Applying for a Promising Innovative Medicine (PIM) designation

Guidance

A Promising Innovative Medicine (PIM) Designation is an early indication that a medicinal product is a candidate for the Early Access to Medicines Scheme (EAMS), intended for the treatment, diagnosis or prevention of a life-threatening or seriously debilitating condition, with the potential to address an unmet medical need.  The designation will be issued after an MHRA scientific designation meeting on the basis of non-clinical and clinical data available on the product, in a defined disease area.  Following the PIM designation, the applicant completes the clinical development programme and continues with an application under the EAMS Scientific Opinion (SO) assessment step – see later guidance. A PIM designation is a prerequisite to enter the EAMS SO step.

When to apply for a PIM Designation

Applicants are encouraged to apply when data from early stages in a clinical development programme indicate that the medicinal product fulfils the designation criteria, namely the product is likely to demonstrate significant benefit for patients in life-threatening or seriously debilitating conditions.  This is because early regulatory and other stakeholder engagement is generally recommended to maximise the benefits within the scheme.

Applicants may also apply towards the end of their clinical development programme and could consider applying for a PIM designation and the EAMS SO pre-submission meeting (PSM) simultaneously – see later guidance.

The PIM designation criteria

All three criteria, which must be fulfilled in order to gain a PIM designation, are:

Criterion 1: There is a life threatening or seriously debilitating condition and a high unmet need

The severity of the disease should be justified based on objective and quantifiable medical or epidemiologic information, in terms of mortality and morbidity, with special emphasis on patient quality of life. For high unmet need, the Applicant should consider if there is no method of treatment, diagnosis or prevention available in the UK for the condition, or if methods already in use in the UK have serious limitations. From a regulatory perspective, methods ‘already in use’ include medicinal products that have a GB or UK marketing authorisation as well as standard of care and non-pharmacological therapies. The health technology assessment, commissioning or supply status of a product is not taken into account by the MHRA. A critical review of the methods already in use for treatment, diagnosis or prevention in the UK should be provided, including an evaluation of the performance of these methods based on quantifiable data (e.g. data on survival, disease progression/relapses, or patient-reported outcomes). The Applicant should provide a justification for why methods already in use are not adequate.

Criterion 2: The medicinal product is likely to offer a major advantage over methods of preventing, diagnosing or treating the condition already in use in the United Kingdom.

The Applicant should submit preliminary evidence, based on clinical data, indicating that the advantage and magnitude of effect claimed for the product is predicted to be of significant relevance to the patients and will address their unmet need. The major advantage could be improved efficacy, or similar efficacy but better overall tolerability, compared to methods already in use. A well-argued evaluation of the likelihood of achievement of the product’s claims should be provided, based on the totality of information available at the time of designation. This should include direct or indirect comparison to methods already in use.  From a regulatory perspective, methods ‘already in use’ include medicinal products that have a GB or UK marketing authorisation as well as standard of care and non-pharmacological therapies. The health technology assessment, commissioning or supply status of a product is not taken into account by the MHRA.

Criterion 3: The potential adverse effects of the medicinal product are likely to be outweighed by the potential benefits, allowing for a reasonable expectation of a positive risk-benefit balance

The potential adverse effects of the medicinal product are likely to be outweighed by the benefits, allowing for the reasonable expectation of a positive benefit/risk balance. A positive benefit/risk balance should be based on preliminary scientific evidence, as justified by the applicant, that the safety profile of the medicinal product is likely to be manageable and acceptable in relation to the estimated benefits.

The wording of the PIM condition in the designation application

The applicant is encouraged to seek the broadest possible indication in a defined condition for the PIM designation. This would allow for future sequential EAMS SO indication submission(s), where appropriate (e.g., different line setting, treatment combination), without the need to seek a new PIM designation. The final wording of the PIM indication will be agreed at the PIM designation meeting.

Joint PIM designation/ pre-submission meeting

For the joint PIM designation/PSM applications, both a PIM designation application template and a PSM template should be submitted at the time of the request. You will be invited to a single meeting where both the PIM criteria and the aspects of an EAMS SO application will be addressed. You do not need to replicate information provided in the PIM in the PSM request form (you may cross refer from your PSM form to the PIM application for relevant information). See also section 2. 

How to apply

Companies seeking a PIM designation should complete the PIM designation template in full, indicating how the product fulfils the criteria of designation.

Completed forms should be sent by email to the MHRA’s EAMS coordinator (eams@mhra.gov.uk).

PIM designation application meeting and decision process

Your submitted designation application will be reviewed by the assessment team and an agreed designation meeting date will be set (normally within 6 weeks of the receipt of your request). The focus of the designation meeting is restricted to the potential of the medicinal product to fulfil the three criteria and is expected to last for up to one hour. You should prepare a PowerPoint presentation (maximum of 20 minutes length), covering your position. Please provide the presentation to the EAMS coordinator at least 5 working days in advance of the meeting. Following the designation meeting, the assessment team will make a recommendation to the internal scientific consistency review group, who will determine whether to grant a designation or not (usually within 4weeks).

If you are awarded a designation, you will receive a positive designation letter, which will include your unique EAMS number. This number should be included with any future application for an EAMS SO step. You will be encouraged to utilise the MHRA’s scientific advice services to help you with your ongoing and future development plans.  You should note that the PIM designation does not have an expiry period; rather this is a statement at one point in time, that the product shows promise in a particular patient setting and is suitable for future application to the EAMS SO step. Your designation letter is shared in confidence with contacts at: NHS England,  NICE advice, Department of Health Northern Ireland (NI), Scottish Government Directorate General Health & Social Care, Scottish Medicines Consortium (SMC), Area Drug & Therapeutics Committee (ADTC), Welsh Health Technology Assessment (HTA) at All Wales Therapeutics & Toxicology Centre (AWTTC), Welsh Government Department of Health and Social Services, and Office for Life Sciences (OLS).

If you are not awarded a PIM designation, you will receive a letter explaining why your submission was not considered to fulfil the designation criteria. You may still find it helpful to utilise the MHRA’s scientific advice service to help you with your ongoing and future development plans. A negative application cannot be appealed, but a future application may be submitted if you consider that you are now able to meet the criteria.

