How scientific advice works
What is scientific advice?
Scientific advice is about advising medicine developers on the most appropriate way to generate robust evidence on a medicine’s benefits and risks.
For a medicine to be authorised, medicine developers have to demonstrate that it is effective, safe and of good quality.
During a medicine’s development, 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.
Then, when applying for a marketing authorisation, the developer submits all the data generated on the medicine to EMA. The Agency assesses this information and determines whether or not the medicine is safe and beneficial to patients.
Scientific advice is not:
Why does EMA provide scientific advice?
EMA provides scientific advice because:
- better designed studies are more likely to generate robust and complete data to show whether or not a medicine works and is safe. The sooner it can be shown that a new medicine works and is safe, the sooner it can be made available to patients;
- providing advice means that patients are not deprived of beneficial medicines simply because poorly designed trials failed to demonstrate that the medicine works and is safe;
- better study designs avoid patients taking part in studies that will not produce useful evidence;
- more effective development means that the limited scientific resources available are used in the best way for the benefit of patients.
Did you know..?
Two out of three development programmes submitted for scientific advice were considered not suitable for a future assessment of the medicine’s benefits and risks, according to an analysis done in 2015. Following scientific advice, 63% of these trials were modified to include a better way to assess the medicine’s effectiveness or a more appropriate comparator.
Scientific advice is particularly helpful for medicine developers who may have limited knowledge about medicine regulation, such as some academic groups or micro, small and medium sized enterprises (SMEs).
Scientific advice is also relevant for innovative therapies for which scientific guidance has not been developed yet or is limited.
For medicines that target conditions for which there are no satisfactory treatments and that have shown promising initial results, EMA provides extra regulatory support, including scientific advice at key development milestones, through an initiative called PRIME (Priority Medicines).
Why are medicine regulators the ones giving scientific advice?
Medicine regulators have a unique knowledge and experience of how medicines should be developed gained from years of assessment of medicines. It is their duty to share this knowledge and promote a more effective medicine development for the benefit of patients.
Does EMA provide advice in any other way?
Yes. EMA develops scientific guidelines to advise medicines developers on the best way to study their medicines; however these obviously have to address general situations and will not cover non-standard, innovative approaches as they are developed. Scientific advice therefore complements and builds on existing guidelines but is tailored to the specific case, and can eventually be used to update or develop new guidelines.
Guidelines provide general advice on the best methods and study designs to be used when developing certain types of medicines, such as vaccines or antibiotics or medicines for certain diseases such as cancer. However, guidelines only address general situations; they cannot cover new and innovative approaches coming along. In addition, their development takes time.
To complement guidelines, specific scientific advice is therefore provided on request for the development of individual medicines. The advice provided builds on existing scientific guidelines but is tailored to the specific medicine and the group of patients intended to be treated.
The development and update of guidelines in turn incorporate knowledge and experience gained through scientific advice and experience with the assessment of medicines, in particular with innovative medicines.
For example, when a novel endpoint is recommended in a number of recent scientific advice requests, the relevant guidelines are revised to include reference to the new endpoint. In this way, knowledge gained during scientific advice is shared with the wider scientific community.
How is scientific advice paid for?
Applicants pay an administrative fee for scientific advice. The provision of scientific advice by EMA is required by the EU legislation, which also defines the administrative fees to be charged to the applicant.
Reductions apply for certain types of medicines and applicants: there is a 75% fee reduction for medicines for rare diseases, known as orphan medicines; micro, small and medium sized companies (SMEs) have a 90% fee reduction.
In 2018, about a third of the 63 scientific advice finalised were provided to SMEs and a quarter related to orphan medicines. Thanks to fee reductions SMEs, who are the originators of a great number of innovative medicines, can access scientific advice during the development of their medicines.
What happens during scientific advice?
During scientific advice, experts respond to specific scientific questions related to 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. During scientific advice EMA does not evaluate the results of the studies and in no way concludes on whether the benefits of the medicine outweigh the risks.
What kind of questions are addressed during scientific advice?
Questions during scientific advice can relate to:
- quality aspects (manufacturing, chemical, pharmaceutical and biological testing of the medicine);
- non-clinical aspects (toxicological and pharmacological tests designed to show the activity of the medicine in the laboratory);
- clinical aspects (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 riskmanagement
- methodological issues (statistical tests to use, data
analysis, modelling and simulation).
Examples of questions addressed during scientific advice are:
- 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 alternative?
- Are the plans to follow the long-term safety of the product appropriately designed?
Who is involved in scientific advice?
Dozens of experts from a range of disciplines are involved in responding to the questions asked.
At EMA, the Committee for Medicinal Products for Human Use (CHMP) is responsible for assessing marketing authorisation applications. One of its roles is also to support research and development by providing scientific advice. This task is passed by the CHMP to EMA’s Scientific Advice Working Party (SAWP). The answers to the questions asked by the developer are elaborated by the SAWP, and then the final advice is formally adopted and issued by the CHMP.
The SAWP has up to 36 members, who are experts from medicine regulators around the EU, from academia, and from EMA’s committees for orphan medicines, advanced therapies, medicines for children and pharmacovigilance and risk assessment. About a fifth of its members are also CHMP members. This overlap allows the longer-term knowledge and expertise gathered on a medicine during scientific advice to be used during the later assessment of the application for marketing authorisation by the CHMP.
Are patients involved in scientific advice?
