Ethical Questions Linked to Rare Diseases and Orphan Drugs – A Systematic Review

Figures & data

Table 1 Publication Statistics in Selected Publications

Keywords	Database	All	English
			Article	Conference	Review
“ethics” AND “rare” AND “disease”	Scopus	535	307	109	8
	PubMed	1643	1580	3	26
	Web of Science	126	91	1	23
“ethical” AND “orphan”	Scopus	137	73	3	25
	PubMed	108	99	0	18
	Web of Science	76	55	1	9
“ethical” AND “orphan” AND “drug”	Scopus	75	43	2	17
	PubMed	64	57	0	15
	Web of Science	34	23	0	6
“ethical” AND “rare” AND “disease”	Scopus	458	245	7	106
	PubMed	661	615	0	140
	Web of Science	222	142	59	4

Table 2 The Most Frequently Represented Journals in Relation to Keywords

Journals	Number of Publications
BMJ Open	22
Medicine	10
European Journal of Human Genetics	10
Orphanet Journal of Rare Diseases	9
Advances in Experimental Medicine and Biology	7
Journal of Medical Ethics	7
Zhonghua Shiyan Yanke Zazhi Chinese Journal of Experimental Ophthalmology	7
Genetics in Medicine	7

Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of search process.

Table 5 Main Objectives and Findings of Research in the Ethical Area for Rare Diseases

