Today, the U.K.’s MHRA unveiled details of its new International Recognition Procedure, which will allow the MHRA to rely on marketing authorizations by reference regulators from several countries for a wide range of products, including generics and those that received expedited review. The agency also opened consultation on its planned retirement of the European Commission Decision Reliance Procedure.
Background: MHRA’s reliance on European Commission decisions and the intend to expand recognition to additional regulators
- The official exit from of the U.K. from the E.U. on February 1, 2020 started a year-long transition period; The E.U. pharmaceutical law ceased to apply to the U.K. (excluding Northern Ireland) as of January 1, 2021. The Medicines and Healthcare products Regulatory Agency (MHRA) has been releasing guidance for the pharmaceutical and medical device industry to aid product development and approval after the separation. The European centralized marketing authorization procedure is no longer a valid medicines approval pathway for the U.K.
- The MHRA implemented the European Commission Decision Reliance Procedure ( ECDRP) to ensure swift approval of new medicines, allowing MHRA to rely on EC approval decisions for marketing authorization applications. The procedure is available for E.U. medicines authorized through the centralized procedure seeking a marketing authorization in Great Britain. When the ECDRP is invoked, the MHRA will ensure a product’s compliance with applicable regulatory requirements, but will generally perform a less detailed review of the application, relying in part on the decision taken by the EC. This reliance procedure was implemented on January 1, 2021, for a planned two-year span, but last September, MHRA extended the effective period for the procedure to the end of 2023. [See AgencyIQ’s analysis of the ECDRP.]
- Sponsors who submit an application to MHRA soon after an EMA opinion is issued will see faster marketing authorization assessment for Great Britain. (Great Britain, or Britain, includes England, Scotland, and Wales, but not Northern Ireland). MHRA’s guidance highlights that marketing authorization applicants should submit their application immediately upon receipt of a positive opinion from EMA’s Committee for Medicinal Products for Human use (CHMP).
- On January 24, 2023, the MHRA reiterated the continuation of the ECDRP through 2023, with an extension to “certain other regulators.” In the same press release, the regulator announced its “new international recognition framework, which will have regard to decisions already made by the European Medicines Agency and certain other regulators.” Medicines developers can apply through the new framework beginning January 1, 2024. The EMA’s CHMP positive opinions may be used in applications after December 31, 2023 through the new framework.
- The MHRA aims to include more regulators in its reliance procedure to enable faster access in the British market. The procedure, along with more detailed guidance, will be forthcoming, according to an announcement in March 2023. The guidance will also provide the transition processes for applications still under evaluation through the current reliance procedure. The U.K. government is providing 10 million pounds to support the development of the new recognition route. [See AgencyIQ’s analysis of the March announcement].
- In May 2023, the MHRA revealed which regulators will be included in the scheme: Australia, Canada, the E.U., Japan, Switzerland, Singapore and the U.S. The MHRA notes that the new pathway will be parallel to its innovation pathway (the Innovative Licensing and Access Pathway, or ILAP), which integrates “early regulatory advice with health technology assessment advice.” The regulator hopes to “streamline assessments of specific products” allowing “cutting-edge medicines” onto the U.K. market more quickly. The MHRA will retain the responsibility to assess and approve medicines and can also reject applications if the provided evidence is not robust enough. The regulator promised guidance would be released but no timeline was provided. [See AgencyIQ’s analysis of the announcement.]
The MHRA just opened a public comment period on its plan to end the ECDRP by the end of 2023
- Regulation 58(4C) of the Human Medicines Regulation 2012 gives the MHRA the power to rely on EC decisions for approving medicines in the U.K., according to the consultation document. The ECDRP was intended as an alternative route to obtain U.K. marketing authorization, ensuring post-Brexit stability in the medicines market for a three-year period ending December 31, 2023. The MHRA now proposes to amend the Human Medicines Regulation 2012 to remove this power, while Simultaneously proposing a “more considered approach” to assessing applications, including a pathway to including other regulators’ decisions.
- However, the MHRA must also ensure continued access to medicines in Northern Ireland, which remains part of the U.K. Medicines for Northern Ireland are currently regulated under the Protocol on Ireland and Northern Ireland. Through a somewhat complicated process, the Windsor Framework will enable the MHRA to issue marketing authorizations that are also valid in Northern Ireland to ensure medicines are available there at the same time as in Great Britain, though with safeguards to prevent passage of MHRA-authorized medicines back through Northern Ireland and into the E.U. These provisions meet requirements of the Northern Ireland Act 1998 Section 75, which mandates that public authorities ensure Northern Ireland is treated equally, as well as ensuring rural meets are met according to requirements Rural Needs Act (NI) 2016. Any changes to the current ECDRP scheme will have to mesh with all of these regulatory requirements. [See AgencyIQ’s analysis of the Windsor Framework for more background on relations between Northern Ireland and Great Britain.]
