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Challenges for orphan medicines entering the European market

December 11, 2024 | Health Economics, Market Access, Orphan Drugs, clinical evidence, orphan medicine, rare disease

We explore the various challenges facing orphan medicines entering the European market and offer solutions to help improve patient access.

Part 1: Disease knowledge and awareness

There are an estimated 7,000 rare diseases worldwide for which there is no current treatment, affecting up to 30 million people in Europe and 300 million people wordwide.¹ “Rare diseases are not so rare” is indeed a suitable slogan repeated by advocates throughout the world to highlight the collective importance of this group of diseases.²

When exploring individual treatments, the rarity of rare diseases is a challenge. Rare diseases affect a small proportion of the population (<1/2,000 people in Europe), usually from birth or childhood, and are often severe.³ With such small populations, gathering disease knowledge and raising awareness can be a challenge with rare diseases.

Any medicine or device should have a pricing and market access strategy that is underpinned by a good understanding of the target patient population, including the current and anticipated future treatment pathway, epidemiology, patient subgroups and severities, and unmet needs. Consequently, gathering disease knowledge and raising awareness of patients’ needs is the first hurdle facing manufacturers looking to launch an orphan medicine or orphan device.

This series explores the challenges facing orphan medicines seeking to achieve market access in Europe. In this first article we focus on the first roadblock – disease knowledge and awareness.

Challenges in disease knowledge and awareness

Market access teams looking to launch an orphan product in Europe often find that:

Disease background data (including treatment pathway, patient subgroups, and epidemiology) are scarce and the science is typically complex
The unmet need is difficult to define because of the small patient population, diagnostic challenges, and patient heterogeneity
The relatively low proportion of patients in each market typically make the disease a lower priority for regulators and payers versus more common disease areas
Clinical research organisations may need to apply more creative recruitment strategies to enrol patients onto rare disease clinical trials
Delays to (or lack of) diagnosis prevent early clinical trial enrolment and can lead to therapeutic windows being missed. For example, if a potentially life-changing gene therapy must be provided within the first 2 years of life, delays in time to diagnosis and ultimate access to the therapy are crucial

Solutions to improve patient access

Pharmaceutical and medical technology companies need to invest in activities around disease knowledge and education, perhaps more significantly than in other more common disease areas, including learning from best practice and worst practice analogue case studies.

Early stakeholder engagement, including policy makers, academia, payers, clinicians, and, importantly, patient advocacy organisations, is ever more critical to plan effectively for clinical and economic evidence development and operational activities.

Patient-led collaborations in rare diseases, such as the HERCULES programme for Duchenne muscular dystrophy, demonstrate how patient organisations, industry, and payer organisations can collaborate to develop disease-level knowledge and tools. This enables and accelerates access to innovative medicines for patients with rare diseases.

Pharmaceutical and medical device companies also need to identify and develop or collaborate on resources, such as patient registries and real-world data capabilities. Payers are increasingly open to models of reimbursement with data collection agreements (i.e. registries tied to relevant real-world evidence) to surpass the typical access delay whilst supporting evidence development and protecting their budget impact.

Finally, to improve patient access, manufacturers must also overcome barriers to diagnosis and increase investment in diagnostic tools to better define patient subgroups, such as research on biomarkers that have a proven relationship with clinically meaningful outcomes.

In the next article in this series, we will look at challenges in clinical evidence development, with the series then exploring economic evidence development and operational challenges.

If you’d like to discuss these topics with us or hear more about how we can help you overcome your current challenges in a rare disease area, email info@mtechaccess.co.uk.

This article was originally published at: https://mtechaccess.co.uk/challenges-orphan-medicines-entering-european-market-disease-knowledge-awareness/

Part 2: Clinical evidence development

Clinical evidence generation is a crucial stage in the market access journey for all new treatments, but can be a more significant hurdle for orphan medicines.

The characteristics of rare diseases make meeting payer evidence requirements difficult. When a non-rare disease treatment enters the market, a payer is typically presented with high quality evidence from the manufacturer, including extensive Phase 3 clinical trial data for the new treatment and comparisons with other currently available interventions. This depth of evidence is often unavailable for rare diseases.

