Rare disease and orphan medicines – Will government policy change the paradigm?
Angela McFarlane, Vice President, Strategic Planning, North Europe, IQVIA talks about orphan and ultra-orphan diseases, and the diagnostic odyssey which many are forced to undertake
There is nothing rare about rare diseases, and 3.5 million people in the UK will be impacted by one at some point in their lives. The diagnostic odyssey for patients in the UK is 4-7 years.1,2
Having received a diagnosis, what is unfortunately still rare are treatments for the condition – of the 7,000 rare diseases identified, only 400 have a licensed treatment.3However, obtaining a license is only the start of the challenge – approved medicines must navigate the daunting barriers of access and adoption to realise their promise for patients. Could the Innovative Medicines Fund (IMF) be that catalyst for improving access to innovative orphan medicines, just as the Cancer Drugs Fund (CDF) has been for cancer treatments? 4
Before we explore that question, let’s look at how issues are improving for people with rare disease, namely the global leadership the UK is showing, in respect of accelerating diagnosis of rare disease.
In 2015, the National Disease Registration Service (NDRS) was set up to develop and run a comprehensive population-based registration service, collecting and qualityassuring data on congenital anomalies and rare diseases across the whole population in England.5 Since 2015, it has realised national coverage of over 1,400 congenital anomaly or rare disease datasets out of over 6,000 collected.
In 2013, the UK Government launched the 100,000 Genomes Project to investigate whether whole genome sequencing (which involves reading through 3 billion pairs of letters in the human genome) could help improve diagnosis and accelerate the discovery of precision medicines.6Five years later, the UK became the first national health system in the world to offer WGS to people with undiagnosed rare diseases and cancer as part of routine care. The 100,000 Genomes Project has transformed the diagnosis of the 8-in-10 rare diseases with genetic causes, and the creation of the NHS’s Genomic Medicines Service – as well as the 50-fold goal of achieving five million sequences, offering further new hope to people with a rare disease. 7
Earlier this year, Genomics England announced the Newborn Genomes Programme (NGP) in which up to 200,000 babies’ genomes will be sequenced and analysed for a set of actionable genetic conditions which may affect their health in early years.8 The programme aims to ensure timely diagnosis, access to treatment pathways, and enable better outcomes and quality of life for babies and their families. The NGP will co-design and run an ethics-approved research pilot embedded in the NHS to explore how, and whether, to offer whole genome sequencing (WGS) to all newborns, to accelerate diagnosis and access to treatments for rare genetic conditions.
On the 11th November 2021, a study published in The New England Journal of Medicine,led by Professor Mark Caulfield and Professor Damian Smedley, analysed the diagnostic and clinical impact of genetic sequencing within the NHS. 9 Analysing the genomes of 4,660 people from 2,183 families led to a new diagnosis in 25% of patients. Many of these patients have spent years enduring the diagnostic odyssey. One such patient in the study is a 10-year-old girl who endured multiple hospital visits during her seven-year journey to diagnosis at an estimated cost to the NHS of £375,000. Once the WGS had identified her underlying problem, she went on to have a bone marrow transplant which cured her disease, costing £70,000.
As a result of Caulfield and Smedley’s work, 25% patients received more focussed care, such as family screening and therapies to help manage the condition. For patients with conditions such as intellectual disability, vision, and hearing disorders, the diagnostic yield was even higher at 40-55%. This will pave the way for accelerating the discovery of precision medicines, and attract even more clinical research to the UK for paediatric and rare disease.
Figure 1:Over one third of planned UK launches in the next three years will be dedicated to orphan or ultra-orphan medicines 10F
The orphan medicines discovery landscape is transforming
In August 2021, IQVIA conducted primary market research amongst global C-Suite pharma and biotech leaders regarding the overall attractiveness of the UK for conducting clinical trials and launching new medicines, following the UK’s exit from the EU Bloc.10 Over 200 global industry leaders participated in the survey, and the results were a vote of confidence in the UK. Respondents called out the UK’s performance in respect of research and discovery of COVID-19 vaccines and treatments, and the impactful new UK Government Life Sciences Policies, from the MHRA, NICE and the Office for Life Sciences.
