What scientific advice can and cannot settle
European scientific advice is the European Medicines Agency's guidance to a developer on the tests and trials a medicine needs, and it rests on a legal task of the agency. It binds neither the developer nor the agency, yet it is weighed when the marketing authorisation application is reviewed. It is worth seeking early in development, and applications that follow it succeed more often. In the Russian Federation in 2013, which had no such procedure, a sponsor could reach the authorities' official opinion only through a clinical study application.
Who gives the advice and on what basis
Article 57(1)(n) of Regulation (EC) No 726/2004 makes advising undertakings on the tests and trials needed to demonstrate quality, safety and efficacy one of the tasks of the European Medicines Agency. The agency established the procedure on that basis in 1996, to support the timely and sound development of high-quality, effective and safe medicines for the benefit of patients.
Through its Scientific Advice Working Party, the agency gives advice to help developers design trials that are scientifically sound and generate adequate data for the benefit-risk assessment by its Committee for Medicinal Products for Human Use. Scientific advice is the agency's key instrument for supporting the development of high-quality, effective and safe medicines that meet the needs of patients, and by giving it the agency also protects patients from taking part in clinical trials unlikely to lead to the approval of new medicines.
The Committee for Medicinal Products for Human Use issues the advice on the recommendation of the Scientific Advice Working Party. The working party is a multidisciplinary group of a chair and up to 36 members chosen for complementary expertise, which together covers a broad range of therapeutic areas and of aspects of development, including manufacturing, preclinical pharmacology and toxicology, clinical pharmacology and pharmacokinetics, gene and cell therapies, clinical trials and statistics. It draws on a network of European experts and interacts regularly with the FDA, health technology assessment bodies, the World Health Organization and patient organisations. The working party bases its advice on the applicant's position on the questions asked and on current scientific knowledge, and the advice is sent to the applicant as a letter once the committee has adopted it. The advice is confidential before authorisation, and once the medicine is authorised it is included in the European public assessment report, after redaction of confidential information.
What the advice covers
The agency's scientific advice is available for any medicine under development and supports the development of high-quality, effective and safe medicines. It is open to all medicines for human use, whether or not they are eligible for the centralised procedure. It covers the development strategy, including its nonclinical, clinical and quality aspects, down to the design of a study and the choice of endpoints. Advice can be requested at any point in development, including after authorisation. Its questions may concern any part of development, including quality, nonclinical and clinical aspects and methodological issues such as statistical tests, data analysis, and modelling and simulation. Its scope also takes in biosimilar development, risk management plans, paediatric and geriatric development and orphan development.
Protocol assistance is the scientific advice for orphan medicines, requested before the marketing authorisation application by applicants whose product holds an orphan designation, and it follows the same procedure as regular advice. Beyond the usual scope of advice, it can cover the clinical development strategy for generating the data that demonstrate significant benefit within the designated orphan indication or that concern orphan similarity.
What the advice binds and what it does not
Requesting advice is voluntary, and sponsors are not obliged to comply with it. The advice binds neither side, but it is taken into consideration when the marketing authorisation application is reviewed, and the applicant has to justify any deviation from it well. It applies throughout the EU but does not usually preclude further consultation with national competent authorities.
The advice is intended to support an efficient evaluation of the marketing authorisation application by giving guidance on the requirements for generating appropriate data for the benefit-risk assessment, and it is not a pre-evaluation of data to support a planned application or an evaluation of the product's approvability. Nor is it a pre-assessment of a medicine's benefits or risks. Giving advice does not guarantee that the medicine will receive a marketing authorisation. The assessment of the data a development programme generates is independent of the advice given. The advice is separate from the assessment of the marketing authorisation application, which takes place later, and it does not pre-empt the committee's recommendation on whether the medicine can be authorised. A positive recommendation rests on an assessment that concludes an overall positive benefit-risk balance.
The agency gives its assessment of what the sponsor plans to do. The procedure is a way to communicate with the agency and to test the sponsor's decisions against the expectations of the assessors. A common misconception is to view the procedure as a way to advertise the treatment to the agency, and sponsor teams, or the more inexperienced ones, quite often try to do so.
