Key words
rare diseases - otorhinolaryngology - medical ethics - orphan drugs
1. Introduction
Rare disease diagnosis and therapy present major challenges for all people involved,
including the affected patients, their relatives, and the medical, therapeutic, and
nursing staff. Rare diseases represent a very heterogenic group. The majority
(~80%) of orphan diseases are at least partly related to genetic
aspects. They often lead to symptoms with childhood onset and exhibit a chronic
course, and are rarely curable. Rare diseases are also characterized by particular
regulatory, economic, and research-related aspects. By definition, rare diseases
affect a low number of patients, making it difficult to conduct trials due to the
wide distribution of patients suffering from a given disease.
Rare diseases are extremely challenging in terms of both diagnosis and therapy.
Affected patients often need interdisciplinary care provided by a team of experts,
and their treatment typically requires specific qualifications, skills, and
equipment. Additionally, they may have special needs regarding the
doctor–patient relationship, in terms of “shared decision
making” [1] and communication with
physicians who will provide further treatment. Moreover, the optimal methods for
good treatment and care are often unclear. These factors contribute to delayed
diagnoses, and patients’ feelings of isolation. However, in recent years,
rare diseases have been increasingly the focus of public attention [2].
Many typical diseases encountered in the field of oto-rhino-laryngology, head and
neck surgery are considered rare diseases based on their prevalence. As this
discipline is mainly defined by the affected body region (head and neck), it
frequently overlaps with other disciplines, and oto-rhino-laryngologists inevitably
encounter manifestations of rare diseases. Notably, the first manifestations of rare
diseases are commonly in the head and neck area. Thus, oto-rhino-laryngologists must
be familiar with rare ENT-specific diseases. They should have knowledge about the
diagnostics; the available resources (e. g. centers, networks, and
registries); the particularities of the doctor–patient relationship and
follow-up, including communication with family doctors; and the role of self-help
and support groups. For university medical professionals and the scientific
community, areas of specific interest may include the particularities of this field
of research, including European networking and research funding, information
management, public outreach, teaching and education, and the regulatory aspects
(orphan drugs).
2. Definition
The specific definition of a rare disease (also called orphan diseases) varies among
different countries. In the European Union (EU), a disease is considered rare when
it affects no more than 5 of 10 000 people (50:100 000 or 1:2000).
In contrast, a rare disease is defined by a maximum prevalence of 1:1500 people (7.5
per 10 000 people) in the United States (US), 1:2500 (4 per 10 000)
in Japan, 1:10 000 in Australia, and even 1:100 000 in Switzerland
[2]
[3]. In the EU, most rare diseases affect only one person or even less per
100 000 people. However, about 5000–8000 different rare diseases
affect an overall total of 27–36 million people in the EU, i. e.
6–8% of the EU population. In Germany alone, about 4–6
million people live with rare diseases.
Notably, the term of “Orphan” is also used to describe diseases and
therapies (e. g. “Orphan Drugs”) that are actually rather
common (e. g. many tropical diseases) but which are neglected due to
economic reasons, including the absence of economic incentives to develop therapies.
However, these diseases will not be discussed in the present article.
3. Orphanet
Orphanet is a database summarizing the available resources relating to rare diseases
and medications for rare disease treatment (so-called orphan drugs), created with
the stated goal of “gathering and improving knowledge on rare diseases so as
to improve the diagnosis, care and treatment of patients with rare
diseases”. Orphanet aims to provide high-quality information about rare
diseases, and to ensure equal knowledge access for all stakeholders. Orphanet also
maintains the Orphanet rare disease nomenclature (ORPHA code), which is
essential for improving the visibility of rare diseases in health and research
information systems” [4]. Orphanet was
established in 1997 in France by the French National Institute for Health and
Medical Research (INSERM). In 2000, this initiative became a European endeavor,
supported by grants from the European Union.
Specifically, Orphanet provides [4]
[5] ([Fig.
