How EMA evaluates medicines for human use

The European Medicines Agency (EMA) is responsible for the scientific evaluation of applications for centralised marketing authorisations in the European Union (EU). This authorisation procedure allows pharmaceutical companies to market the medicine and make it available to patients and healthcare professionals throughout the European Economic Area (EEA) on the basis of a single marketing authorisation. 

Preparing an application

What happens before a medicine assessment starts?

A few months before the assessment starts, EMA provides guidance to medicine developers to ensure that their applications for marketing authorisation comply with legal and regulatory requirements to avoid unnecessary delays.

To obtain marketing authorisation, medicine developers need to submit specific data on their medicine. EMA then carries out a thorough assessment of these data to decide whether or not the medicine is safe, effective and of good quality and is therefore suitable for use in patients. 

EMA provides companies with guidance on the type of information that needs to be included in a marketing authorisation application. 

About 6 to 7 months before submitting an application, medicine developers can meet with EMA to ensure that their application complies with legal and regulatory requirements. This means that the application includes all the different aspects required by EU legislation and needed to demonstrate that a medicine works as intended.

These meetings involve a range of EMA staff responsible for various areas such as quality, safety and efficacy, risk management or paediatric aspects, who will follow the application throughout the assessment.

EMA encourages developers to request such pre-submission meetings as they aim to increase the quality of the applications and avoid unnecessary delays.

Who bears the cost of medicine evaluation?

European legislation requires that pharmaceutical companies contribute to the costs of regulation of medicines. As the companies will earn revenues from the sales of medicines, it is fair that they should bear most of the financial costs of regulating them. This means that EU taxpayers do not have to support all the costs of ensuring the safety and effectiveness of medicines.

Companies pay an administrative fee upfront before EMA assessment starts. The administrative fee applicable for each procedure is defined by EU legislation. 

What information needs to be submitted in a marketing authorisation application?

The data submitted by medicine developers in their application for marketing authorisation must comply with EU legislation and include information on:

• the group of patients the medicine is proposed to treat, and whether there is an unmet medical need addressed by the medicine;
• the quality of the medicine including its chemical and physical properties, such as its stability, its purity and biological activity;
• compliance with international requirements for laboratory testing, medicine manufacture and conduct of clinical trials (‘good laboratory practice’, ‘good clinical practice’ and ‘good manufacturing practice’);
• the medicine’s mechanism of action, as investigated in laboratory studies;
• how the medicine is distributed in, and eliminated by, the body;
• the benefits observed in the patient group at whom the medicine is aimed;
• the medicine’s side effects observed in patients, including in special populations such as children or the elderly;
• the way risks will be managed and monitored once the medicine is authorised;
• what information is intended to be gathered from follow-up studies after authorisation.

Information about any possible (known or potential) safety concerns with the medicine, the way risks will be managed and monitored once the medicine is authorised and what information is intended to be gathered from follow-up studies after authorisation is described in detail in a document called the ‘risk management plan’ (RMP). The RMP is evaluated by EMA’s safety committee, PRAC, to ensure its suitability. 

The information to be provided to patients and healthcare professionals (i.e. the summary or product characteristics or SmPC, labelling and package leaflet) must also be supplied by the developer and is reviewed and agreed by the CHMP. 

Where do data on the medicine come from?

Most of the evidence collected on a medicine during its development comes from studies funded by the medicine developer. Any other data available on the medicine (for example from existing studies in the medical literature) must also be submitted by the applicant and will be assessed.

Studies that support the marketing authorisation of a medicine have to comply with strict rules and are conducted in a regulated setting. International standards, called good clinical practice, apply to the study design, recording and reporting to ensure that studies are scientifically sound and conducted in an ethical manner. The type of evidence needed to determine the benefits and risks of a medicine are defined by EU law and must be adhered to by medicine developers. Inspections can be requested by EMA to verify compliance with these standards.

EMA supports the conduct of high-quality studies through initiatives such as the European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA) and the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) which bring together expertise from independent academic centres across Europe. Thanks to these initiatives additional sources of evidence can complement the evidence provided by medicine developers, in particular in the context of the continuous safety monitoring of a medicine after its authorisation.

For more information, see:

• European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA)
• European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP)

Assessment process

What is the key principle underpinning a medicine’s assessment? 

The balance between the benefits and risks of a medicine is the key principle guiding a medicine’s assessment. A medicine can only be authorised if its benefits outweigh the risks. 

All medicines have benefits as well as risks. When assessing the evidence gathered on a medicine, EMA determines whether the benefits of the medicine outweigh its risks in the group of patients for whom the medicine is intended. 

