A biological medicine is defined by the European Medicines Agency (EMA) as ‘a medicine whose active substance is made by a living organism.1 In the broadest sense these substances are produced by, or extracted from, a biological source and they need for their characterisation and determination of their quality a combination of physio-chemical-biological testing, together with testing of their production process and control.2 Biological medicines can include vaccines, immunotherapies, biosimilars, gene therapy, and stem cell or tissue therapy.3
Biological medicines offer treatment options for patients with chronic and often disabling conditions such as diabetes, autoimmune diseases, and cancers. Most biological medicines in current clinical use contain active substances made of proteins. These can differ in size and structural complexity, and they range from simple proteins like insulin or growth hormone to more complex ones such as coagulation factors or monoclonal antibodies.4
A biosimilar is a biological medicine which is highly similar to another already approved biological medicine (the 'reference medicine') and that exhibits similar biological activity, quality, safety and efficacy based on a comprehensive comparability exercise2. Biosimilars are approved according to the same standards of pharmaceutical quality, safety and efficacy that apply to all biological medicines. The EMA is responsible for evaluating the majority of applications to market biosimilars in the European Union.
A biosimilar is not regarded as a generic of a biological medicine. This is mostly because of the natural variability and complex manufacturing process of biologicals which do not allow an exact replication of the molecular micro-heterogeneity.4
The most relevant EU GVP modules for biological and biosimilar medicines are those relating to RMPs, PSURs, Signal management and aRMM. This derives directly from the product’s intrinsic complexity and variable/unique life-cycle that in turn requires diligent and close follow-ups to ensure the product’s safety. Below, we will go into detail about what are the necessary considerations for each module for this type of medicine.
All marketing authorisation applications and some variations (e.g. new manufacturing process of a biological/biosimilar) submitted in the EU after July 2012 (CEP, MRP/DCP) should include a risk management plan (RMP). In addition, any updates to the RMP of a reference product should be applied to the relevant biosimilars unless justified (e.g. where available information suggests that the clinical concern prompting the update was product-specific and not related to the active substance or other common excipients).
RMP Part I – Product Overview
Important information about its composition (e.g. origin of active substance of biologicals, relevant adjuvants or residues for vaccines);
RMP Part II – Safety Specification
Module SI - Epidemiology of the indication(s) and target population(s)
Not required for biosimilars.
Module SVI - Additional EU requirements for the safety specification
For all biologicals, the potential for infections caused by residuals of biological material used in the manufacturing process as well as contaminations introduced by the manufacturing process should be presented in relation to the potential for transmission of infectious agents.
Module SVII - Identified and potential risks and SVIII - Summary of the safety concerns
The potential for immunogenicity and associated clinical consequences should be fully evaluated and discussed as part of the initial MA application (or variation for example following a change in the manufacturing process) in the relevant sections of the “Summary of clinical safety” of the RMP. Immunogenicity may occur during the life-cycle of a biological, but is not in itself a specific safety concern. It should be included in the RMP only if discussion warrants its classification as an important risk (identified or potential) or as missing information. In such instances, it should be defined as precisely as possible so that specific pharmacovigilance measures can be put in place.
In case of a significant change to the manufacturing process requiring an amendment of the RMP, potential immunogenicity and clinical consequences should be included in the safety specification.
If no specific potential clinical concern has been identified (other than the significant manufacturing change with uncertain clinical consequence), the missing information listed in the updated safety specification should refer to “immunogenicity following a significant change to the manufacturing process”.
For biosimilars, the summary of safety concerns should be the same as the reference product unless otherwise justified. Such justification may include situations where a risk associated with the reference product is known to be associated with a component, manufacturing process or other factor that is not associated with the INN or where elements of the safety specification are specific to a particular use (e.g. indication or route of administration) that is absent in some products (but potential for off-label use should be considered).
Important risks or missing information relating to uncertainties identified from the comparability exercise for the biosimilar should be included in the RMP as well as evaluating the need for aRMM or aPV activities. Any other proposed differences in the safety specification of a biosimilar compared to the reference product should be duly justified based on the outcome of the comprehensive comparability exercise.