1]) the following: an inventory, classification, and encyclopedia of rare
diseases with associated genes; information about drugs for rare diseases (orphan
drugs); a list of self-help organizations; a list of experts and institutions, as
well as expert centers; a list of medical labs offering diagnostic services; a list
of current research projects, clinical trials, registries, and biobanks; and a
collection of specific articles (Orphanet report series). The Orphanet database can
be used to look up diseases, clinical signs and symptoms, classifications, genes,
and handicaps (activity impairments regarding daily life or their functional
consequences) associated with rare diseases. The functional Orphanet thesaurus is
based on the ICF classification of the World Health Organization (International
Classification of Functioning, Disability and Health – Children and Youth,
ICF-CY, WHO 2007). The Orphanet nomenclature contains a “heterogeneous
typology of entities of decreasing extension, including: groups of disorders,
disorders, and sub-types. A disorder in the database can be a disease, a
malformation syndrome, a clinical syndrome, a morphological or a biological anomaly
or a particular clinical situation (in the course of a disorder). They are organized
into groups and further divided into clinical, etiological or histopathological
sub-types” [4]. When seeking
information about a rare disease, search criteria can include the disease name,
ORPHAcode, gene symbol/name, OMIM or MIM number (“Online Mendelian
Inheritance in Man”, a database registering the human genes and their
mutations), or International Classification of Disease (ICD)-10 code.
Orphanet also provides access to an encyclopedia of rare diseases for experts,
comprising a series of expert-authored and peer-reviewed information, including
“Review Articles, clinical practice guidelines, diagnostic criteria,
guidance for genetic testing, Practical Genetics, clinical genetics review,
emergency guidelines, anesthesia guidelines, disability factsheets, and summary
information on the disease in a language other than the seven languages of
Orphanet” [4]. For professionals and
patients, Orphanet provides information about self-help groups (patient
organizations, umbrella organizations, and alliances) that specialize in a certain
disease or disease groups, which may be sorted geographically (according to country,
region, or city.)
Fig. 1 The internet opeing page of Orphanet, the portal for rare diseases and orphan drugs.
In 2019, a cooperation was forged between Orphanet and the “International
Clinical Trials Registry Platform” (ICTRP) – Registry of the World
Health Organization
(https://www.who.int/ictrp/en/).
Incorporation of the Orphanet registry has significantly improved the identification
of clinical trials for rare diseases for ICTRP users
(http://apps.who.int/trialsearch/).
Finally, the “Orphanet Report Series” is a published series of
reports that are available as downloads, with different focuses covering the whole
spectrum of rare diseases. These reports include the following topics: list of rare
diseases, epidemiological report with available prevalence data, list of orphan
drugs, overview of available registries for rare diseases in Europe, annual activity
report, list of relevant (research) infrastructures in Europe, results of the
Orphanet survey regarding user satisfaction, and a list of all experts who have
contributed to the contents of the Orphanet database [4].
3.1 Orphanet Journal of Rare Diseases
The “Orphanet Journal of Rare Diseases” is the official journal
of Orphanet, founded in 2006, and published by BioMed Central (SpringerNature)
“Open Access”. It specifically focuses on research regarding
rare diseases, including review articles and clinical trials, as well as
articles on public health and orphan drugs.
4. Orphan Drugs
Since 1983, the term orphan drug has been used to define medications applied for the
treatment of rare diseases. In this terminology, “Orphan Drug”
refers to the above-mentioned definition of rare/orphan diseases, based on
varying prevalence rates in different regions. In addition to the definition of rare
diseases based on prevalence, the term orphan drug also applies to drugs lacking
economic profitability. Due to the small market and correspondingly low sales during
legal patent protection — combined with high development costs —
orphan drugs are not of great interest to the pharmaceutical industry. This is also
the case for drugs intended for a market with low purchase power, as is typical of
diseases that are common in poorer countries, particularly tropical diseases;
however, this use of the term will not be discussed in the present article.
To promote and develop orphan drugs, the political authorities in the US issued the
“Orphan Drug Act” (ODA) in 1983 [6]. The main incentive provided to pharmaceutical industries is the right
of exclusive marketing (7 years under the ODA). Additionally, the ODA provides
research funding for companies and academic research groups, and reduced fees in the
approval process and tax reductions, while drugs for rare diseases are under
evaluation for therapeutic potential. In the context of the Orphan Disease Act of
the US Food and Drug Administration (FDA), the “Orphan Drug
Designation” programs include the “Humanitarian Use Device (HUD)
Designation”, the “Orphan Products Clinical Trials Grants”,
the “Pediatric Device Consortia (PDC) Grant”, and the
“Orphan Products Natural History Grants”. Since their introduction,
these programs have promoted a significant increase in the field of developing drugs
for rare disease treatment. In the US, this includes the market introduction of over
600 orphan drugs since the start of the program [7].