In addition, since not everything is known about a medicine’s safety at the time of its initial authorisation, the way risks will be minimised, managed and monitored once the medicine is more widely used is also an integral part of the assessment and is agreed at the time of authorisation.

While the authorisation of a medicine is based on an overall positive balance between the benefits and risks at population level, each patient is different and before a medicine is used, doctors and their patient should judge whether this is the right treatment option for them based on the information available on the medicine and on the patient’s specific situation. 

Did you know..? In some cases, for example when a medicine is intended to treat a life-threatening disease for which there is no satisfactory treatment or if the disease targeted is very rare, EMA can recommend marketing authorisation on the basis of less complete or limited evidence on the medicine, provided that further data are provided at a later stage. As for all marketing authorisations, it must still be demonstrated that the benefits of the medicine outweigh the risks. For more information, see: Conditional marketing authorisation Guideline on good pharmacovigilance practices: Module V – Risk management systems (Rev. 2)

Who is involved in the assessment of marketing authorisation applications?

A committee of experts, each supported by a team of assessors, evaluates the applications.

EMA’s Committee for Medicinal Products for Human Use (CHMP) assesses applications submitted by medicine developers and recommends whether or not a medicine should be granted marketing authorisation. The committee is composed of one member and an alternate from each EU Member State, as well as from Iceland and Norway. It also has up to five co-opted members which are EU experts in relevant fields such as statistics and quality of medicines, nominated by the committee.

When conducting an assessment, the CHMP members are each supported by a team of assessors in the national agencies, who have a range of expertise and will look at the various aspects of the medicine, such as its safety, quality and the way it works.

The CHMP also works with other EMA committees during the assessment. These include the:

• Committee for Advanced Therapies (CAT) which leads the assessment of advanced therapy medicines (gene therapy, tissue engineering and cell-based medicines);
• Pharmacovigilance Risk Assessment Committee (PRAC) for aspects related to the medicine’s safety and risk management;
• Paediatric Committee (PDCO) for aspects related to the medicine’s use in children;
• Committee for Orphan Medicinal Products (COMP) for orphan-designated medicines. 

How does the CHMP work?

Peer review and collegial decisions are at the heart of the CHMP assessments.

For each application for a new medicine, two committee members − known as rapporteur and co-rapporteur  − from different countries are appointed to lead the assessment (for generics only one rapporteur is appointed). They are appointed according to objective criteria to make best use of the available expertise in the EU.

The role of the rapporteur and co-rapporteur is to conduct the scientific evaluation of the medicine independently from each other. They each form an assessment team with assessors from their national agency and sometimes from other national agencies.

In their assessment reports, each team summarises the data from the application, presents its judgments of the medicine’s effects and its views on any uncertainties and limitations of the data. They also identify questions that will have to be answered by the applicant. The two separate assessments take into account regulatory requirements, relevant scientific guidelines and experience in the evaluation of similar medicines. 

In addition to the rapporteur and co-rapporteur, the CHMP also appoints one or more peer reviewers from amongst the CHMP members. Their role is to look at the way the two assessments are performed and ensure that the scientific argumentation is sound, clear and robust. 

All the CHMP members, in discussion with colleagues and experts in their national agencies, also contribute actively to the evaluation process. They review the assessments made by the rapporteurs, provide comments and identify additional questions to be addressed by the applicant. The initial assessment and the comments received from peer reviewers and other committee members are then discussed during a plenary meeting of the CHMP. 

As a result of the discussions and as new information becomes available during the assessment, either from additional experts or from clarifications provided by the applicant, the scientific arguments are refined so that a final recommendation, representing the committee’s analysis and opinion on the data, is developed. This can sometimes mean, for example, that the committee’s view on the benefit and risk of the medicine may change during the evaluation and diverge from the initial assessments performed by the rapporteurs. 

Can the CHMP request more information during the evaluation?

During the evaluation, the CHMP raises questions on the evidence provided in the application and asks the applicant to provide clarifications or additional analyses to address these questions. Responses have to be provided within an agreed timeframe.

The CHMP can raise objections or concerns which can relate to any aspect of the medicine. If unresolved, major objections preclude marketing authorisation.

Major objections can relate for example to the way the medicine was studied, the way it is manufactured, or to the effects seen in patients such as the magnitude of the benefits or the seriousness of the side effects. 

What additional expertise can the CHMP rely on?

Experts with specialised scientific knowledge or clinical experience are often consulted during the evaluation to enrich the scientific discussion.

Additional experts can be called upon by the CHMP at any time during the assessment to provide advice on specific aspects raised during the evaluation.

