is obviously important in eyes of regulators and sound medical judgment and clear rationale is required for public health impact to be accepted by them.

·        Public health impact provides basis for risk benefit profile of a product and thus forms a very important and somewhat controversial part of PSUR and esp RMP.

·        As per SCOPE WP8 assessor guidance document: assessors have to consider same rationale as above while reviewing potential public health impact (Same regulatory thinking for both PSUR and RMP with regards to potential public health impact) which is: In assessing the public health impact of individual risks, one should consider the following points, which are intended to be illustrative rather than comprehensive: extent of product use (size of treated populations), frequency and health consequences (including consideration of seriousness, preventability and reversibility).

Life of a safety concern in RMP:

Risk minimization activities:

·        Risk minimisation measures are interventions intended to prevent or reduce the occurrence of adverse reactions associated with the exposure to a medicine, or to reduce their severity or impact on the patient should adverse reactions occur.

·        Planning and implementing risk minimisation measures and assessing their effectiveness are key elements of risk management.

·        Risk minimisation measures may consist of routine risk minimisation or additional risk minimisation measures.

·        Routine risk minimisation is applicable to all medicinal products, and involves the use of different tools, which are described in detail in GVP Module V.

·        Additional risk minimisation measures are described in detail in GVP Module XVI.

·        Safety concerns of a medicinal product are normally adequately addressed by routine risk minimisation measures.

·        In exceptional cases however, routine risk minimisation measures will not be sufficient for some risks and additional risk minimisation measures will be necessary to manage the risk and/or improve the risk-benefit balance of a medicinal product.

·        Risk minimisation measures aim to optimise the safe and effective use of a medicinal product throughout its life cycle.

·        The risk-benefit balance of a medicinal product can be improved by reducing the burden of adverse reactions or by optimising benefit, through targeted patient selection and/or exclusion and through treatment management (e.g. specific dosing regimen, relevant testing, patient follow-up).

·        In determining if additional risk minimisation activities are needed, safety concerns should be prioritised in terms of frequency, seriousness, severity, impact on public health and preventability.

·        Careful consideration should then be given to whether the goal can be reached with routine minimisation activities, and, if not considered sufficient, which additional minimisation measure(s) is (are) the most appropriate.

·        Additional risk minimisation measures should focus on the most important, preventable risks and the burden of imposing additional risk minimisation should be balanced with the benefit for patients.

·        Successful implementation of additional risk minimisation measures requires contributions from all stakeholders, including marketing authorisation applicants/holders, patients and healthcare professionals.

·        Clear objectives and defined measures of success with milestones need to guide the development of additional risk minimisation measures, and close monitoring of both their implementation and ultimate effectiveness is necessary.

·        The nature of the safety concern in the context of the risk-benefit balance of the product, the therapeutic need for the product, the target population and the required clinical actions for risk minimisation are factors to be considered when selecting risk minimisation tools and developing an implementation strategy to accomplish the desired public health outcome.

·        The evaluation of effectiveness should facilitate early corrective actions if needed and may require modifications over time.

How does RMM work (by TGA) :

Types of risk minimisation activities:

-         Risk prevention – identifying those at particular risk through testing and not prescribing, adjusting dose etc.

-         Risk mitigation – usually relies on monitoring during therapy to identify increase risk and allow intervention

-         Neither preventable or able to be mitigated – may be acceptable depending on risk-benefit profile

Points to consider for proposing RMM:

Each safety concern needs to be individually considered and the selection of the most suitable risk minimisation measure should take into account:

·        The seriousness of the potential adverse reaction(s)

·        Severity (impact on patient)

·        Preventability

·        Clinical actions required to mitigate the risk

·        The indication

·        The route of administration

·        The target population

·        The healthcare setting for the use of the product.

Who should monitor effectiveness of RMM:

·        Directive 2001/83/EC indicates that the marketing authorisation holder shall “monitor the outcome of risk minimisation measures which are contained in the risk management plan or which are laid down as conditions of the marketing authorisation.

·        The Directive and Regulation (EC) No 726/2004 also include provisions for the Agency and the national competent authorities to monitor the outcome of risk minimisation measures which are contained in the risk management plans (RMPs) or measures that are laid down as conditions.