In 2000, the European Union implemented the “Orphan Medicinal Product
Regulation”, with the aims of defining a common procedure for the
designation of drugs as orphan drugs, and creating incentives for orphan drug
research, development, and distribution. Within the European Medicines Agency (EMA),
the Committee for Orphan Medicinal Products (COMP) regularly issues recommendations
for acknowledging the status of “Orphan Drug”. An application for
designation of a medicinal product as an orphan medicinal product may be submitted
if the sponsor can establish that a medicinal product is intended for the diagnosis,
prevention, or treatment of a life-threatening or chronically debilitating condition
that 1) affects no more than five in 10 000 persons in the community; or 2)
that without incentives it is unlikely that the marketing of the medicinal product
in the community would generate sufficient return to justify the necessary
investment. Additionally, the applicant must demonstrate that the community
presently has no satisfactory method of diagnosis, prevention, or treatment of the
condition in question, or if such a method exists, that the medicinal product will
be of significant benefit to those affected by that condition [8]. Upon approval of an orphan drug in the EU
registry, the applicant has market exclusiveness for the approved indication for 10
years. Additionally, the application fees are partially remitted to the
pharmaceutical company, and other important cost savings may be achieved by the
simplified approval procedure. The drugs with orphan status approved in the EU are
listed in the Orphanet database, and published in the “Lists of medicinal
products for rare diseases in Europe”.
According to the act on the restructuring of the medicines market (AMNOG) of 2010,
additional benefit from an approved drug must be confirmed. However, since orphan
drug approval is only issued when the disease is rare and no adequate therapy
already exists, the necessity of confirming an additional benefit of an orphan drug
may be neglected. This facilitation only applies to drugs that have a low turnover
due to their approval for rare diseases. It does not apply to pharmaceutical
companies that have achieved a turnover of over 50 million Euro with their orphan
drug, in which case, the confirmation of additional benefit must be submitted. The
requirement of proving an additional benefit might be one reason why the FDA has
approved more oncological drugs compared to the EMA, particularly for subgroups of
oncological diseases with higher prevalence [9].
Controversies have arisen regarding “undesired side effects” of the
regulatory and funding programs in the context of orphan drug development. There is
the possibility of manipulation (“gaming the system”) for profit
maximization [10]. The increasing number of
approved orphan diseases may include biomarker-defined subgroups of non-orphan
diseases, particularly in the field of oncology [11]. Reports have described the use of piecemeal tactics for non-orphan
diseases with the aim of achieving drug approvals by exploiting the competitive
advantages in the context of the orphan drug status [12]
[13]. Reduced research and
development costs (smaller clinical trials or observational studies), accelerated
review processes at the approval authorities, reduced or minimal competition, and
other aspects have led to a situation where orphan drugs rank among the most
expensive and most lucrative drugs on the world market [14]. Therefore, the incentive systems will have
to be reviewed.
5. Clinical Trials and Biometric Aspects
5. Clinical Trials and Biometric Aspects
From a biometric perspective, the development of therapies for rare diseases
encounters numerous problems regarding the performance of clinical trials as a
precondition for therapy approval. Complicating factors include the low disease
prevalence, heterogeneity of the patient populations, geographical dispersion, and
high percentage of pediatric patients. Clinical trials for rare diseases usually
include very small numbers of patients, presenting challenges regarding an efficient
study design and specific biometric methods for outcome analysis with limited
populations. In general, in the ethical assessment of any clinical trial, one must
evaluate the biometric quality with regards to study design, calculation of case
numbers, and statistical analysis, as methodologically poor research in humans must
be considered unethical [15].