79% confirmed that the UK will remain a priority launch country for their company, with 74% stating that the UK would be a Tier 1 early launch country over the next three years.
The promise for people with rare diseases was even more exciting, with over one-third of the new medicines launches planned in the UK being for orphan or ultra-orphan medicines.
Changes to the approval landscape and the advent of the IMF
Headlines for breakthrough rare disease medicines, such as the triple therapy for the cystic fibrosis gene therapy, Zolgensma, which NICE ruled had an ‘exceptional impact’ for babies with severe spinal muscular atrophy (SMA), majored on deals and list price.11,12Little was reported about the time the negotiations took, and the number of other promising orphan medicines that didn’t make it over the line with either NICE or NHS England, due to the unique challenges orphan medicines face in research and data generation. Consequently, over the last five years, patients living with rare diseases in the UK and their carers have been dissatisfied with the medicines approval processes for rare disease treatments, according to a survey of this community by the Genetic Alliance and Alexion. 13 Typically, patients believe the UK processes are unfair on those living with a rare disease, and the system is both too slow, and not resourced for rare diseases.
“ As a result of Caulfield and Smedley’s work, 25% patients received more focused care, such as family screening and therapies to help manage the condition”
Narrow eligibility requirements for the Highly Specialised Technology (HST) programme means that many treatments can struggle to secure approval from NICE for routine use on the NHS. In most cases, those that do secure approval often see their use restricted to certain subpopulations of their licence. The result is that patients in the top five European countries, such as Germany, Italy, and France, have better access to medicines than counterparts in England. Yet, England is ahead of most European countries, including Scotland, and restrictions to medicines might be valid given the evidence available.14
However, steps are being taken by Government and the NHS to reduce these inequalities, through initiatives such as the review of NICE’s methods and processes, the implementation of the Rare Disease Framework, and development of the Innovative Licensing and Access Pathway (ILAP). Former Minister for Innovation, Baroness Nicola Blackwood – who herself suffers from a rare disease and endured her own diagnostic odyssey – set up the Accelerated Access Collaborative and launched the NICE methods review and the Commercial Framework, announcing the new £500m Innovative Medicines Fund as part of the 2019 Conservative manifesto.
The IMF will seek to expand on the existing Cancer Drugs Fund (CDF) for the purpose of improving access to rare disease treatments, among others. This is an important step. No single initiative can solve the access to treatment challenges facing patients and their carers in England, but the IMF can address the fundamental issue of data uncertainty for rare disease treatments at the time of their first assessment by NICE.
The IMF could be a catalyst for improving access to orphan medicines. However, it is important to note that it should not be seen as a bypass for improvements to these medicines being approved for routine commissioning. IMF should ensure that system challenges, such as biomarker testing at the seven regional Genomic Laboratory hubs, do not further delay patients with life threatening diseases with access at a local level to these nationally approved innovations.
In March 2021, Alexion and AstraZeneca rare disease commissioned IQVIA to work with the rare disease community and thought leaders in the UK medicines access policy, on the development of a white paper. This was launched in September 2021 – The Innovative Medicines fund – acatalyst for access to rare disease treatments.15
“ As a result of Caulfield and Smedley’s work, 25% patients received more focused care, such as family screening and therapies to help manage the condition”
The paper is designed to:
Support the rare disease community response to the public engagement exercise on the IMF, to be led by NHS England during 2021
Support the wider efforts of the rare disease community to improve outcomes for those with rare diseases and their families
Shape future policy for the IMF, and provide recommendations for NHS England and NICE to optimise design and implementation
Support all stakeholders who contributed to the much-anticipated consultation on the forthcoming IMF, by providing an evidence-based narrative from leaders in the rare community, and benchmark data from IQVIA.
The paper makes a series of recommendations for consideration by those finalising the IMF, to ensure that orphan medicines take their rightful place in it.
“ To drive access for patients, rare disease medicines must have the same opportunity for IMF-funded access as a medicine for any other disease”
Recommendation 1: Ambition To drive access for patients, rare disease medicines must have the same opportunity for IMF-funded access as a medicine for any other disease.
Recommendation 2: Entry and exit criteria The IMF must have clear but flexible entry and exit criteria that can accommodate rare disease medicines, as well as other medicines.