Additional risk minimisation measures:

·        Rationale: When additional risk minimisation measure(s) are introduced a rationale should be provided for those additional measures;

·        Objectives: Each proposed additional risk minimisation measure(s) should include defined objective(s) and a clear description of how and which safety concern is addressed with the proposed additional risk minimisation measure(s);

·        Description: This section of the RMP should describe the selected additional risk minimisation measures, including tools that will be used and key elements of content;

·        Implementation: This section of the RMP should provide a detailed proposal for the implementation of additional risk minimisation measures (e.g. setting and timing or frequency of intervention, details of the target audience, plan for the distribution of educational tools; how the action will be coordinated where more than one marketing authorisation holder is involved);

·        Evaluation: This section of the RMP should provide a detailed plan with milestones for evaluating the effectiveness of additional risk minimisation measures.

More about ARMM:

Additional risk minimisation measures may differ widely in purpose, design, target audience and complexity.

These measures might be used to guide appropriate patient selection with the exclusion of patients where use is contraindicated, to support on-treatment monitoring relevant to important risks and/or management of an adverse reaction.

Examples of ARMM:

·        Educational programmes

·        Controlled access programmes

·        Other risk minimisation measures

Educational programs:

·        Targeted communication with the aim to supplement the information in the SmPC and PL.

·        Any educational material should focus on actionable goals.

·        Provide clear and concise messages describing actions to be taken in order to prevent and minimise selected risks.

·        Educational materials should therefore be built on the premise that there is an actionable recommendation for targeted education and that applying this measure is considered essential for minimising an important risk and/or for optimisation of the risk-benefit balance.

·        Can address more than one safety concern and can be delivered using a combination of tools and media (e.g. paper, audio, video, web, in-person training).

·        The content of any educational material should be fully aligned with the currently approved product information for a medicinal product, such as the SmPC and PL, and should add rather than duplicate SmPC and PL information.

·        Any evident or hidden promotional stuff does not belong here.

 Educational tools:

Educational tools should refer the reader to the SmPC and the package leaflet.

In addition to an introductory statement that the educational material is essential to ensure the safe and effective use and appropriately manage important selected risks, elements for inclusion in an educational tool could provide:

·        Guidance on prescribing, including patient selection, testing and monitoring

·        Guidance on the management of such risks (to healthcare professionals and patients or carers)

·        Guidance on how and where to report adverse reaction of special interest.

Effectiveness of risk minimisation measures:

To evaluate the effectiveness of additional risk minimisation measures two categories of indicators should be considered:

·        Process indicators

·        Outcome indicators (measurable and concrete)

Process indicators:

-         Process indicators are necessary to gather evidence that the implementing steps of additional risk minimisation measures have been successful.

-         Process indicators are measures of the extent of implementation of the original plan, and/or variations in its delivery.

-         Process indicators should complement but not replace the assessment of the attainment of the objectives of the risk minimisation measures (i.e. outcome indicators).

Examples of process indicators:

-         Reaching the target population (receipts)

-         Assessing clinical knowledge (surveys)

-         Assessing clinical actions (prescribing behaviours)

Outcome indicators:

Outcome indicators provide an overall measure of the level of risk control that has been achieved with any risk minimisation measure in place.

The ultimate measures of success of a risk minimisation programme are the safety outcomes, i.e. the frequency and/or severity of adverse reactions in relation to patients’ exposure to the medicine outside of an interventional study setting and these safety outcomes should be the outcome indicator.

Possible scenarios for RMM effectiveness:

The conclusion of the evaluation may be:

1-     Risk minimisation are adequate at present and should remain unchanged.

2-     Modifications are to be made to existing activities.

3-     Alternatively, the assessment could indicate that risk minimisation is insufficient and should be strengthened.

How to strengthen RMMs?

·        Through amendment of warnings or recommendations in the SmPC or package leaflet

·        Improving the clarity of the risk minimisation advice

·        Adding additional tools

·        Improving existing tools

 4-Another decision may be that the risk minimisation is disproportionate or lacking a clear focus and could be reduced or simplified.

How to downgrade or simplify RMMs?

·        Decreasing the number of tools

·        Frequency of intervention

·        Eliminating interventions proved to be non-contributory to risk minimisation.

 -         In all circumstances, the burden on the patient and the healthcare system should be given careful consideration.