The MHRA does not publish positive or negative PIM designations, however the MHRA publishes summary information on the number of applications.

Application Form for a PIM Designation

 PIM application form.

Fees

The fee for the PIM designation become payable within 30 days following written notice from the MHRA requiring payment of those fees. The fee is not refundable if your application is not successful.

Pre-submission meeting for EAMS Scientific Opinion

Guidance

To apply for an EAMS Scientific Opinion (SO), the Applicant must:

• hold a Promising Innovative Medicine (PIM) designation (see section 1)
• request and attend a pre-submission meeting (PSM)

The aim of the PSM is to ensure that the suitability criteria for the scheme are likely to be met and to discuss the format of the data to be submitted to support the benefit/risk opinion. It is not a comprehensive pre-assessment step.

In general, medicinal products should be supplied under the EAMS for at least 6 months prior to the corresponding UK or GB marketing authorisation (or the relevant extension of indication variation). The EAMS SO application should be timed accordingly. The PSM request form should include the estimated timelines for UK or GB marketing authorisation or extension of indication.

Real world data (RWD) collection proposals should be included in the PSM request form. Whilst data should not be specifically collected for the purpose of research under the scheme, real world data collected may have research value and this should be planned for and addressed via consent processes – see section on RWD collection.

To apply for a PSM, the Applicant should submit a completed request form. Following receipt of the request, the MHRA will arrange a mutually acceptable date for the meeting, which will be arranged at the earliest available opportunity. 

There is no fee payable for the PSM.

After the PSM, the MHRA will make a recommendation as to whether the product is considered a suitable candidate at this time for an EAMS SO application. This will be communicated by letter.   

Request form for a Pre-Submission Meeting

Pre-submission meeting request form

Applying for the EAMS Scientific Opinion (SO)

Guidance on your application

The information below should be considered as a guide only and the final content and structure of the dossier will be considered at the PSM. The submitted dossier should follow the electronic Common Technical Document (eCTD) format if available at the time of submission. Therefore, the Applicant should complete Modules 1 – 5 of the eCTD as far as possible and include all relevant data that are available.

Non-CTD data can be provided and the format should be discussed and agreed at the pre-submission meeting. For example, if a study is on-going and interim data are submitted, or if a full clinical study report (CSR) is not yet available, a summary of the results obtained after database lock addressing the main sections of a CSR and presenting the data in the form of tables, charts, figures would be acceptable, with the protocol and statistical plan provided in annex. Individual patient listings and Serious Adverse Event (SAE) narratives should be available on demand. Specific EAMS aspects of modules 1 and 2 of the CTD are described below. The use of hyperlinks is strongly encouraged.

Module 1

A completed EAMS application form and appropriate cover letter should be submitted. The cover letter should include the proposed timetable submission slot and the EAMS number. The product information will be described in the ‘EAMS Treatment Protocol’, which details the conditions for use, ensuring safe and efficacious use of the product. The EAMS treatment protocol (TP) templates that should be used can be obtained from the EAMS coordinator or assessment team during the PSM.

An EAMS Risk Management Plan (see further guidance below) should be submitted.

Scientific opinion application form (MS Word Document, 365356 KB)

Module 2

Module 2 should contain the overviews and summaries, prepared by suitably qualified and experienced experts.

Quality

The Quality Expert Report should include a summary of each section listed in the eCTD, with sufficient data presented in flow charts/tables/figures to assist rapid review and assessment. In addition, the qualification/ validation status of the assay methods should be listed and provisional specifications provided. Process control criteria should be clearly and concisely presented and justified, with a summary of risk assessments, where relevant. The Quality Expert should also provide a critical review of the data and highlight key information in the report. A list of the Drug Product batches used in nonclinical and clinical trials should be given, so that clear links can be made with these sections. Reference (with hyperlinks) to Module 3 should only be made where further details are provided in support of the expert’s discussion and conclusion reached in the Quality Expert Report.

Non-clinical

The non-clinical overview should provide a critical review of the available non-clinical pharmacology, pharmacokinetic and toxicology data, highlighting potential target organs/tissues. Systemic exposures in the non-clinical species at no observed adverse effect levels and at toxic doses, in comparison to those in humans at the maximum recommended human dose, should be discussed; this information may be summarised in tabular form to aid review. Any mechanistic studies that have been conducted to elucidate reported toxicities and/or their relevance to man should also be highlighted.

Clinical

The clinical overview should be a concise summary of the clinical information, with sufficient data presented in flow charts/summary tables/figures to assist rapid review and assessment. Individual study synopses should be appended but Clinical Summaries (section 2.7) are not mandatory.

EAMS criteria

A specific additional section which confirms that the product meets the EAMS criteria should be provided as an annex to the clinical overview with the following EAMS criteria headings, namely:

(i) Demonstrate that there is a life threatening or seriously debilitating condition and a high unmet need,

(ii) Demonstrate that the medicinal product offers a major advantage over methods of preventing, diagnosing or treating the condition already in use *in the United Kingdom,

(iii) Demonstrate that the potential adverse effects of the medicinal product are outweighed by the potential benefits, allowing for a reasonable expectation of a positive risk-benefit balance,

(iv) To supply the product to or within the United Kingdom (or a part thereof) for use as part of the Scheme, and

(v) To manufacture, or secure the manufacturing of, the product to a consistent quality standard and in compliance with good manufacturing practice,

• From a regulatory perspective, methods ‘already in use’ include medicinal products that have a GB or UK marketing authorisation as well as standard of care and non-pharmacological therapies. The health technology assessment,  commissioning or supply status of a product is not taken into account by the MHRA.

Timing of EAMS SO application  

In general, medicinal products should be supplied under the EAMS for at least 6 months prior to the corresponding UK or GB marketing authorisation (or the relevant extension of indication variation). The EAMS SO application should be timed accordingly. The clinical overview should include a section that describes the current and planned clinical programme, and the estimated timelines for UK or GB marketing authorisation.