Most statistical design and analysis methods for clinical trials have been developed
and evaluated for study populations of at least several hundred patients. These
methods are not always suitable for therapy evaluation when the sample size is small
— as is naturally the case for orphan diseases. It is unknown whether there
is a specific cut-off value for sample sizes, below which standard methods can no
longer be considered adequate. Therefore, current investigations use statistical
methods to assure that high significance is achieved in small patient populations.
Such methods include, for example, the inclusion of multiple or composite endpoints
for conclusions regarding therapeutic effects, which may improve the statistical
power of biometric tests [16]
[17].
In the context of orphan diseases, real-world evidence (RWE) trials are
another possible means of coping with the natural problems of randomized clinical
trials, which still represent the gold standard of clinical research. In medicine,
real evidence refers to evidence from observational data that are collected during
clinical routine, outside of the setting of randomized clinical trials. Analysis of
real-world data may support the benefit assessment of drugs used in the context of
rare diseases. Data availability has been improved by progressive digitization [18]
[19],
suggesting that in the future real-world evidence will play a major role in the
development, benefit assessment, and regulatory processes (approval) of therapies
for orphan diseases [20]
[21]
[22]
[23].
Even if the common guidelines for clinical trial conduction (e. g. ICH
guidelines) also apply for clinical trials of rare diseases, the EMA and the
committee for Medicinal Products for Human Use (CHMP) have developed and published
specific guidelines for the performance of clinical trials with small study
populations: EMA/CHMP guideline on clinical trials in small
populations
[24]. Additionally, the
International Rare Diseases Consortium (IRDiRC) has issued
recommendations developed by a task force for clinical trials in small populations
(Small Population Clinical Trials Task Force, SPCT) [25]
[26].
6. Ethical Aspects
Based on the four medico-ethical principles of Beauchamp and Childress [27], and in the context of decision making and
weighing in the context of rare diseases, we must observe the patient’s
right of autonomy (autonomy principle), the principle of avoiding damage
(non-maleficence, “primum non nocere”), the principle of care
(support, beneficence), and the principle of justice. The decision of how much a
society should spend on investigations of orphan diseases and their therapies
represents a moral dilemma. On one hand, these diseases affect only a small
percentage of the individuals in a society. From a utilitarian perspective, the
allocation of major resources for rare diseases is morally wrong because it does not
maximize the aggregated overall benefit, i. e. the sum of welfare of all
individuals in a society. On the other hand, society has a moral obligation to not
abandon those people who are affected by an incurable orphan disease. Additionally,
the medical field has the professional obligation of scientific progress,
i. e. to increase our knowledge about diseases and their therapies. Hence,
with regard to justice, the different principles contradict each other,
depending on the standpoint from which they are assessed [28].
A recent example is the discussion about the world’s most expensive drug to
date — Zolgensma (onasemnogene abeparvovec) — produced by the Swiss
pharmaceutical company Novartis. Gene therapy with Zolgensma slows muscle loss in
severe spinal muscular atrophy (SMA1), which originates from an inherited homozygous
defect in the SMN1 gene. Based on gene therapy by means of an adenoviral vector,
Zolgensma leads to the integration of a functioning variant of the SMN1 gene into
the spinal cord motoneurons, supporting their survival and maintenance of their
function. Our knowledge of the benefit of Zolgensma is mainly based on a small trial
including 12 children, of whom the majority achieved head control, and two-thirds
can sit without support. Twenty-four months after application, all children were
still alive [29]. In 2020, the European
Medicines Agency approved the drug. The costs for the singular gene therapy amount
to about 2 million Euro, and this so-called “value-based pricing”
has been the subject of controversial discussions. According to the producers,
single therapies that approach the genetic cause of a disease require different
assessment compared to chronic therapies. In Germany, this gene therapy will go
through the necessary benefit assessment process, according to AMNOG, during the
upcoming months. It is of particular medico-ethical, political, and medico-economic
relevance that the medication was originally developed in non-profit and
donation-funded labs in the USA and France [30].
The utilitarian point of view, in the sense of maximizing the common welfare,
is the basis of economic evaluation for prioritization in health politics. However,
there is no full consensus regarding which values must be maximized. One typical
measure is the so-called loss of healthy life years (disability-adjusted life years;
DALY). The DALY concept was first presented in 1993 by the World Bank, and is
intended to measure the importance of different diseases for the society, including
the efficiency of interventions (prevention and treatment), as “economic
unit per DALY gained” [31]. Besides
the principle of maximization, there is also the indigence and equality principle.