-         It is also important to monitor if the risk minimisation intervention may have had unintended (negative) consequences relevant to the public health question under consideration, either in the short and/or long term.

-         Examples of unintended consequences may include undue burden on the healthcare system, or discontinuation of a product in patients even if the risk-benefit balance was positive for them.

Effectiveness of RMM in EU RMPs and PSURs:

·        Section 16.5 of the PBRERs deal with RMM effectiveness whereas in the RMP part V: Risk minimisation measures “Evaluation of effectiveness of RMM’ discusses RMM effectiveness.

·        Both documents address RMM effectiveness, however, focus of these sections differs in them.

·        Focus of RMM effectiveness section in RMP is how this informs risk minimisation and/or pharmacovigilance planning.

·        In the PSUR, there should also be evaluation of how the implemented measures impact on the safety profile and/or risk-benefit balance of the product.

·        In general, the focus should be on information which has emerged during the reporting period or since implementation of the most recent risk minimisation measure(s) in the EU.

·        Where there is parallel submission of a PSUR and an RMP update to the competent authorities of the EU regulatory network, the use of a common content module should be considered.

·        Results of the assessment(s) of the effectiveness of risk minimisation measures should always be included in the RMP.

·        As part of this critical evaluation, the marketing authorisation holder should make observations on factors contributing to the success or weakness of risk minimisation measures.

·        This critical analysis may include reference to experience outside the EU, where relevant.

·        The evaluation of the effectiveness of risk minimisation measures should focus on whether these have succeeded in minimising risk.

·        This should be analysed using a combination of process and outcome indicators.

·        It may be appropriate to distinguish between risk minimisation measures implemented at the time of initial marketing authorisation and those introduced later in the post-authorisation phase.

·        Proposals for changes to enhance risk management should be presented in the regional appendix of the PSUR.

·        The RMP should be updated to take account of emerging information on the effectiveness of risk minimisation measures.

·        Methods to measure the effectiveness of risk minimisation measure should be proportionate to the risks being minimised.

Points to consider while describing outcomes of RMM effectiveness:

·        The evaluation should provide context by a) briefly describing the implemented risk minimisation measure(s), b) defining their objective(s), and c) outlining the selected process and outcome indicators.

·        The evaluation should incorporate relevant analyses of the nature of the adverse reaction(s) including its severity and preventability. Where appropriate logistical factors which may impact on clinical delivery of the risk minimisation measure should also be included.

·        The evaluation should include an examination of the delivery of the risk minimisation measures in routine clinical practice, including any deviation from the original plan. Such an evaluation may include the results of drug utilisation studies.

·        Outcome indicators should normally be the key endpoint when assessing the attainment of risk minimisation measures objectives.

When to measure effectiveness of RMM?

Periodic review of the effectiveness of one or more specific tools or the overall programme, as appropriate, should be planned.

Time points of particular relevance :

-         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.

-         Whenever effectiveness is evaluated, careful consideration should be given on the need for continuing with the additional risk minimisation measure.

Effectiveness evaluation should address different aspects of the risk minimisation:

-         The process itself (i.e. to what extent the programme has been implemented as planned), its

-         Impact on knowledge of the target audience

-         Behavioural changes in the target audience (i.e. the measure(s) in affecting behavioural change)

-         The outcome (i.e. to what extent the predefined objectives of risk minimisation were met, in the short and long term).

Special topics:

1-     Special consideration @ RMP for ATMP:

·        Source: Article 14(2) of Regulation (EC) No 1394/2007

·        Kind of molecules included as ATMP (remember GST):

1-     Gene therapy medical products

2-     Somatic cell medical products

3-     Tissue engineered products

·        It provides for a specific framework for RMP for advanced therapy medicinal products (ATMP).

·        The marketing authorisation applicants/holders should adapt the risk management plans of ATMP, considering and discussing the anticipated post-authorisation follow-up needs, focusing on particularities of these medicinal products.

·        The specific RMP content requirements for ATMP should be discussed with the competent authority before the submission.

·        Because of the nature of these products, risks may occur that are not normally a concern with other medicinal products including risks to living donors, risks of germ line transformation and transmission of vectors.

·        These risks need to be taken into consideration when developing the safety specification for ATMPs.

2- EU RMP’s US cousin: REMS

Risk evaluation and mitigation strategies, RMP version in the US submitted to the USFDA.