RMP Part III - Pharmacovigilance Plan
The need for continuous life-cycle signal detection and pharmacovigilance specific to the product including batch-specific issues, particularly following a significant change to the manufacturing process, should be discussed.
The pharmacovigilance plan should discuss the clinical setting of the product’s use and how this may impact on product name and batch recording and reporting (e.g. whether used in primary or tertiary care) and what additional activities or risk minimisation measures may be required to support product traceability (e.g. provision of ‘sticky’ labels, bar coding).
Routine pharmacovigilance activities
Additional pharmacovigilance activities
For significant changes to the manufacturing process that require an RMP update, given that the product name usually does not change, there should be a particular emphasis on batch-specific pharmacovigilance for an agreed time period at the time of submission of manufacturing change variation. This period of surveillance should start after approval of the variation once new batches are on the market.
If immunogenicity is included in the safety specification then relevant strategies for its evaluation in the post-authorisation setting should be proposed as an aPV activity. The plan may include bio-analytical methods (e.g. in vitro assays, serology studies), non-clinical studies, interventional clinical studies or observational epidemiological approaches. Any analytical and clinical endpoints relevant to the potential risk should be clearly defined to support their characterisation in passive surveillance (e.g. via targeted follow up), aPV activities or epidemiological studies.
For these reasons, determination of the optimal strategy for evaluation of immunogenicity in the RMP should be a multidisciplinary approach, with input from experts in the quality, non-clinical, clinical, pharmacovigilance and epidemiological fields. Whether the risk is specific to a product or batch, the potential root cause should be determined with the idea of risk minimisation or elimination measures (e.g. improved assays, manufacturing steps).
Post-authorisation safety studies
If an existing registry is to be used or a new registry is to be established, a comparator or non-exposed group should preferably be included. Joint disease registries are encouraged.
Any specific safety monitoring imposed on the reference product or class should be addressed in the pharmacovigilance plan, unless otherwise justified (e.g. if the safety concern was specific to the reference product and not included in the safety specification of the biosimilar). Where applicable and feasible, MAH of biosimilars should participate in any pharmacoepidemiological studies already in place for the reference product, unless otherwise justified.
RMP Part V - Risk minimisation measures
The evaluation of any new clinical risk associated with a biological/biosimilar should include a root cause analysis to evaluate the ability for risk minimisation or elimination via analytical studies or bioassays (e.g. improved assays, manufacturing steps).
As a general principle in order to improve traceability of biologicals, all SmPCs should include a prominent statement that the name and batch number of the administered product should be clearly recorded in the patient’s file.
Related wording should also be included in educational material, direct healthcare professional communication and product promotional material as applicable. Use of other tools such as sticky/tear-off labels in the packaging should also be considered to facilitate accurate recording. Use of available bar code-scanning technology and infrastructure should also be encouraged where appropriate. All aRMM in place for the reference product should be included in the RMP of biosimilars and vice-versa. Any deviation from this (e.g. when the risk minimisation is linked specifically to the reference product) should be justified.
Update of the RMP
All updates can be initiated by the MAH or by the HA. Updates to the RMP should address the safety specification, pharmacovigilance plan and risk minimisation measures. For cases when the comparability evaluation identifies a potential impact of the manufacturing change in terms of clinical relevance, particular attention should be paid to describe as a routine pharmacovigilance activity how batch-specific evaluation can be done in order that the pre- and post-change products can be easily distinguished during a relevant time period after the manufacturing change.
Following an update to the RMP, subsequent PSURs should specifically evaluate reports and any other information that might indicate a new clinical risk related to a process change. This evaluation should relate to the specific concern included in any updated safety specification of the RMP based on the manufacturing change. The cycle of submission of the PSURs may also be amended (and re-instated) accordingly in line with the updated RMP.
Management and reporting of adverse reactions
When reporting ICSRs, HA and MAH shall provide all available information on each individual case including the product name and batch number(s). For this purpose, Member States and MAH should encourage HCP to provide patients and carers with information on the product name and batch number(s) of any biological/biosimilar administered.
A follow-up procedure should be put in place to obtain the batch number where it is not indicated in the initial report.