When to seek advice
Scientific advice opens a scientific dialogue on all aspects of a medicine's development, trial design included, and it should be sought early enough for appropriate changes to be made where necessary. Some medicines fail to obtain authorisation because of deficiencies in trial design and the inability to show that their benefits outweigh their risks. That deprives patients of new medicines, and it means patients may take part in trials unsuited to generating data for regulatory assessment.
Asking early gives direction on the best methods and study designs, so the sponsor is not surprised later in development to find that the agency is not in agreement or not aligned. It also helps the sponsor perform the appropriate tests and studies. The sponsor's overall aim is marketing authorisation, which is very costly to reach, so the sponsor wants to be sure the application will not be rejected. Early feedback also helps keep patients out of studies that will not produce anything useful. Advice promotes a more efficient use of resources during development by giving feedback on the most suitable study designs and methodologies and by reducing the risk of deficiencies in study designs at later stages.
Protocol assistance is usually sought before the sponsor's planned pivotal trials, so that the agency's feedback comes early.
Who seeks advice
The procedure is of particular interest to developers of innovative medicines for rare indications or of products for which guidelines are insufficient, and to developers planning to deviate from the scientific guidelines. It is recommended for small and medium-sized enterprises and start-ups, which get high-level scrutiny at reduced fees.
In 2020 the fee for scientific advice ranged from €44,400 to €89,000 depending on its scope, and reductions of up to 100% could be granted for certain types of submission, for example where the applicant is a small or medium-sized enterprise or holds an orphan designation for the product.
The number of requests has risen steadily since the procedure was established in 1996. The number of protocol assistance requests has also risen over the years. Requests for scientific advice on human medicines rose by 16% from 2013 to 2014. Uptake of the voluntary procedure remained strong, with 549 procedures in 2019, 18% more than in 2018. Most 2019 requests concerned medicines in phase III and clinical questions: 57% phase III, 29% phase II, 11% phase I and 3% phase IV, and 51% clinical, 26% preclinical and 23% quality.
As regulatory requirements and the time to reach the market increase, ensuring that development follows an optimal path becomes critical to timely access to effective treatments, so requesting advice is highly encouraged and likely to become even more important. The agency constantly updates its processes and launches new pilot projects to expand the available options.
Outcomes of following the advice
Compliance with the advice obtained has a major impact on the probability of a successful marketing authorisation application. Between 2000 and 2012, the success rate of marketing authorisation applications was 85% for applicants whose trial design was acceptable at the time of advice or was modified to follow it, against 41% for those with non-compliant designs, and designs compliant with the advice were associated with fewer major objections during the committee's review.
Among marketing authorisation applications with an opinion between 2008 and 2012, two out of three programmes submitted for scientific advice had poor clinical trial designs, inadequate to generate data for assessing the benefits and risks of the medicine. A design that was acceptable at the time of advice, or a deficient design changed to conform with the recommendations, raised the likelihood of a positive outcome equally, with success rates of 84% and 86% respectively, against only 41% where a deficient design was not adapted. Compliance with advice on trial design was also associated with fewer major objections during the assessment and with an assessment procedure 61 days shorter on average, so the medicine may reach patients earlier.
Between 2000 and 2013, 55% of applicants for orphan marketing authorisations requested advice, against 42% of applicants for other marketing authorisations. Compliance with protocol assistance was associated with a higher success rate of marketing authorisation applications than non-compliance, 80% against 36%.
Where no advice procedure exists
In the Russian Federation in 2013, regulatory authorities gave no scientific advice. To obtain the opinion of regulatory experts, sponsors and contract research organisations often had to resort to unofficial expert recommendations from the health ministry. Opinions obtained this way may not be reliable and are not supported by any written document, and different experts may hold different views on the same issue.
To obtain the official opinion of the authorities, a sponsor had to apply for approval of a clinical study, which took 35 working days. If permission was refused, the authorities issued a letter with recommendations for modifying the study proposal, but even after every recommendation was accepted the health ministry was likely to issue a second list of requirements, with no guarantee of acceptance. In the USA and Europe, where scientific advice is routine, the study design, primary endpoints and choice of control group can be disputed, and a modified protocol draft can be submitted for review by the experts. When the expert joins the discussion, the sponsor can defend its point of view and provide evidence that the authorities had misunderstood or were wrong. In Russia such an exchange was difficult to imagine outside an arbitration court.