Foreword Free

In the decade building up to the adoption of the Orphan Medicinal Products Regulation¹  by the EU in 2000 there was almost no interest in developing interventions for small populations of patients with rare conditions.

Rare diseases were generally considered as being unusual, generally incurable and not very important – the subject for academic curiosity for a small group of research active clinicians, but not a significant issue for healthcare planners or providers. ‘Rare’ equated to ‘small numbers’, which were not significant and probably too difficult to do much about.

Since the adoption of the Orphan Medicinal Products Regulation there has been a sea change in thinking about rare diseases. The Committee for Orphan Medicinal Products (COMP) and the European Medicines Agency has recommended (June 2013) the grant of 1123 orphan designations, and 66 ²  drugs for rare diseases have been given a marketing authorisation (MA). New therapies are being made available for hitherto intractable and incurable rare conditions at the rate of 8–10 new MA per year and there is now strong interest from academics, clinicians and the commercial sector in this issue. Developments in Europe followed a similar pathway to those in the USA, where the adoption of the Orphan Drugs Act in 1983 led to a sustained interest in developing therapies for rare conditions in what had previously been a desert for investment opportunities, with little publically funded investment in basic research, and even less private sector money going into creating commercially viable drugs from promising research.

Why has this happened? What has changed that has brought rare diseases from the margins of medicine to centre stage? It's tempting to see this as a planned development, underpinned by logic and a rational decision-making process, but the truth is that serendipity has played a significant role in creating the opportunity to make serious progress in the care and support available for patients and families with rare disease.

Crucial to successfully placing rare diseases on the health and policy agenda were the advances in understanding the molecular basis of disease made possible by the Human Genome Project. This created the framework for systematic biomedical research, and the opportunity to try to hypothesise systematically about logical interventions in basic genotypic mechanisms that resulted in the phenotypic manifestation of rare diseases.

Simultaneously there was an emerging confidence amongst patients and patient organisations that they had a right to have a say in the development of services and support for those affected. This resulted in a more assertive and unified approach to engage with other stakeholders, in politics, industry, academia and medicine, based on partnership rather than gratitude for crumbs that fall from the table that was the pursuit of blockbuster cures for common diseases.

Coincidentally, this blockbuster strategy adopted by the large pharmaceutical companies was faltering and pharma pipelines were emptying. Science lead development was taking industry away from a ‘small molecules: big populations’ model to a ‘big molecules: small populations’ approach, often with start-ups and small or medium sized companies (SMEs) providing the entrepreneurial leadership and the innovative thinking. Today, rare disease research and development is a key plank in the planning of most large pharmaceutical companies. This would have been unthinkable in the years leading up to the millennium. The success of a small number of pioneering biotechnology companies such as Genzyme and Amgen demonstrated that it was possible to create feasible alternative business models that would deliver health gain and a return on investment.

A fourth element in this mix was the granting of competence in the field of public health to the European Commission by the Maastricht Treaty in 1992. While the delivery of health care remains a jealously guarded national prerogative, rare diseases were seen as being one issue where there was a clear potential for demonstrating European Added Value and in so doing giving a purpose to DG Sanco (the Directorate for Health and Consumer Affairs) to involve itself in health policy without alienating Member States. This led to the creation of the Rare Disease Task Force in 2003, and ultimately to the publication of the Communication of the Commission³  in 2008 and the subsequent unanimous adoption by the Council of Health Ministers of the EU of a recommendation on rare diseases in 2009.⁴  This called on Member States to produce national plans or strategies for improving services and support for rare diseases by the end of 2013. These documents contained calls to action in respect of coding and classification, research, centres of expertise, the clinical added value of orphan drugs and patient empowerment. These are the key elements of any effective strategy, and the adoption of the Recommendations opened a window that allowed for the creation of concerted campaigns to respond to the unmet medical needs of rare disease patients across the whole of Europe.

The insights from the Human Genome Project and other international collaborations which aimed to address the fundamental biology of health and disease had an impact on the research community too. Traditional priority areas were adjusted to make space for rare diseases, both because they were seen as important in themselves, but also because of the insight they could provide into common complex diseases in the context of a growing awareness of the importance of personalised (or stratified) medicine and the development of targeted therapies for genotypically distinct but phenotypically similar common diseases. Ultimately, this resulted in the formation of a strategic partnership between DG Research in the European Commission, the National Institutes of Health in the USA and a growing number of research funding agencies such as the UK's National Institute for Health Research, known as the International Rare Disease Research Consortium (IRDiRC).⁵  This has set itself the ambitious target of a diagnostic for every rare disease and two funded new orphan therapies by 2020.

Advances in biology, increased opportunities for treating rare diseases, a growing sense of empowerment and engagement by patients at patient advocacy groups and realisation amongst politicians and policy makers that ‘rare’ did not equate with uncommon, simply because of the large number of different rare diseases that have been identified, has resulted in rare diseases being recognised as a significant public health issue. Paradoxically this has coincided with a downward trend in the economies of much of the developed world, putting healthcare decision makers between a rock and a hard place. The opportunity to do more, coupled with increasing awareness of finite resources necessitated the creation of new systems for licensing novel therapies and determining policy with regard to clinical utility and reimbursement. This brings me to the final element in my thesis, namely the role of the regulations and Health Technology Assessment (HTA) bodies. The transitional gold standard of the large, multicentre randomised double-blind trial does not work for drugs developed for tiny populations and while patients have no interest in drugs that do not work, new methods for proving quality, safety and efficacy need to be developed if orphan drugs are to make it onto the market. Financial constraints are increasingly important, and the role of HTA bodies is rapidly growing in significance. Again traditional methods do not work, simply because its data is lacking in most instances to form a robust assessment of clinical effectiveness and a rational policy for determining patient access, pricing and reimbursement. The challenge facing many healthcare providers and payment agencies today is to develop systems which will provide a framework that carries the trust of patients and families, or which will enable fair decision making in healthcare and resource allocation now and sustainably into the future. Patients and other key stakeholders are actively engaging to try and bring this about, but the shape of a sustainable healthcare future for rare disease patients is not yet clear anywhere across the globe.

So, we have a potent mix of elements, all of which have come together to raise the profile of rare diseases and the patients of families affected by them. Rising to the challenge is a critical priority for all involved if patients are to see their expectations for effective therapies realised, scientists to generate the insights that will create clinical service improvements for doctors and the possibility of a return on investment for industry. Regulators, policy makers and politicians are intimately involved as well if we are to see the promise realised and a sustainable, affordable healthcare system that incorporates current scientific understanding and good clinical practice intertwined in systems that provide timely, appropriate, user-friendly care for rare disease patients wherever they live across the globe.

The years since the adoption of the Orphan Drugs Act in the USA, and the Orphan Medicinal Product Regulations in the EU have seen rapid developments that have brought hope to patients and their families living with the daily consequences of unmet medical needs. This book is a timely contribution to the literature in this fast-changing field. It will serve as a useful primer to those new to the subject, and for those already engaged it provides a reminder of the breadth of the field today, reinforcing the importance of rare diseases as a subject for pioneering research, as a commercial opportunity for innovative pharma and biotech companies, but most of all as a call to action on behalf of the patients and families with rare diseases for whom there is as yet no effective therapy. This book demonstrates clearly that there is no disease that is too rare, too difficult or too expensive not to warrant the attention of the scientific and clinical community, industry, policy makers and politicians alike in the search for a response to the needs of patients, and the importance of sustainable progress towards the continued production of novel therapies for currently unmet needs.

Alastair Kent Director, Genetic Alliance UK and Chair, Rare Disease UK