- The consultation asks two substantive questions of respondents. Question 1 reads, “The MHRA proposes to amend the Human Medicines Regulations 2012 to remove the power contained in regulation 58(4C), which allows the MHRA to rely on the decision of the European Commission to approve a medicine for the GB market. This will end the temporary procedure known as the ECDRP on the scheduled date of 31 December 2023. Do you support this proposal?” Respondents can answer with “yes,” ”no,” or “unsure,” and may provide further detail on their answer.
- Consultation question 2: “Do you think the proposals could impact people differently with reference to their protected characteristics covered by the Public Sector Equality Duty set out in section 149 of the Equality Act 2010 or by section 75 of the Northern Ireland Act 1998? If so, please provide details below.” Respondents can answer with “yes,” ”no,” or “unsure,” and may provide further detail on their answer.
- The consultation is open until September 27, 2023. Responses can be provided through an online survey, to be considered by the MHRA and aid decisions during the “drafting of secondary legislation and finalizing any proposals.”
- The other three reliance procedures remain in place: the Access Consortium, Project Orbis and the Mutual Recognition Decentralized Reliance Procedure (MRDCRP). The Access Consortium is a work-sharing initiative involving Australia, Canada, Singapore and Switzerland, to enhance international cooperation and increase regulator capacity. Project Orbis, coordinated by the U.S. FDA, supports concurrent application review for oncology products. Current partners include participating regulators in the U.S., Australia, Brazil, Canada, Israel, Singapore, Switzerland, and the U.K. The MRDCRP allows the MHRA to consider marketing authorizations by other E.U. Member States that were approved through the decentralized and mutual recognition procedures.
In parallel, the MHRA released guidance on its new International Recognition Procedure, which takes effect January 1, 2024
- The International Recognition Procedure (IRP) will replace the ECDRP. The MRDCRP will be integrated with the IRP beginning January 1, 2024, when the IRP will be open to applicants with reference regulator (RR) approval for the “same product” (see below for more on reference regulators). Any applications received before December 31, 2023, will be assessed under the current ECDR and MRDCR procedures. A positive opinion from the EMA’s Committee for Medicinal Products for Human Use (CHMP) or a positive end-of-procedure outcome under the mutual recognition and decentralized procedures will constitute “approval,” qualifying for IRP participation.
- The MHRA defines “same product” as “as having the same qualitative and quantitative composition (active substance(s) and excipients), and the same pharmaceutical form, from Applicants belonging to the same company or group of companies or which are ‘licensees.’”
- “The MHRA will conduct a targeted assessment of IRP applications,” according to the new guidance, though exactly what will constitute a “targeted assessment” is not included in the current guidance. Trusted, or reference, regulators are those which were previously announced: Australia’s Therapeutic Goods Administration, Health Canada, SwissMedic for Switzerland, the Health Science Authority of Singapore, Japan’s Pharmaceutical and Medical Device Agency, the U.S. Food and Drug Administration, the EMA and competent authorities of Member States.
- Products eligible to qualify for the IRP include chemical and biological new or known active substances (Regulation 50), generics (Regulation 51), biosimilars (Regulation 53) and fixed combination products (Regulation 55).
- However, certain application pathways are categorically excluded from the IPR. Bibliographic applications (Regulation 54) are generally excluded from the IRP. Additionally, herbal and homeopathic preparations approved through traditional herbal registrations, homeopathic registrations (Simplified Registration Scheme) and homeopathic national rules authorizations (National Rules Scheme) are also categorically excluded from the IRP.
- Under the IRP, the MHRA won’t be able to approve medicines for Northern Ireland approved under the E.U. centralized procedure until 2025, when the Windsor Framework takes effect. IRP approvals using the E.U. centralized procedure as reference will then apply to the entire U.K. Currently, the MHRA can only approve products from the centralized procedure for Great Britain, which excludes Northern Ireland. Medicinal products for Northern Ireland must either hold an EC centralized authorization, or a U.K. national authorization applying E.U. law (either purely U.K. national or through the MRDCRP), based on provisions set out in Article 5(4) of the Protocol on Ireland and Northern Ireland (applicable legal texts are listed in Annex 2). These provisions expire on December 31, 2024.
