Rare challenges: Meeting patient needs and delivering medical innovation in ultra-rare diseases
pharmafile | December 12, 2016 | Feature | Business Services, Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing | Alexion, ultra rare disease, ultra-rare disease
Dr Emma Harvey, senior medical director at Alexion Pharmaceuticals UK, shares her views on the challenges of working in the field of ultra-rare diseases and the importance of meeting unmet patient needs. Having worked in specialised medicine for a number of years – previously on autoimmune diseases and in the field of severe, systemic fungal infections – many of the challenges apply to rare diseases, although rare diseases also bring their own unique challenges.
Rare diseases and the unmet need
Rare diseases may affect just a handful of people (5:10,000 for rare diseases or 1:50,000 for ultra-rare diseases), sometimes as few as one in a million. However, the impact these conditions have on patients, their families and society is profound. Many rare diseases are severe, chronic and progressive, with high mortality rates. 75% affect children – and 30% of those affected die before their fifth birthday. Of the estimated 8,000 rare diseases, the majority do not have an effective treatment option.
For many years, patients with rare disease felt neglected by the medical community and the pharmaceutical industry since, due to the rarity, there was a lack of research and understanding of their diseases. A few decades ago, there was a sea change: the rare disease patient community joined together and helped to raise greater awareness of these rare conditions. Over time, they have raised awareness of the need to improve the standard of care for patients living with a rare disease, and demanded equality of access to new treatments and care. The Orphan Drug Act was initiated in the U.S. in 1983 and, in 1999 the European Regulation on Orphan Medicinal Products was introduced. These regulations provided important incentives to the pharmaceutical industry to actively invest in research and development in rare diseases although many challenges remain.
The pathway to diagnosis
Reaching a diagnosis for a rare disease can be a long and challenging experience because the conditions are often unknown, misunderstood, or misdiagnosed. Misdiagnosis brings with it the risk of iatrogenic disease, as the patient is treated for the presumptive diagnosis rather than for the actual underlying disease. There are many SWANs (syndromes without a name), as they are known, which add to the challenge of diagnosis. On average, it takes nearly five years to confirm the correct diagnosis. Around 40% of rare disease patients are misdiagnosed more than once. Those affected see a doctor on average seven times before they are diagnosed. If you consider that many of these diseases may be genetic in origin, there is a risk that families will have more than one affected child, with second and subsequent siblings being born before the diagnosis can be made. The burden on such families is significant. Many of these diseases are ultimately fatal. Losing one child to an ultra-rare genetic disease is a devastating thing to go through. Imagine knowing that you might lose all your children?
It would be easy to say that clinicians should do a better job in diagnosing rare diseases. However, with around 6,000–8,000 rare diseases identified, this is not an easy task. Symptoms may overlap with those of more common illnesses. The mantra drilled into medical students is that ‘common things occur commonly’, and so rare diseases are usually at the bottom of a very long list of differential diagnoses, and woe betide the medical student who dares to raise the spectre of a rare disease on a teaching ward round. Diagnosis is often dependent on pattern recognition and whether a physician has seen the disease before. The rarer the disease, the more complex it can be to diagnose. Ongoing education is needed to help raise awareness of rare diseases to ultimately improve diagnosis and disease management.
Education and disease awareness is an area where the pharmaceutical industry can really make a difference for patients through providing robust medical education programmes, which include rare diseases in the differential diagnosis and provide diagnostic pathways to help physicians identify rare diseases.
Research and innovation to discover new treatments
Clinicians sometimes say that there is no point making a diagnosis of a rare disease unless there is an approved and accessible drug treatment. Of the identified rare diseases in the world, only 5% currently have an available drug treatment. Therefore, there is also significant unmet medical need for the patients living with these conditions. It is important to be able to differentiate drug treatment from other appropriate treatments, and to highlight the immense relief that many families obtain just from having a name to attach to a condition. Having a diagnosis enables access to patient support networks, and knowing you are not facing a disease alone can be invaluable. Allied healthcare professionals, such as physiotherapists and occupational therapists, can make a big difference to the experience of living with a rare disease, and having a diagnosis can also allow access to such things as disability benefits, social care and the support which can be provided by patient groups.
While overall investment in R&D for rare diseases has increased, hurdles and challenges persist. Any drug development carries a considerable amount of risk, but this is heightened in rare diseases for a number of reasons:
- There is often limited knowledge and understanding of the disease area even amongst the medical community. Experts are few and far between, and each ‘expert’ may only have treated one or two such patients in their lifetime.
