Regulatory Intelligence - Year Round Up
An overview of the key regulatory intelligence updates from FDA, EC, EMA & MHRA released in 2023.
Authored by:
Badrudiin Olow
Associate Consultant
Food and Drug Administration (FDA)
FDA Finalizes Guidance on Benefit-Risk Assessment for New Drug and Biological Products
The FDA finalized guidance that clarifies how the benefits and risks of a drug or biologic factor into the agency’s decisions on whether to approve a new drug application (NDA) or biologics license application (BLA). This guidance first articulates important considerations that factor into the Center for Drug Evaluation and Research’s (CDER) and the Center for Biologics Evaluation and Research’s (CBER) benefit-risk assessments, including how patient experience data can be used to inform the benefit-risk assessment.
The guidance further discusses how sponsors can inform FDA’s benefit-risk assessment through the design and conduct of a development program, as well as how they may present benefit and risk information in the marketing application. Additionally, the guidance outlines opportunities for interaction between FDA and sponsors to discuss benefit-risk considerations in connection with the development of an NDA or BLA.
FDA releases draft guidance on recommendations to modernise clinical trials
The FDA has released draft guidance with updated recommendations for good clinical practices (GCPs) aimed at modernising the design and conduct of clinical trials. The updates are intended to help pave the way for more efficient clinical trials to facilitate the development of medical products. The draft guidance is adopted from the International Council for Harmonisation’s (ICH) recently updated E6(R3) draft guideline that was developed to enable the incorporation of rapidly developing technological and methodological innovations into the clinical trial enterprise. This draft guidance, once finalised, would update the existing guidance titled, E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1). This draft guidance was open for public comment for 60 days.
The FDA issues draft guidance to support accelerated approval of oncology therapeutics
The FDA issued draft guidance which provides recommendations to sponsors of anti-cancer drugs or biological products on considerations for designing trials intended to support accelerated approval. Given the limitations of single-arm trials, the FDA states that a randomized controlled trial is the preferred approach to support an application for accelerated approval. This guidance describes considerations for designing, conducting, and analyzing data for trials intended to support accelerated approvals of oncology therapeutics.
FDA issues draft guidance for finding optimal dosages for new cancer drugs
The FDA issued a draft guidance to help sponsors identify the optimal dosage(s) for human prescription drugs or biological products for the treatment of oncologic diseases during clinical development and prior to submitting an application for approval for a new indication and usage. In particular, the draft guidance recommends a new approach in selecting optimal dosages for modern, targeted oncology drugs, including kinase inhibitors and monoclonal antibodies. Since these targeted therapies demonstrate different dose-response relationships compared to cytotoxic chemotherapy, dose-finding trials should include pharmacokinetics (PK) sampling and an analysis plan such that PK data are of sufficient quality and quantity to allow an adequate characterization of the PK (e.g., linearity, absorption, elimination) of an oncology drug following the administration of multiple dosages. The guidance does not address selecting starting doses for first-in-human trials nor does it address dose optimization for radiopharmaceuticals, cell and gene therapy products, microbiota or cancer vaccines.
European Commission (EC)
The EC has proposed a revision of the EU pharmaceutical legislation
The EC proposed an ambitious revision of the EU pharmaceutical legislation which will be the first major review of the pharmaceutical legislation since 2004. The EC states that it will adapt the legislation to the needs of the 21st century. One major change included in the draft legislation is the reduction of the minimum period of regulatory protection for innovative medicines to eight years, down from 10 years under the existing legislation. The reform will also include a Council Recommendation on antimicrobial resistance. The reform will consist of two legislative proposals which will include a new Directive and a new Regulation. The EC have prepared a Frequently Asked Questions document concerning the revision of the pharmaceutical legislation which can be accessed here.
Canada joins the list of third countries recognised by the European Commission for the importation of active substances
The EC proposed an ambitious revision of the EU pharmaceutical legislation which will be the first major review of the pharmaceutical legislation since 2004. The EC states that it will adapt the legislation to the needs of the 21st century. One major change included in the draft legislation is the reduction of the minimum period of regulatory protection for innovative medicines to eight years, down from 10 years under the existing legislation. The reform will also include a Council Recommendation on antimicrobial resistance. The reform will consist of two legislative proposals which will include a new Directive and a new Regulation. The EC have prepared a Frequently Asked Questions document concerning the revision of the pharmaceutical legislation which can be accessed here.
European Medicines Agency (EMA)
The EMA launches Stepwise Paediatric Investigation Plan (sPIP) pilot programme
The EMA launched a stepwise paediatric investigation plan pilot programme (sPIP) intended to allow greater flexibility for sponsors of innovative medicines in developing PIPs. According to the sPIP guidance, EMA and sponsors may agree to a partial paediatric development program before agreeing to a full PIP later, as additional information about a drug becomes available.
A stepwise PIP would apply to cases where there is a lack of crucial information needed to decide on certain parts of the PIP, such as whether a clinical study for a whole age group is necessary. sPIPs must contain a minimum set of data (including condition, preliminary outline of planned studies based on available evidence and a PIP completion date) as a basis which should consider the state-of-the art scientific knowledge and current drug development experience in the relevant field.
