Scientific advice and protocol assistance

At any medicine development stage, a developer can ask guidance and direction from EMA on the best methods and study designs to generate robust information on how well a medicine works and how safe it is, regardless of whether the medicine is eligible for the centralised authorisation procedure or not.

Scientific advice helps to ensure that developers perform the appropriate tests and studies, so that no major objections regarding the design of the tests are likely to be raised during the evaluation of the marketing authorisation application. This also helps avoid patients taking part in studies that will not produce useful evidence.

For human medicines, scientific advice and protocol assistance are given by the Committee for Medicinal Products for Human Use (CHMP) on the recommendation of the Scientific Advice Working Party (SWAP) However, in the case of medicines that are intended to treat, prevent or diagnose a disease causing a declared public health emergency, scientific advice is given by the CHMP based on recommendation of the Emergency Task Force (ETF).

• Requesting scientific advice or protocol assistance from EMA
• Qualification of novel methodologies for medicine development
• Parallel scientific advice and special development aspects or product types

Prospective applicants who are completely new to scientific advice or have little prior interaction with medicines regulators may benefit from reviewing the journey of a medicine for human use assessed by EMA in this interactive timeline, as a first step.

This timeline explains all stages - from initial research to patient access - including how EMA supports medicine development, assesses the benefits and risks and monitors the safety of medicines.

The full text is available as aFrom laboratory to patient: the journey of a centrally authorised medicine.

For information on how to request scientific advice from EMA, see Requesting scientific advice or protocol assistance from EMA.

EMA gives scientific advice by responding to specific questions posed by the medicine developer on the development of a particular medicine. 

The developer of a medicine presents the way it plans to develop its medicine and identifies questions and possible solutions. EMA then gives advice on the developer’s proposals.

Scientific advice is prospective in nature. EMA does not pre-evaluate the results of the studies and in no way concludes on whether the benefits of the medicine outweigh the risks.

Scientific advice from EMA is not legally binding on EMA or on the medicine developer with regard to any future marketing authorisation applications for the medicine concerned.

Scientific advice and protocol assistance are particularly useful to medicine developers when:

• they are developing an innovative medicine and there appears to be no or insufficient relevant detail in EU guidelines or guidance documents, or in Pharmacopoeia monographs, including draft documents or monographs released for consultation;
• they are developing new or repurposed medicines targeting (re)emerging pathogens for which there is an unmet medical need but insufficient or no guidance is available;
• the developer chooses to deviate from scientific guidelines in its development plan;
• the medicine developer has limited knowledge about medicine regulation, such as some academic groups or micro, small and medium sized enterprises (SMEs).

Medicine developers can request scientific advice or protocol assistance either during the initial development of a medicine before submission of a marketing authorisation application or later on, during the post-authorisation phase.

Questions during scientific advice can relate to:

• quality aspects (e.g. manufacturing, chemical, pharmaceutical and biological testing of the medicine);
• non-clinical aspects (e.g. toxicological and pharmacological tests designed to show the activity of the medicine in the laboratory);
• clinical aspects (e.g. appropriateness of studies in patients or healthy volunteers, selection of endpoints, i.e. how best to measure effects in a study, post-authorisation activities including risk management plans);
• methodological issues (e.g. statistical tests to use, data analysis, modelling and simulation);

• overall development strategy (e.g., conditional marketing authorisation, bridging strategy for generics, safety database), significant benefit for maintaining orphan designation, and paediatric developments.

  Examples of questions

  • Are the patients to be included in a study sufficiently representative of the population for whom the medicine is intended?
  • Are the planned measures to assess the benefits of a medicine valid and relevant?
  • Is the proposed plan to analyse results appropriate?
  • Does the study last long enough and include enough patients to provide the necessary data for the benefit-risk assessment?
  • Is the medicine being compared with an appropriate control?
  • Are the plans to follow the long-term safety of the product appropriately designed?

Questions about the topics below are outside the scope of scientific advice:

• Compassionate use, advanced therapy medicinal product (ATMP) classification, PRIME eligibility, and accelerated assessment
• Changes to the key elements of Paediatric Investigation Plan (PIP) measures and paediatric waivers or deferrals, which EMA addresses via a paediatric procedure
• Matters of a purely regulatory nature (please use the ‘Submission Details’ field in your submission via the IRIS portal)
• Adequacy of existing data for assessment of a regulatory application (e.g. a clinical trial application or marketing authorisation application). However, please include existing data expected to inform the discussion of questions on further development steps in the scientific advice briefing documentation

Examples of questions

• Could the proposed modelling and simulation approach replace study X in the agreed PIP? (only the PDCO can endorse such matters)
• Are the proposed active substance/finished product specifications acceptable? (as opposed to: Is the plan to derive the specifications acceptable?)
• Are the non-clinical data adequate to support a first-in-human study? (this would require a full review of the non-clinical data before EMA can respond and the question would belong to a clinical trial application under national competent authority remit)
• Are the phase 3 study results adequate to support marketing authorisation? (this is a question for the marketing authorisation application)

Protocol assistance is the special form of scientific advice available for developers of designated orphan medicines for rare diseases.

In addition to scientific advice, developers of orphan medicines can receive answers to questions relating to the criteria for authorisation of an orphan medicine. These include:

• the demonstration of significant benefit within the scope of the designated orphan indication;
• similarity or clinical superiority over other medicines. This is relevant if other orphan medicinal products exist that might be similar to the product concerned and which have market exclusivity in the same indication.

Scientific advice and the assessment of the benefits and risks of a medicine are different by nature.

Scientific advice looks at how a medicine should be tested in studies to generate robust evidence, while the assessment at the time of marketing authorisation looks at the evidence generated to determine whether the medicine’s benefits outweighits risks, regardless of any advice previously given.

Scientific advice can make the evaluation of a medicine easier and quicker because the evidence is likely to be more robust, appropriate and complete, but it does not affect the stringent assessment of safety and efficacy.

Complying with scientific advice therefore increases the chances of receiving marketing authorisation but it does not guarantee it.

During the development and assessment phases, the detailed advice given to a medicine developer is not made public. This is because disclosing information at this stage may undermine research and development efforts and discourage research in new medicines.

However, information is made available after a medicine obtains marketing authorisation. All medicines whose assessment report was finalised after 1 January 2019 include a summary of the developer’s questions and key elements of EMA's advice and whether or not the developer complied with this advice within the assessment report.

During a declared public health emergency, EMA publishes a list of medicines that have received informal or formal advice from the CHMP and the ETF.

In addition, the full advice can be made available upon request. For more information, see Access to documents.

Scientific advice is also one of the main sources for updating EMA scientific guidelines on medicine development, including, in particular, disease-specific guidelines.

The European Medicines Agency (EMA) carries out scientific advice in cooperation with other decision-making bodies in the European Union (EU) and beyond. It also offers scientific advice on special development aspects and / or product types, as follows:

• Parallel scientific advice processes - with the United States Food and Drug Administration (FDA), and with the EU Member State Coordination Group on HTA (HTACG)
• Scientific advice for special purposes - on clinical trials and post-authorisation safety studies (PASS)
• Scientific advice for special product types - on medicine repurposing, for biosimilar medicines, and on medicines required during public health emergencies

For more information, see:

• Parallel scientific advice and special development aspects or product types