According to the definition, each single rare disease does not frequently occur;
however, the entirety of rare diseases affects a relatively high number of people.
Thus, Gericke and co-authors asked two relevant questions [28]: “What level of resources should be
devoted to orphan disease research overall?” and “What level of
resources should be allocated to each individual disease?”. Further problems
in the context of economic assessment arise regarding the allocation of resources
for research purposes, due to the extreme uncertainty regarding success or benefit.
The minimal market needed to arouse industry interest in developing an orphan drug
is estimated as 100 million US dollars [32],
and it is probably actually much higher.
Besides the utilitarian point of view, there is also a legal claim. This is
mentioned, for example, in the Charter of Fundamental Rights of the EU regarding
access to medical care and the right of medical service within the context of the
respective national law. However, strictly speaking, this does not affect the right
or the claim of research funding for presently non-existing therapies [28]. In terms of the principle of care
(support, beneficence), the requirements of provision and weighing apply for
the actors, as well as the balance of service, risk, and costs.
The concept of non-abandonment applies to the field of rare diseases since
they are neglected due to the low or absent economic incentives for research and
development—at least without governmental incentives. The different levels
of political and social efforts described in this article, which aim to increase
knowledge about rare diseases and to improve the diagnosis, care, and treatment of
patients suffering from rare diseases, must be assessed in the context of
non-abandonment. These various moral obligations require (financial) support of the
investigation of orphan diseases and their therapies, including the development of
orphan drugs, on multiple levels [28]. The
success of these political and social activities is clearly confirmed by the
significantly increased number of approved medicines for the treatment of rare
diseases [7].
Nonetheless, many ethical aspects and challenges in the field of rare diseases remain
unsolved. Many issues are related to the different standards and rules in various
countries, and could be improved by stronger international and global approaches.
The composition of the decision-making bodies plays an important role in terms of
weighing and solving ethical dilemmas, and in fairly distributing resources [33]. Advances in DNA sequencing, and current
developments in genome editing and genome surgery (e. g. the
CRISPR/Cas method, and in vivo gene therapy using adenoviral vectors) will
likely introduce new medico-ethical challenges, including in the field of orphan
diseases [34]
[35]
[36]
[37].
7. Legal Aspects and Outpatient Specialist Care[1]
7. Legal Aspects and Outpatient Specialist Care[1]
Few legal regulations exist regarding the topic of rare diseases. In fact, rare
diseases are explicitly mentioned only in in Germany in §116b of the
5th Social Security Code (SGB V), in the context of regulating the
outpatient specialist care. Since rare diseases are defined only based on their
prevalence, there is no limitation to severe courses. Thus, a suspected diagnosis
is
sufficient to gain access to specialist treatment [38].
Rare diseases are also relevant in the context of so-called off-label use,
i. e. when medicines are applied for indications that are not included in
the current approval. Such applications are only allowed in exceptional cases
— at least with regards to statutory health insurances — and the
presence of an extremely rare disease that cannot be systematically investigated is
considered as such an exception. This is cited in the settled case-law of the BSG
(see BSG judgement dated March 19, 2002 – B 1 KR 37/00 R, NJW 2003,
460), and in the so-called “Nikolaus judgement” of the Federal
Constitutional Court (Bundesverfassungsgericht). According to the guiding principle,
it is incompatible with the fundamental rights (Art. 2 Abs. 1 GG) combined with the
welfare state principle (Art. 2 Abs. 2 Satz 1 GG) to exclude patients with statutory
health insurance from deliberately chosen medical treatment of a life-threatening
or
regularly lethal disease for which generally acknowledged medical standard therapy
is not available, if there is a reasonable prospect of a cure or a noticeable
positive effect on the disease course (BVerfG, Judgement dated December 6,
2005–1 BvR 347/98, NJW 2006, 891). According to these requirements,
§ 31 Abs. 1 S. 4 SGB V states that in single medically justified cases,
physicians may prescribe medicines that are actually excluded from specific medical
care [39]
[40].