Recommendation 3: Funding IMF funding should not be ringfenced by disease area or medicine type, and must not operate on a ‘first-come, first-served’ basis.
Recommendation 4:The IMF should have a flexible budget linked to horizon scanning.
Recommendation 5:Funding for the IMF should be tabled as part of negotiations on the 2024 Voluntary Scheme for Branded Medicines Pricing and Access (VPAS).
Recommendation 6: Data collection The IMF should allow for bespoke data collection, taking a medicine-bymedicine approach to outcomes, data sources and the time required. The IMF must recognise the complexity and difficulty of evidence generation in rare diseases.
Recommendation 7: Governance An external IMF multi-stakeholder group should be formed, reporting annually on IMF performance using Key Performance Indicators (KPIs) broken down by disease and orphan status.
Alignment with other initiatives
Recommendation 8: The IMF must be aligned with the evolving access landscape, including initiatives such as the ILAP, NICE Methods and Processes Review and UK Rare Diseases Framework.
UK collaboration Recommendation 9:
The four UK nations should hold discussions to leverage lessons from the IMF – and their own funds – and explore the scope to increase the value of the evidence generated. The four UK nations should also work together to ensure access to innovative medicines, including rare disease medicines, is equitable across the UK.
Angela McFarlane, Vice President, Strategic Planning Northern Europe, IQVIA, works with the UK Government, NHS, Pharmaceutical and Biotech Industry and Patient Organisations on pioneering collaborations that will improve NHS patient access to clinical trials, RWE studies and innovative medicines. She founded the Clinical Research Coalition to embed learnings from the pandemic, the output of which became Lord Bethell’s Clinical Trial Transformation programme.
In 2018, she was nominated by Pharmaceutical Marketing Europe as one of the 30 most influential women in UK Healthcare and in September 2019 appointed by the UK’s CSO as an Ambassador for Women in Science and Engineering.
PATIENT EXPERIENCE
Every number has a face: Are you valuing the patient voice?
Considering the needs of patients during drug development is a crucial step to guaranteeing the most inclusive treatments possible for them. Many pharma companies lose sight of the patient experience when developing treatments so, how can they improve?
Imagine having to choose which risk you are willing to take to slow the progression of your disease. Could you give up the freedom to have children in opposition to when you and your partner want? Could you risk a potentially fatal rare brain infection as a potential cost of care? Could you risk kidney or thyroid disease just for the sake of a treatment?
These are the life-changing decisions that people living with multiple sclerosis (MS) are forced to make when choosing to begin the most aggressive form of treatment. Like many living with a rare condition, these patients rely on a drug to improve their health and quality of life. MS patients who do require the most aggressive treatment place their hopes in ocrelizumab, natalizumab, and alemtuzumab.
A patient’s drug regimen is the most promising gateway back to a normal life. Patients with aggressive MS often find they must sacrifice their body and dreams to avoid disability.
My question is: why are MS patients forced to make these life-altering decisions when most are diagnosed in their 20s, 30s, and 40s? Those living with MS may have been consulted at the time, but viewed the substantial risk as one worth taking until a better treatment was developed. If so, was their voice heard throughout the drug development process when creating the new drugs for the future? I wish I had the answers.
Involving patients from the beginning of drug development may prevent treatments, such as for MS from being developed without consideration of the patients’ needs and wants. Patients and patient advocacy groups are the true experts in their condition; these individuals understand the patient experience and can shed light on the reality of living with MS. Not involving patients in the R&D process devalues their expertise and hinders the effectiveness of a treatment. To develop, manufacture, and sell a treatment to a population successfully, the voice of the patient is critical.
Understanding a disease goes beyond the science. While pharmaceutical companies must ensure that a drug is both safe and effective for patients, they need to understand how a patient population will perceive the treatment being offered. By hosting focus groups with patients and patient group leaders who are affected by the condition, pharma companies can learn exactly what the community wants, needs and expects from a treatment. That information can be used to ensure that a product or drug is delivered in a way that best suits the targeted patient population. This point rings true, whether you are developing the first treatment for a rare disease or creating a new treatment for a condition that already has a current therapeutic on the market.
