MEDICINE, LAW & SOCIETY 
Vol. 14, No. 2, pp. 479–494, October 2021 
https://doi.org/10.18690/mls.14.2.479-494.2021 
© 2021 University of Maribor, University Press 
Accepted  
04. 07. 2021
Revised 
09. 09. 2021
Published 
29. 10. 2021
Keywords 
biologic  
medicinal  
product, 
orphan  
drugs,  
biologics, 
rare  
diseases,  
biosimilars 
INTERNATIONAL COOPERATION AS A 
PREREQUISITE FOR IMPROVEMENT OF 
ACCESS TO ORPHAN BIOLOGIC MEDICINES 
Zbigniew Więckowski 
Cardinal Stephan Wyszynski University in Warsaw, Law and Administration Faculty, 
Institute of Legal Studies UKSW, Warsaw, Poland. 
E-mail: z.wieckowski@uksw.edu.pl 
CORRESPONDING AUTHOR 
z.wieckowski@uksw.edu.pl 
Abstract Rare diseases constitute a global problem. 
Worldwide, 350 million people suffer from such diseases. The 
number of diagnosed cases are on the rise. Only a small 
percentage of those suffering have the opportunity to be 
treated with modern therapies. Medicines used to treat rare 
diseases are called orphan drugs. Biologic medicines developed 
for orphan drug indications, besides patent protection, have a 
period of regulatory and market exclusivity. After this period 
of time has elapsed, access to orphan drugs could be improved 
by the introduction of biosimilar medicines. The biggest 
challenge is to develop effective legal, tax and economic 
incentives to stimulate the development of biosimilar 
medicines for orphan indications. The regulatory agencies - 
EMA in the EU and the FDA in the USA - play a key role in 
increasing access to orphan biologics. Undoubtedly, the 
international cooperation, especially the mutual recognition of 
registration procedures between countries, and the creation of 
a common vocabulary and the unification of incentives for the 
pharmaceutical industry would have the positive impact on 
access to modern therapies. 
480 MEDICINE, LAW & SOCIETY.  
1 Introduction 
Rare diseases constitute a global problem. Worldwide, 350 million people suffer 
from such diseases (Klimova et al., 2017), including 25-30 million in the US (Stoller, 
2018) and 30 million in the EU (European Commission, n.d.). Unfortunately, the 
number of diagnosed cases are on the rise. About 80 percent of rare diseases have a 
genetic basis (Liu et al., 2019), while the remaining 20 percent may be linked to 
infection, allergy or environmental factors (Slade et al., 2018). More than half of rare 
diseases emerge during childhood. Rare diseases cause more than 30 percent of 
hospital admissions in children's hospitals and account for 40 to 45 percent of deaths 
before the age of 15 (Gunne et al., 2020). Currently, only a small percentage of those 
suffering from rare diseases have the opportunity to be treated with modern 
(biologic or gene) therapies (Maldonado et al., 2021). 
The current pandemic has exacerbated problems for people with rare diseases, as 
they are among the most vulnerable to COVID-19 (Chowdhury, Al Sium & Anwar, 
2021; EURORDIS, 2020). 
There is no single, universally accepted definition of a rare disease (Richter et al., 
2015). According to Regulation No 141/2000 of the European Parliament and of 
the Council of 16 December 1999 on orphan medicinal products (EUR-Lex, n.d.), 
a rare disease is a disease with a prevalence of no more than five per 10.000. The 
official definition of an ultra-rare disease was adopted by the European Union in 
Regulation No 536/2014 of the European Parliament and of the Council of 16 April 
2014 (EUR-Lex, n.d.). It indicates that an ultra-rare disease is a disease with an 
average incidence of no more than one in 50.000 people. In the US, any disease 
affecting fewer than 200.000 people is considered rare (usually 7.5 cases per 10,000 
persons). The definition comes from the Orphan Drug Act of 1983 (e-CFR, n.d.). 