Finally, the question has been raised about the liability in cases of
non-recognition of a rare disease. Jurisdiction has decided that a
(hospital) doctor is not liable for diagnostic errors of diseases that are
practically not encountered (OLG Koblenz, Judgement dated January 27, 2014–5
U 1383/13, MedR 2015, 38 ff).
8. German National Action Alliance for People with Rare Diseases (Nationales
Aktionsbündnis für Menschen mit Seltenen Erkrankungen;
NAMSE)
8. German National Action Alliance for People with Rare Diseases (Nationales
Aktionsbündnis für Menschen mit Seltenen Erkrankungen;
NAMSE)
The National Alliance for People with Rare Diseases (NAMSE) in Germany was founded
in
2010 as an association of the Federal Ministry of Health, the Federal Ministry of
Education and Research, and the Alliance of Chronic Rare Diseases (Allianz
Chronischer Seltener Erkrankungen, ACHSE), together with 25 partners (exclusively
umbrella organizations and associations of the most important actors in healthcare),
by adopting a common declaration as a coordination and communication institution.
This alliance was formed with the objective of initiating better healthcare for
patients with rare diseases based on already existing structures and European
experiences. It pools existing initiatives, networks researchers, and physicians,
and summarizes information for physicians and patients (www.namse.de).
Since 2011, the Federal Ministry of Education and Research (BMBF) has also
contributed to the International Rare Diseases Research Consortium (IRDiRC)
with promotion of national associations for rare diseases, which was founded by the
European Commission and the US National Institute of Health (NIH). Contributors to
the IRDiRC comprise over 50 international partners, including research funding
organizations like the BMBF, patient associations, and industry partners. Also in
2011, the “GKV Versorgungsstrukturgesetz” (Healthcare Structures
Act) introduced outpatient specialist care (Ambulante
spezialfachärztliche Versorgung, ASV) with §116b SGB V. This is a
new healthcare sector in which panel physicians and hospital outpatient departments
care for patients according to standardized requirements.
In 2014, the central information platform on rare diseases, called ZIPSE, was
established to provide quality-assured knowledge and information about rare diseases
to patients and their relatives, as well as to medical, therapeutic, and nursing
staff (www.portal-se.de). This platform does not provide primary information, but
rather links to already existing and quality-assured proposals regarding rare
diseases, such as Orphanet, ACHSE, SE atlas, and centers for rare diseases.
In 2013, NAMSE published a national action plan including 52 proposed measures to
coordinate and organize future action of the German healthcare and social system in
the context of rare diseases. This plan describes a three-stage center model. The
criteria for type A centers (reference centers) and type B centers (centers of
expertise) were established and operationalized by a NAMSE task force, and published
by the partners in 2014.
One element of NAMSE is a project called the Open Source Registry System for Rare
Diseases (OSSE), which is funded by the German Federal Ministry of Health.
The aim of this project is to allow patient associations, hospitals, researchers,
and other involved people to establish patient registries using an open-source
software, which will lead to strengthening the national registry landscape. In the
context of OSSE, a minimal dataset was developed, which has since been replaced by
an EU version. This dataset should be the basis for all participating registries,
to
allow and foster the retrievability of and the exchange with registries
(www.osse-register.de).
Since 2009, centers for rare diseases have been established at German
University Hospitals, which are committed to the healthcare of patients with orphan
diseases. One action of NAMSE is the provision of the healthcare atlas for people
with rare diseases (Versorgungsatlas für Menschen mit seltenen
Erkrankungen, se-atlas). This internet portal offers information and a
comprehensive overview of healthcare possibilities and self-help organizations for
people with rare diseases, their relatives, physicians, non-medical staff, and the
general public. Links are available regarding centers for rare diseases in Germany,
an overview of umbrella institutions, an overview of certified institutions, and an
overview of European reference networks (ERN) (www.se-atlas.de)
For rare diseases within the field of oto-rhino-laryngology, head and neck surgery,
the European Reference Network for craniofacial anomalies and ear, nose, and neck
disorders is a relevant example (https://ern-cranio.eu). The topic
of rare diseases has also been integrated into the national competence-based catalog
of learning targets of medicine (NKLM) and dental medicine, the new licensing
regulations for physicians, the healthcare strengthening act of the statutory health
insurances regarding the development of enabling regulations for university
outpatient departments (§ 117 SGB V), and the Hospital Structure Act with
consideration of specific tasks for hospital centers due to particular provisions.