Real world data (RWD) collection

In addition to data collection in accordance with the pharmacovigilance requirements, proposals for the collection of RWD can be considered (encouraged but not mandatory). The generation of evidence from the analysis of RWD is often integral for the assessment of innovative treatments. While RWD can supplement clinical trial data, particularly in the rare disease setting, there is a responsibility on the data collectors to ensure the data collection does not form a clinical trial. The MHRA has published a guideline on this approach . The collection of RWD should always be done while adhering to best practice and the company is also encouraged to seek joint Scientific Advice from the MHRA and NICE pertaining to RWD collection to ensure substantial deviations from current and ongoing clinical care do not occur.

Whilst the collection of RWD under the scheme is not primarily for the purpose of research, it is recognised that data may have research value once collected. Where it is possible that data which is being collected may be used for the purpose of research, this must be addressed as part of the consent process. Patients consenting to the collection of their data under the scheme should additionally be provided with information about the potential for future research use and asked whether they consent to their data being used for such purposes. Further information can be found on the Health Research Authority (HRA) website.

The data to be collected should be described in a protocol and can be more extensive than the requirements for the treatment protocol, pharmacovigilance requirements and registry data collection. It is acknowledged there may be overlap for some data collected in the registry and this should be highlighted in the protocol.

Collection of RWD specifically within EAMS can be conducted without the need for authorisation under the Clinical Trials Regulations provided the following considerations are clarified in the protocol:

• Data collection should be in relation to the clinical management of patients receiving the EAMS product rather than to answer a specific research question under a protocol. Protocols that pose specific new clinical hypotheses would usually be evaluated in a clinical trial as part of the development programme and EAMS data collection is not to be considered as a substitute for well conducted clinical trials.     
• Data collection may be used to support regulatory or health technology appraisal (HTA) / commissioning access decisions (in discussion with the relevant authorities). Please provide a rationale for why you are collecting the data and what the data might be used for. For example, RWD may be used by the company to clarify the validity of the clinical data and the setting of the data collection (e.g. confirm similar NHS patient population attributes as seen in the clinical trial group).
• Data collection could compare the ‘real world’ situation with previous clinical trial data to ensure the risk-benefit for the patients in EAMS remains positive.  

The full protocol for collection of RWD will be reviewed at the time of the SO review and the company may be asked for clarifications to ensure the above considerations are met for exemption from a clinical trial authorisation (CTA) application.

In the event a SO is revoked before a marketing authorisation then continued data collection would require a CTA application under the Clinical Trials Regulations.

Whilst patient consent to data collection is not a requirement of access to an EAMS medicinal product, specific patient consent to collect RWD is required.

The company is reminded that consent for collection of RWD needs to be evidenced in writing, dated and signed.  Participants must be provided with clear information informing them of the benefits of their data to the company, that they can decide to withdraw consent for data collection at any time and clarifying patient confidentiality.  

Any other approvals should be obtained as appropriate, including a positive Ethics Committee opinion if applicable.

When to submit your application and procedure

The EAMS dossier should be submitted in electronic format via the MHRA portal by the date specified and agreed after the pre-submission meeting. Submission deadline dates can be found in the Dates for Submission section of the EAMS webpageLate or invalid dossiers will not be able to enter the scheme on the preferred date. For help and advice regarding the submission process, please contact the EAMS co-ordinator at eams@mhra.gov.uk.

Procedure

Once the procedure has started, Applicants will receive an initial SO decision by Day 45 of the procedure timetable. This follows consultation with the Commission on Human Medicines (CHM).  If the preliminary SO is positive, the procedure follows the Day 75 timetable, with a clock stop period of up to 15 days.

If preliminary positive at Day 45, the MHRA will inform specific NHS colleagues in confidence that a Day 45 preliminary positive SO has been reached for the product and the condition. This is to allow preparation time in the NHS should the final SO be positive. If the preliminary SO is negative, the procedure follows the Day 90 timetable, with a 30-day clock stop (this may be extended to 60 days in exceptional circumstances).

The clock stop period allows time for an Applicant to respond to outstanding major (30 days) or minor (15 days) issues. Response to the outstanding issues should be provided within the stated time.

The company is encouraged to engage with the relevant access stakeholders during the procedure as appropriate to help ensure a smooth transition from positive SO to patient access.  

EAMS Scientific Opinion Time Table (PDF, 121 KB, 1 page)

Positive Scientific Opinion

A positive SO is issued if the criteria for the EAMS are fulfilled. The applicant will first be asked to provide comments on draft versions of the TPs, NHS Medical Director (MD) letter and public assessment report (PAR). Once these are agreed, the applicant will receive a positive SO letter and the final agreed TPs, NHS MD letter and PAR.  The NHS, HTA and OLS contacts (as previously described under PIM designation) are then informed of the positive SO and receive a copy of the final agreed TPs, NHS MD letter and PAR. The Applicant and the NHS, HTA and OLS contacts are informed that the SO will be live on the EAMS webpage in 48 hours.  The positive SO is then published on the MHRA EAMS webpage alongside the TPs, NHS MD Letter, and PAR.

The SO is valid for one year and expires at this time unless renewed, or at the time of the grant of the marketing authorisation or extension of indication. Further information generated during the SO year should be provided to the MHRA as per the agreed Risk Management Plan and the requirements for Periodic Reports (see below).

Any new information that the SO holder considers may impact the benefit/risk balance must be reported as soon as is reasonably practicable after the SO holder becomes aware of it. Failure to do so may result in withdrawal of the SO. If the data submitted change the positive benefit/risk scientific opinion, the MHRA reserves the right to withdraw the SO. The EAMS SO holder should inform the agency if there are any changes that might impact the EAMS criteria, such as approval of a new medicine that may change the major advantage considerations. See also section below Notifying the MHRA of relevant changes in relation to the EAMS medicinal product.

Negative Scientific Opinion

There is no right of appeal for negative opinions and negative opinions will not be published. The negative opinion letter will include feedback for the negative grounds.

The NHS, HTA and OLS contacts are not informed of a negative SO.

