V.B.5. RMP part II “Safety specification”

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. It should include a summary of the important identified risks of a medicinal product, important potential risks, and missing information. It should also address the populations potentially at risk (where the product is likely to be used i.e. both as authorised and off-label use), and any outstanding safety questions that warrant further investigation to refine the understanding of the risk-benefit balance during the post-authorisation period.

The safety specification forms the basis of the pharmacovigilance plan and the risk minimisation plan. The safety specification consists of eight RMP modules, of which RMP modules SI-SV, SVII and SVIII correspond to safety specification headings in ICH-E2E. RMP module SVI includes additional elements required to be submitted in the EU.

Although the elements outlined in V.B.5.2. to V.B.5.9. serve as a guide only, it is recommended that applicants/ marketing authorisation holders follow the structure provided when compiling the safety specification.

Details of specific requirements for initial marketing authorisation applications are included in V.C.1.1.

V.B.5.1. General considerations for generic products and advanced therapy medicinal products

V.B.5.1.1. Generics

For generic medicinal products the expectation is that the safety specification is the same as that of the reference product or of other generic products for which an RMP is in place. If discrepancies exist between approved RMPs for such products, then the applicant is expected to propose and justify the most appropriate safety specification for their product. Exceptionally, the applicant for a new generic medicinal product may add or remove safety concerns compared with the safety profile of the reference product if this is appropriately justified (for example, when there is a more up to date understanding of the current safety profile or when there are differences in product characteristics compared with the reference product, e.g. there is a risk associated with an excipient present only in some of the products containing the same active substance).

V.B.5.1.2. Advanced therapy medicinal products

Under Regulation (EC) No 1394/2007, certain products for human medicinal use are categorised within the EU as advanced therapy medicinal products. These products are fully defined in the above Regulation but broadly comprise:

• gene therapy medicinal products;
• somatic cell therapy medicinal products;
• tissue engineered products.

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 (see V.B.5.8.).

V.B.5.2. RMP part II, module SI “Epidemiology of the indication(s) and target population(s)”

This RMP module should include incidence, prevalence, outcome of the (untreated) target disease (i.e. indications) and relevant co-morbidity, and should when relevant for assessment of safety and risk management be stratified by age, gender, and ethnic origin. Risk factors for the disease and the main existing treatment options should also be described. The emphasis should be on the epidemiology of the proposed indication in the EU. Differences in the epidemiology in different regions should be discussed (where epidemiology varies across regions). This section should also describe the relevant adverse events to be anticipated in the (untreated) target population in EU, their frequency and characteristics. The text should help anticipate and interpret any potential signals and help identify opportunities for risk minimisation. The text should be kept concise and should not include any element of a promotional nature.

V.B.5.3. RMP part II, module SII “Non-clinical part of the safety specification”

This RMP module should present a high-level summary of the significant non-clinical safety findings, for example:

• toxicity (key issues identified from acute or repeat-dose toxicity, reproductive/developmental toxicity, genotoxicity, carcinogenicity);
• safety pharmacology (e.g. cardiovascular system, including QT interval prolongation, nervous system);
• other toxicity-related information or data.

What constitutes an important non-clinical safety finding will depend upon the medicinal product, the target population and experience with other similar compounds or therapies in the same class. Normally, significant areas of toxicity (by target organ system) and the relevance of the findings to the use in humans should be discussed. Also, quality aspects if relevant to safety (e.g. genotoxic impurities) should be discussed. If a product is intended for use in women of childbearing age, data on the reproductive/developmental toxicity should be explicitly mentioned and the implications for use in this population discussed. Where the non-clinical safety finding could constitute an important potential risk to the target population, it should be included as a safety concern in RMP module SVIII. Where the non-clinical safety finding is not considered relevant for human beings, provision of a brief explanation is required, but the safety finding is not expected to be carried forward to SVII and SVIII as a safety concern.

If, based on the assessment of the non-clinical or clinical data, additional non-clinical studies are considered warranted and proposed to be part of the pharmacovigilance plan, this should be briefly discussed here.

Final conclusions on this section should be aligned with content of module SVII and any safety concerns should be carried forward to module SVIII.

The content of this section should be assessed for relevance over time. Post-authorisation, this section would only be expected to be updated when new non-clinical data impact the list of safety concerns. Safety concerns identified on the basis of non-clinical data which are no longer relevant and/or have not been confirmed when sufficient relevant post-marketing experience and evidence are gathered, can be removed from the list of safety concerns.