‘Social listening’ is one way to gain insight into a particular patient experience. Joining an open patient support group on Facebook to see which conversations are being had by those living with the condition can prove enlightening. You’ll uncover truths that you may have never contemplated before. You’ll learn the good, the bad, and the ugly in an authentic, unfiltered, and raw way. Whether you want to learn more about what it’s like to live with that condition, or which treatments are currently available (if any) for it, these communities provide the insight you need to develop a drug that addresses their unmet needs.
To illustrate this point, a senior executive involved in the development of a treatment for progressive MS told me that her company initially wanted to use bottles with safety caps. She insisted that she needed to first sit down with a group of progressive MS patients to test the prototype bottles before proceeding with the design. It was during this focus group that she realised that progressive MS patients didn’t have the manual dexterity to open the bottles. Had she not insisted on speaking with those who would be taking the treatment, her company never would have been aware of this significant insight.
“ It is easy to get bogged down in the science of a drug and forget about the patient experience of those who are relying on your research. Rare disease patient populations may be small, but each number is a human being”
I encourage you to explore a rare disease patient group’s website for your specific condition of interest, as the insights from patient forums can be invaluable. You will find an array of first-hand information about a condition’s cause, symptoms, and quality of life. The questions, answers, concerns, and lived experiences are all there. This is particularly important for those who are developing treatments in the rare disease space.
Jason Colquitt, CEO of Across Healthcare, emphasises this critical need when he asks, “How can we appropriately help care for rare disease patients without giving them an appropriate voice? Co-production, a non-healthcare concept first described in the 1970s, has proven that those who are affected by a service are the best ones to help design it. Input from the patient should be a top priority when delivering care and facilitating research in the rare disease space.”
I am delighted that rare diseases are beginning to gather more interest from the pharma industry. Through drug repurposing and adopting a co-production, collaborative approach, the pharma industry is giving hope to rare patients who were previously overlooked due to low patient population numbers and a high cost of drug development. The pharma industry alongside the healthcare and academia sectors are now investing in rare research, and are placing a higher value on the patient voice. These sectors are actively collaborating with rare disease patients and support groups to deliver treatments that are better targeted to the patient populations they serve.
Rare disease patient groups have more than earned their seat at the table. Their efforts have proven the value of putting patients at the heart of rare disease research and care. Despite having limited time, funding, and resources, rare disease patient groups have successfully organised patient consultations at NICE, supported the delivery of highly specialised services for ultra-rare diseases, and launched their own rare disease patient registry to aid in research. Rare disease support groups have shown why it is crucial for the pharma industry to value the patient voice. They have lobbied tirelessly for patients and their loved ones to gain access to the treatments needed to improve their lives.
I agree with Donovan Quill, President and CEO of Optime Care, when he says, ‘Patient-first’ has become a buzzword for many specialty pharmacy organisations that merely focus on profits. A true patient-first approach can enable pharma companies, pharmacists, physicians and other members of the care team to better address compliance and adherence to treatment, improve outcomes and enhance quality of life for patients. From day one, patient-first experts provide ongoing support and are available to answer questions. For many with rare diseases, and especially for those starting a new medication, this level of support is comforting and effective.”
Patient-first cannot become a buzzword, nor can it be a box to check half-heartedly. Rare disease patients and their support groups are watching. They will hold you accountable and demand equitable, inclusive treatment that meets their needs. The pharma industry, rare disease patient groups and rare patients all have the same goal: to create tailored treatments that are safe, effective, and designed with patients’ needs in mind.
My challenge to the pharma industry is to never lose sight of the patient experience when developing rare disease treatments. It is easy to get bogged down in the science of a drug and forget about the patient experience of those who are relying on your research. Rare disease patient populations may be small, but each number is a human being who has dreams, hopes and fears. Rare diseases are cruel, unfair and overwhelming. Living with one can challenge, devastate and isolate. The treatments you create are what keep the fire and hope alive for rare patients and their families.
If you only remember one message from this article, I would like it to be this:
See the people, not the profits. Every number has a face. Every number has those who love them. Every number has a life to live. Every number depends on you. Listen to those you serve. Listen to the patient voice.
