Key features of the Voluntary Harmonisation Procedure (VHP)
by Liron Sarid-Krebs
The VHP procedure fosters simultaneous initiation of the authorisation procedure for clinical trials in more than one European MS by submitting a single application. It is coordinated by the CTFG, which was established by the EU heads of medicines agencies (HMA) for the implementation of the EU clinical trials directive in the EU/EEA (1).
The process consists of three phases and involves a REF-NCA, which takes the lead in the scientific assessment and the consolidation of the grounds for non-acceptance (GNA). The first two phases are composing the submission to the CTFG, the VHP administrator (VHP-A), while the last phase is the formal submission of a CT to each NCA according to the national regulations (Figure 1). The main objectives of the CT assessment during a VHP are to ensure the quality of the investigational medicinal product (IMP) and the safety of the trial subjects. Therefore, at the final phase of CT submission to the different NCAs, no further scientific discussion on the agreed documents of the VHP is anticipated (2).
As part of the efforts to fight the coronavirus pandemic and to make the best use of the available resources, the European Medicines Agency (EMA) upheld their support for harmonisation of data collection and robust methodology for COVID-19 clinical trials across Europe (3). Consequently, a fast-track VHP has been widely endorsed by different MS, to accelerate and support the submission of large, multinational trial protocols for the investigation of potential treatments for COVID-19 (4).
Phase 1: Request for VHP and validation of the application
The VHP request can be sent at any time to the clinical trials facilitation group (CTFG) via email/Eudralink, including the VHP documentation package, a list of participating member states (MS) and a suggestion for a reference national competent authority (REF-NCA). Upon receipt of the request and VHP-documentation, the VHP-A allocates a VHP number and forwards the complete VHP-documentation to the participating national competent authorities (P-NCAs).
Phase 2: Review of the CTA by the NCAs of the participating MS
Assessment step I: If no GNA are communicated in the response of the REF-NCA to the applicant, and the P-NCAs unanimously consider the CTA acceptable for this MN-CT, then the final phase, the submission of the CTA in each P-NCA, can start. If a consolidated list of GNA is forwarded to the applicant by the REF-NCA, and the applicant decides to proceed, then assessment step II starts on receipt of the responses together with a revised CT documentation by the VHP-A. These response documents (e.g. protocol, IMPD or IB) affected by the GNA should contain not only responses to the GNA but preferably final draft versions of the modified documents including track changes and a clean version. A lack of response from the applicant within the allotted time or a withdrawal of the application will terminate this VHP procedure. A resubmission via a new VHP would still be possible.
Assessment step II: The applicant’s response document is immediately dispatched by the VHP-A to all P-NCAs for review. If consensus is achieved that all GNAs have been resolved, and the revised version of the CTA is considered approvable by all P-NCAs, then the final step of the CTA submission in each P- NCA can start. If no consensus is achieved among the P-NCAs, several outcomes are possible after all P-NCAs have expressed their views and possible solutions:
approval (i.e. a unanimous decision of the NCA that the original or the revised version of the CTA is approvable),
conditional approval (i.e. a unanimous decision of the NCA that revised documents have to be submitted and agreed before the CTA can be submitted and approved nationally. Questions or clarification on conditions shall be provided by the REF-NCA),
denial (i.e. a unanimous decision of the NCA that the revised version of the CTA is not approvable) or a
divergent decision (i.e. not all P-NCA are in agreement and the open points need to be resolved before or in the national procedure).
Phase 3: National step, with formal CTAs to all concerned NCAs
Once a notification has been received, stating that the CTA is considered acceptable (at the end of the VHP assessment step I or II), a CTA has to be submitted in each participating MS as outlined in the clinical trial directive and according to national regulations of the MS. It is agreed by the MS, that after a positive VHP, no scientific discussion on the agreed documents of the VHP (e.g. Protocol, IB, IMPD) will be started again by the NCA.
It is worth noting that while the VHP is generally applicable for routine multinational assessments it has been established during the pandemic as a process that allows fast review of newly submitted applications for clinical trials for COVID-19 treatment and vaccines. In our experience, review times of 5 days for the applications and 10 days for the response were practiced. In addition to the VHP steered by the MS, EMA has developed several other rapid procedures to accelerate the regulatory pathways and to support scientific and regulatory decisions and challenges arising from the COVID-19 pandemic (5).
Biopharma Excellence has significant knowledge and hands-on experience with regulatory submissions. During the coronavirus pandemic, we have supported the development and submissions of a variety of products with respect to accelerated procedures initiated specifically for developers of vaccines and therapies against COVID-19. If you require support concerning your regulatory submission or wish to learn more about our services in general, please get in contact with us.
In a nutshell:
The VHP request can be sent at any time to the clinical trials facilitation group (CTFG), including the VHP documentation package, a list of participating member states (MS) and a suggestion for a reference national competent authority (REF-NCA)
Review of the scientific documentation by the NCAs of the participating MS occurs with two assessment steps and is led by the REF-NCA
Submission of the clinical trial application (CTA) in each participating MS is the final phase of a successful VHP process, and no further scientific discussion on the agreed documents of the VHP is anticipated at this stage.