V.B.5.4. RMP part II, module SIII “Clinical trial exposure”

In this RMP module, in order to assess the limitations of the human safety database, summary information on the patients studied in clinical trials should be provided in an appropriate format (e.g. tables/graphs) at time of submission of the initial RMP or when there is a major update due to new exposure data from clinical studies (e.g. in a new indication). The content of this section should be assessed for relevance over time and, in the absence of new significant clinical trial exposure data, this section does not need to be updated.

The size of the study population should be detailed using both numbers of patients and, where appropriate, patient time exposed to the medicinal product. This should be stratified for relevant categories; stratifications would normally include:

• age and gender;
• indication;
• dose;
• other stratifications should be provided where this adds meaningful information for risk management planning purposes (e.g. ethnic origin).

Paediatric data should be divided by age categories (e.g. ICH-E11 (3) ); similarly the data on older people should be stratified into age categories reflecting the target population (e.g. 65-74, 75-84 and 85 years and above).

Unless clearly relevant and duly justified, data should not be presented by individual trial, but pooled. Totals should be provided for each table/graph as appropriate. Where patients have been enrolled in more than one trial (e.g. open label extension study following a trial) they should only be included once in the age/gender/ethnic origin tables. Reasons for differences in the total numbers of patients between tables should be explained.

When the RMP is being submitted with an application for a new indication, a new pharmaceutical form or route of administration, the clinical trial data specific to the application should be presented separately at the start of the module as well as being pooled across all indications.

V.B.5.5. RMP part II, module SIV “Populations not studied in clinical trials”

Populations that are considered under missing information should be described in this RMP module.

Information on the low exposure of special populations or the lack thereof (e.g. pregnant women, breast-feeding women, patients with renal impairment, hepatic impairment or cardiac impairment, populations with relevant genetic polymorphisms, immuno-compromised patients and populations of different ethnic origins) should be provided where available and as appropriate. The degree of renal, hepatic or cardiac impairment should be specified as well as the type of genetic polymorphism, as available.

If the product is expected to be used in populations not studied and if there is a scientific rationale to suspect a different safety profile, but the available information is insufficient to determine whether or not the use in these circumstances could constitute a safety concern, then this should be included as missing information in the RMP. Excluded populations from the clinical trial development programme should be included as missing information only when they are relevant for the approved and proposed indications, i.e. “on-label”, and if the use in such populations might be associated with risks of clinical significance. In discussing differences between target populations and those exposed in clinical trials it should be noted that some differences may arise through trial setting (e.g. hospital or general practice) rather than through explicit inclusion/exclusion criteria. When such populations are proposed as missing information, then RMP module SIV should also include a discussion on the relevant subpopulations.

If there is evidence that use in excluded populations is associated with an undesirable clinical outcome, then the outcome should be included as an important (potential) risk.

V.B.5.6. RMP part II, module SV “Post-authorisation experience”

If post-marketing data are available from post-authorisation experience in other regions outside EU, where the product is already authorised or from other authorised products containing the same active substance, from the same marketing authorisation holder, the data should be discussed in this RMP module.

It should only provide an overview of experience in the post-authorisation phase that is helpful for risk management planning purposes. It is not the intention to duplicate information from the PSUR.

Additionally, a discussion on how the medicinal product is being used in practice and on-label and offlabel use, including use in the special populations mentioned in RMP module SIV, can also be included when relevant for the risk identification discussion in module SVII.

Where appropriate and relevant for the discussion in SVII, data on use in markets outside the EU from indications not authorised in EU should also be summarised, and the implications for the authorisation in the EU should be discussed.

V.B.5.7. RMP part II, module SVI “Additional EU requirements for the safety specification”

In addition to safety topics required by ICH-E2E (see GVP Annex IV), the following should be addressed in the EU-RMP: the potential for misuse for illegal purposes, and, where appropriate, the proposed risk minimisation measures, e.g. limited pack size, controlled access programme, special medical prescription [DIR Art 71(2)] (see also V.B.8.).

V.B.5.8. RMP part II, module SVII “Identified and potential risks”

This RMP module should provide a focussed discussion on the identification of important identified and important potential risks, and missing information (i.e. safety concerns).