The Federal Joint Committee (Gemeinsamer Bundesausschuss, G-BA) has decided that
special tasks must be financed via center supplements because they are services for
patients from other hospitals (e. g. interdisciplinary boards) or
overarching tasks (e. g. keeping and evaluating registries). Since 2016,
high-throughput sequencing for diagnostics of rare diseases has been included in the
general assessment standard (Einheitlicher Bewertungsmaßstab, EBM). With the
sample dataset of 2020, the DIMDI published standardized codes for rare diseases.
Beside the alpha ID code and the ICD-10 code, they also contain the so-called
ORPHAcode from Orphanet. In 2020, the BfArM published the alpha ID SE version for
2021, containing the respective ORPHAcode from Orphanet for a large number of the
rare disease entries. The 2021 version includes 8043 diagnoses with ORPHA code.
Another project that was established by the Federal Ministry of Health as part of
NAMSE is the central information portal about rare diseases (Zentrales
Informationsportal über seltene Erkrankungen, ZIPSE). At the end of 2019,
this project was taken over by the Foundation of Health Knowledge (Stiftung
Gesundheitswissen). Here, patients and relatives can find an overview of the
medical, therapeutic, and nursing service providers in the field of rare diseases.
Quality-assured information, particularly concerning diagnostics, therapy,
self-help, healthcare institutions, research, and registries, are listed according
to specific criteria (adapted from
https://www.portal-se.de/ziele).
9. Alliance of Chronic Rare Diseases (Allianz chronischer seltener Erkrankungen,
ACHSE)
9. Alliance of Chronic Rare Diseases (Allianz chronischer seltener Erkrankungen,
ACHSE)
ACHSE is a network of self-help organizations, which is intended to be a voice,
multiplier, and mediator to address the needs and problems of patients with rare
diseases. It promotes knowledge about these diseases within the population, and
among interested representatives, physicians, and therapists. ACHSE tasks include
the support of patients and relatives, networking of physicians and therapists,
research funding, sensitization of the public, representation of political
interests, and improvement of information and knowledge management (adapted from
www.achse-online.de). Moreover, the ACHSE participates in the annual
“Rare Disease Day”, which is an international day
dedicated to rare diseases on the last day in February (www.rarediseaseday.org).
This campaign primarily addresses the general public, politicians and healthcare
politicians, industry representatives, researchers, therapists, and all people who
are interested in rare diseases.
10. Research and Research Funding
10. Research and Research Funding
Investigating rare diseases can lead to insights regarding fundamental biomedical
processes and correlations, and the discovery of knowledge that is also essential
for identifying causes and origins of frequently occurring diseases. In 1657,
William Harvey wrote that “… Nature is nowhere accustomed more
openly to display her secret mysteries than in cases where she shows traces of her
workings apart from the beaten path; nor is there any better way to advance the
proper practice of medicine than to give our minds to the discovery of the usual law
of Nature by careful investigation of cases of rarer forms of disease.
…” [41]. Researchers,
pharmaceutical industries, and sponsors have long understood that scientific
experience related to the investigation of rare diseases provides benefits in the
context of frequent diseases, and useful knowledge about their mechanisms and
therapies. This is largely because many orphan diseases result from single gene
mutations, allowing scientists to observe the sequelae of gene defects, as they
could in a well-controlled experiment. A good example is the investigation of
familial hypercholesterinemia, which led to the development of statins [28].
For the clinical and patient-oriented investigation of rare diseases, it is extremely
important to work in supra-regional or international structures. In this context,
disease registries play a central role. A disease registry with clear
quality criteria regarding completeness may serve as a basis for the generation of
evidence through high-quality clinical trials, particularly non-randomized
trials.