Title	Number of Citations	Country	Objective	Used Principles	Finding
(Juth, 2017)^Citation22	18	Sweden	Justify the lack of orphan drug cost effectiveness	Principle of need	Orphan drugs should be subsidized more than common disease medications
(Boy et al, 2011)^Citation23	26	Brazil	Highlight ethical issues related to orphan drug public funding	Ethical consideration secondary	Major ethical conflict concerns the distribution of orphan drugs
(Gericke et al, 2005)^Citation7	111	German	Introduces conflicting ethical approaches to funding orphan drug research and development.	Explaining various ethical approaches and their consequence for orphan drug R&D	Independent international bodies may stimulate orphan drug R&D
(Hyry et al, 2015)^Citation24	13	EU countries	Survey and support compassionate use programs in the EU and beyond.	Analysis of relevant ethical, legal, and economic aspects	Propose a registry of drugs offered on a compassionate use basis to help patients get treatment
(Kesselheim, 2012)^Citation25	12	US	Discusses ethical consequences of the orphan drug act and pitfalls in accelerated approving orphan drugs	Essay	Rare disease afflicted patients are willing to take unnecessary risk, the fda lowers its standards in this area
(Rodriguez-Monguio et al, 2017)^Citation5	32	US	Assess the effectiveness of incentives for orphan drug r&d	Literature search	Current incentives do not stimulate orphan drug r&d efficiently
(Rosselli et al, 2012)^Citation26	12	Colombia	Consider ethical and economic aspects of a high-cost orphan disease in a marginalized population	Essay	Cost-effectiveness does not apply in marginalized populations affected by rare diseases, special regulation and financing schemes considering intangible costs and benefits should be applied
(McCormack et al, 2013)^Citation16	29	EU countries	Describe how an interdisciplinary advisory group responded to particular ethical issues	Description	New rare disease therapies raise new ethical issues that require interdisciplinary bodies with expert knowledge and patient experience
[^Citation27]	0	US	Address the ethical and practical issues of sponsoring rare disease R&D when relocation to trial sites is needed		In the area of rare diseases, unlike elsewhere, relocation support is desirable
(Gelinas et al, 2019)^Citation28	4	Pakistan	Ethical and economic considerations regarding lysosomal storage diseases in Pakistan	Review	It is necessary to find ways to balance the needs of the many and the needs of the few, so that patients with rare diseases receive care but not at the expense of basic healthcare to be provided to all individuals.
(Afroze & Brown, 2017)^Citation29	0	EU countries	Address conflict of interest in research and medical treatment	PubMed query	Dealing with non-financial conflicts, in particular centralisation of surgical care, should be done more as accurately as financial ones
(Schmiedeke et al, 2019)^Citation30	14	EU countries	Identifying challenges of ethical evaluation	Desk research, case study	Proposal of a heuristic template to collect patient data in registry research. Output I suggestion of Heuristic template for patient information in association with clinical registry research
(Hansson et al, 2012)^Citation18	9	EU countries	Determining and solving ethical issues when establishing an ethics committee at project management level	A co-construction of healthcare professionals, ethics professionals and patients	Recommendations for improvement to achieve a successful and mutually respectful cooperation of researchers and patients.
(Duchange et al, 2014)^Citation13	3	Israel	Review of the ethical aspects of whole exome and whole genome-sequencing studies	Summary of results of e-workshop	Diagnostic tools for the benefit of rare disease patients
(Farberov et al, 2013)^Citation12	7	US	Address various inequalities that orphan disease patients suffer from	Essay	Appeals to eliminate health disparities by improving ways to diagnose, and treat orphan diseases
(Kinney, 2014)^Citation4		EU countries	Analyse ethical aspects of funding R&D in rare diseases	Essay, desk research	Propose an ethical framework the fair allocation of resources for the prevention, diagnosis and treatment of rare diseases
(Pinxten et al, 2012)^Citation31	2	Australia	Analyses funding of rare disease therapies in australia and related ethical issues	Essay, desk research	There is a need to maintain a separate
(Taylor et al, 2018)^Citation32	2	France	Review both ethical and economic issues of non-profit drug r&d, and the impact of pricing strategy of for-profit companies targeting the same segment	Review, approaches to pricing drugs	There is a pricing challenge for the non-profits as affordable prices may hinder R&D in the area
(Jarosławski & Toumi, 2018)^Citation32	2	France	Review both ethical and economic issues of non-profit drug r&d, and the impact of pricing strategy of for-profit companies targeting the same segment	Review, approaches to pricing drugs	There is a pricing challenge for the non-profits as affordable prices may hinder R&D in the area
Hews-Girard et al (2020)^Citation34	0	Canada	The aim of this paper is to examine scientific objectivity in rare disease research from a philosophical viewpoint and, in doing so, demonstrate the need to redefine it to reflect the current scientific environment	Review, ethical objectivity, justice and beneficence, objectivity, subjectivity	Concepts of objective subjectivity and transformative criticism highlight the need to evaluate scientific processes and knowledge with respect to their trustworthiness rather than apparent neutrality.
Wellman-Labadie O. and Zhou Y. (2010)^Citation35	189	US	This study investigates issues associated with the United States Orphan Drug Act.	Desk research - A comprehensive orphan drug database was compiled from FDA data and corporate annual reports of major pharmaceutical companies.	Suggested reforms include price regulation, subsidy paybacks for profitable drugs and the establishment of an International Orphan Drug Office.
Gershon E.S. and Alliey-Rodriguez N. (2013)^Citation37	62	US	Present risk calculations, discuss the ethical implications in the risk counselling process.	Use data from recent mega-analyses and reviews of ethical issues in mental disorders presented by these risks	Risk counselling may need to be accompanied by psychotherapy to address ethical concerns and issues of genetic disease stigma.
(Encina et al, 2019)^Citation33	0	Chile	The research present and analyze the main challenges of the Chilean healthcare system in area of rare disease (legislation and ethical context)	Review	Policy suggestions, including the introduction of patient registry and the involvement of the public in decision-making regarding healthcare preferences and funding.

Figure 2 Co-occurring keywords in PubMed.

Figure 3 Co-occurring keywords in Scopus.

Figure 4 Co-occurring keywords in Web of Science.

Figure 5 Top 20 most recent keywords and most cited keywords to the keyword search.

