Sizing Up the UK’s Proposed Investigational Marketing Authorisation

A consultation on the Medicines and Healthcare products Regulatory Authority’s (MHRA) proposed rare disease therapies regulatory framework has recently closed. The overall aim of this framework is to reduce the practical and scientific challenges that hamper the development of therapies for rare diseases. The cornerstone of the proposal is the introduction of an Investigational Marketing Authorisation (IMA) which would facilitate controlled early access to a therapy while further data is generated. 

In this article, we look at what the IMA route could offer medicine developers, how this compares to the early access routes in the EU, and what still needs to be ironed out.

A New Fast Track for Rare Disease Therapies?

As originally proposed, an IMA would be a single, flexible authorisation that combines clinical trial approval with a continuously reviewed marketing authorisation (MA). This route would only be available for the approval of therapies that meet a range of requirements, including that the indicated disease has a prevalence of less than 1 in 50,000 in the UK. 

A pre-agreed safety and efficacy monitoring plan will sit alongside the activity, providing a structure for periodic review of the real-world evidence at set intervals.  The trade-off for participating in this intended faster route to authorisation is continuous regulatory scrutiny, or, more positively, continuous regulatory support via regular discussions with the MHRA. 

There are no limits on the types of medicinal therapies which might be included, including advanced therapeutic medicinal products (ATMPs).  A first hurdle is to obtain a rare disease designation (“RD designation”) for which there is a set of eligibility criteria which include the requisite level of unmet clinical need, and the quantifiable barriers that would otherwise be faced in conducting a standard clinical development programme. 

Once in receipt of a RD designation, IMA applicants would then need to satisfy the requirements of UK clinical trials legislation, ethical standards, and Good Clinical Practice. Applicants would also have to justify the benefit-risk balance of the therapy, as with any other MA. Evidence could include in silico data, predicative knowledge, innovative trial designs and new approach methodologies.  A scientific meeting might be arranged with the MHRA to develop and agree the key principles of any clinical trial ahead of any IMA.

An IMA would be granted based on compelling, but limited, evidence, and would be subject to enhanced regulatory oversight (achieved, for example, via rolling data submissions, periodic safety reviews and potential post-authorisation obligations). If granted, it would enable controlled patient access during development as well as before a full (or conditional) MA is obtained. Notably, regulatory data protection periods would not commence until the IMA is converted into a full (or conditional) MA.  

On the whole, the proposal has been received positively. For example:

• In its response to the consultation, the BioIndustry Association stated that it “strongly welcomes the MHRA’s leadership in developing a new regulatory framework for rare disease therapies”. However, it also recommended broadening the eligibility criteria beyond the prevalence threshold, and providing greater regulatory clarity around evidentiary thresholds, review timelines and decision-making processes. 

• The Health Research Authority’s response supports the establishment of a “regulated, evidence-generating pathway” as an alternative to relying on off-label use. But it emphasised that public confidence in the framework “will depend on maintaining strong participant protections, transparent reporting of evidence, and meaningful public involvement”.

Existing EU Alternatives 

There is no single equivalent to the IMA in the EU regulatory framework. Instead, the EU offers a range of tools that seek to accelerate access to rare disease therapies. For example, the PRIority MEdicines (PRIME) scheme run by the European Medicines Agency (EMA) provides enhanced regulatory support to any medicine targeting an unmet medical need. Its principal benefit is eligibility for accelerated assessment, which reduces EMA review of MA applications from 210 to 150 days. Critically, unlike the IMA, PRIME does not confer patient access or any form of MA. 

The closest analogue to the IMA’s authorisation function is the EU’s conditional MA (which is also available in the UK). Conditional MAs can be granted on less comprehensive data where the benefit-risk balance is positive, the medicine fulfils an unmet medical need, and the benefit of immediate availability outweighs residual uncertainty. 

Conditional MAs may convert into a standard MA once post-authorisation obligations are discharged. Unlike the IMA, a conditional MA does not confer clinical trial authorisation. Conditional MAs granted in the EU are recognised in the UK via Route B of the UK’s International Recognition Procedure.  

The RD designation and subsequent route to authorisation is therefore a new and innovative regulatory procedure.  Receipt of an RD designation from the MHRA provides significant value that companies can highlight in investor presentations for future funding applications.

Practical considerations for drug developers and investors

• If the IMA proposal is adopted as currently proposed, developers of treatments for rare diseases, and their investors should weigh the following:

1. whether the resources required to navigate the IMA process (including rolling submissions, periodic safety reviews, and potential post-authorisation obligations) is justified by the value of earlier UK access alone, particularly given the relatively small UK patient populations involved;

2. balancing ‘1.’ against the advantages of getting to market earlier and thus being able to generate real world data for other regulatory applications; and

3. whether the level of scrutiny is one which would be helpful, or not, to the development process.

• The IMA’s acceptance of innovative evidence types may not align with the data packages required by the EMA or U.S. Food and Drug Administration. Developers should therefore seek early clarity on whether evidence generated under an IMA will be accepted internationally. Even if the data developed during the process is not or only partially acceptable, real-world evidence generated once the IMA or MA is granted might be helpful to support applications in other countries where obtaining that evidence remains more difficult.  If that is the case, then the MHRA’s bold and innovative approach will be beneficial to the UK which could become a preferred location for development of rare disease medicines. 

• In theory, the potential for early regulatory approval is appealing. However, data relied on for the grant of an IMA would be significantly less mature than is considered by the UK’s health technology assessment body, the National Institute for Health and Care Excellence (NICE), when making pricing and reimbursement decisions. The MHRA is currently working with NICE on suitable adaptations to the UK’s health technology appraisal framework for this novel IMA/ MA and we await with interest to see how practical the solution is that is proposed.

Conclusion

The IMA’s potential value lies in compressed development timelines, on-going scientific and regulatory support, a single pathway to clinical trials and an MA, thus leading to reduced capital demands, and decreased risk of late-stage attrition. These aspects, plus the initial RD designation, and the potentially earlier commercial viability could improve the attractiveness of rare disease medicines for investment. 

We nevertheless await the determination of the appropriate reimbursement pathway. If that is resolved in a way that is positive for manufacturers, with there being no equivalent in the EU, the MHRA’s proposed IMA could position the UK as a genuinely attractive jurisdiction for the development of therapies for rare diseases.

At this point, available sources do not specify when the Government’s response to the consultation is expected. In any event, the timeline for implementation will be influenced by how quickly any necessary legislative changes can be made. 

In the interim, the consultation document explains that pilot opportunities, such as regulatory sandboxes or similar approaches, may be created to enable early demonstration and testing of the framework’s principles.  Companies with rare disease therapies should watch the development of this pathway to see whether it might offer them an opportunity to get to market more quickly in the UK and potentially beyond.

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