Withdrawal of opinion

The MHRA will withdraw the EAMS positive SO, if following scientific assessment, the benefit/risk is considered to be no longer favourable, or when a marketing authorisation or extension of indication is granted, or when the agreed EAMS winding down period expires (see below). The EAMS PAR will be moved to the webpage for expired SOs and the MHRA will communicate the withdrawal of the SO via the appropriate channels, in order to protect public health or note approval of a marketing authorisation.

Renewal of opinion

The SO expires after one year or at the time of the grant of a marketing authorisation or extension of indication. Renewal of an EAMS scientific opinion should be requested at least 2 months before expiry of the opinion by completing the EAMS periodic updates/ renewal template.

Application Form

EAMS periodic updates/renewal template

Pharmacovigilance

Guidance for the fulfilment of pharmacovigilance obligations

The early access to medicines scheme (EAMS) aims to give patients with life threatening or seriously debilitating conditions access to medicines that do not yet have a marketing authorisation when there is a clear unmet medical need. Regulation 167G of The Human Medicines Regulations 2012 as amended (HMR) outlines the pharmacovigilance obligations for holders of an EAMS scientific opinion, which seek to ensure that relevant information on the risk-benefit balance of an EAMS medicinal product is collected and reported to the MHRA and that proportionate risk management planning is undertaken. This website aims to provide guidance for the fulfilment of these obligations.

Nothing in the regulations precludes the holder from utilising existing pharmacovigilance systems, processes and personnel to fulfil its obligations for the EAMS medicinal product, where such a framework is in place for its authorised medicinal products. If a marketing authorisation is granted in respect of the product to which the scientific opinion relates, the pharmacovigilance requirements in HMR Part 11 that apply to UK marketing authorisations supersede those of the scheme.

Risk management planning

In accordance with HMR regulation 167G (1)(a), a risk management system must be agreed with the licensing authority and operated by the EAMS scientific opinion holder in accordance with the risk management plan (RMP).

Applicants are required to submit an EAMS RMP when applying for a scientific opinion (Step II application). The EAMS RMP should describe the product’s safety profile and should include a description of a suitable series of pharmacovigilance activities in support of the safe and effective use of the product in line with the EAMS Treatment Protocol. These activities would likely include a registry, in which case a full protocol will need to be agreed before a positive opinion is issued. Any required additional risk minimisation measures (e.g. patient cards, checklists, educational materials) should also be described in the EAMS RMP and mock-ups of these materials will need to be approved by the MHRA before the EAMS product is made available for use.

The template for the EAMS RMP is available here:

Full EAMS RMP template

An abridged version of this template may be used in the event that there is an RMP approved for the product in an authorised indication in the UK that is relevant to the use through the EAMS. This would usually apply for a drug authorised for marketing for which the important safety concerns can be expected to be the same to those in its use through EAMS. The RMP approved for the authorised product in the UK must be submitted alongside the abridged EAMS RMP. The template for the abridged EAMS RMP is available here:

Abridged EAMS RMP template

Registry requirements

The data collected in a registry must be of relevance to the use of the product whilst the product is prescribed under the scheme. The purpose is to ensure the safe and effective use of the product in line with the EAMS Treatment Protocol. Given the scheme is designed for products where there is a high unmet medical need, comparative data are likely to be limited and thus a drug, rather than disease, registry is likely to be the most appropriate design.

The data that needs to be collected depends on the nature of the known or potential safety concerns. If there are no specific safety concerns, it is still of utmost importance that the product is being used in line with the EAMS Treatment Protocol and a full understanding of the real-life use is obtained. Therefore, the following information should be collected:

• Condition which the product is being used for;
• Patient details including age, gender/sex and race/ethnicity;
• Dose and duration of treatment;
• Other relevant dosing information (e.g. if proposed dosing is weight-based, patients’ weight would need to be collected);
• Underlying co-morbidities;
• Concomitant medications;
• Adverse events.

If the EAMS Treatment Protocol specifies measures that are prerequisites for use, for example baseline biomarker status, these should routinely be collected and recorded in the registry. If other factors are known to be strongly predictive of efficacy outcome, these should be recorded.

If a specific safety concern has been raised during the review, then factors related to this safety concern should be recorded. For example, if there are concerns with respect to cardiovascular toxicity, then collecting baseline data on history of cardiovascular disease and events or NYHA functional class may be relevant.

The registry should capture all medically-confirmed adverse events, with transmission to the MHRA as appropriate (see section on Management and reporting of adverse drug reaction reports below).  All reports of adverse events should be assessed to determine whether they are possibly related to the EAMS product. An adverse event should be classified as an adverse drug reaction if there is a reasonable possibility of a causal relationship with the product. The registry data should categorise events by seriousness (serious or non-serious) and the reporter and the EAMS scientific opinion holder should include an assessment of causality and relatedness where possible.

Patient informed consent forms should not be submitted within the EAMS RMP as these are not assessed by the MHRA.

Management and reporting of adverse drug reaction reports

Collection and management of adverse event and adverse drug reaction reports

In accordance with HMR regulation 167G (1)(b), EAMS scientific opinion holders must record and maintain adverse reaction reports related to the EAMS medicinal product and must ensure that these reports are electronically or physically accessible at a single point within the United Kingdom.

EAMS scientific opinion holders must establish appropriate procedures to collect and collate all reports of suspected adverse reactions associated with the EAMS medicinal product originating from any source (HMR regulation 167G (1)(d)(i)). The procedures should be developed to allow the acquisition of sufficient information for the scientific evaluation of those reports and to ensure that collected reports are authentic, legible, accurate, consistent, verifiable and as complete as possible for their clinical assessment.

As a general principle, data received from the primary source should be treated in an unbiased and unfiltered way and inferences as well as imputations should be avoided during data entry or electronic submission. The reports should include the verbatim text as used by the primary source or an accurate translation of it. The original verbatim text should be coded using the appropriate terminology (refer to section Format of individual case safety reports).