Blayne Baker is the Marketing and Engagement Manager at Findacure, a UK rare disease charity that is building a united rare disease community driven by patient groups. Findacure envisions a world in which all rare diseases have treatments made together with patients, for patients. If you’d like to learn more about Findacure’s work and how you can partner with them, please email Blay
Not so rare diseases: The cumulative burden of underdiagnosis
Dr Anne Pariser from the NCATS illuminates the impact of under-research, underfunding and underrepresentation in the sphere of rare diseases, and looks ahead at the future of therapies and innovations for rare disease care
Pharmafile: What are the significant changes we’ve seen in drug development for rare diseases in the past 10 years?
Dr Anne Pariser: The overwhelming majority of rare diseases are single gene disorders – or monogenic disorders – where there’s a mutation in just one gene and sometimes as little as one base pair within the gene. If you can find the mutation in the gene, and then work backwards to find out what that gene does, what it transcribes, that gives us a target (to work towards). If we have a target to go after, we can design drugs, or genetic or other advanced therapeutics with considerable precision to go right after whatever that problem is. The vast majority of modern drug development is using this targeting strategy, so in addition to changing how we approach drug development, it also opens up the possibility of personalised medicine, and we’re starting to see some examples of this. 1
What role does genetic research play in advancing the standard of treatment available for rare disease patients?
A lot of rare disease patients go through what we call the diagnostic odyssey; it often takes years to get an appropriate diagnosis. Now it’s a lot easier and less expensive to do genomic analysis.
In England, for example, with the 100,000 Genomes Project, they’re trying to move more rapidly towards characterising young children and sick babies in the NICU to try to make these diagnoses earlier. Once you know what’s wrong, it opens the possibility of trying to develop targeted therapies that could be both highly efficacious, but also improve the safety of the drugs, because now you’re only treating a selected subset of patients who are likely to respond.
Previously, you have outlined the ‘large and growing medical footprint of rare diseases in society’. What are the effects of this footprint, and how has the footprint changed over the past five years?
It is hard to find rare disease patients and it can be very hard to diagnose patients. We know there are a lot of people out there who aren’t diagnosed. This is probably an underestimation, but here in the US we estimate about 25 to 30 million patients have a rare disease. That’s about one in 10 people, but it may actually be higher than that because there’s so many people that haven’t been diagnosed, and that percentage should be similar pretty much anywhere you would look around the world. These estimates are derived from some genomic studies based on what we know about diseases. We just published a paper on a project called ‘The Ideas Initiative’, where we were trying to do a pilot to estimate the cost burden of rare diseases, with cost being a surrogate for illness. People who are high users of a medical system tend to have serious illnesses. That’s not a huge surprise, but you can quantify costs, and it’s a lot more difficult to quantify pain and suffering. It is very difficult to even find rare disease patients in medical records or health system databases. The majority of rare diseases – probably about 75% – don’t have a specific medical record code. About 50% don’t even have a general code, so they’re often lumped into these very high level terms like ‘congenital anomaly unspecified’, ‘seizure disorder’, or ‘unspecified motor delay’. About one in ten people have rare diseases illnesses, and that’s a large public health problem which hasn’t really been identified. It also hasn’t been prioritised, and this leads to all kinds of downstream effects: difficulty getting appropriate care, and difficulty even telling people what they have. And 95% of rare diseases don’t have a treatment. Has this footprint changed over the past five years? Probably not, because these patients have always been there. I think our ability to recognise this now and try to call attention to it has been increasing.
How does suffering from a rare disease multiply the existing difficulties in access to healthcare?
I can only really speak from the US perspective; we have a very fragmented healthcare system. You add a serious illness – for which there are a few disease experts or expert centres to care for these patients – to the existing problems with fragmented care, lack of coverage, out of pocket expenses. People who don’t live in urban centres will need to be treated at a tertiary care centre or a super specialist, and there may only be a couple for each disease in the country, so they’re often having to travel long distance to access care. We suspect that it may take longer to get a diagnosis if you’re in a rural area, or in a place that does not have access to a medical expert. Think of any problem in a healthcare system, and then throw a rare disease on top of that, and it just makes it worse.
What changes are needed in the next two years to better meet the needs of patients with rare diseases, and which should be prioritised?
