End Points for Trials: Getting Them Right When Numbers Are Small and Change Is Modest

Clinical trials in the eld of rare diseases suffer from a number of weaknesses: (1) due to the small number of participants, a statistically signi cant bene t may be dif cult to reach; (2) clinical trials are often too short to capture the complex natural history of a rare disease; (3) de ning bene t in disorders in which there are often no well-de ned and validated markers/surrogates for monitoring disease progression and treatment response is dif cult; and (4) access to health care, which is different across countries, often limits patient enrollment in clinical trials. As a result, only 57% of approved orphan drugs have been tested in a randomized clinical trial before approval [62]. Furthermore, rare diseases are frequently diagnosed and managed in childhood, and this presents a challenge to clinical studies, since designing trials of pharmacological interventions in children can be problematic and/or extremely slow.

Orphan Drug Development

To date, only about 5% of all rare diseases have a targeted treatment [63]. Generally, the rst stage in drug development is research into the mechanisms and pathogenesis of a given disease. Once a promising compound has been identi ed, the next stage is to test its safety and ef cacy in animals. The lack of knowledge about the pathogenesis of most rare diseases limits identi cation of pharmaceutical targets, and the scarcity of animal models that authentically recapitulate human disease is a huge obstacle to preclinical studies and orphan drug development. In turn, the scarcity of funds invested and human resources devoted to investigating rare diseases accounts for the dif culty faced by pharmaceutical companies to invest in this area. Furthermore, for some conditions, clinical trials need to be multinational and geographically dispersed owing to limited regional expertise and the small number of patients affected by the disease. These hurdles, combined with the estimated low return on investment due to extremely small markets and costly drug development, discourage pharmaceutical company interest and hamper development of drugs for rare diseases, despite the huge unmet medical need.

However, there has been some important progress with regard to drug research that has eased the pathways to developing drugs and obtaining approval in rare diseases [64–68]. These include regulatory and economic incentives for pharmaceutical companies willing to develop drugs for rare diseases via the orphan drug acts [69]; the recognition by regulatory agencies of the highly individualistic nature of problems encountered in drug development for rare diseases, such as demonstrating the ef cacy of novel therapies in trials of relatively small numbers of patients; and the development

of public–private partnerships with a goal to facilitating the discovery of effective new therapies.

Importance of Referral Centers

Who should or is able to adopt a broad clinical perspective on the needs of patients affected by rare diseases? Given the number and diversity of these disorders, it is impossible for community physicians to have knowledge about all of them. Although the “optimum” for a general lung specialist, going forward, may be to better incorporate rare disease training into the pulmonary fellowship curriculum, at this time, referral to centers with expertise in the speci c lung disease or group of diseases is strongly encouraged. Joint clinics that share expertise are also important. A tuberous sclerosis clinic, for example, should comprise geneticists, neurologists, psychiatrists, nephrologists, and pulmonologists. Similarly, a neuro bromatosis clinic should have a geneticist working alongside pulmonologists, pediatric neurologists, endocrinologists, and ophthalmologists, to cite only two rare disorders. Multidisciplinary specialist clinics and coordinated services are the key to delivering proper care in rare disorders, but they can only be found in dedicated centers. This, in turn, allows patients to have the highest possible chance of success through sharing of expertise and resources and maximizing cost-effective use of resources by concentrating them where appropriate. A multidisciplinary approach through specialist centers has proven successful in diagnosing and treating cystic brosis, which is now included in neonatal screening programs in several countries with ready access to genetic counseling and support for parents of children diagnosed at birth [70]. This model now needs to be reproduced for other disorders.

Looking at the Future

In addition to exploring areas in which shortand medium-­ term progress can be made, there is a requirement for a long-­ term vision. This must include attention to education. Primary and secondary care providers need to be aware of the range of rare diseases, whereas patients need education and guidance on the implications of their disease and on where they can reach out for information in order to not be left truly orphaned and disenfranchised. Most importantly, future generations of doctors need to develop a lower index of suspicion for rare diseases. This can only be achieved by creating and providing structured training to medical students, which involves courses on all the diagnostic and management skills required in caring for patients with rare diseases. It would be highly desirable if the content of these courses could be harmonized across national boundaries, which would have the added advantage of enhancing the

Fig. 2.1  Research priorities and roles of stakeholders in rare lung diseases

Industry

Develop novel therapies

Create competitive environment

Promote early access programs

Share knowledge and information

Medical and research community

Improve diagnosis

Identify disease mechanisms and causes Develop guidelines for diagnosis and treatment Implement Task Forces and activities to address priorities and gaps

Authorities and

regulators

Promote research for, and access to, new therapies

Establish and promote best practices, operating procedures, quality standards, and roadmaps to address priorities

Inform stakeholders of opportunities and emerging issues

Provide incentives and foster innovation Grant timely and equal access to treatment