The sPIP would then be complemented through subsequent planned PIP modifications as agreed with the EMA's Paediatric Committee at the time of the initial PIP assessment and following the availability of new information. The modification of sPIPs follows the same procedure as the modification of any other agreed PIP. This approach would provide clear deadlines for the development of the full PIP and would avoid a high number of minor modifications submitted on an ad-hoc basis.
The EMA has published a new guideline addressing the clinical evaluation of vaccines intended for the prevention of infectious diseases
The EMA published a new guideline addressing the clinical evaluation of vaccines intended for the prevention of infectious diseases, effective from 01/08/2023. The guidance includes considerations for trials intended to document the safety, immunogenicity, and efficacy of new candidate vaccines and to support changes in the prescribing information of licensed vaccines. It also considers the need for and use of vaccine effectiveness studies. In response to recurring issues arising in scientific advice and in application dossiers, this revised guidance includes a discussion of disease and patient-related factors to consider when planning and interpreting the results of comparative immunogenicity trials.
The EMA has announced that from 31 January 2023, all initial clinical trial applications in the European Union (EU) must be submitted via the Clinical Trials Information System (CTIS)
The EMA announced that from 31 January 2023, all initial clinical trial applications in the EU must be submitted via the CTIS. CTIS is now the single-entry point for sponsors and regulators of clinical trials for the submission and assessment of clinical trial data. This follows a one-year transition, during which sponsors could choose whether to apply for a new clinical trial in the EU/EEA in line with the Clinical Trials Directive or under the new Clinical Trials Regulation (CTR), which entered into application on 31 January 2022. The CTR foresees a three-year transition period, from 2022 to 2025. The first milestone was reached on the 31 January 2023; in the following two years, by 31 January 2025, all ongoing trials that were approved under the Clinical Trials Directive will be governed by the new Regulation and will have to be transitioned to CTIS.
Medicines and Healthcare Products
Regulatory Agency (MHRA)
MHRA announces the International Recognition Procedure (IRP)
The MHRA announced that it will establish new regulatory recognition routes for medicines using approvals from Australia, Canada, the European Union, Japan, Switzerland, Singapore and the United States. These new recognition routes will provide patients access to safe and effective medicines that have been approved by trusted regulatory partners in other countries and mark the start of a new international recognition framework for medicines that will be in place by the first quarter of 2024.
Therefore, from 1 January 2024, the EC Decision Reliance Procedure (ECDRP) will be replaced by this new International Recognition procedure (IRP). The Mutual Recognition/Decentralised Reliance Procedure (MRDCRP) will be incorporated under the umbrella of IRP. The new framework will allow the MHRA to make the most of the expertise and decision-making of trusted regulatory partners to streamline assessments of specific products. As a result, cutting-edge medicines that have been approved in other countries will get to UK patients more quickly, with cost reductions and streamlined regulatory processes for industry. The MHRA will still be responsible for approving all ‘recognition route’ applications under the new framework, ensuring that all products are safe and of sufficient quality to be licensed in the UK.
The MHRA further published updated guidance relating to the IRP in November 2023 to include information on the new online Eligibility Checker tool. From 20 November 2023, applicants should use this new tool to determine whether their Marketing Authorisation Application (MAA) is suitable for IRP and to identify which route (A or B) to follow, before submitting an IRP application. The new IRP itself becomes operational from 1 January 2024. The updated guidance also includes information on submitting an MAA, the IRP product lifecycle, and electronic common technical dossier (eCTD) guidance for marketing authorisations and lifecycle.
MHRA and Genomics England to launch pioneering resource to better understand how genetic makeup influences the safety of medicines
The MHRA announced it will be the first drug safety regulator in the world to pilot its own genetic ‘biobank’, launching 1 June 2023, in a joint venture with Genomics England to better understand how a patient’s genetic makeup can impact the safety of their medicines. The Yellow Card biobank, which will contain genetic data and patient samples, will operate alongside the MHRA’s Yellow Card reporting site for suspected side effects and adverse incidents involving medicines and medical devices.
It forms part of a long-term vision for more personalised medicine approaches, as scientists will use the repository of genetic information in the biobank to determine whether a side effect from a medicine was caused by a specific genetic trait. The biobank pilot officially began on 1 June 2023 with participant recruitment commencing on 1 September 2023. The sequencing of participants’ genetic material will begin in Spring 2024, with initial research findings from the pilot due to be published in 2025. Genomics England will be supporting the MHRA with sequencing and storage of genetic material through use of their well-established and secure infrastructure.
MHRA to streamline clinical trial approvals in biggest overhaul of trial regulation in 20 years
Following consultation, the MHRA will introduce a series of new measures with support from partners to make it faster and easier to gain approval and to run clinical trials in the UK. Under the new framework, clinical trials application processes in the UK will be more proportionate, streamlined, and flexible without compromising on safety, helping to cement the UK as an attractive destination for trials, including global “multi-site” trials. The MHRA will also implement a timeline for completion of an application review within a maximum 30 days in general, with a maximum 10 calendar days for a decision to be granted once the regulator has received any final information. The legislative changes will result in a regulatory framework that is as future-proof as possible, responsive to different types of trials and innovative designs, and supportive of new ways of carrying out trials such as decentralised trials. Additionally, a legal mandate will be introduced to register the trial in a World Health Organisation public register, and the requirements to publish a summary of results within 12 months of the end of the trial as well as share trial findings with participants in a timely manner and suitable format. Comprehensive new guidance will be introduced to accompany the new legislative measures.
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