Medicines used to treat rare diseases are called orphan drugs (European Medicines 
Agency, n.d.). The term ‘orphan drug’ is derived from the fact that pharmaceutical 
companies were not interested in developing such drugs due to the lack of financial 
incentives (the development of orphan drugs is done also in the public, non-profit 
institutions, for example: The Cancer Research UK Cancer Therapeutics Unit at The 
Institute of Cancer Research, London, the Institute for Applied Cancer Science at 
MDAnderson Cancer Center, see more: Workman, Draetta, Schellens, Bernards, 
Z. Więckowski: International Cooperation as a Prerequisite for Improvement of Access to 
Orphan Biologic Medicines 481. 
2017). Many countries have introduced incentives and financial assistance to 
promote the development of therapies for orphan drugs. In terms of financial 
incentives, exemptions from various types of administrative fees are the most 
frequent. Tax incentives are less common, but also occur. Non-financial incentives 
are most common: patient access to therapy under ‘compassionate use’, 
administrative advice, special reimbursement procedure rules (DZP, PEX 
PharmaSequence, 2020). In terms of reimbursement proceedings involving orphan 
products, the range of methods employed is extremely wide. In Belgium and 
Slovakia, for example, it is possible to be exempted from having to provide a 
pharmacoeconomic assessment. In Bulgaria, Sweden, Romania and the Netherlands, 
multi-criteria analysis (MCA) is used in health technology assessment (HTA). In the 
Czech Republic, reimbursement is proposed for a transitional period. In France, 
orphan products benefit from an accelerated assessment process. In Germany, there 
is an exemption from proving therapeutic benefit if the cost of the therapy does not 
exceed a certain level (DZP, PEX PharmaSequence, 2020). 
The largest and clinically most effective group of orphan drugs are biologic 
medicines such as monoclonal antibodies, vaccines and blood clotting factors. In 
recent years, biologic drugs have revolutionised treatment in many therapeutic areas 
(Świerczyński & Więckowski, 2019; 2020). They are used primarily in the fields of 
dermatology and oncology and to treat rheumatic disease. During the past year, 
significant progress was made in the development of therapies for rare diseases in 
the USA when the Food and Drug Administration (FDA) authorised 32 new drugs 
and biologics with orphan drug designation (Food and Drug Administration, 2021). 
The overall regulation of biologic medicines is well-established and does not require 
wide-scale changes. Biologic medicines developed for orphan drug indications, 
besides the patent protection, have a period of regulatory and market exclusivity. 
After this period of time has elapsed, access to orphan drugs could be improved by 
the introduction of biosimilar medicines (Dowlat, 2016). The biggest challenge is to 
develop effective legal, tax and economic incentives to stimulate the development 
of biosimilar medicines for orphan indications. Without competition from biosimilar 
medicines there is a risk that the original product will continue to monopolize the 
market. This leads to the maintenance of high prices (Moon, 2017; World Health 
Organization, 2018) and makes biologic orphan products relatively expensive, and 
out of the reach of poorer nations and populations (Chan et. al., 2020; Miller & 
482 MEDICINE, LAW & SOCIETY.  
Lanthier, 2018). Among numerous hurdles limiting the availability of biosimilar 
medicines for orphan indications is a long clinical development pathway, similar to 
that of the original medicine. One of the major problems is that, most likely due to 
lack of sufficient economic incentives, most orphan products do not have generic, 
possibly biosimilar, equivalents. There is a biosimilar version for orphan biological 
molecules in clinical development in only eleven percent of the cases, compared to 
23 percent of all biological drugs (Bruce, 2021). 
The first step to increase patient access to orphan medicines is to propose a coherent 
legal model for them. Proposed legal solutions need to be internationally acceptable 
due to the specificity of rare diseases and the limited number of patients at the 
national level. 
Because of its pioneering approach to the subject, the international perspective 
initially should be limited to the US and EU. These regions not only have the greatest 
market potential, but also the greatest level of legislative advancement to date. The 
regulatory agencies - the European Medicines Agency (EMA) in the EU and the 
FDA in the US - play a key role in increasing access to orphan biologics. 
