Treating rare diseases: the challenge of orphan drugs

DOI: https://doi.org/10.58248/RR83

What are orphan drugs?

Orphan drugs refers to drugs used to diagnose and treat rare diseases, defined as those affecting 5 in 10,000 people or fewer in the UK. They are referred to as ‘orphan’ because pharmaceutical companies may be unwilling to invest in their research and development, as so few people have the rare disease that the drug is used to treat.

There are approximately 7,000 known rare diseases. While they are individually rare, the Department for Health and Social Care estimates that, collectively, 3.5 million people in the UK live with a rare disease, and one in 17 people are affected at some point in their lives.

Examples of rare diseases include cystic fibrosis, Huntington’s disease and sickle cell disease. Ivacaftor, a drug used to treat the underlying cause of cystic fibrosis, is an example of an orphan drug. 5% of rare diseases have treatments, and some can be treated with commonly used drugs.

Researchers have outlined the positive effects that orphan drugs can have on quality of life for people with rare diseases. Examples include paediatric neuroblastoma, where orphan drugs have increased patients’ life expectancy, and narcolepsy, where orphan drugs have reduced health-related issues.

How are orphan drugs different to non-orphan drugs?

Research and development

Designing and carrying out clinical trials for orphan drugs, and attracting attention and research funding, can be difficult due to the small number of people affected by each rare disease. Larger clinical trials often give more reliable results, but orphan drug trials are often smaller. This makes the research and clinical trials less likely to be commercially viable.

In 2022, the UK Government commissioned the O’Shaughnessy review that examined commercial clinical trials (paid for by the private sector, such as pharmaceutical companies).

This was followed by new clinical trials legislation, which became law in April 2025. This legislation more closely aligns UK and EU clinical trials regulations, which can better support international collaboration. This is often required when researching orphan drugs, due to the small number of people with a specific rare disease.

Researchers have highlighted other challenges, including that trials tend to be focused on certain diseases. A 2023 UK Rare Diseases Research Landscape report found that a small number of rare diseases (such as cystic fibrosis and Huntington’s disease) were associated with multiple trials while the majority were not associated with any.

Marketing authorisation

Drugs are licensed before being prescribed or sold in the UK. This is called marketing authorisation, and it is granted by the Medicines and Healthcare products Regulatory Agency (MHRA) to drugs that meet safety and quality criteria. In the UK, orphan product designation  can be applied for at the same time as the application for marketing authorisation. This means orphan drugs are given ‘market exclusivity’ for up to 10 years after marketing authorisation, and a similar drug for the same disease cannot be brought to the market by a third party during that time.

MHRA orphan product designation requires the following criteria:

• the product must be intended to prevent, diagnose or treat a life-threatening or chronic disease
• there must not be more than 5 in 10,000 people living with the disease (or it must be unlikely that the orphan product will generate enough income to justify investment)
• there is no satisfactory alternative to this product (or if a product exists, the new orphan product must be significantly more beneficial)

Patient advocacy groups, such as Genetic Alliance UK, report that that navigating the UK marketing authorisation process for orphan drugs can be challenging.

There is no specific regulatory pathway for orphan drugs in the UK. The MHRA introduced an Innovative Licensing and Access pathway (ILAP) in 2021. The pathway is aimed at ‘innovative’ products, including those for rare diseases, and aims to “smooth” the process of marketing authorisation. Not all orphan drugs are considered innovative, so not all go through ILAP.

Drug development and authorisation in other countries

Marketing authorisation for orphan drugs is different in the EU and the USA. Both allow earlier registration of a drug as ‘orphan’, prior to application for marketing authorisation. This means developers can benefit from incentives during research, development and the regulatory review process. For example:

• the EU provides incentives such as free scientific advice on how to design clinical trials and reduced market authorisations fees
• the FDA in the USA provides grants and tax credits for clinical testing and waives application fees

Approval for use in the NHS

If an orphan drug receives marketing authorisation from the MHRA, it can be assessed by the National Institute of Health and Care Excellence (NICE) to determine clinical and cost effectiveness. NICE approval is normally required before a drug is made routinely available in the NHS in England.

Most orphan drugs are assessed through NICE’s technology appraisal programme. This is the same way NICE considers non-orphan drugs. The Innovative Medicines Fund is an additional NHS fund aimed at providing quicker access to “promising treatments”, including orphan drugs.

Highly Specialised Technology evaluation

A subset of orphan drugs are referred by NICE and the Department of Health and Social Care (DHSC) to the NICE Highly Specialised Technology (HST) evaluation, a specific form of technology appraisal.