In accordance with the ICH-E2D guideline¹, two types of safety reports are distinguished in the post-authorisation phase: reports originating from unsolicited (spontaneous) sources and those reported as solicited. The same concept applies to adverse drug reactions related to an EAMS medicinal product.

Reports of suspected adverse reactions received within the scope of an approved EAMS where the systematic collection of adverse events is not required should be considered spontaneous reports. Equally, any unsolicited suspected adverse drug reaction reports relating to the EAMS medicinal product, but not derived from a study or any organised data collection system, should also be classified as spontaneous reports.

Reports of suspected adverse reactions received within the scope of an approved EAMS where the systematic collection of adverse events is required, e.g. via a registry or from any other organised data collection system, should be considered solicited reports.

EAMS scientific opinion holders should also record reports of overdose, off-label use, abuse, misuse, medication error, occupational exposure, lack of therapeutic efficacy and use during pregnancy (via maternal and paternal exposure) or breastfeeding when becoming aware of them. Reports with no associated suspected adverse drug reaction should not be submitted as individual case safety reports (ICSR), but should be considered in the relevant sections of the periodic report (see section Periodic reporting), as applicable, to support the scientific evaluation and interpretation of safety data, and the overall benefit-risk profile of the EAMS medicinal product.

Assessment of reports

Solicited reports originating from EAMS should undergo an appropriate causality assessment to consider whether they refer to suspected adverse reactions and therefore meet the minimum validation criteria (see section  Validation of reports). For all solicited reports, the EAMS scientific opinion holder should have mechanisms in place to record and document complete and comprehensive case information and to evaluate that information, in order to allow the meaningful assessment of individual cases and the submission of valid ICSRs related to the EAMS medicinal product. The EAMS scientific opinion holder should therefore exercise due diligence in establishing supporting procedures, in following-up those reports (refer to section Follow-up of reports) and in seeking the view of the primary source as regards the causal role of the EAMS medicinal product on the notified adverse event. Where this opinion is missing, the EAMS scientific opinion holder should exercise its own judgement to perform a causality assessment based on the information available in order to decide whether the report is a valid ICSR, which should be submitted in accordance with the time frames and modalities presented in HMR regulation 167G (1)(c) and (d)(ii).

A valid case of suspected adverse reaction initially notified by a consumer cannot be downgraded to a report of non-related adverse event if a contacted healthcare professional subsequently disagrees with the consumer’s suspicion. In this situation, the opinions of both the consumer and the healthcare professional should be detailed in the narrative section of the ICSR. This information can also be submitted in a structured manner in ICH-E2B format, which provides the means to transmit the degree of suspected relatedness expressed by several primary sources for each reported drug event combination.

Similarly, a solicited report of suspected adverse reaction should not be downgraded to a report of non-related adverse event when the EAMS scientific opinion holder disagrees with the reasonable possibility of causal relationship expressed by the primary source on the EAMS medicinal product. The opinions of both the primary source and the recipient should be recorded in the narrative section of the ICSR or in structured manner in line with ICH-E2B.

EAMS scientific opinion holders should also assess the seriousness of the reported reaction. As described in ICH-E2A², a serious adverse reaction corresponds to any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly/birth defect. Further guidance on assessing the seriousness of adverse drug reactions is described in the EU guideline on good pharmacovigilance practices (GVP), Module VI (latest revision)³.

The ICSR seriousness criterion should not be downgraded from serious to non-serious if the notified recipient disagrees with the seriousness reported by the primary source.

Any suspected transmission of an infectious agent via a medicinal product should be considered as a serious adverse reaction and such cases should be submitted within 15 days in accordance with the requirements described in section Submission of adverse drug reactions.

Validation of reports

Only valid ICSRs qualify for submission to MHRA. In accordance with ICH-E2D, all reports of suspected adverse reactions should be validated before submitting them to the licensing authority to make sure that the minimum criteria are included in the reports.

The following four minimum criteria are required for ICSR validation:

1. One or more identifiable reporter
2. One single identifiable patient
3. One or more suspected substance/medicinal product
4. One or more suspected adverse reaction

As detailed in ICH-E2D, if an event is spontaneously reported, even if the relationship is unknown or unstated, it meets the definition of an adverse reaction.

The lack of any of the four elements means that the case is considered incomplete and does not qualify for submission as an ICSR. EAMS scientific opinion holders are expected to exercise due diligence in following-up the case to collect the missing data elements and follow-up activities should be documented. Reports, for which the minimum information is incomplete, should nevertheless be retained for data integrity purposes and completeness.

When the missing information has been obtained (including for example when the medicinal product causal relationship with the reported adverse event is no longer excluded), the ICSR becomes valid for submission and the guidance provided in section Submission of adverse drug reactions should be followed.

Follow-up of reports

EAMS scientific opinion holders must collect follow-up information on any adverse drug reaction report related to an EAMS medicinal product (HMR regulation 167G (1)(d)(ii)), if the information in the initial suspected adverse reaction report is incomplete. These reports should be followed-up as necessary to obtain supplementary detailed information significant for the scientific evaluation of the cases. This is particularly relevant for monitored events of special interest, reports of pregnancy, cases notifying the death of a patient, or cases reporting new risks or changes in the known risks. This is in addition to any effort to collect missing minimum criteria for report validation (see section Validation of reports). Any attempt to obtain follow-up information should be documented.

Follow-up methods should be tailored towards optimising the collection of missing information. This should be done in ways that encourage the primary source to submit new information relevant for the scientific evaluation of a particular safety concern. The use of targeted specific forms should avoid requesting the primary source to repeat information already provided in the initial report and/or to complete extensive questionnaires. Therefore, consideration should be given to pre-populating some data fields in those follow-up report forms to make their completion by the primary source easy.

New follow-up information should always be clearly identifiable in the case narrative (required for serious reports of suspected adverse reactions) and should also be captured in structured format as applicable.

EAMS scientific opinion holders should submit follow-up ICSRs in accordance with the timelines described in HMR regulation 167G (1)(c) and (HMR regulation 167G (1)(d)(ii)) if significant new medical information has been received. Significant new information relates to, for example, a new suspected adverse reaction, a change in the causality assessment, and any new or updated information on a case that impacts on its medical interpretation. Medical judgement should therefore be applied for the identification of significant new information requiring to be submitted as a follow-up ICSR.

