When and why sponsors should seek MHRA advice

Sponsors seek scientific advice from regulatory agencies during clinical development for multiple reasons. They may wish to confirm that their study is adhering to recommendations, to discuss deviations from those recommendations or to highlight the absence of recommendations and propose next steps. In the UK the MHRA has long provided scientific advice to sponsors. Post-Brexit, at 91�� we have noticed a decline in interest in MHRA advice, possibly due to longer timelines. We know of at least one occasion where the lead time was greater than eight months to schedule a meeting. Despite the delayed timelines for sponsors, MHRA advice is worth the wait.

In this article we look at options for interacting with MHRA and suggest how to leverage that advice to progress your clinical trial. This article is the second in a series of blogs examining the UK as a location for clinical trials. You can read the previous article here.

When to seek scientific advice from MHRA

There are several cases where MHRA scientific advice is worthwhile for strategic agency interactions:

In early development through an innovation task force (ITF) meeting. This is particularly apt for novel compounds or higher risk non-clinical testing strategies, when there is a desire to confirm broad plans but an application for first in human (FIH) trials is premature
Between the lab and the clinic. A pragmatic discussion of non-clinical data may permit the performance of more rapid FIH studies
In parallel to other end of phase 2 (EOP2) meetings. Particularly for products ineligible by default for the centralised procedure, where there is a desire to seek out payer feedback on chosen endpoints to satisfy both regulators and payers (parallel advice with payers) and prior to joint scientific consultations (JSC) being more widely rolled out
Where support is sought for either a future ACCESS (a joint assessment procedure without restriction) or (a joint assessment scheme for oncology products) route to market
As a non-EU participant during rounds of agency consensus building, prior to pursuing EU national or EMA advice

Benefits of MHRA advice

The MHRA has replicated several EU advice pathways, including:

Innovation Task Force forum through the MHRA��s Innovation Office
National scientific advice through MHRA Scientific Advice
Free scientific advice on pediatric development questions
Pre-submission meetings in advance of marketing authorisation application (MAA) or IR procedures

As with other national procedures, the MHRA offers both written and in person scientific advice. The option for a face-to-face meeting offers an advantage over EMA scientific advice which typically end with a written response. The MHRA also offer meetings of over one hour at an additional cost. These longer meetings can be used to cover extensive questions or when additional discussion is necessary. Not all regulators offer similar meetings. With meetings conducted in English as a first language setting, there is a reduced risk of nuance being lost in translation in the meeting minutes. Another important advantage for small and medium enterprises (SME) is that MHRA��s fees for advice are typically significantly lower than with comparable international regulatory agencies.

Early interactions with MHRA Innovation Office

The MHRA Innovation Office is a key feature of the agency. It promotes the development and approval of innovative healthcare products by offering free tailored regulatory advice. It can guide access to accelerated approval pathways and support for companies less experienced in regulatory affairs. Enquiries from SMEs represent the highest proportion of the total Innovation Office enquiries at 37%, as seen in the Innovation Office graphic below.

Source:

Case study 1: SME with innovative medicinal product

A small enterprise was developing an innovative medicinal product for a drug with limited analogues for reference and no established precedent to follow. The company was considering a strategy to reach agreement on their high-level development plan in advance of Phase I trial planning. An ITF meeting was recommended as this allowed the opportunity to interact with the MHRA face-to-face and to receive initial feedback on their plans before their formalisation. An ITF meeting offered additional benefits to the developer including opportunities to advertise a successful initial interaction with a leading health authority, reassurance that their approach was acceptable or guidance as to what may require further consideration ahead of clinical studies and providing a framework for future scientific advice interactions. The developer found the ITF meeting to be helpful and took reassurance from the MHRA feedback that they were close to prepared to proceed with their milestone first in human trial in the UK.

Parallel payer advice

Parallel advice with payers, specifically the National Institute for Clinical Excellence (NICE), has been available for several years. While parallel joint scientific consultations (JSC) were piloted by EMA and EUnetHTA for several years, it was originally restricted during the pilot by scarcity. It is still restricted to products that are undergoing a full marketing authorisation application via the centralised procedure. In the UK there are no restrictions on who may request parallel advice between NICE and the MHRA. NICE remains a reference payer, offering the opportunity for a boost in the involvement of these parties in your clinical development planning in advance of pivotal trials.