Did you know..? External experts are consulted in about a quarter of the assessments of new medicines (excluding generics).

The CHMP can request the support of and ask specific questions to its working parties which have expertise in a particular field such as biostatistics, or a therapeutic area such as cancer. The members of EMA’s working parties have an in-depth knowledge of the latest scientific developments in their field of expertise.

The committee can also call upon external experts through its scientific advisory groups or ad-hoc expert groups. These groups, which include healthcare professionals and patients, are asked to respond to specific questions on the potential use and value of the medicine in clinical practice. 

Did you know..? EMA regularly exchanges views on ongoing medicines’ assessments with other regulatory agencies such as the United States Food and Drug Administration, Health Canada and the Japanese regulatory authorities. These discussions can relate for example to clinical and statistical issues, strategies to manage the risks and studies to be conducted after authorisation. For more information, see: Cluster activities

How are patients and healthcare professionals involved?

Patients and healthcare professionals are involved as experts and provide their views on whether the medicine can address their needs.

Patients and healthcare professionals are invited to take part as experts in scientific advisory groups or ad-hoc expert groups. Patients contribute to discussions by highlighting, for example, their experience of the disease, their needs and what risks they would consider acceptable in view of the expected benefits. Healthcare professionals may advise on groups of patients with unmet needs or the feasibility of measures proposed to minimise the risks associated with a medicine in clinical practice. 

In addition, individual patients can be invited to CHMP plenary meetings in person or via teleconference or consulted in writing (The Outcome Report on Pilot to involve patients in benefit/risk discussions at CHMP meetings is available).

Did you know..? In 2018, patients and healthcare professionals were involved in the assessment of about one in four new medicines (excluding generics).

What are the measures to safeguard experts’ independence?

Independence is safeguarded by a high level of transparency and the application of restrictions if certain interests are considered to potentially impact impartiality.

EMA policies on handling competing interests have been put in place to restrict the involvement of members, experts and staff with possible competing interests in the Agency’s work while maintaining EMA’s ability to access the best available expertise.

Members and experts of committees, working parties and scientific advisory groups or ad hoc expert groups submit a declaration of interests prior to any involvement in EMA activities.

The Agency assignsan interest level to each declaration of interests based on whether the expert has any direct or indirect interests (financial or other) that could affect their impartiality. Prior to involvement in a specific EMA activity, EMA checks the declaration of interests. If a competing interest is identified, the member or expert is either excluded from the activity or will have a restricted involvement. 

Members’ and experts’ declarations of interests and information on restrictions applied during scientific committee meetings are publicly available in the meeting minutes.

In addition, members of the committees, working parties, scientific advisory groups (and experts attending these meetings), and EMA staff have to abide by the principles set out in the Code of conduct of the European Medicines Agency.

Did you know..? The declarations of interests of all the experts, including patients and healthcare professionals, who take part in EMA activities are published on the EMA website. EMA also publishes annual reports on its independence which include facts and figures on declared interests and resulting restrictions.

How does the CHMP make its final recommendation?

The final CHMP recommendation is reached by a formal vote. Ideally, the CHMP will come to a consensus and unanimously recommend either the approval or refusal of the marketing authorisation; such a consensus is reached in 90% of cases. However, when a final recommendation by consensus cannot be reached, the committee’s final recommendation will represent the majority view. 

What information is publicly available during the evaluation of a new medicine and once a decision has been made?

EMA provides a high level of transparency about its medicine assessment by publishing of meeting agendas and minutes, reports describing how the medicine was assessed and the clinical study results submitted by medicine developers in their applications.

The list of new medicines that are being evaluated by the CHMP is available on the EMA website and updated every month.

EMA also publishes the agendas and minutes of all its committees’ meetings, where information on the stage of the assessment can be found. 

Once a decision has been taken on the authorisation or refusal of a marketing authorisation, EMA publishes a comprehensive set of documents called the European public assessment report (EPAR). This includes the public CHMP assessment report, which describes in detail the data assessed and why the CHMP recommended authorising or refusing authorisation.

For applications received after 1 January 2015, EMA also publishes the clinical study results submitted by medicine developers in support of their marketing authorisation applications. For older applications, clinical study results can be obtained through a request for access to the document. 

Detailed information on what EMA publishes and when on human medicines from the early development to the initial evaluation and the post-authorisation changes can be found in EMA's guide to information on human medicines evaluated by EMA.

Did you know..? As of October 2018, EMA had published the clinical study results submitted by medicine developers in their applications for over 100 medicines recently assessed by EMA. These are available for public scrutiny on EMA’s dedicated website on clinical data.