Situations where the seriousness criteria and/or the causality assessment are downgraded (e.g. the follow-up information leads to a change of the seriousness criteria from serious to non- serious, or the causality assessment is changed from related to non-related) should also be considered as significant changes and thus be submitted as a follow-up ICSR.

Follow-up of pregnancy exposure reports

Reports of pregnancy, where the embryo or foetus may have been exposed to the EAMS medicinal product (either through maternal exposure and/or if the suspected medicinal product was taken by the father), should be followed-up prospectively in order to collect information on the outcome of the pregnancy and the development of the child after birth. The reports should contain as many detailed elements as possible in order to assess the causal relationships between any reported adverse reactions and the exposure to the suspected medicinal product. In this context the use of standard structured questionnaires is recommended.

EAMS scientific opinion holders should continue to collect, record and report follow-up information on the pregnancy outcome even after the EAMS scientific opinion ceases to have effect. Individual cases with an abnormal outcome associated with the EAMS medicinal product following exposure during pregnancy are classified as serious reports and should be submitted in accordance with the requirements outlined in section Submission of adverse drug reactions. This especially refers to:

• reports of congenital anomalies or developmental delay in the foetus or the child,
• reports of foetal death and spontaneous abortion, and
• reports of suspected adverse reactions in the neonate that are classified as serious.

Submission of adverse drug reactions

Adverse drug reactions to an EAMS medicinal product should be electronically submitted to MHRA via ICSRs as structured data with the use of controlled vocabularies for the relevant data elements where applicable.

Format of individual case safety reports

EAMS scientific opinions holders should consequently apply the following internationally agreed ICH guidelines and standards to ensure correct data entry and the appropriate use of terminologies:

• ICH M1 Terminology - Medical Dictionary for Regulatory Activities (MedDRA), which should be used at the lowest level term (LLT) level in the ICSRs.⁴ EAMS scientific opinion holders should follow the recommendations of the MedDRA Maintenance Support Service Organisation (MSSO) regarding the switch to a new MedDRA version.
• The latest version of the Guide for MedDRA Users MedDRA Term Selection: Points to Consider.⁵
• The guidelines applicable for the ICH-E2B formats:

ICH-E2B(R2)	- ICH-M2 EWG - Electronic Transmission of Individual Case Safety Reports Message Specification6
	- ICH-E2B(R2) - Maintenance of the ICH Guideline on Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports7
ICH-E2B(R3)8	- ICH Implementation guide package including the ICH-E2B(R3) Implementation Guide for Electronic Transmission of Individual Case Safety Reports (ICSRs) - Data Elements and Message Specification
	- ICH-E2B(R3) Implementation Working Group - Electronic Transmission of Individual Case Safety Reports (ICSRs) – Questions & Answers

The latest version of these documents should always be taken into account.

EAMS scientific opinion holders are reminded that the ICH-E2B(R3) standard became mandatory on 30 June 2022.

Submission modalities of individual case safety reports

For an EAMS product with no nationally licensed indication(s) in the UK

In line with HMR regulation 167G (1)(c) and (d)(ii) the following submission requirements apply to valid unsolicited and solicited ICSRs reported by healthcare professionals and non-healthcare professionals in relation to EAMS medicinal products in the context of use under the EAMS. This is relevant irrespective of the condition of use of the EAMS medicinal product and of the expectedness of the adverse reaction.

• Serious ICSRs
• The EAMS scientific opinion holder must submit all serious ICSRs that occur within or outside the UK to the MHRA within 15 days from the date of receipt of the reports.
• Non-Serious ICSRs
• The EAMS scientific opinion holder must submit all non-serious ICSRs that occur in the UK to the MHRA within 90 days from the date of receipt of the reports.

EAMS scientific opinion holders must send all UK ICSRs and serious non-UK ICSRs directly to the MHRA via either ICSR Submissions or Gateway. Guidance on how to register and to make submissions is available on the MHRA website⁹, ¹⁰.

For an EAMS product with nationally licensed indication(s) in the UK (including in Great Britain and/or Northern Ireland)

Adverse reaction reports related to EAMS medicinal products with an existing UK marketing authorisation in a different indication should be submitted to the MHRA in accordance with requirements in HMR Part 11, regulation 188(1). This includes reports received in the context of use under the EAMS. No duplicate reporting under regulations 167G (1)(c) and (d)(ii) is required.

Periodic reporting

In accordance with HMR regulation 167G(1)(e), periodic reports on the use of the EAMS medicinal product must be submitted to MHRA. These reports should provide:

• details of any suspected adverse drug reaction to the medicinal product,
• a summary of any significant new data on the quality, safety or efficacy of the medicinal product concerned,
• details of recent authorisations of (or variations to) other medicinal products for indications that overlap with the EAMS indication
• any proposed updates to the medicinal product information,
• all data the holder has relating to the volume of prescriptions, including an estimate of the population exposed to the medicinal product in the United Kingdom, and
• a scientific evaluation of the risk-benefit balance of the medicinal product.

See the template for the preparation of periodic reports

Periodic reports should usually be submitted on a three-monthly basis for the first year after positive scientific opinion. A one-month period for preparation of the report is permitted, i.e. the first periodic report would have a data lock point at three months post-opinion and be submitted within four months post-opinion. A final periodic report should be provided following scientific opinion expiry and is to be submitted within one month after EAMS SO expiry.

For products that have had a positive EAMS opinion for one year or more, submission of periodic reports on a less frequent basis (e.g. six-monthly) may be considered.

Periodic reports should be emailed to eams@mhra.gov.uk. 

The same template should also be used to renew the scientific opinion after a year.

Notifying the MHRA of relevant changes in relation to the EAMS medicinal product

In accordance with HMR regulation 167G(1)(f), the EAMS scientific opinion holder must notify the MHRA without delay if it detects important new risks, changes to risks or changes to the risk-benefit balance. 