Challenges of generating clinical evidence

Orphan drug manufacturers frequently face the following challenges when generating clinical evidence:

Due to the small target population and the severity of most rare diseases, trial design and enrolment is challenging and far from the ideal double-blinded, comparative, parallel design of gold-standard randomised clinical trials. My colleague, Shona Lang (Director – Systematic Review), previously explored this and other related challenges in her article ‘How clinical judgement can strengthen evidence-based medicine’
Due to the rarity and chronic nature of many of these diseases, it is often difficult to demonstrate a statistically significant impact on a mortality outcome within a randomised trial duration; thus, trials may rely on biomarkers and surrogate endpoints. For payers, this adds uncertainty around the clinical evidence, as impact on hard endpoints is key
Rare disease indications are often heterogeneous and patients enrolled in trials may have associated co-morbidities, which, coupled with small patient numbers, further contribute to evidence generation challenges. Whilst this suboptimal level of clinical evidence is acknowledged and addressed at the regulatory level, guidance is scarce or non-existent at national and subnational payer level¹
Manufacturers looking to develop an orphan medicine or orphan device often need to address the requirements for paediatric medicines at an early stage for regulatory approval, given that many rare diseases affect children²
Furthermore, the regulatory environment for orphan medicines is well-established, but is less mature for orphan devices. In July 2024, the European Commission published new guidance to define orphan devices and address some of the challenges faced by manufacturers of medical devices indicated for use in rare diseases³

It should be noted that some countries have adapted their reimbursement processes to recognise these differences. A recent study found that 13/32 European countries use supplemental appraisal/reimbursement processes for orphan medicines.⁴ These allow application of different evidence requirements and thresholds (e.g. higher incremental cost-effectiveness ratio thresholds may be accepted by the National Institute for Health and Care Excellence (NICE) when products are assessed via the highly specialised technologies route) or may lead to exemption from the health technology assessment (HTA) process in some markets (e.g. Germany) if certain criteria are met. On the other hand, where specific processes do not exist for orphan medicines, manufacturers need to understand how the general processes and requirements may challenge successful reimbursement in those countries.

From January 2028, orphan medicines will be eligible for assessment under the European Union Joint Clinical Assessment (EU JCA) process. Each member state will be required to fill out a population, intervention, comparator(s), outcome(s) (PICO) survey to allow the EU JCA committee to identify national needs. The finalised PICOs will be communicated to the manufacturer prior to the dossier submission.⁵ It will be extremely challenging for manufacturers to generate evidence that satisfies all the PICOs, and national HTA bodies will continue to be responsible for reimbursement decisions. My colleague, Samantha Gillard (Director – HTA), discusses this in her article ‘EU Joint clinical assessment – implications for Pharma and Medtech’.

For orphan devices, the national HTA and reimbursement environment is even less mature. The Haute Autorité de Santé (HAS) in France, NICE in England, and Gemeinsamer Bundesausschuss (G-BA) in Germany do not have specific appraisal or reimbursement processes for orphan devices, suggesting that they will be assessed under the same pathways as non-orphan medical devices

Solutions to improve clinical evidence generation for rare diseases

To improve opportunities for broad and timely access of orphan medicines and orphan devices, manufacturers need to minimise the high level of uncertainty in their clinical data. This may be achieved by:

Identifying biomarkers and start/stop criteria to better define the patient population and treatment duration
Applying and/or developing disease-specific patient-reported outcomes and health-related quality of life tools
Identifying surrogate endpoints with proven clinical utility
Designing and implementing post-launch evidence development plans and capturing real-world data

With all of these approaches, manufacturers must consider the view of all stakeholders, including policy makers, regulators, payers, clinicians, and patient advocacy organisations.

If you’d like to discuss these topics with us or hear more about how we can help you overcome your current challenges in a rare disease area, email info@mtechaccess.co.uk.