Undoubtedly, both the mutual recognition of registration procedures between the 
EU and the US, and the creation of a common vocabulary and the unification of 
incentives for the pharmaceutical industry would have an impact on access to 
modern therapies. At present, the legal basis, regulatory pathways and approval 
requirements for orphan and biosimilar biological drugs in the US and the EU are 
very different. 
Cooperation between the EMA and the FDA formally began in 2003. Currently, the 
agencies maintain almost daily contact. The cooperation takes place mainly through 
working groups called “clusters” (Teixeira, Kweder & Saint‐Raymond, 2020; 
European Medicines Agency, n.d.). 
The EMA-FDA cooperation on orphan drugs has been ongoing since 2008 and 
mainly concerns orphan drug designation, product development proposals, 
administrative simplification, exchange of opinions, drafting of guidance documents, 
as well as opportunities for collaboration at conferences and workshops. 
Z. Więckowski: International Cooperation as a Prerequisite for Improvement of Access to 
Orphan Biologic Medicines 483. 
The primary successes of the cluster have included the development of common 
procedures for the submission of applications for orphan drug designation and 
annual reporting on the status of development of designated orphan drugs. 
For example, in June 2020, officials from the European Commission (EC - DG 
SANTE), EMA and FDA held a bilateral regulatory dialogue meeting. The meeting 
reviewed current joint initiatives, discussed strategic priorities for the coming years 
and identified areas where cooperation can be further strengthened. Among the 
various topics discussed were orphan and paediatric medicines. Officials shared 
information on the initiatives being undertaken by each agency and discussed 
possible collaboration on data analysis to characterise rare diseases (European 
Medicines Agency, 2020). 
The initiatives cited above are examples of cooperation based largely on the 
exchange of opinions, experience and information between the two agencies. There 
is no doubt that, in order to effectively improve the availability of orphan biologicals, 
it is necessary not only to have greater institutional cooperation but, above all, to 
have mutual recognition and far-reaching harmonisation of rules. From the 
perspective of patients suffering from rare diseases, the optimal solution would be 
to reject the primacy of national jurisdictions in favour of supra-state structures. An 
international consensus is therefore required and an international convention must 
be adopted which could provide a framework for potential cooperation. 
The paper is divided into four parts. In the first, I present the current state of the art 
on orphan medicines from the American and the EU legislation perspective. The 
second section examines the most frequently identified problems that prevent 
unrestricted access to orphan biological drug therapies. The third section provides 
arguments in favour of the importance of international cooperation on the subject 
of orphan biologics. The paper ends with a summary and conclusions. 
484 MEDICINE, LAW & SOCIETY.  
2 Orphan medicines – American and the EU legislation – state of the 
art 
The US was the first country in the world to address the issue of orphan drugs 
(Orphan Drug Act, 1983 “ODA”). Since the passing of the ODA, more than 950 
orphan drugs and biologics have been approved in the US, compared with ten in the 
previous decade. The US model was followed in subsequent years by Japan 
(Sakushima, Takeda & Aoi, 2021) the EU and Australia (Neelakandan, Venkatesh & 
Gomez, 2019). Japan (Orphan Drug Act, 1993) and Australia (Orphan Drug 
Program, 1997) were the next countries to introduce a definition of a rare disease in 
their legal system. These definitions stated that a rare disease is a disease that affects 
fewer than 40 (in the case of Japan) and 11 (in the case of Australia) patients per 
100.000 people. The US regulations have thus become a starting reference for 
regulations emerging in other jurisdictions. Despite the many initiatives taken by EU 
institutions in recent years to ensure greater access to orphan drugs, the US still 
dominates this area (National Organization for Rare Disorders, 2021). 
In the EU, rare diseases received their special status after the adoption in 2001 of 
legislation on medicines for rare diseases and in 2006 the regulation on medicines 
for children. For the period of May-July 2021, the European Commission launched 
an open public consultation on the revision of the rules on medicines for children 
and rare diseases. The consultation follows an evaluation of the existing rules 
published in the summer 2020. While the evaluation confirmed that the legislation 
stimulates research and development for medicines to treat children and rare 
diseases, it also revealed some shortcomings in the current system, primarily 
concerning the development of medicines in areas of high unmet patient demand 
and their availability to all patients in all Member States (European Commission, 
2021). 