Follow up of reports
As previously stated, the definite identification of the concerned products with regard to their manufacturing is of particular importance when it comes to suspected adverse reactions related to biological/biosimilars. Therefore, all appropriate measures should be taken to identify the names of the products and their batch numbers. Furthermore, it is recommended to specify in the case narrative if information on the batch number has been requested if this was missing in the initial ICSR. It is paramount to also consider the mandatory follow-up in the EU of information for the identification of suspected biological/biosimilar medicines.
Overview of signals: new, ongoing, or closed and signal and risk evaluation.
Following a significant change to the manufacturing process (which will require submission of an updated RMP), PSURs should specifically evaluate reports and any other information that might indicate a new clinical risk related to a process change. The required data on batch-specific exposure patterns will support such evaluation. This should be presented in the context of the specific concern that is included in any updated safety specification of the RMP on account of the manufacturing change.
The signal management process remains the same as for generic medicines but for biologicals it is especially important due to the reasons previously mentioned. In particular, due to the inherent variability in the manufacturing process that may potentially alter the immunogenicity of the product leading to clinical consequences. Signal detection for biologicals/biosimilars should therefore be specific to the product, as well as the active substance. When a signal is detected, all efforts should be made to identify a common root cause, such as the batch.
Important differences between a reference product and a biosimilar should be identified during the product life-cycle based on the available information. Any clinical consequences of potential emerging immunogenicity (as a theoretical risk) should be monitored throughout the product life-cycle.
Post-authorisation exposure information is needed for signal management, but biologicals are often prescribed or dispensed in the hospital setting and the required exposure information may not be available in population-based databases. MAH should make every effort to obtain data on actual usage of a specific product.
Any signal should be evaluated in the context of batch-specific exposure data, including numbers/codes of delivered or sold batches, their size and the regions or countries where they have been delivered. Strengthening routine pharmacovigilance processes will facilitate earlier detection of new risks and changes in product safety or quality over time.
For new signals, case-by-case judgements are required on whether or not the signal may apply to the concerned product or to all products with the same active substance. However, inadequate evidence on the specificity of a signal detected for a biosimilar may justify application of a regulatory action to the reference product, and vice versa.
The additional monitoring status is particularly important for all biological/biosimilar medicinal products, which are priorities for pharmacovigilance. Any biological/biosimilar authorised after 1 January 2011 shall be included in the list of medicinal products that are subject to additional monitoring. They shall be removed from the list under the mandatory scope five years after the Union reference date unless the period of additional monitoring is extended.
Direct Healthcare Professional Communication
Call for reporting
For biological/biosimilars include a reminder to report the product name and batch details.
Information on the manufacturing process and its variability, the active substance and its mode of action, as well as the excipients and possible residues, should be communicated to patients and HCP for their good understanding.
Encouraging reporting of suspected adverse reactions requires some specific information for biological/biosimilars. It should be communicated to patients and HCP that adverse reactions may arise even if a medicinal product has previously been well tolerated (e.g. due to manufacturing variability or changes, or long-term or delayed onset effects) and that reporting of suspected adverse reactions occurring even after long-term use or with unknown features is important.
With a view to adverse reaction reporting and effective risk management, traceability is a major objective in managing the appropriate use and pharmacovigilance of biologicals and hence constitutes a specific communication objective for biologicals. Communication should therefore emphasise the importance of providing the product name (or INN and name of the MAH) and batch number(s) when reporting suspected adverse reactions.
Other specific safety communication objectives in relation to biologicals may aim at avoiding errors in storage and handling, in particular as regards cold chain requirements and administration which frequently requires specific medical devices.
aRMM: Additional Risk Minimization Measures.
aPV: Additional Pharmacovigilance Activities.
EU: European Union.
HA: Health Authority.
HCP: Healthcare professionals.
ICSR: Individual Case Safety Report.
INN: International non-proprietary name.
MAH: Marketing authorisation holder.
NCA: National competent authorities
PSUR: Periodic Safety Update Report.
RMP: Risk Management Plan.
SmPC: Summary of Product Characteristics.