In April 2025, NICE adopted new criteria for drugs to be considered by the HST evaluation, which are summarised below:

• the disease is ‘ultra rare’ and debilitating (affecting 1 in 50,000 people or fewer in England and is a lifelong diagnosis with an exceptionally negative impact)
• the technology is an innovation (it should be a new chemical or biological entity, and should not be repurposed technology)
• no more than 300 patients in England are eligible for the technology, and it is not an individualised medicine (this refers to a personalised medicine which is developed based on a person’s unique genetic profile)
• the technology is likely to offer substantial additional benefit (significantly redresses reduced length of life or demonstrates substantial improvements in severely impaired quality of life) for people with the rare disease over existing established treatments

The table below shows the number of new drugs approved by NICE between 2023/2024 and 2024/25.

NICE considers the cost per ‘quality adjusted life year’ (QALY) gained during the technology appraisal process. Drugs which provide an additional year of life at full health for less than £20,000 to £30,000 per patient per year are likely to be approved.

NICE can apply a higher threshold to some medicines. For drugs that meet the HST criteria, this is up to £300,000 per patient.

HST criteria only apply to a small number of drugs. Most orphan drugs are not assessed using HST and must meet the £20,000 to £30,000 QALY threshold to be approved. A 2024 survey of pharmaceutical companies cited the fact that most orphan drugs are not assessed using HST as a reason why a quarter of drugs approved by the MHRA were not submitted to NICE for evaluation. The survey also found that most companies did not expect to launch all the drugs they had in development for rare diseases in the UK.

Genetic Alliance UK, a charity for people affected by rare conditions, and LifeArc, a medical research organisation, have highlighted that the NICE technology appraisal QALY threshold means that some orphan drugs ‘fall in the gap’ between the HST for ‘ultra-rare diseases’ and the ‘normal’ technology appraisal, which applies to all other drugs.

There is evidence that the number of reimbursed orphan drugs is higher in Spain, Germany, France and Italy than in the UK (‘reimbursed refers to NICE approval for such drugs which allows them to be prescribed by the NHS). Figures from the European Federation of Pharmaceutical Industries and Associations ranked the UK second in terms of orphan drug availability in 2013 and 11th in 2024. Some researchers have highlighted that a reason for this difference is because other countries reimburse drugs that demonstrate limited benefits, and that these drugs do not meet the criteria for approval by NICE.

The diagram below shows the process for the discovery and registration of drugs in England, the EU and the USA.

The Rare Cancers Bill 2024

The Rare Cancers Bill 2024 is a backbench bill (PDF) related to rare cancers that proposed a review of the law on marketing authorisations for orphan drugs. This bill passed the Commons in July 2025. If brought into law, it would compel the Secretary of State for Health and Social Care to carry out a review of legislation relating to orphan drugs used in rare cancer treatment.

The House of Commons Library noted that the bill received “unanimous cross-party support at second reading and in committee”, and that the Parliamentary Under-Secretary of State for Health and Social Care, Ashley Dalton MP, “expressed the government’s support for the bill at each stage”.

Challenges and ethical considerations

The discovery, development and manufacture of medicines is largely carried out by pharmaceutical companies. While some universities and research institutes may discover new drugs, their development and manufacture usually involve pharmaceutical companies, due to the costs involved.

Researchers have suggested that as the pharmaceutical industry may concentrate research in areas where there is likely to be a higher return on investment, it may not be so keen to research medicines for rare diseases. Some researchers have argued that some pharmaceutical companies are setting prices too high for orphan drugs. They have highlighted that patients who take on risks by participating in clinical trials may not be able to receive the drug if it does not become available on the NHS.

NICE recognises that there are social value judgements used in its guidance for the approval of drugs. This encompasses:

• utilitarianism (maximising the health of the community, which can sometimes override the interests of minorities)
• egalitarianism (distributing healthcare resources to allow a fair share of opportunities for all)

NICE has acknowledged that each time a drug for a rare disease is recommended through the HST programme, it is allocating financial resources that would otherwise have been used for a drug that would likely generate greater population health benefits..

Acknowledgements

POST is grateful to Nick Moody,  a POST PhD fellow funded by Midlands Innovation, for researching and writing this briefing.

POST would like to thank the following people for kindly giving up their time during the preparation of this article:

Dr Jin Ding, Research Fellow, University of Exeter Business School

Professor Paul Martin, Department of Sociology Studies, University of Sheffield

Matthew Hanchard, Department of Sociology Studies, University of Sheffield

Andrew Bartlett, Department of Sociology Studies, University of Sheffield

Eva Hilberg, Department of Sociology Studies, University of Sheffield

Rachael Brooker, Head of Partnerships for Rare Diseases, LifeArc

Joseph Ewing, Senior Executive Adviser, LifeArc

The Association of the British Pharmaceutical Industry

Department of Health and Social Care

Medicines and Healthcare products Regulatory Agency

Further reading:

Research briefing on The Rare Cancers bill 2024-2025, July 2025, House of Commons Library

Orphanisation project, University of Sheffield

UK Rare Diseases Framework, January 2021 Department of Health and Social Care

Research briefing on patients with rare diseases, March 2023, House of Commons Library

Photo by: Ksenia Yakovleva via Unsplash