There are two procedures that can be used for initial marketing authorization applications using the International Recognition Procedure
- Eligibility for either the Recognition A or Recognition B procedure depends primarily on when the product was approved by the reference regulator. Certain factors exclude products from eligibility for the Recognition A pathway, and each pathway follows a distinct timeline.
- Recognition A procedure: To qualify, the reference regulator must have given approval for the product within the last two years, and the manufacturing process must be unchanged. The procedure takes 60 days (calendar days) from application validation with no clock stop. Major objections may revert the application to the Recognition B procedure. Additionally, must provide evidence of Good Manufacturing Practice (GMP) compliance when submitting the IRP application. Finally, no Recognition B procedure criteria should apply in order to qualify for the Recognition A procedure.
- Recognition B procedure: The qualifying product must have been approved within 10 years through a reference regulator and at least one of 24 listed conditions must apply. These conditions include, for example, holding a conditional and exceptional circumstance authorization from the reference regulator, or seeking such authorization from the MHRA. Changes since reference regulator approval, such as adding manufacturing sites, changes to the process or analytical methods, and lack of GMP certification of a site, among other conditions, may qualify a product for this procedure. The Recognition B procedure must also be used for certain product types such as orphan drugs, advanced therapy medicinal products, cutting-edge technologies, first-in-class active substances, and authorizations where the pivotal trial involved single arms and/or use of real-world data.
- The Recognition B procedure follows longer timelines and includes a clock stop. The procedure takes 110days from validation of the submitted application. A clock stop at day 70 allows applicants 60 days to respond to MHRA’s questions (bringing the maximum total timeline to 170 days). Should major objections remain at day 110, then the timeline will revert to the U.K. standard 210-day approval timeline.
The IRP can be applied throughout the medicine’s entire lifecycle
- The same reference regulator should be used for IRP applications throughout the product’s lifecycle. The recognition procedure can be used for line extensions, variations and renewal applications for products authorized through national, MRDCRP and the ECDRP pathways. If the marketing authorization holder proposes to use a different reference regulator, the change should be justified through, for example, showing benefit to patients. Post-authorization changes to a product approved through the IRP may also be submitted to the MHRA alone, on a national basis.
- Post-authorization IRP applications will follow standard MHRA timelines (i.e., either 60 or 100 days shortened from 210 days standard), though the timelines only apply to initial marketing authorization applications.
- The impact of post-authorization changes will be evaluated in light of the impact on U.K. patients. The MHRA reserves the right to reject a variation application if there isn’t robust evidence. Whether a variation application should be submitted through a national route depends on the impact on patient safety in the context of the “UK clinical situation.” In any case, the IRP procedure does not change marketing authorization holder obligations with regard to pharmacovigilance reporting.
Agency IQ has pulled out some key considerations in the IRP application process
- Eligibility for Recognition A and Recognition B procedures is determined by an online application form (link still to be provided by the MHRA), completed by the sponsor at least six weeks before the intended submission date. In certain cases, the form should be emailed to [email protected] at least six weeks before IRP submission. According to the guidance, these include when the form indicates eligibility for either procedure and the product has a new active substance; additionally, the form should be emailed six weeks in advance if it indicates that “triage” is required by the MHRA.
- A quick note on nitrosamines: The nitrosamine risk assessment based on the MHRA guidance must have been completed before an approval through the IRP can be granted. [See AgencyIQ’s analysis of the U.K.’s nitrosamine guidance.]
- Applicants must be established in the U.K. or the E.U./European Economic Area to qualify for the IRP. Additionally, the MHRA expects “that the Applicant for an IRP application is the same company or belongs to the same (legal) group of companies as the MAH of the RR procedure.” Third parties may be considered if they can provide assurance that all submission and reporting obligations can be fulfilled throughout the medicines lifecycle.
- IRP applications will need to be submitted through the Human Medicines Portal, similar to other applications. Applicants will be requested to indicated whether the application is a Recognition A, Recognition B, or variation. The application must be submitted as a single electronic Common Technical Document sequence following E.U. format but including the U.K.-specific module 1. The MHRA provides a listing of all documents, which must be in English, that should be submitted depending on which reference regulator is used. For example, if SwissMedic is used as reference regulator, then the submission should include all assessment reports (i.e., quality, non-clinical, clinical and risk management plan), questions to the application, summaries of meetings between sponsor and SwissMedic, the approval letter, final product information, and post marketing reviews.
- Cover letters accompanying an IRP application must include specific information. The cover letter should note which recognition procedure is followed, the RR, a declaration that “all iterations of the RR assessment reports have been submitted,” the type of approval obtained from the RR (e.g., conditional or standard approval), any conditions for approval through the IRP, and justification of adverse reactions included in the Summary of Product Characteristics, among other requirements.