Table 3 Clusters of Keywords in Web of Science

Cluster 1	Diagnosis, individual, ethic, family, ethical issue, gene, alzheimer, genetic, ethical aspect, genomic, newborn screening, whole exome sequencing, whole genome sequencing, ethical challenge, precision medicine, schizophrenia, incidental finding
Cluster 2	Cancer, chemotherapy, tumor, woman, case report, informed consent, female, malignancy, ethical concern, ethical approval, pregnancy, rarity, trisomy, poor prognosis, newborn
Cluster 3	Rare disease, orphan drug, decision, policy, decision-making, expert, survey genetic testing, ethical dilemma, orphan disease, pharmaceutical industry, family member, clinical practice, patient advocacy organization, new drug
Cluster 4	Disorder, registry, biobank, clinical research, drug development, placebo, ethical consideration, enzyme replacement therapy, rare condition, drug administration
Cluster 5	Child, participant, consent, hypertension, questionnaire, adolescent, caregiver, severe malaria
Cluster 6	Parent, relationship, expectation, interview, investigator, rare disease research

Figure 6 The relationship between the phrase ethical issue and linked keywords in Web of Science.

Figure 7 The relationship between the phrase rare disease and linked keywords in Web of Science.

Figure 8 Co-authorship of countries.

Table 4 List of Leading Countries Related to the Keyword Search

Country	Documents	Citations
United States	254	3466
United Kingdom	146	1780
France	76	1168
Canada	71	1695
Italy	69	1139
Germany	68	1201
Australia	50	875
Netherlands	43	634
Spain	34	615
Belgium	32	296
Switzerland	29	453
China	28	152
Sweden	28	367
Brazil	26	397
India	26	248
Japan	23	536
South Africa	18	131
Austria	14	216
Poland	14	150
Portugal	12	278

Figure 9 Sum of citations per year of the keyword search of “ethics” AND “rare” AND “disease”, “ethical” AND “orphan”, “ethical” AND “orphan” AND “drug” and “ethical” AND “rare” AND “disease”.

Table 6 Key Questions Related to Rare Diseases and Orphan Drugs

How to allocate financial resources?^Citation7,Citation10,Citation18,Citation24,Citation26,Citation30^–^Citation32,Citation34,Citation35	How much a society should spend on orphan diseases? Why should a profit-making enterprise donate a drug? How many resources should be devoted to orphan diseases overall? How many resources should be allocated to each individual orphan disease? Should rare diseases enjoy economically favourable exceptions? Should scientific advancement in common diseases be prioritized over that in rare diseases? Why fund rare disease therapies? “How to achieve access to rare disease therapies in an equitable manner?”
Is there any place for compassion and accelerated approval of orphan drugs?^Citation7,Citation35	Are there any ethical reasons for offering orphan drugs for free? Is it only sentiment or also a coherent ethical theory? Does the moral obligation to distribute resources extend outside a particular country to other countries?
Should there be any limits to prevalence for a disease to qualify as a rare one?^Citation7,Citation24,Citation25,Citation29	Do patients with rare diseases perceive their illness differently than patients with more common diseases?
How to encourage cooperation in fighting rare diseases across nations and various groups of stakeholders?^Citation9,Citation12,Citation16,Citation23,Citation32,Citation35	Are there any internationally coordinated approaches? What, if anything, hinders international approach to rare diseases? In what way(s) can an international body, eg, WHO, help international cooperation aimed at tackling rare diseases?
Who should decide on what action to take? Is it a good idea to establish ethics committees for rare diseases?^Citation5,Citation7,Citation22,Citation27^–^Citation29	Who decides what the rightful place of orphan drugs in resource allocation system is? Who and what should determine the boundaries of moral obligations of beneficence and distributive justice? Should these be determined by national boundaries, political constituencies, economic influence or industrial profitability?

Table 7 The Moral Dilemma of Funding Orphan Drug Research and Development

Approach to Achieving Justice and Cost-Effectiveness
No to investments in orphan drugs Economic values first Group over individual	Yes to investments in orphan drugs Non-economic values first Individual over group
Approach/Principle
Utilitarian approach	Rights-based approach
Distributive justice	Beneficence
Opportunity cost	Non-abandonment
	Solidarity
	Rule of rescue
	Scientific advancement

Note: Source: authors.

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