Thanks to the work undertaken on amending current EU legislation, there is a 
chance of improving access to modern therapies. The issue of orphan medicinal 
products is high on the European Commission's agenda, as is improving the greater 
availability and affordability of medicines. At the same time, the European 
Commission is currently developing its pharmaceutical and intellectual property 
strategy. Julie Maréchal-Jamil from Medicines for Europe is right saying: “How we 
prioritize the shaping of an environment favorable to off-patent competition in this 
Z. Więckowski: International Cooperation as a Prerequisite for Improvement of Access to 
Orphan Biologic Medicines 485. 
space will condition the landscape in the next decade. We foresee that the EU 
framework currently in the making will help significantly grow the proportion of 
biosimilar medicines available in orphan indications” (Bruce, 2021). 
This is an important time to propose greater international cooperation as the 
biologics legal pathway is unlikely to change markedly and research into orphan 
biologic medicines is at a crucial point. The first biologic orphan medicines 
registered in the EU will lose patent protection in the next few years (some 28 
biologic orphan medicines will be eligible for competition by 2028) and the methods 
by which biosimilar orphan medicines will gain access to the market are yet to be 
shaped (Bruce, 2021). 
The EMA has highlighted the benefits of international cooperation. The EMA 
shares its experience in the regulation of biosimilar medicinal products with member 
state agencies as well as other regulatory bodies from other parts of the world. At 
the same time, the EMA points to a fundamental problem that represents a 
significant barrier to improving access to modern therapies, including orphan 
biologics: “[it] is difficult because different legal and regulatory frameworks are 
applicable in each country and govern the development and approval of biosimilar 
medicines across the world” (Bruce, 2021). 
The revision of EU legislation and the unprecedented international cooperation in 
the fight against the COVID-19 pandemic provides hope that now is the best time 
to launch an international initiative on rare diseases. A strategy of limiting itself to 
individual nation states does not serve the cause. An important example of a 
comprehensive multilateral agreement reached through international consensus is 
the WHO Agreement on Trade-Related Aspects of Intellectual Property Rights 
(TRIPS), which established minimum requirements for patent protection (Athreye, 
Piscitello & Shadlen, 2020). TRIPS shows that through consensus-building, and 
where there is will to do so, the international community can agree on issues 
affecting humanity at the global level.  
486 MEDICINE, LAW & SOCIETY.  
3 Problems to be solved 
The concept of reaching international consensus on stimulating access to modern 
therapies could be a part of the worldwide debate on the future of law for biologic 
orphan drugs. The most frequently identified problems that prevent unrestricted 
access to orphan biological drug therapies include: 
a) the lack of sufficient incentives to conduct drug trials involving a limited
patient population (including tax incentives) (Day et al., 2018);
b) short periods of data exclusivity and market exclusivity (Sarpatwari et al.,
2018);
c) the difficulty of properly identifying patients for clinical trials (Gaasterland
et al., 2019);
d) the limited number of clinical sites with sufficient experience to conduct
trials for a given disease (Gelinas, Crawford, Kelman & Bierer, 2019);
e) long clinical development pathways for orphan biosimilars that differ little
from that of the originator drug;
f) inefficient reimbursement (Czech, 2019);
g) g)lack of clear regulation on automatic substitution (Afzali, Furtner,
Melsheimer & Molloy, 2021);
h) lack of unified terminology in the field of biologics;
i) limited market size and associated difficulties for the potential emergence
of biosimilar medicines.
A further consideration is patents, which are often one of the main barriers to the 
marketing of all alternative pharmaceuticals such as ‘me-too’ medicines, biosimilars 
and generics. In the context of patent law, two basic questions concerning biologic 
orphan drugs arise:  
1) should this kind of invention be treated as common good (part of the public
domain)?
