The objective of the new European regulation, applicable in all member states, is the harmonisation of the approval process for clinical trials and the introduction of a common evaluation for multinational trials. This is achieved through reducing bureaucracy during the authorisation procedures. The decision for ‘regulation’ rather than a ‘directive’ prevents regulatory autonomy at a national level in member states. However, this means that the rules are applicable throughout the EU.
The central aspects of the legislation include an authorisation dossier, a single portal for submitting authorisation applications, and a rapid evaluation procedure involving all the member states where the trial will be conducted as well as precise time frames.
The first application of the regulation commenced in September 2018; Directive 2001/20/EC remains valid for a maximum of three years after the application date of the regulation. There will be a transition period for the old and the new procedures, which means that both will be in parallel for a maximum of three years. An application for approval may be submitted one year after its entry comes into force, in accordance with the old or the new legislation.
Decisions, decisions
The new regulation defines a clinical trial as having three criteria. The first of these is to investigate or confirm the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal products. The second is to detect any side effects of one or more drugs. The third is to study the absorption, distribution, metabolism or excretion of one or more medicinal products, in order to establish their safety and/or efficacy.
A clinical trial is also clearly distinguished from a noninterventional study. If a study meets additional criteria, it is defined as a clinical trial. This criteria includes a candidate that is assigned in advance to a specific treatment strategy that does not correspond to the normal clinical practice of the member state concerned; if the decision to prescribe the experimental medicinal product is taken at the same time as the decision to include the subject in the clinical trial; or if patients are undergoing diagnostic or monitoring procedures that go beyond normal clinical practice. If a clinical study does not meet any of these conditions, it is considered a non-interventional study and the regulation does not apply.
Close cooperation
A key aspect of the new regulation is close cooperation between the member states, with a single submission of the application for experimentation in all states in which the trial will be conducted. This also includes a joint assessment by all national authorities, guided by a member state that will act as rapporteur.
Clinical trials will also be categorised as being either traditional or low-level interventions. There is also a significant increase in transparency of the data generated, with a greater involvement of the public and patients. This includes the introduction of a patient into the research team and the publication of a final report in plain language.
The evaluation report produced must be divided into two sections, science and ethics, which can be presented at the same time or in separate phases. The final decision lies with the member state. In terms of the science part, this needs to include a statement of knowledge, clinical question, hypothesis to be tested, clinical relevance, goals, end points, safety measures as well as risks and benefits. The ethical aspect must include patient information, informed consent, a letter to the treating physician, details on how to enrol, insurance, suitability of research team and site as well as any refunds. The rules allow for free choice of the involvement of ethics committees during the evaluation process, as long as this falls within the established time limits.
Clinical clarity
In November of this year, the EMA released a new document summarising the changes to the Clinical Trials Regulation. The agency has now provided clearer guidance on the publication of withdrawn applications in cases where it will be resubmitted in the future. The new guidance notes state: “In light of the resubmission of the regulatory procedure, the agency will generally consider the postponement of the publication of the clinical data package for the withdrawn marketing application, with the understanding that the clinical data package will be published for the withdrawn product, once there is an outcome of the decisionmaking process for the resubmitted regulatory application.”
Clarification was also made on the publication of studies when the trial is still ongoing.
“Exceptionally, in cases where the main period/phase of a clinical study is still ongoing at the time of publication, this specific study will not be subject to publication until the last subject completes the study. In such cases, the applicant/MAH will be asked to provide a statement for publication where they commit to submit the study once completed. The other clinical documents that were considered during the evaluation and formed part of the decision-making process remain subject to publication.”
The update also included additional guidance on the potential need to submit an updated anonymisation report and/or written responses to the comments transmitted by the EMA on the anonymisation report before the submission of the Final Redacted Document package.
“During the consultation phase, in parallel with the assessment of CCI, EMA will also review the anonymisation report to check whether the applicant/MAH followed the anonymisation guidance and applied it consistently throughout the documents. EMA will transmit its comments (by Day 47), if any, to the applicant/MAH but does not formally adopt the anonymisation report.
“If required, the applicant/MAH will be asked to send a revised anonymisation report and/or written responses to the comments transmitted by EMA (by Day 61). The agency will review the documents and conclude on whether the comments have been addressed in a satisfactory manner. The outcome of the final review will be communicated to the applicant/MAH within seven calendar days from the date of receipt of the revised report and/or the response document.
“If required, the applicant/MAH will be asked to send a revised anonymisation report and/or written responses to the comments transmitted by EMA by Day 61.”
The text was amended to address flagging the availability of a checklist to assist applicants/MAHs with the preparation of the Final Redacted Document package.
“In order to support applicants/ MAHs with the preparation of the Final Redacted Document packages, a validation checklist is made available in annex 1.14. Please note that this checklist should be seen as an additional tool meant to improve the quality of the submitted packages and should not be included in the submitted document packages.”
Streamlined standards
Compared with Directive 2001/20/EC, these standards have been simplified to allow for more efficient trial procedures. This includes an option for the experimenter to refrain from notifying the sponsor about adverse events if this is provided in the protocol. In addition, there is a direct disclosure of suspected negative side effects by the sponsor to the European EudraVigilance database and a more straightforward presentation of the sponsor’s annual security report. Furthermore, the annual safety report is not presented for authorised medicinal products that are used within the limits of their authorised indication.
The regulation will also form the basis for the creation of a freely accessible EU clinical trial portal and database containing information on all ongoing trials in the EU. The portal aims to provide a hub for all communications on clinical trials in Europe. There will be a single EU number for each clinical trial, an EU number for each medicine without marketing authorisation, information in an accessible format and an interface for users in all EU languages. The database will be continuously updated and available to the public unless the information is considered to be confidential – personal data, for example.
The new regulation will pave the way for a rapid approval process and improved communication between sponsors, national authorities and ethics committees. Although the short processing deadlines and the complex assessment procedure require a high level of technical competence, the legislation should facilitate an increase in the amount and quality of clinical trials within the EU.
Steps for end-to-end publication of clinical reports
The revised guidance released by the EMA In November of this year included a more explicit explanation of the main steps of the end-to-end process for the publication of clinical reports:
Day 0: submission of the Redaction Proposal Document package by the applicant/MAH.
Day 1: receipt of the Redaction Proposal Document package by the EMA clinical data publication team.
Day 10: validation outcome is sent to applicant/MAH.
Day 47: redaction conclusion is sent to applicant/MAH.
Day 54: applicant/MAH provides written agreement to the redaction conclusion on CCI.
Day 61: upon request, Zapplicant/MAH provides updated anonymisation report and/or written responses on the recommendations/comments on the anonymisation report.
Day 74: submission of the Final Redacted Document package by the applicant/MAH.
Day 84: publication of the Final Redacted Document package.