Patients are often involved in scientific advice. They are invited to share their real-life perspective and experience in relation to a particular medicine in their disease area. This can help medicine developers and regulators understand better what will work for that patient group and what they consider important.
Additional external experts may also be consulted, further widening the pool of expertise the SAWP can call on.
In 2018, one in five scientific advice procedures involved patients, and the SAWP members considered that in almost every case (90%) patients provided added value to the scientific advice. In about one in four cases, the scientific advice recommended that the development plan be modified to reflect patient advice.
What are the measures to safeguard experts’ independence during scientific advice?
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 of the SAWP and any other experts involved submit a declaration of interests prior to any involvement in EMA activities.
The Agency assigns each declaration of interests a level of risk based on whether the expert has any direct or indirect interests (financial or other) that could affect their impartiality. Before the start of a new scientific advice procedure, EMA checks the declaration of interests of every member or expert and if a competing interest is identified, the member or expert will have restricted rights.
Restrictions include no participation in the discussion on a particular topic or exclusion from voting on the topic.
Does giving scientific advice influence EMA’s assessment of the medicine?
Scientific advice and the assessment of the benefits and risks of a medicine are different by nature: while scientific advice looks at how a medicine should be studied to generate robust evidence, the assessment at the time of marketing authorisation looks at the evidence from the studies to determine whether the medicine’s benefits outweigh its risks, regardless of any advice previously given.
The questions raised during scientific advice and those addressed during the assessment of a medicine are fundamentally different: scientific advice addresses questions related to the most appropriate way to test and study a medicine; during the assessment of a medicine, the CHMP looks at the results of these studies and, based on these, determines whether the benefits of the medicine outweigh its risks and therefore whether it can be authorised for use in patients.
Giving scientific advice should make the evaluation of a medicine easier and quicker because the evidence to be generated is likely to be more robust, appropriate and complete. But it doesn’t affect the regulator’s stringent assessment of safety and efficacy, nor means that the medicine will automatically pass that assessment. Better evidence means that it is easier to conclude on the benefit-risk balance but does not necessarily mean that the medicine will be authorised – it might show more clearly that a medicine is harmful or not effective. Medicine developers that have had and followed scientific advice may therefore still not get approval for marketing. And conversely, medicine developers who did not follow the advice may still get approval for marketing.
While the scopes of these processes are distinct, the longer-term knowledge and expertise about the medicine that is gathered during scientific advice is useful in understanding more about the medicine and will be of use during the assessment of the application for marketing. In both processes, all the decisions taken are collegial and based on extensive discussions and consultations. No single SAWP or CHMP member can force a decision to go a particular way – it has to be agreed by a majority.
Complying with scientific advice increases the chances of receiving marketing authorisation but it does not guarantee it. An analysis done in 2015 showed that 15% of companies who complied with scientific advice provided by EMA received a negative opinion at the time of applying for marketing authorisation. This compares with 25% overall.
What does EMA publish on the outcomes of scientific advice?
During the development and assessment phases, the detailed advice given to a company is not made public. This is because disclosing information at this stage may undermine research and development efforts and so discourage research in new medicines.
However, information is made available as soon as a medicine obtains marketing authorisation.
In June 2018, EMA started publishing more detailed information on the scientific advice provided during the medicine development in the assessment report of medicines that received EMA PRIME support (i.e. medicines that target conditions for which there are no satisfactory treatments and that have shown promising initial results), and this initiative has been rolled out for all medicines with assessment reports finalised after 1 January 2019.
In particular, a summary of the developer’s questions is included at the beginning of the assessment report and key elements of the advice provided can be found in the relevant sections of the report. In addition, information on the company’s compliance with this advice is included.
Medicines’ assessment reports are published on the EMA website as soon as the European Commission has made a final decision on marketing authorisation.
In addition, the full advice can be made available upon request.
Scientific advice is one of the main sources for updating EMA scientific guidelines on medicine development. Disease-specific guidelines are regularly updated to incorporate knowledge and experience gained through scientific advice and through the assessment of medicines. In this way the outcome of scientific advice becomes available to all.
1. Notifying EMA
A medicine developer who wishes to request scientific advice first needs to notify EMA and send a briefing document.
A meeting can be organised, in particular for first users of scientific advice or for complex medicines.
2. Formal request and validation
The developer then sends a list of specific scientific questions and proposed responses.
EMA determines whether the questions are valid or not for scientific advice.
3. Appointment of coordinators
For each scientific advice procedure (or ‘protocol assistance’ procedure for orphan medicines) validated, two members of the SAWP who have sound expertise to address the scientific questions are appointed as coordinators.
4. Coordinators form assessment teams and prepare report
Each coordinator forms an assessment team calling on assessors from their national agency or other EU agencies.
Each team prepares a report addressing the scientific questions; they draft a list of issues for discussion with all the other members of the SAWP and may ask the applicant for any additional documents or clarifications.
5. Meeting with developer (if requested by SAWP)
If the SAWP wishes to discuss specific issues with the medicine developer it will organise a meeting, particularly where it disagrees with the proposed plan and proposes alternative development plans.
6. Consulting experts
Additional external experts may also be consulted, further widening the pool of expertise the SAWP can call on.
7. Consulting patients
Patients are also often consulted. If EMA decides to respond to the medicine developer in writing, patients are asked to provide comments; if EMA decides to meet with the medicine developer, patients are invited to attend.
7. EMA final response
The SAWP consolidates a response to the scientific questions. Final advice is discussed and adopted by the CHMP and then sent to the medicine developer.