Part 2 was originally published here: https://mtechaccess.co.uk/challenges-orphan-medicines-entering-european-market-clinical-evidence/

Part 3: Economic evidence development

4 roadblocks facing orphan medicines seeking to achieve market access in Europe - Economic evidence development

“It has been accepted that orphan medicinal products are not normal goods, but neither are they luxury goods that you can choose not to have. As a society, we do have an inclination to fund those most in need. Why this happens is still a matter of debate, but it has been shown that there is willingness to care for those more in need”, says Oriol de Sola-Morales, a former Director of a regional HTA Agency in Spain and founding member of the international body EUnetHTA² in The European Journal of Health Economics (2019).

In this age of rampant innovation coupled with economic recession and increasing budget pressure, healthcare system affordability is more critical than ever, especially in an area with high price-per-treatment tags. The list of the most expensive drugs is now headed by advanced, potentially curative therapies that are administered once, and which often target rare diseases. Thus, there is a significant need to model the economic benefits of such high-cost medicines and demonstrate the overall economic value to payers and healthcare systems.

Despite a greater willingness to fund and award higher prices to orphan medicines, as shown in the quote above, pharmaceutical manufacturers still need to balance affordability by healthcare systems with the capacity to recoup investments made with a smaller target population and typically highly innovative technologies.

Where separate HTA processes exist and are already adapted to the orphan medicine reality, manufacturers should aim to meet the criteria and requirements for selection via these routes. Where this is not possible, manufacturers must navigate the regular frameworks and processes, and anticipate and overcome hurdles posed by payers. The disease knowledge and awareness and clinical evidence development challenges described in Parts 1 and 2 of this series combine to make economic modelling in rare diseases particularly difficult.

Challenges in generating economic evidence

Below, Calum Jones (Associate Director – Health Economics) explains the challenges faced by health economists when looking to demonstrate the value of orphan medicines:

If the natural history of the disease is poorly understood such that few, if any, previously published model structures can be leveraged, structural conceptualisation of the patient pathway will likely be intellectually demanding and require multiple assumptions. This may necessitate the development of a de novo Payers may struggle to accept this heightened uncertainty in the economic impact of the new orphan therapy.
The core underlying clinical trial(s) for the new treatment may have several submission-undermining issues, including a limited duration (for what may be a chronic debilitating disease), the use of surrogate endpoints rather than true clinical outcomes, and small patient numbers leading to weakly powered trials with wide confidence intervals around estimated effect sizes.
A heterogenous patient population can complicate the use of assumptions that apply to the whole patient cohort, e.g. identification of the minimum clinically meaningful time interval to detect differences between the new treatment and comparator (i.e. the model cycle length).
Existing literature may provide little or no data on effective comparators for the new intervention nor on management costs for the rare disease.
High prices for new rare disease treatments, a relative lack of standardisation in disease management, and substantial uncertainties in underlying effectiveness and cost data can often cause incremental cost effectiveness ratios to exceed commonly accepted thresholds.

Solutions to improve economic evidence generation for rare diseases

The benefits and costs associated with treating a rare disease often extend indirectly beyond the patient. Existing HTA processes infrequently consider indirect effects by default; however, manufacturers can aim to communicate significant socioeconomic benefits and costs linked to patients’ economic participation, and associated alleviation of the caregiver burden.²

Metrics for capturing humanistic and societal costs and benefits include patient quality of life, caregiver quality of life, loss of productivity (patient and caregiver), hours of formal and informal care provided, and loss of employment.

Patient registries and real-world data linked with country-relevant healthcare resource utilisation measures can also support the economic argument for a new orphan medicine where long-term data from clinical trials are often scant.

The disease pathway structure and/or accompanying assumptions for a rare disease can often be informed by previously published economic models in analogue or proxy disease areas. For example, while the evidence base for neurodegenerative disorders as a whole is growing, this is not true for distinct subsets of this disease area. Consequently, modelers exploring the cost-effectiveness of a new motor neurone disease treatment (compared to standard of care) may benefit from pragmatically leveraging previously published model structures and assumptions relating to Alzheimer’s or Huntington’s disease, while diligently outlining the inherent limitations of doing so.

Learnings taken from proxy diseases should generally be applied conservatively, with the conceptualised patient pathway and chosen model type always validated by key clinical experts experienced in the management of the rare disease in question. Rationales should be clearly stated and, if possible, referenced.