2) what is the optimal regime of intellectual property protection for orphan
biologics?
Z. Więckowski: International Cooperation as a Prerequisite for Improvement of Access to 
Orphan Biologic Medicines 487. 
Proposed changes could include modifications, such as creating a subtype of patent, 
a sui generis protection of genetic components of biological drugs and strengthening 
the rules on business confidentiality (Świerczyński & Więckowski, 2019a). 
A problem associated with the increased availability of orphan biologics is one that 
is often overlooked: patient loyalty to the drug. This is often a consequence of the 
so-called "diagnostic odyssey" that patients with rare diseases experience. It 
frequently takes months, and sometimes years, of research to find the cause of 
patients’ conditions. Patients who successfully finished an “odyssey” during the 
lengthy diagnostic process often become extremely loyal to a drug. The same is true 
for medical specialists, who develop a bond of loyalty by working with the 
responsible parties, possibly the drug manufacturers. This should not come as a 
surprise, especially as doctors themselves often encourage manufacturers to 
continue research and support them in passing on the necessary knowledge (IQVIA, 
2020). 
4 Importance of cooperation 
The legal model for orphan biologic medicines will fulfil its function if it is created 
and accepted by the international community. The development of the legal model 
is important because:  
1) a transparent and reliable legal model for orphan biologics is a necessary
condition for the successful development of health care systems as a whole
at a time when there is an increasing global prevalence of rare diseases;
2) orphan biologic medicines drive up the cost of healthcare; indeed, orphan
biologics have been called “niche-busters” as they consume a significant
part of health budgets because of their extremely high cost;
3) the observation of the changes currently taking place in the field of access
to vaccines against COVID-19 to provide a global solution within a short
time-span leads to the conclusion that significant changes are required also
in the regulation of orphan biologics. Access to modern therapies should
not be restricted. It is a global goal to make them widely accessible in third-
world countries, which have no specific orphan biologic medicines
legislation, and where the majority of patients can neither access nor afford
modern therapies (Kontoghiorghe et al., 2014);
488 MEDICINE, LAW & SOCIETY.  
4) the dynamic development of the market for biosimilar drugs in recent years
is related to the expiration of the exclusive rights (data exclusivity and
market exclusivity) of reference orphan biologic products. As biologics are
increasingly approved with data from post-authorization and real-world
evidence, there are questions related to the accessibility of this data once
exclusivities have expired;
5) the expiration of patents relates to orphan biologic medicines that are highly
profitable blockbuster drugs. It is advisable to make in-depth analysis on
the need to prepare legal regulations dedicated to biosimilar medicinal
products, especially since manufacturers of innovative orphan biologics
expect many incentives for their development. This leaves the important
question of what would be needed to support necessary biosimilar
competition in this field;
6) the introduction of orphan biosimilar products has the potential to reduce
healthcare costs, generating significant savings and better patient access to
rare disease medicines;
7) it can lead to changes to regulatory law governing clinical trials, assisting
market development of orphan biosimilar drugs and access to patients;
8) the automatic substitution (practice at pharmacy level of dispensing one
medicine instead of appropriate another without consulting the prescriber)
has the potential to enhance access to biologic therapies. The key issue is to
determine whether patient safety concerns can be countered with an
increased availability of medicines;
9) of the development of telemedicine and e-health platforms. Health care
systems are currently undergoing significant changes due to the rapid
development of information technology including use of artificial
intelligence and developments introduced during the COVID-19 pandemic
crisis. Developers of orphan biologics identified one of the significant
hurdles they face as the identification of patients for trial recruitment. It is
almost impossible to find the required number of patients within a
reasonable time period. Changes in technology may lead to increased
availability of orphan biologic medicines, mainly through the support of the
qualification process for the biological treatment of patients (Schaefer et al.,
2020).
Z. Więckowski: International Cooperation as a Prerequisite for Improvement of Access to 
Orphan Biologic Medicines 489. 
