In a letter dated 21 November, the EMA has said that, "to the greatest extent possible", experts involved in providing scientific advice in the pre-MA application phase will not subsequently be involved as rapporteurs in evaluating an MA application for the same medicine.
The EMA will record any "prior prominent role" as a coordinator for scientific advice and take this into account during the rapporteur appointment process. In exceptional circumstances, where an overlap is justified, these reasons will be documented. The EMA also intends to introduce a log of scientific advice related to a particular evaluation in the medicinal product's publicly available authorisation documentation, known as a European Public Assessment Report ("EPAR").
These changes build on the steps already taken by the EMA to improve transparency, including that CHMP assessment reports now include a summary of the type of questions discussed in the scientific advice process.
The basis for the European Ombudsman's inquiry: overlapping roles which may impact impartiality
This marks the latest development in the European Ombudsman's inquiry into the EMA's pre-submission activities, the decision of which was made in July this year.
Applicants applying for a centralised MA for a medicinal product must submit their application to the EMA in accordance with Regulation (EC) 726/2004. The EMA's Committee for Medicinal Products for Human Use ("CHMP") assesses whether the information provided adequately demonstrates the medicine's safety, efficacy and quality. This process is overseen by two rapporteurs, who are appointed by the CHMP according to what it determines to be the "best available expertise". This process culminates with the CHMP's submission of an opinion to the European Commission on whether it should grant a MA in respect of the drug, or not.
Prior to submitting an MA application, the applicant can seek scientific advice from the EMA on a range of topics, including how best to design and carry out clinical trials. By providing this service, the EMA aims to ensure that clinical trials are fit for purpose, that patients are not exposed to useless or inadequate clinical trials, and that the value of data that clinical trials generate is maximised.
Formally, the scientific advice is adopted and conveyed by the CHMP but in practice the CHMP's Scientific Advice Working Party ("SAWP") is responsible for preparing the advice. Crucially, there is overlap in these two groups; around one fifth of SAWP members are also members of the CHMP. In practice, this means that there is nothing to stop a scientific coordinator from later acting as a rapporteur in the assessment of the same medicine. The EMA confirmed that:
"In approximately ten percent of MAA evaluations in 2017 and 2018, one of the rapporteurs had also acted as a coordinator. EMA identified one case in 2017, and one case in 2018, where both rapporteurs had also been coordinators for the same medicine."
Despite the roles being different (coordinators advise on clinical trial design, whereas rapporteurs advise on the results of such trials), the Ombudsman was concerned that this overlap could lead to a perception of bias in the MA application process. In particular, scientific coordinators might feel bound by their earlier advice when evaluating an MA application and, because of a perceived risk of reputational damage, those experts may be reluctant to change their view.
The EMA's response: committed to transparency
During the course of the inquiry, the EMA sought to explain how its existing safeguards were adequate. In particular, all members of the CHMP and the SAWP are subject to the EMA's policy on handling of competing interests, which requires them to submit a declaration of interests prior to any involvement in EMA activities. The EMA commented that scientific advice is not binding on the applicant or the EMA but that applicants who follow the advice are more likely to have their drugs approved.
The EMA stated that there are circumstances where it would be justified for a scientific coordinator to later be appointed as a rapporteur. For example, where an application concerns an area of science or medicine where qualified experts are scarce. If such an expert were precluded from performing both roles, the EMA argued that it could be detrimental to public health.
The Ombudsman's recommendations
At the conclusion of the injury, the Ombudsman recommended that the following measures would help to ensure impartiality in the MA process:
- The EMA should seek to ensure a separation between scientific coordinators and rapporteurs who are subsequently involved in evaluating a MA application for the same medicine.
- When appointing rapporteurs to evaluate MA applications, the CHMP should take into account whether individuals were already involved as coordinators in providing advice on the same medicine in the pre-submission stage.
- In exceptional circumstances, if the EMA has no option but to appoint a rapporteur who also acted as a scientific coordinator, the justification for this decision should be documented, and the reasons published in the EPAR.
- In any event, the EMA should ensure that at least one of the two rapporteurs had no "prominent" role in the pre-submission activities concerning that medicine.
- Finally, that the EMA should include in the EPAR a detailed log of all relevant pre-submission activities, including the names of the experts involved.
The EMA's recent letter acknowledges that the recommendations: "will significantly help in striking even further a good balance between providing the best possible scientific advice and guaranteeing the independence of the medicine assessment which take place at a later stage, taking due consideration of expertise needs and while, most importantly, ensuring that these procedures are correctly understood and perceived by the public"
The EMA is due to provide a further update of its progress to the Ombudsman in the first quarter of 2020.
Impact: how might this affect the EMA's activities going forwards?
Whilst the Ombudsman's recommendations are indeed welcome, there is little to suggest that the task of finding professionals who are experts in a particular field, but who have not previously been prominently involved in the drug's development, will become any easier. Instead, with the heightened interest in highly specialised and personalised drugs, it seems likely that this will become increasingly challenging. In reality, the EMA's implementation of these recommendations might have little impact on this process as the intrinsic problem remains unsolved.
Ordinarily, the content of scientific advice is considered confidential and should not be made public prior to the submission, or during the assessment of, an MA application. However, individuals are able to make requests for access to such advice, in accordance with EU rules on public access to documents, in particular Regulation (EU) No 1049/2001. These requests are examined by the EMA on a case-by-case basis. A number of EMA decisions to disclose, for example, clinical trial reports have been challenged at the General Court of the European Union, with relatively limited success to date.
Given the scrutiny that the EMA has faced over its internal processes relating to the MA application process, might this encourage even greater transparency of the EMA's involvement in the drug development process? If this were to materialise, applicants might be less enthusiastic about seeking scientific advice from the EMA if there is an increased risk of their confidential development plans being disclosed to their competitors. It remains to be seen whether increased transparency at the EMA will be followed by national medicines regulators in national MA procedures.
Authored by: Charles Brasted, Jane Summerfield and Hannah Kerr-Peterson