·        Timetable: 18 months, 3 years, 7 years

Elements of REMS:

·         Medication guides for patients

·         Plan for HCP communication

Elements to assure safe use:

·         Training of HCPs

·         Patient selection

·         Restriction of use/distribution

·         Monitoring/registry

FDA can ask for REMS based on:

·         Size of the affected population

·         Seriousness of the disease to be treated

·         Safety profile

·         Expected benefits

·         Expected treatment duration

·         New molecular entity

3-- RMP submission in Australia: The TGA perspective:

-         MAH needs to submit Australia specific annexure.

Things to consider about risk management of medicines in Australia include:

– Indigenous population

– large Asian population

– rurality/lack of specialist services

– Differences between state and federal control over some aspects of how medicines are used (e.g. scheduling and extemporaneous compounding)

– Risk management activities proposed for other jurisdictions may require adaption to Australian systems.

The Australian Specific Annex (ASA)

ASA required to provide Australian specific information not included in EU RMP:

? ASA should follow the format detailed in the RMP Q&As document

? ASA template under discussion with ARCS working group

? Specified information is required to evaluate the application in the Australian context.

4-- Some additional key pointers about RMP:

·        A medicinal product can only have one “current” approved version of an RMP.

·        In the post-authorisation phase, submission of a new or updated RMP outside of another regulatory procedure constitutes a variation in accordance with the Guidelines on Variations.

·        Within the EU, the regulatory oversight of RMPs for medicinal products authorised centrally lies with the Pharmacovigilance Risk Assessment Committee (PRAC).

·        For the RMP assessment, the PRAC appoints a PRAC rapporteur who works closely with the (Co-)Rapporteur(s) appointed by the CHMP and Committee for Advanced Therapies (CAT) (for ATMPs) or with the Reference Member State, as appropriate.

·        With the exception of some patient registries, it is expected that over time the additional pharmacovigilance activities in the RMP will be completed and thus removed from the RMP.

·        Only key literature referenced in the RMP should be included in RMP annex 7. This should be in the format of electronic links or references if already included elsewhere in eCTD.

·        Information in the RMP should be provided in enough detail whilst avoiding unnecessary text that distracts from the key issues to be considered for risk management of the product.

·        However, the safety specifications in the RMP should not be a duplication of data submitted elsewhere in the dossier, unless the sections are intended to be common modules with other documents such as the PSUR.

·        Where applicable, the information in the RMP should provide an integrated overview/discussion focusing on the most important risks that have been identified.

5-- Questions to ask while drafting RMP:

-         What is the target population? What is the clinical need? Is there likely to be widespread use?

-         From a public health perspective what are the key risks?

-         What is the global perspective?

-         Do these risks require additional pharmacovigilance? Why?

-         Does the potential for off-label use/medication error need to be managed?

-         What warnings/precautions should be included in the Product Information?

-         Are product warnings sufficient ? Why?

6- Routine PVG activities vs Risk minimization activities examples:

We keep using terms such as routine PVG activities and RMM activities in PSURs and RMPs.

Here are the examples for both:

Routine PVG activities:

-         Clinical trials

-         Post-authorisation safety studies

-         Drug utilisation studies

-         Patient registries

-         Physician surveys

-         Prescription event monitoring

Risk minimization activities:

-         Product information/labelling

-         Education programs

-         Prescriber checklists

-         DHCP letters

-         Controlled access programs

-         Medical software alerts.

7- Take home messages for Australian RMPs as per the TGA:

RMPs – take home messages

-         There is no one size fits all approach to risk management.

-         Risk management should be product/disease/target population specific.

-         Risk minimisation technologies (e.g. prescriber software alerts) are becoming increasingly available – think outside the box!

-         Australia is different – what works for another jurisdiction may not work here.

-         Public health and safety are the key priorities.

8- Ouch! Regulatory queries and concerns for RMP (TGA and general perspectives):

Items for improvements in the RMP/ASA:

? Misclassification of risk-minimization activities, pharmacovigilance activities, routine and additional activities

? Submission of partially updated RMPs (lots of cross referencing within the document, all should be updated)

? Submission of “Australian RMP” (partly modified EU-RMP)

? Avoid statements which are imprecise such as:

– “Recommendations have been acknowledged”, but no outcome is described;

– “Which of these recommendations should we address”, without addressing recommendations at s31

– “Is considering whether to”, rather than “commits to”.