Such emerging safety issues should be notified to eams@mhra.gov.uk no later than three working days after establishing that a validated signal or a safety issue from any source meets the definition of an emerging safety issue. This is in addition to the ICSR submission requirements when the emerging safety issue refers to a single case of suspected adverse reactions.

When notifying an emerging safety issue, the opinion holder should describe the safety issue, the source(s) of information, any planned or taken actions with timelines, and should provide any relevant documentation available at the time of initial notification. Any further information relevant to the issue should be provided to the MHRA as soon as it becomes available.

In alignment with GVP Module IX for authorised medicines, an emerging safety issue is defined as a safety issue considered by the EAMS scientific opinion holder to require urgent attention by the MHRA because of the potential major impact on the risk-benefit balance of the medicinal product and/or on patients’ or public health, and the potential need for prompt regulatory action and communication to patients and healthcare professionals.

Examples include:

• major safety issues identified in the context of ongoing or newly completed studies, e.g. an unexpectedly increased rate of fatal or life-threatening adverse events;
• major safety issues identified through spontaneous reporting or published in the scientific literature, which may lead to considering a contra-indication, a restriction of use of the medicinal product or its withdrawal from use in clinical practice;
• major safety-related regulatory actions outside the UK, e.g. a restriction of the use of the medicinal product or its suspension.

Pharmacovigilance record retention

The EAMS scientific opinion holder must record all pharmacovigilance information required under HMR regulation 167G and must maintain all pharmacovigilance records for at least five years beginning on the date on which the EAMS scientific opinion ceases to have effect in accordance with regulation 167D (1) (regulation 167G (1)(g)(i) and (ii)).

In particular, documentation of the following pharmacovigilance information and their retention must be ensured:

• All elements of the risk management system as agreed with the MHRA, including the approved RMP (regulation 167G (1)(a)).
• Adverse reaction reports associated with the EAMS medicinal product (regulation 167G (1)(b)), including the original source data or images thereof.
• Records demonstrating the submission of serious and non-serious initial and follow-up adverse reaction reports to MHRA within the legal timelines (regulation 167G (1)(c) and (d)).
• Quality procedures supporting the collection of accurate and verifiable data for the scientific evaluation of suspected adverse reaction reports (regulation 167G (1)(d)(i)).
• Periodic reports and records of their submission to the MHRA (regulation 167G (1)(e)).
• Records and information relating to the identification, assessment of new risks, changed risks and changes to the risk-benefit balance of the EAMS medicinal product and their notification to the MHRA (regulation 167G (1)(f)).

During the retention period, retrievability of the complete and accurate records should be ensured. The EAMS scientific opinion holder must make available any pharmacovigilance records available to the MHRA on request (HMR regulation 167G (1)(g)(iii)).

Records can be retained in electronic format provided that the electronic system has been appropriately validated and appropriate arrangements exist for system security, access and back-up of data. If records in paper format are transferred into an electronic format, the transfer process should ensure that all of the information present in the original format is retained in a legible manner and that the media used for storage will remain readable over time.

There should be appropriate structures and processes in place to ensure that pharmacovigilance information and records are protected from destruction during the applicable record retention period.

Documents transferred in situations where the business of an EAMS scientific opinion holder is taken over by another organisation should be complete.

It should be ensured that the fundamental right to personal data protection is fully and effectively guaranteed in all pharmacovigilance activities in conformity with legal provisions.

If a marketing authorisation is granted in respect of the product to which the scientific opinion relates, the requirements in regulation 167G (1)(g)(ii) and (iii) continue to apply after the EAMS scientific opinion ceases to have effect, notwithstanding the pharmacovigilance record retention requirements for authorised medicinal products outlined in HMR Schedule 12A paragraph 12(5) and the Commission Implementing Regulation (EU) 520/2012 Article 12(2).

Labelling and supply aspects

Labelling of EAMS medicines should meet the requirements presented in the British Pharmacopoeia (Unlicensed Medicines).   

Pack presentation

The pack presentation for EAMS supply is typically non-commercial in nature, however where the EAMS indication represents an unlicenced indication for a product which is the subject of a marketing authorisation, an overlabelled commercial presentation may be used, subject to MHRA approval.

The EAMS scheme can be applied to the whole of the UK (Great Britain and Northern Ireland) therefore a single pack presentation for EAMS is appropriate, regardless of territory.  Where an overlabelled commercial presentation is proposed, a single pack presentation may be used over all territories, regardless of whether different commercial packs are provided in Northern Ireland and Great Britain. 

Manufacture and assembly in the UK

In line with the Human Medicines (Early Access to Medicines Scheme) (Amendment) Regulations 2022, EAMS has a statutory basis.  

The types of UK Manufacturing Licences under which an EAMS medicine may be manufactured or assembled comprise: 

• A Manufacture/Importation Authorisation (MIA)
• A Manufacture/Importation Authorisation for Investigational Medicinal Products (MIA (IMP))
• A Manufacture/Importation Authorisation for unlicensed (“Special”) medicines (MS)

The manufacturing licence should authorise the proposed activity (e.g. primary packaging).

Requirements for importation of EAMS supplies into the UK

Importation requirements for EAMS supplies into the UK should meet current requirements, as follows:

• UK sites with a Manufacturing and Import Authorisation for Investigational Medicinal Products (MIA(IMP)) are permitted to import EAMS intermediates/supplies.
• UK sites with a Wholesale Distribution Authorisation (WDA(h)) are permitted to import EAMS medicines from an approved country for import (GB) or the EEA (NI). 
• UK sites with a Manufacturer/Importer Authorisation (MIA) are permitted to import EAMS medicines from third countries not on the list of approved countries for import (GB) or outside of the EEA (NI).
• UK sites with a Manufacturer “Specials” Authorisation (MS) are permitted to import EAMS medicines from third countries not on the list of approved countries for import (GB) or outside of the EEA (NI).

No importation notification requires to be submitted to the MHRA for an EAMS medicine.

Instructions for product labelling/packaging

The Applicant should submit a proposal in line with requirements applicable to unlicensed medicines manufactured or prepared in accordance with medicines legislation. The requirements were previously included as guidance in Supplementary Chapter V of the British Pharmacopoeia 2007.