- Previous AgencyIQ analysis raised a lot of questions, and this guidance answers some. For example, the MHRA specifies that all documents must be submitted in English, eliminating any requirement to address any translations. Limited approvals (e.g., conditional authorization) by RRs are acceptable, but would only qualify for the Recognition B procedure. However, although the IRP applies to the full product lifecycle, the new guidance is silent on how lapses in fulfilment of post-authorization requirements would be addressed. [See AgencyIQ’s analysis of the announcement.]
- The IRP will apply broadly to almost all medicinal products, although procedure times may vary. Although the initial announcement hinted that “specific products” and “cutting-edge medicines” would be eligible, the IRP will broadly apply to all medicines, including generics and biosimilars, if the indication and posology is in line with the U.K. reference product. Additionally, sponsors should follow guidance for reference products not sourced in the U.K., E.U., or E.A.A. However, “cutting-edge medicines” will follow a longer timeline under the Recognition B procedure.
- The MHRA seems to eliminate the “issue” of different data submission requirements by relying on assessment reports and regulator-sponsor interactions. AgencyIQ had asked how the MHRA would deal with the U.S. FDA’s requirement for sponsors to submit raw data for that agency’s independent analysis, while the EMA relies on clinical summaries. The initial marketing authorization application through the IRP seems not to require any data submission per se. The MHRA specifies that it should include “documentation on the RR’s approval decision,” along with “all iterations of the RR’s unredacted assessment reports for the initial authorisation and any major post-authorisation procedures,” and “the final product information” as approved by the reference regulator.
- The true impact of the IRP remains to be determined, and depends on various factors not addressed by the current guidance. The MHRA only refers to a “targeted assessment of the IRP application,” a statement with no detail about how the regulator will deal with population differences between the RR and U.K. population or with (potentially shifting) differences in risk tolerances between regulators. There is currently no guidance on how the MHRA would take varying risk-benefit assessment thresholds into account, although the regulator notes that it will assess applications with U.K. patients in mind. Additionally, it is currently unknown what the uptake of IRP approvals from payers, healthcare systems and patients will be.
- There are still some open questions: Are there any specific requirements for choosing the reference regulator if the product is approved in more than one eligible jurisdiction? How would the MHRA deal with any changes in law that have an impact on the product for IRP approvals? Additionally, the guideline currently has no specific provisions for combination products and diagnostics.
- The recognition pathway could reduce challenges for medicines developers. The pathway would provide some degree of certainty that a drug approved in one of the recognized jurisdictions will also be likely approved in Britain, but much will depend on details of the MHRA’s assessment process, such as thresholds for differences in the safety and efficacy it deems acceptable. Depending on how the pathway is implemented, it could also mean that the same data could be submitted in the same format, significantly reducing the administrative burden for medicines developers.
- However, the IRP also creates new challenges with respect to products for Northern Ireland authorized through the E.U. centralized procedure. The MHRA notes that the IRP only provides a Great Britain authorization (i.e., excluding Northern Ireland) for products approved through the centralized procedure until the Windsor Framework takes effect on January 1, 2025. Although initial marketing authorizations through the IRP would cover Great Britain, and the E.U. approval would cover Northern Ireland, how would post-authorization lifecycle changes after the application of the Windsor Framework be handled?
- More medicines could be expected to enter the British market. One major aim of this new pathway is that after implementation of recognition more medicines will be available. The U.K. is a smaller market, not often chosen as a company’s primary entry point for a new product. Therefore, recognition of approvals in those larger jurisdictions such as the U.S., Japan and the E.U. that are initially targeted by medicines developers could speed entry of products into the U.K. More medicines developers may also include the U.K. in their primary market entry strategy if approvals of other jurisdictions are recognized.
- The MHRA is holding a webinar on the new pathway from 11am to 12pm BST on September 14. Sponsors interested in this pathway may consider registering for this event as it will provide additional information on the new pathway. The registration deadline is 5pm BST on September 8, 2023.
- The application form must come online before sponsors can test the IRP waters, and AgencyIQ anticipates that we may also see additional guidance, though MHRA did not promise any more details beyond the qualification form. Still, the agency may issue refinement of current requirements or more detail addressing points raised above.
- The consultation on the elimination of the ECDRP is open until September 27, 2023. Interested sponsors can submit comments through the online form.
Key Documents and Dates
- MHRA guidance – International Recognition Procedure, August 30, 2023
- Consultation on end to the European Commission Decision Reliance Procedure, August 30, 2023
- Comments close September 27, 2023