? Anything referenced in the RMP/ASA should be included in the annexes

? Submission of one RMP for a product with more than one indication.

09-- What TGA looks for?

-         Clear and comprehensive description of evaluation plan

-         Consideration of a number of measures, not just knowledge and awareness

-         Use of outcomes data

-         Evaluation of consumer-directed activities

-         Well-justified goal for success

-         Sharing experience through publication/dissemination

10- Working in PSUR team vs RMP team: what it looks like?

-         Both verticals are closely related.

-         Teams work in collaboration.

-         Ideally team members should be cross trained in both verticals and allowed to work in both kind of reports, but most companies just don’t get it!

-         RMP requires more communications with stakeholders compared to PSUR as they need to discuss extensively with QPPV and regulators!

-         RMP can be better planned and work-life balance is better compared to aggregate teams (not always the case, but I’d go with 90% teams).

-         Resource sharing should be the norm in RMP and PSUR verticals but that’s not the case mostly.

-         Some companies have DSRM departments, which may include RMP and PSUR teams.

Regulators and RMP compliance (TGA):

·        RMP compliance insights from TGA:

·        RMP document = written agreement applied as a condition of registration

·        Compliance activities help to ensure that required risk management activities are conducted, and appropriate risk management systems maintained.

RMP evaluation will ensure RMP commitments are:

-         Clearly documented

-         Feasible and measurable

If TGA identifies potential non-compliance, they will:

-         Contact MAH to clarify compliance status

-         Support MAH in developing a plan to achieve compliance

-         Continue to monitor to ensure future compliance

If TGA identifies continued non-compliance, they will:

-         Formally request information on how MAH will achieve compliance

-         Continue to monitor to ensure future compliance

Serious non-compliance will be referred internally to TGA enforcement area:

·        Outcomes of these regulatory actions may be published on the TGA website.

Insights from SCOPE work group in assessing RMP as per SCOPE WP8:

The assessors/regulators should consider following points while reviewing RMP:

Anticipate all needs, consider timetable and plan accordingly.

Collaboration with ChMP people:

·        Collaboration with ChMP pre-clinical and clinical assessor is required If it is a RMP for a new application for a new substance, as both pre-clinical data and safety data from the clinical trial program are important for determining what should be included in the safety specification.

·        In case of medication error, it may also be useful to collaborate with a quality assessor.

·        The assessment of the safety specification is now the responsibilities of the CHMP Rapporteurs (usually from another MS than the Pharmacovigilance Risk Assessment Committee (PRAC) rapporteur).

·        They are to ensure that the safety specification is an accurate representation of the non-clinical and clinical dossier and to flag any key safety findings relevant to the RMP.

·        The PRAC rapporteur has to assess the Pharmacovigilance Plan and Risk Minimisation Plan based on the RMP provided by the Applicant and the CHMP Rapporteurs’ assessment of the Safety specification.

·        At the end of the procedure, the PRAC assessment report is to be merged with the CHMP assessment report.

·        For new medicines of major public health interests (high medical need) accelerated assessment has recently been introduced. This procedure reduces the timeframe for review of an application for a marketing authorisation from a maximum of 210 days to 150 days. For this procedure the collaboration between PRAC Rapporteur and CHMP Rapporteurs are critical for the best assessment of the RMP.

·        Assessors have to use assessment templates for their review.

·        Regulators have to ensure consistency of any RMP with other RMP of same molecule and same drug class.

·        EMA has recently launched the PRIME scheme to support development of medicinal products of major public health interest through early and enhanced scientific and regular dialogue.

·        Once you have agreed which are the “important” risks, you must decide if they should be categorised as an identified risk or a potential risk.

·        If the risk is seen in the clinical trials and there is either a plausible mechanism or the incidence is greater than placebo or background rates in the targeted population, this should be considered an identified risk.

·        If the background rate is higher or about the same as seen in the clinical trials, it might not be an identified risk.

·        If the background rate is lower than that seen in the clinical trials, it is more probable that this is an identified risk.

·        If the risk is seen only in pre-clinical studies, it should be considered a potential risk.

·        If this is a known class effect, but not seen in the clinical trials etc., it should be considered a potential risk.