Many of the problems cited above could be avoided if international action were 
taken. Certainly, an immediate priority is to harmonise: a) the regulation of orphan 
drugs and b) periods of data and market exclusivity. Secondly, it is important to 
develop globally applicable incentives for the manufacture of biosimilar orphan 
products. There needs to be international consensus on this. This seems difficult, 
but not impossible, as the example of the TRIPS Agreement demonstrates.  
The only way to improve access to biological treatments for rare diseases is through 
not only international cooperation but also the joint development of rules and 
regulations. Only a global approach to the problem can bring about significant 
change. 
There is no shortage of examples of international cooperation in expanding access 
to therapies for rare diseases. A few include:  
The International Rare Diseases Research Consortium (IRDiRC) - brings together 
national and international organisations (governmental and non-profit), 
pharmaceutical and biotechnology companies, patient organisations and researchers 
to promote international collaboration and the development of research on rare 
diseases worldwide. It brings together entities from Africa, Asia, Australia, North 
America and Europe (IRDiRC, n.d.). 
EURORDIS-Rare Diseases Europe - a non-profit organisation of 962 rare disease 
patient organisations from 73 countries (EURORDIS, n.d.). 
The European Joint Programme on Rare Diseases (EJP RD) - brings together more 
than 130 institutions from 35 countries: 26 EU Member States (Austria, Belgium, 
Bulgaria, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, 
Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Poland, 
Portugal, Romania, Sweden, Slovakia, Slovenia, Spain) seven associated countries 
(Armenia, Georgia, Israel, Norway, Serbia, Switzerland, Turkey), UK and Canada 
(EJP RD, n.d.). 
490 MEDICINE, LAW & SOCIETY.  
All these initiatives substantiate the need for international cooperation. So far, 
however, the dominant model of cooperation has been the non-governmental one, 
at the level of, above all, patient organisations and non-profit institutions. Although 
initiatives of this kind are extremely valuable, standing alone they are insufficient. 
Action must be taken that will result in the adoption of specific legal regulations. 
Only the global approach will markedly improve access to modern forms of therapy, 
including biological or gene therapies. The current model, which is based solely on 
calculations involving individual national markets, is ineffective and often 
perpetuates monopolistic models in the area of access to medicines. A supranational 
agreement is required, for example, within the European Union, and uniform rules 
are needed for access to medicines used to treat rare diseases. The experience of the 
European Commission's negotiations with the responsible entities supplying the 
COVID-19 vaccine shows that, after the necessary adjustments (failure of the 
AstraZeneca agreement), joint EU purchases of medicines to treat rare diseases are 
possible. 
5 Conclusions 
Plans for international cooperation in the area of providing wider access to biologic 
orphan products requires specific tasks to be undertaken. Medicines for Europe has 
proposed the following, with which I fully concur: 
1) Introduction of regulatory incentives to support the development of
products developed after the expiry of patent protection for the original
product, reflecting the incentives and facilities available to manufacturers of
innovative products.
2) The adoption of a streamlined approach to the development of biosimilar
medicinal products, in particular with regard to clinical comparability (non-
mandatory).
3) The need to ensure conditions for the global development of orphan
biosimilars.
4) Reducing time limits for pricing and reimbursement decisions on orphan
products. This would ensure that biosimilars can be brought to market as
soon as the regulatory and intellectual property exclusivity for orphan
originator products expires.
Z. Więckowski: International Cooperation as a Prerequisite for Improvement of Access to 
Orphan Biologic Medicines 491. 
5) Pricing and reimbursement conditions should be tailored to the specificities
of orphan biosimilars. The current rules are not fit for purpose and do not
allow responsible entities to obtain a sufficient return on their investment
(Bruce, 2021).
Although it may seem difficult to establish rules for satisfactory cooperation between 
multiple parties, there seems to be no better solution than to work together 
internationally to improve access to orphan biologic products. 
Note 
This article was written due to the performance of the scientific research project no. 
2017/25/N/HS5/01505 titled: Legal model of biosimilars financed by the National Scientific Center. 
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