If you’d like to discuss these topics with us or hear more about how we can help you overcome your current challenges in a rare disease area, email info@mtechaccess.co.uk.

Part 3 was originally published here: https://mtechaccess.co.uk/challenges-orphan-medicines-europe-economic-evidence/

Part 4: Operational challenges

Orphan medicines reimbursement cost the health systems of EU member states about €20–25 billion between 2000 and 2017. This was in addition to the EU and national public funding invested in research.¹ Such high costs, downstream of regulatory incentives, create national and local access challenges which are bottlenecks to fulfilling the promise of addressing the needs of rare disease patients across EU countries.

The market access journey for orphan medicines is complex. Nevertheless, more companies, both large and small, are entering the rare diseases market. Worldwide orphan drug sales are forecast to grow at a compound annual growth rate of 12.3% from 2019 to 2024, which is approximately double the rate forecast for the non-orphan drug market.²

Interestingly, smaller biotech/pharma organisations are overrepresented on the list of the top 20 orphan R&D products (Phase 3) in the pipeline (forecasted sales), whereas larger pharmaceutical companies tend to develop these assets at a later stage, after company acquisition or in-licensing strategies.

At Mtech Access, we are excited to be in a position to support companies looking to launch their orphan medicines in Europe, some of whom may be embarking on this journey for the first time. In this final article, I look at the operational challenges such companies may face when launching into the European market.

Operational challenges

Launch planning and preparation is especially challenging for orphan medicines, whose manufacturers can face the following hurdles:

Given the low number of patients, a wide geographic dispersal often means there are fewer medical staff and resources than for other disease areas. For example, patients from several regions or even neighbouring countries may be treated at one or two specialist treatment centres. On the other hand, the prevalence of certain rare diseases, especially genetic diseases, may be significantly greater in particular regions or countries than in others, which may justify prioritising staff and resources to those areas. Manufacturers may even plan to launch in those countries first, even if they are typically not their priority markets.
Engagement with payers, clinicians, and patient organisations is crucial to ensure optimal patient access at launch, particularly with rare diseases due to the disease awareness and clinical challenges discussed in the previous articles of this series. However, manufacturers need to navigate legal and ethical hurdles in planning for these interactions. Failure to comply with best practices may result in significant damage to a company’s reputation, as has happened with some past orphan medicine launches.
The high price/value often associated with these medicines further exposes manufacturers to increased public scrutiny.
Finally, manufacturers need to map and navigate different national and subnational HTA processes and requirements.

Solutions to improve patient access

International collaboration and HTA is becoming more relevant and can support manufacturers looking to launch a new orphan medicine. For example, EUnetHTA, which has now published several assessments in high-cost disease areas, provides an assessment shortly after regulatory approval, thus pooling resources, setting evidence standards, and accelerating assessments and access to patients in several geographies. With the associated geographical dispersal, legal, and ethical hurdles and reputation risk, development of a thoughtful and coordinated engagement plan is perhaps more crucial than in other disease areas, as it is key to align regional and affiliate strategy and incentives with broader global strategy coordination.

Furthermore, manufacturers need to anticipate and address potential funding gaps, predicted through engagement with national, regional, and local funding bodies. For example, manufacturers can participate in horizon scanning consultations, improve forecasting, and look to create innovative payment mechanisms to address budget impact concerns. Early access programmes, conditional licensing, and managed entry agreements can all support progressive patient access. Registry-linked real-world data collection can in turn address payer concerns around clinical and economic uncertainty. For example, recent orphan medicine launches have offered retroactive rebates, deferred payments and instalment options, and outcomes-based/pay-for-performance contracts.

Finally, manufacturers can proactively engage with public bodies looking to address challenges related with orphan medicine access through public-private partnerships. For example, companies or their partners have collaborated with public health bodies in the prevention, detection, and diagnosis of rare diseases.³

If you’d like to discuss these topics with us or hear more about how we can help you overcome your current challenges in a rare disease area, email info@mtechaccess.co.uk.

Part 4 was originally published at: https://mtechaccess.co.uk/orphan-medicines-europe-operational-challenges/

This content was provided by Petauri Evidence