- There is a need to identify sufficient numbers of patients to participate in clinical trials which often results in a large number of trial sites in multiple countries with the expectation that each may only enrol one or two patients—or none at all. The costs involved in setting up each site are the same as for common diseases, and so the development costs for trials in 50 patients may not be significantly different to the costs for a trial in 5,000 patients with a common disease. And there are often hurdles in physically getting the patients to the sites for treatment.
- The rarity and complexity of these diseases means that often we do not fully understand their causes. This typically means having to undertake natural history studies to better understand the course of the disease before or in parallel to the clinical trial programme.
- There are increased regulatory risks since there is usually no approved therapy for a given ultra-rare disease, and no well-established road map for regulatory approval. The clinical study programme needs to be designed, with in most cases no pre-defined clinical endpoints. It is therefore critical in rare diseases to work with clinical experts, academics and regulators to determine the important endpoints for development trials that would reflect clinical benefit to the patients. The study designs which are then implemented for regulatory purposes may not address the expectations of the reimbursement authorities, and this then presents an additional hurdle.
Patient groups can play an extremely important role in drug development in a number of areas. First, each clinician may only have one or two patients under their care, but an active patient group may know of other identified patients and can therefore be pivotal in ensuring patients who are suitable for a clinical trial can be referred to research centres to expedite rapid recruitment. Patients and patient groups can also enhance disease knowledge through pharmacogenomics and understanding the genetic basis of disease.
Rare Disease Day 2017 will in fact recognise the crucial role that patients play in research, acknowledging that patients are true partners from the beginning to the end of the research process. For pharma companies, as long as these partnerships are truly transparent, there should not be any cause for concern over potential breaches in compliance. Rare Disease Day 2017 will occur on 28 February 2017, and will be the tenth international Rare Disease Day coordinated by Eurordis (European Organisation for Rare Diseases).
From innovation to access
Once a drug for a rare disease is developed and subsequently approved by regulatory authorities, the challenges don’t stop there. Considerable work is needed with governments and reimbursement bodies around the world to ensure that patients have access to these new therapies. Whilst the regulatory processes have been largely centralised and harmonised, the same cannot be said for reimbursement. There are lengthy country-by-country pricing and reimbursement requirements before patients can have access to a therapy. Traditional cost-effectiveness evaluations are not designed to effectively or fairly assess the value of a given therapy for a rare or ultra-rare disease. This is driven not only by the small size of the patient populations, but also the general lack of recognised or measurable health utilities for rare and ultra-rare diseases, as well as a lack of alternative therapies upon which to base any comparative cost evaluation.
The weight of evidence required by the regulatory authorities may also be very different from the weight of evidence required by the reimbursement authorities. With rare diseases, regulatory authorities recognise the serious unmet medical need and may grant accelerated approval or conditional approval, knowing that additional efficacy and safety data will be forthcoming. However, the evidence required for reimbursement may not be sufficient and does not allow for additional clinical data to be submitted during the review process, except in exceptional circumstances. This is a fundamental disconnect.
In the UK, NICE established the Highly Specialised Technology (HST) programme, providing a distinct pathway for the appraisal of medicines for very rare diseases, recognising the unique challenges of evaluating these medicines and the diseases they treat. The programme has gone some way to addressing the challenges, but each rare disease needs to be assessed on its own merits and a ‘one size fits all’ process may not be appropriate given the wide variation in each rare disease. NICE and NHS England are subsequently consulting on revising the methodology for evaluating HSTs for rare diseases.
Overall, more needs to be done to find innovative ways to assess treatments for such small patient populations. Disease awareness campaigns and patient group initiatives play an important role but ultimately, decision makers need to recognise the significance of these challenges and the need for innovative solutions, across the spectrum from disease diagnosis, through drug development, reimbursement and adoption of a new drug on to a hospital formulary, to ultimately reach the patient.
Dr Emma Harvey
Emma Harvey is a specialist pharmaceutical physician. She studied medicine at University College and the Middlesex School of Medicine. After obtaining Membership of the Royal College of Physicians, she joined the pharmaceutical industry. She has worked in a number of different pharmaceutical companies in national, European and International functions. She completed post-graduate medical training in Pharmaceutical Medicine, receiving a Diploma of Pharmaceutical Medicine and entered the Specialist Register at the General Medical Council (GMC). She is a Fellow of the Faculty of Pharmaceutical Medicine.
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