Expert advice

The UK has an international reputation for high-quality clinical research and scientific leadership. This plays a key role in attracting global industry to invest in the UK. Leading clinical academics based within the National Health Service (NHS) enable these studies, supported by a clinical research workforce most of whom are also embedded within the NHS. In the post-Brexit period beginning in January 2020, the UK industry published over 5,000 papers, 11% of which were highly cited. These papers have been used to support 283 patent applications and on average these papers were cited more than six times the global average. This demonstrates the high impact of the research and breadth of knowledge and expertise the UK offers.

Source:

The primary options for scientific advice in Europe are from EU national authorities and the European Medicines Agency (EMA). Prior to Brexit, the MHRA was part of these arrangements and a leading contributor to EMA scientific services, including advice. As many as 20% of scientific evaluations were performed by the MHRA. Leaving the EU means that the MHRA no longer participates in the Committee for Medicinal Products for Human Use (CHMP) advice, however the MHRA retains its elevated level of expertise.

Flexibility

In our experience, the MHRA has demonstrated a degree of flexibility during scientific advice, in comparison with other international authorities. This does not mean MHRA has lower standards but rather it is more willing to consider valid alternatives. This is particularly helpful in early development when looking to move into FIH studies in the clinic, as illustrated by the case study below.

Case study 2: First-in-human studies of a novel biologic

The developer of a novel biologic sought to enter FIH studies and had submitted an IND to the Food and Drug Administration (FDA). During the IND review, the FDA held that the necessary toxicology studies in non-human primates had not been performed to their satisfaction. The FDA requested additional non-clinical testing be performed. Non-human primate studies are complex, with long lead timelines and high costs.

91�� Regulatory Consulting staff prepared a scientific advice briefing package for submission to the MHRA. The package debated the FDA��s position with reference to relevant ICH Safety guidelines. As a single discipline topic, a meeting was quickly scheduled to present the case presented to the MHRA. The MHRA accepted the case as outlined and suggested that the developer consider targeting minimum effective dose for their FIH study rather than human equivalent dose (HED) calculated from the no-observed adverse event level (NOAEL) of the most sensitive species. The developer submitted their FIH study to the MHRA immediately thereafter, with small modifications.

Partnering with MHRA throughout product development

In the past, an important part of regulatory strategy was relationship-building with a European regulator early in the development. Having established a positive working relationship the sponsor would request the same Agency as rapporteur when their drug reached MAA stage. Since then things have changed, and the rapporteur and co-rapporteur are appointed by the EMA without the sponsor��s input. With the UK��s EU departure the opportunity to work with the same regulatory partner throughout development is restored. Having joined Project Orbis and ACCESS there may now be benefits to engaging with the MHRA as a reference agency. With Orbis the MHRA can refer products to the FDA for consideration and in ACCESS the MHRA are considered a leading agency amongst those participating for providing collaboration during development. For sponsors we suggest the following steps:

Arrange early ITF engagement to outline unprecedented or innovative development aspects, followed by early scientific advice before FIH studies in the UK
Seek end-of-phase 2 advice from MHRA, NICE, and FDA to ensure endpoints meet regulator and payer requirements
Obtain pre-submission advice from MHRA based on preliminary phase 3 results, potentially gaining strong advocacy from the agency

This approach can be further augmented as a strategy through additional, single-issue meetings (such as in relation to quality issues), MHRA PIM-D and ILAPv2 where applicable.

Conclusion

Seeking MHRA scientific advice is worthwhile both because of the quality of the advice and its affordability. MHRA advice helps sponsors to overcome regulatory obstacles by agreeing on alternative pathways. With in person meetings sponsors avoid lengthy delays while they await a written response. They can develop a clear strategic plan and may be able to leverage MHRA advice to advance their products through other regulatory authorities.

91�� Regulatory Affairs has the knowledge, skills and expertise to help you navigate complex global regulatory requirements and emerging issues. For support when interacting with regulatory agencies contact us.

91��