The following 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 when they lead to risks of the product:

• 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). Where harm from overdose has occurred during clinical trials this should be explicitly mentioned and, where relevant, the important risks following overdose should be included as safety concerns in RMP module SVIII and appropriate risk minimisation proposed in RMP part V;
• 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. Where applicable an indication should be given of how these have been taken into account in the final product design. Further guidance on medication errors is provided in Good Practice Guide on Risk Minimisation and Prevention of Medication Errors , Annex 2 – Design features which should be considered to reduce the risk of medication error (4) which includes an extensive list of potential medication errors and the consequence to the patients. Important risks related to medication errors in the post marketing period should be discussed in the updated RMP and ways of limiting the errors proposed;
• potential for transmission of infectious agents due to the nature of the manufacturing process or the materials involved. For live attenuated vaccines any potential for transmission of mutated live vaccine virus, and the potential of causing the disease in immunocompromised contacts of the vaccine should be discussed with the view of considering them as important potential risks;
• 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 of the product should be considered for inclusion in the safety specifications;
• 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;
• 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. The evidence supporting the interaction and possible mechanism should be summarised, the potential health risks discussed for different indications and populations, and plans to further characterise and minimise the risks described. Important risks derived from interactions should be included as a safety concern;
• risks in pregnant and lactating women, e.g. teratogenic risk – direct or through exposure to semen: contraception recommendations can be considered as risk minimisation measures. Further guidance on risk management in case of exposure of the embryo / foetus to teratogenic agents can be found in the GVP P.III. and GVP Module XVI;
• effect on fertility – appropriate risk minimisation measures should be considered, e.g. routine risk communication and/or additional activities recommending fertility preservation: sperm cryopreservation in men and embryo and oocyte cryopreservation in women;
• risks associated with the disposal of the used product (e.g. transdermal patches with remaining active substance or remains of radioactive diagnostics);
• 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, as described in section 5 of annex I of the PIP opinion (Potential long-term safety/efficacy issues in relation to paediatric use for consideration in the RMP/Pharmacovigilance activities).

For RMPs of ATMPs, the applicants should also consider the possible specific risks in drafting the safety specifications (see Guideline on Safety and Efficacy Follow-up – Risk Management of Advanced Therapy Medicinal Products (5)).

V.B.5.8.1. RMP part II, module SVII section “Identification of safety concerns in the initial RMP submission”

This RMP section should contain the initial identification of safety concerns and is expected to be populated with the initial submission of an RMP, either at the time of the initial marketing authorisation (MA) application or post-authorisation (i.e. for approved products that previously did not have an RMP).

This section is expected to be “locked” and not change after the approval of the initial RMP.

V.B.5.8.1.a. RMP part II, module SVII 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”

In this RMP section the following information should be summarised and discussed:

• 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.

V.B.5.8.2. RMP part II, module SVII section “New safety concerns and reclassification with a submission of an updated RMP”

In the post-authorisation phase, it is expected that new identified and potential risks of the product are presented in the safety section of the dossier (with e.g. signal evaluation, periodic benefit-risk evaluation, or safety variations procedures) together with an evaluation on whether the risks should be considered important and added in the safety specification in the RMP. This discussion should not be duplicated in the RMP, but the details of any new important identified or potential risk should be included in the RMP section described in V.B.5.8.3.

When an important identified or potential risk or missing information is re-classified or removed, a justification should be provided in this RMP section, with appropriate reference to the safety data. The information included in this section may take the form of a statement describing a previous regulatory request, with a reference to the procedure where such request was formulated.

V.B.5.8.3. RMP part II, module SVII section “Details of important identified risks, important potential risks, and missing information”

For RMPs containing multiple products, if there are significant differences between products (e.g. fixed dose combination products) it is appropriate to make it clear which safety concerns relate to which product.

This RMP section applies to all stages of the product’s life cycle.

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, longterm 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).

Presentation of missing information data:

• name of the missing information (using MedDRA terms when appropriate);
• evidence that the safety profile is expected to be different than in the general target population;
• description of a population in need of further characterisation, or description of the risk anticipated in the population not studied, as appropriate.

V.B.5.9. RMP part II, module SVIII “Summary of the safety concerns”

In this RMP module, a list of safety concerns should be provided with the following categories:

• important identified risks;
• important potential risks;
• missing information.