Best practice guidance on the labelling and packaging of medicines advises that certain items of information are deemed critical for the safe use of the medicine (see “Best Practice Guidance on the Labelling and Packaging of Medicines”; MHRA, 2012). These critical items of information, which should be located together on the pack and appear in the same field of view, are: name, strength, route of administration, dosage and warnings (highlighted in bold).

1. The common name of the product.
2. A statement of the active ingredients expressed qualitatively and quantitatively per dosage unit or for a given volume or weight.
3. Route of administration.
4. Instructions for use, including any special warnings.
5. The pharmaceutical form.
6. The contents of the container by weight, volume or by number of doses.
7. Excipients of known effect. For injectable, topical (including inhalation products) and ophthalmic medicines, all excipients.
8. ‘Keep out of reach and sight of children’.
9. The expiry date expressed in unambiguous terms (dd/mm/yy).
10. Any special storage precautions.
11. The EAMS number.
12. The Company name and address.
13. The batch number.

For small containers certain details may be omitted, but the label should contain, as a minimum, the following information:

1. The common name of the product.
2. A statement of the active ingredients expressed qualitatively and quantitatively per dosage unit or for a given volume or weight.
3. Route of administration.
4. The contents of the container by weight, volume or by number of doses.
5. The expiry date expressed in unambiguous terms (dd/mm/yy).
6. The EAMS number.
7. The Company name and address (unless this is included on the secondary packaging).
8. The batch number.

Scientific Opinion Fees

ScientificFind Opinionout Feesmore about the fees we charge at MHRA fees.

All fees become payable within 30 days following written notice from the MHRA requiring payment of those fees. The fee is not refundable if your application is not successful.

Post Marketing Authorisation EAMS period and winding-down period

Continuity of provision of EAMS supplies between marketing authorisation grant and commercial launch

When a UK or GB marketing authorisation (or relevant extension of indication) is granted for the medicine that is the subject of an EAMS Scientific Opinion, the Scientific Opinion usually expires.  Note that marketing authorisations covering Great Britain only will not be issued from 1 January 2025.  Where clinically appropriate and to maintain continuity of care, supply of EAMS medicines should continue to patients already enrolled to the EAMS scheme only, until commercial launch.  During this period, there is no requirement to change the source of EAMS supplies from non-commercial to commercial stock. Other exit strategies should be discussed directly with NHS colleagues. In these circumstances the EAMS webpage will state that the SO has expired, and the EAMS documents will be archived.

Winding-down period

A winding down period is when an EAMS scientific opinion continues to have effect in specified circumstances or for specified purposes (or both) following the grant of a marketing authorisation.

If agreed in advance with the licensing authority, a further period of access to the EAMS medicine under the so-called “winding-down period” may be considered for existing and new patients, after grant of a marketing authorisation and up to the point of product commercialisation. The winding down period is for a maximum of one year in duration, unless agreed with the MHRA. The EAMS medicine should continue to be provided free of charge.

During this period, there is no requirement to change the source of EAMS supplies from non-commercial to commercial stock. The safety sections of the EAMS treatment protocols should be updated in line with the authorised product information, where needed. Supply under the EAMS may be subject to additional specific conditions during the winding down period that may include regional specific differences. This includes restriction of the ability to supply across all 4 nations as a result of alternative scheme availability.

The EAMS webpage will state that a winding down period is in effect.

The EAMS Risk Management Plan will usually continue to apply during the winding down period unless otherwise agreed with the MHRA. Periodic reporting is not required during the winding down period. Where additional risk minimisation measures are required under the terms of the marketing authorisation, a proposal should be made for how these measures will be implemented during the winding-down period.

Please consider the need for a winding down period in your pre-submission meeting discussions. If you have an ongoing EAMS application or current SO, and are considering a winding down period, please contact the EAMS coordinator at the earliest opportunity, so that the specific circumstances of the winding-down period can be discussed and agreed at least 6 weeks in advance of the marketing authorisation.

Geographical scope

The EAMS scheme applies to the whole of the UK (Great Britain and Northern Ireland). In light of the Northern Ireland Protocol (NIP), until and including 31 December 2024 should a marketing authorisation be granted in the EU prior to the grant of a marketing authorisation in Great Britain, the EAMS Scientific Opinion is withdrawn for the territory of Northern Ireland but not for Great Britain.  As above, supply of EAMS medicines to patients already enrolled in the EAMS scheme may continue until the medicine is commercially available.

If a marketing authorisation is granted in Great Britain prior to the grant of an EU marketing authorisation, the Centrally Authorised Products (CAPs) Bridging Mechanism will take effect.

From 1 January 2025, after the implementation of the Windsor Framework, the MHRA will grant new marketing authorisations across the whole of the UK. EU marketing authorisations will no longer be valid in NI. Therefore, the granting of an EU marketing authorisation will not impact the geographical scope of an EAMS Scientific Opinion.   Further guidance on UK-wide licensing is available here:  https://www.gov.uk/government/publications/uk-wide-licensing-for-human-medicines/uk-wide-licensing-for-human-medicines

Footnotes

1. https://www.ich.org/page/efficacy-guidelines
2. https://www.ich.org/page/efficacy-guidelines
3. https://www.ema.europa.eu/en/human-regulatory/post-authorisation/pharmacovigilance/good-pharmacovigilance-practices
4. https://www.ich.org/page/multidisciplinary-guidelines
5. https://www.meddra.org/how-to-use/support-documentation/english
6. https://admin.ich.org/sites/default/files/inline-files/ICH_ICSR_Specification_V2-3.pdf
7. https://admin.ich.org/sites/default/files/inline-files/E2B_R2_Guideline.pdf
8. https://www.ich.org/page/e2br3-individual-case-safety-report-icsr-specification-and-related-files
9. https://www.gov.uk/guidance/send-and-receive-information-on-adverse-drug-reactions-adrs
10. https://www.gov.uk/guidance/register-to-make-submissions-to-the-mhra