First and foremost, we must recognise rare diseases for the serious public health problem that they are. We have the rare diseases as a misnomer; collectively, they’re not rare at all. We are trying to educate people that rare diseases are rather common – not the individual diseases, but the patients with rare diseases. They have serious illnesses and need better care, and are as entitled to research and medical care and efficacious therapies as anyone else. That’s a real priority. We have the tools to improve this diagnostic odyssey, and we have the capability to do it now. What we’re trying to do, through education, is move on that faster. A lot of these diseases are slow, chronic, and progressive. For example, a child may have a delay, maybe not quite meeting their milestones. The tendency is to check again in six months, check again in a year, and this really starts to add up to years and multiple referrals. What we’re trying to do is try to escalate, particularly, our younger patients faster to get genetic testing, and preferably at an expert centre, or children’s hospital that is used to handling these diseases. Most of our diseases don’t have approved treatments, we know there are 1000s of diseases right now – we know the gene, and we know how to at least potentially treat that patient (a gene replacement, a gene silencing, or something that modulates the gene expression). We have the technology to do a lot of this for many more diseases; we now face more operational, logistical issues.
How can translational science help advance therapies for rare diseases?
This is predominantly now a translational problem. Once a person is appropriately diagnosed, it’s then trying to string all the pieces together to use some of the things we already know how to do. That can mean trying to speed up gene therapy development, for example. It’s the same for newer technologies, such as antisense oligonucleotides and gene editing. We estimate that it’s going to take about 2,000 years to get everybody an effective therapy at the rate we are going now. Can we approach this by looking at many diseases at the same time?
We’ve started a programme at NCATS called Platform Vector Gene Therapy (PaVe-GT) where we’re trying to develop four gene therapies at the same time.2The AAV gene therapy is a natural platform; you have the capsid of the virus, hollow out the virus DNA, and put in the human gene of interest. This hopefully will save time, money, and resources, and we can learn from one programme to another. Hopefully, that could set us up well enough that we wouldn’t have to keep repeating a lot of these steps, but we could just move a lot faster. The NIH also just stood up what they’re calling the Bespoke Gene Therapy Consortium, which is examining the commonalities around gene therapy development in the preclinical area and the clinical areas. 3 We can do these one at a time or share the knowledge from one programme to another. Gene editing and antisense oligonucleotides also have that potential as well. Oncology has done quite well in advancing therapeutics through platform approaches, and we’re trying to borrow from their experience with platforms, as well as treating multiple diseases or multiple drugs within a single protocol. We think translational science is the answer to this, so we just need more of it.
‘Rare disease’ encompasses a spectrum of up to 10,000 different disorders. Are there some diseases which are more neglected than others?
Almost all of them are neglected to some degree. We only have therapies for about 5% of rare diseases, so there are 95% to go. Most of these diseases are sometimes referred to as the ‘Ultra-rare Disorders’. That’s not a real definition; it’s rare or it’s not, and in this country, it’s less than 200,000 people with the disease in the US. In Europe, it’s a prevalence estimate of five per 10,000 people with the disease.4 For most rare diseases, they will be classified as rare in either region, because 90% of the rare diseases are what would fall into this ultra-rare category (approximately one in a million or so people with the disease or less). We have lots of diseases, where there’s 100 or fewer patients, or a few thousand or fewer. The real distinction is it’s very hard, even with available financial incentives, to make a business case to develop a drug for 50 people or so. Even when we know what’s wrong, it is trying to harness resources to bring it through a drug development programme, so we really need better solutions.
Dr Anne Pariser, MD is the Director of the Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Sciences (NCATS) NIH. ORDR is dedicated to accelerating rare diseases research to benefit patients, through rare diseases programs such as the Rare Diseases Clinical Research Network, Genetic and Rare Diseases Information Center (GARD), and the NCATS Toolkit for Patient-focused Therapy Development. Dr. Pariser came to NCATS in 2017, and before this, she worked for 16 years at the FDA Center for Drug Evaluation and Research, where she founded the Rare Diseases Program in FDA CDER’s Office of New Drugs in 2010 and served as a Medical Officer and Team Leader for rare diseases drug and biologics product development, review and regulation. Dr. Pariser has 20 years of experience in rare diseases research, and her current research interests include “many diseases at a time” research approaches, such as platforms for gene therapies and other rare disease product development, and informatics approaches to diagnosis.