·        Usually we only want to specify something as missing information if we want to study exposure in those patient groups further.

·        Subgroups of the targeted populations that are expected to frequently use the product and are not included in the clinical development program can be considered as missing information, e.g. patients with impaired renal and hepatic function, children, elderly, pregnant and lactating women, off-label use.

·        Exclusion criteria should not automatically translate into missing information.

·        The assessor should rather consider clinical relevance and likely real-world use to be of importance for the missing information.

·        If the indication implies chronic use, long-term use should be considered as missing information if not studied.

·        If studies of relevant drug-drug interaction have not been done, this should be considered as possible missing information.

·        The challenge is to differentiate between risks that can be efficiently managed by routine Risk Minimisation Measures (RMMs) (information in the SmPC, Patient Information Leaflet (PIL) and the product label) and risks that require additional RMMs.

When regulators will ask for further information in RMP safety concerns?

Identify important potential/identified risks/missing information that needs further characterisation such as:

·        The risk is new, potentially serious or disabling and may not easily be recognised, e.g. the relation between Pandemrix and narcolepsy.

·        The incidence is not known – background incidence in the target population should be discussed.

·        Are there changes in frequency over time for an adverse event?

·        A plausible mechanism is not known.

·        More information on how to minimise the risk is needed, e.g. identifying specific risk groups, identifying the degree of off-label use.

·        In the case of orphan treatments, or products authorised under exceptional circumstances, the safety database may be very limited and robust measures to collect further safety data are needed (e.g. via a registry).

·        The above situations may justify additional PV activities, such as non-clinical studies, clinical trials or non-interventional studies such as Post-Authorisation Safety Studies (PASS).

SCOPE WP8 regulator thinking on assessing need for ARMM:

·        When considering the need for additional RMMs regulators need to consider:

·        Have any specific risk minimisation tools been used in the clinical trials? If yes, is it possible that similar tools are needed in daily clinical practice based on the experiences from the clinical trial program?

·        If additional RMMs have been suggested, are they risk proportionate, justified and adequate?

·        Ask yourself if any specific recommendations are needed for the prescriber or the patient/care givers to manage the risk, e.g. any specific dose recommendations, monitoring recommendations, contraindications or specific warnings. Liaise with the CHMP rapporteur or other assessors for this if necessary.

·        If the RMMs concern children, is there any benefit in asking PDCO for some advice?

·        Will the proposed additional RMMs have any impact on the design of or wording on the package material?

·        If educational material is proposed, consider if it is in line with the GVP module XVI Addendum I – Educational material. Ask yourself if it adds anything to the information already known.

SCOPE WP8 regulatory thinking on RMP updates:

When new information is available either through routine or additional pharmacovigilance it is important to consider if the different parts of the RMP need to be updated. Ask yourself:

1-     Are identified risks sufficiently characterised? Is the management of the risks integrated in the routine clinical practice, e.g. NICE or national clinical guidance? If so, you should consider removing the risk(s) from the safety specification unless specific RMMs are still needed.

2-     Are potential risks real or not? You should consider if they should be upgraded to identified risks or can be deleted.

3-     Is missing information sufficiently characterised? You should assess if any can be deleted.

4-     Are updates on status of studies in the Pharmacovigilance Plan needed?

5-     Are additional RMMs still needed, e.g. if management of the specific risk is integrated in clinical practice (see above) or should new additional RMMs be added if new risks have been identified?

 While researching for this article, I came to know about how much data TGA has provided in PVG and it all is so easy to refer and use.

You can access their slide share here which has 357+ PPTs on PVG including PSUR, RMP and Signal detection! Amazing amazing indeed ??

https://www.slideshare.net/TherapeuticGoodsAdministration?utm_campaign=profiletracking&utm_medium=sssite&utm_source=ssslideview

 I know it’s an exhaustive article, but it covers data from more than 200 pages including 10+ PowerPoints, regulatory thinking including TGA and SCOPE WP8 apart from modules 5,7, XVII and other regulatory documents and real life insights from working in DSRM for 3.5 + years at the time of writing! I hope you liked the article and would love to hear your thoughts on amazing drug safety vertical RMP ??

Found the article interesting?? Here are more articles I have written about PSURs. literature summarization in aggregate reports and EMA expanatory note on PSURs :-)

Read them too!