Among the projects in the field of orphan diseases that are funded by different
institutions in Germany, about half are related to rare cancer diseases. Projects
related to rare genetic diseases are the second most prevalent. At this time,
comprehensive data are not available regarding the resources provided in Germany for
the investigation of orphan diseases and the systematic assessment of all research
activities.
Since 2013, the Federal Ministry for Education and Research (Bundesministerium
für Bildung und Forschung, BMBF) has fostered national research associations
for rare diseases. The activities of these associations are focused on information
about disease origins, as well as diagnosis and therapy research. They cover a broad
spectrum of rare diseases, including immunology, developmental disorders, kidney
diseases, nervous system diseases, and metabolic disorders. The organization
particularly focuses on funding projects oriented towards translation. In February
2018, the BMBF published a guideline regarding the promotion of translation-based
projects in the field of rare diseases.
The BMBF and the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG)
participate in the European Joint Program on Rare diseases (EJP RD). This
program receives financial support from the EU, and entails the cooperation of 130
institutions from 35 countries to create a comprehensive sustainable research
ecosystem from 2019–2024, with the aim of establishing improved coordination
and feedback between research, healthcare, and medical innovation. In addition to
the coordinated access to data, training activities, and accelerated translation
— international research funding is an integral part of this program. It
comprises the promotion of networking meetings for knowledge exchange, and the
cooperation of industry and academia to work on specific research challenges as well
as transnational research associations. For the latter, the contributing 31 research
sponsors from 23 countries have expanded their activities initiated in E-Rare. BMBF
and DFG participated in the first two publications from 2019 and 2020, and two
additional publications are planned (adapted from www.namse.de).
In 2021, the innovation fund of the Federal Joint Committee (Gemeinsamer
Bundesausschuss, G-BA) will promote guideline projects on rare diseases. The funding
occurs in two different ways. On one hand, the innovation fund promotes the creation
or updating of complete guidelines. On the other hand, the fund supports
evidence-based research of the institute of quality and efficiency in healthcare
(Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen,
IQWiG) in the context of single clinically relevant issues regarding guidelines.
The International Rare Diseases Research Consortium (IRDiRC) includes
governmental and non-profit organizations, pharmaceutic and biotechnological
companies, and an umbrella organization for patient interests and scientists with
the objective of promoting investigations of rare diseases worldwide. In 2017, the
IRDiRC formulated a vision for research regarding rare diseases. By 2027, all
patients suffering from known orphan diseases should obtain an accurate diagnosis,
healthcare, and available therapies within one year after their first medical
consultation. Additionally, 1000 new treatment approaches should be
approved—particularly for the rare diseases for which therapy options are
not presently available [42].
Furthermore, several foundations provide funding for the investigation of rare
diseases. One example is the Eva Luise und Horst Köhler Stiftung
für Menschen mit Seltenen Erkrankungen (www.elhks.de) that fosters
improved medical care for people with orphan diseases via targeted research funding.
This foundation mainly addresses relevant challenges associated with new approaches
to quality-assured molecular genetic diagnostics, acceleration of the development
of
specific therapies, and the expansion of expert networks. The annual Eva Luise
Köhler Research Award is one of the most established awards in this research
field.
11. Conclusion
Rare diseases are particularly challenging in terms of diagnostics, pre-clinical and
clinical research, interdisciplinary and multiprofessional management, and adequate
funding—including for accounting, coding, and regulatory aspects. They often
entail specific requirements in the context of the physician–patient
relationship, follow-up, and communication with co-treating physicians. Moreover,
orphan diseases represent a medico-ethical challenge, particularly in the context
of
allocation in terms of healthcare and research. It is highly important to establish
funding for information management and public relations efforts, as well as for
training and education and conscious research — including national and
international networking, registry creation and maintenance, and the establishment
of clinical centers. Additionally, self-help plays an important role in the
well-being of patients and their relatives. They often have the best knowledge about
their diseases, and it may be helpful to combine this knowledge with the expertise
of service providers.
In light of the manifold challenges, over recent years, good results have been
achieved through politically, academically, and self-help established activities,
with contributions of different stakeholders. However, many issues are still present
and require our attention and commitment, in order to diagnose rare diseases without
unnecessary delay, and to provide our patients with access to adequate treatment in
suitable centers.