Patient associations

Increase patients’ awareness of their need and rights Provide information

Advocate for availability of information to patients Establish networks of patient organizations

opportunities for national and international collaborations in the future. The incentive should not be only in teaching but also in terms of sharing. In the big data era, arti cial intelligence, medical technology, and biobanks are excellent ways to exchange information worldwide. According to a recent survey by the EURORDIS Rare Barometer Programme, most patients, regardless of the severity of their disease, have been willing to share their data to foster research and improve health care [71]. However, particularly in the eld of rare diseases, it is important to know “where to go” and to set realistic goals [72] always with an eye on the available resources. The International Rare Diseases Research Consortium (IRDiRC), which unites national and international governmental and nonpro t funding bodies, companies, patient advocacy organizations, and scienti c researchers to promote international collaboration and advance rare disease research worldwide, has set some ambitious (but not unrealistic) goals to be achieved in the next decade, including faster diagnosis, more therapies, and better access to care (Fig. 2.1).

The Arguments for Progress

Economic Burden  The burden of rare diseases in terms of suffering and human life loss is enormous. Similarly, though dif cult to estimate, the economic load of rare diseases is massive [73]. With an overall prevalence of at least one to two million people and conservative approximations of average yearly health-care costs of $5000 per patient, the annual total cost in the United States only is in billions of dollars, according to the National Institutes of Health Of ce of Rare

Diseases. In addition, the rarer the condition, the more tests and health-care visits are usually required to make a correct diagnosis, which, in turn, results in greater expenses, unnecessary tests, and missed opportunities for early intervention. In recent years, the European Union has allocated one billion for rare disease research, which funded 270 projects; hopefully, this effort will boost innovative therapeutic approaches and eventually improve the life of people living with a rare disease [74].

Ignorance Can be More Expensive Than the Research Aimed at Improving Knowledge  Too many health professionals are still unaware of too many rare diseases. Consequent delays or errors in diagnosis are stressful for patients and their families, affect their quality of life, and can be costly or even dangerous by delaying access to appropriate treatments; all this translates into an increase of expenses and a waste of resources for the health-care and social systems. This is particularly unacceptable considering that some rare diseases may be compatible with a normal life if diagnosed on time and properly managed. Therefore, any research that could improve the diagnosis, understanding, or treatments of just some of the estimated 6000–7000 different rare diseases would substantially reduce costs for health-care systems. A patient affected by a rare disease, when properly treated, stops being a consumer of irrelevant tests, ineffective, if not dangerous, treatments, or superfuous hospital admissions.

Patients Deserve Better  The low prevalence of rare diseases means that the numbers of patients who are affected by any given condition are small or extremely small; those affected,

therefore, feel particularly isolated. The isolation felt by these patients is not only geographical but can also lead to marginalization within the society and within health-care systems that are designed for common diseases. In a survey conducted in 2017 in 48 countries, more than 70% of patients reported dif culty in daily activities and more than 50% mentioned that the disease affects their social life [52]. Indeed, 70% of patients reported that they are forced to reduce or discontinue their work and 69% face a reduction in their income. Scienti c knowledge on rare diseases is scarce overall; when it does exist, it is fragmented and scattered across national territory. For most rare conditions, the causes, pathogenetic mechanisms, and epidemiology are unknown, which makes diagnostic methodologies and therapies dif - cult to develop. In turn, this aggravates patients’ vulnerability and puts them at a disadvantage relative to the rest of the society and to patients affected by more common diseases.

The Goal of Clinical Research in Rare

Diseases

Rare lung diseases are often chronic and debilitating and, once diagnosed, may require unconventional, expensive, and long-term treatments. This is the case, for example, of subcutaneously administered GM-CSF for pulmonary alveolar proteinosis [75], alpha-1 antitrypsin replacement for hereditary emphysema [76], or glucocerebrosidase therapy for Gaucher disease [77]. As with more common diseases, the ultimate goal of research in rare diseases is to identify the underlying pathogenetic mechanisms and new targets for therapeutic intervention. The success of sirolimus—a mammalian target of rapamycin (mTOR) signaling inhibitor—in stabilizing lung function, reducing respiratory symptoms, and improving the quality of life of tuberous sclerosis/LAM patients is proof of concept that therapy targeting defective genetic and biochemical pathways can be successful [46, 78].

Concluding Remarks

Rare lung diseases represent a heterogeneous group of disorders with complex pathogenesis, diverse histopathology, and variable natural history and prognosis. In the last decade, there have been major advances in the eld, but much work remains to be done. Most of these conditions are genetically determined. However, unraveling how multiple susceptibility alleles interact with each other and with environmental factors to determine disease risk and phenotypes remains challenging. Studies on rare diseases have several bene cial effects, apart from facilitating the diagnosis and treatment of speci c entities. The establishment of partnership between academic researchers/clinicians, pharmaceutical companies,

patient–parent support groups, and government agencies to solve problems related to rare diseases will also serve as a paradigm for the studies of other diseases. Basic and clinical studies on rare lung disorders are also likely to improve our understanding of the physiological and pathological processes as well as treatment of more common diseases. The development of central databases, registries, and research networks is vital in order to the design and performance of much-needed robust clinical studies across the spectrum of rare lung diseases.

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