Transformative effect of a Humanitarian Program for individuals affected by rare diseases: building support systems and creating local expertise

Successful program implementation requires an infrastructure supporting treatment access, coupled with concurrent development of healthcare ecosystems. Central to this are education, development of diagnostic technologies, disease monitoring, and building of expertise in local centers to eventually develop into destination centers where individuals with LSDs can receive diagnosis, therapy and monitoring of outcomes. Success was underpinned by striving to meet the needs of all stakeholders involving seamless partnership with members of the local treating communities, patient advocacy groups and organizations, and the healthcare system.

Healthcare delivery for LSDs begins with a compassionate case-by-case response at the country level reaching far beyond simply shipping the drug. At its earliest beginnings Sanofi Genzyme recognized the essential need to build skill sets and infrastructure to support complex care for these people. Individual physician training rapidly evolved into medical advisory boards of enterprising local physicians, international expert physicians, and humanitarian initiative staff. These forums served as platforms for training and mentorship by international leaders, such that over time local physicians became thought leaders advancing the science and generating new knowledge in these rare diseases. The medical advisory boards collaboratively developed treatment guidelines, monitoring, and stratification of individuals based on disease pattern, severity, and genotypes. Over time, local expert physicians took increasing leadership in individuals’ selection, considering nuances of disease phenotypes, and treatment plans. Often, the phenotypes encountered had no prior counterpart in world literature, which is primarily European-centric. Technological developments included logistics of cold-chain transport of medication, advanced assessments to monitor the individuals, and transfer of knowledge and capabilities from a country with limited resources to a central laboratory in another country. For example, the development of dry-blood-spot technology for biochemical molecular analysis, and biomarkers studies in LSDs, advanced monitoring of individuals in remote locations without the need to ship whole blood samples to specialist laboratories. Partnership with rare-disease patient advocates and advocacy groups, renowned for their disease knowledge, was invaluable in ensuring free access to additional medical devices. Creation of such comprehensive healthcare systems supported by skilled providers is critical for improving the health of people with LSDs, and providing an established functional framework to elevate advocacy with local authorities to address the huge unmet needs of this underserved population. Achievement of these goals required overcoming disparate cultural, social, trade policy and political barriers.

From its inception, the governance structure has ensured the program remains compliant with ethical standards, institutional policies, and external governmental requirements, and continues to meet the strategic goals and the foundational mission of the Humanitarian Program (Fig. 3). It operates under the guidance of independent medical review boards, whose composition is region-dependent; for instance, the expert medical committee for the Gaucher Initiative comprises leading experts in GD, staff from Project HOPE and Sanofi Genzyme, and a medical ethicist [8].

Prioritization of individuals or countries is driven by the individuals’ need and is agnostic to the likelihood of government reimbursement or competitive market forces. Candidacy for treatment is primarily based on medical need in the following circumstances: when reimbursement is unavailable, until reimbursement is available, when reimbursement is available but the individual does not qualify, and when other local access or assistance programs are unavailable.

The governance structure was tailored to individual country requirements to best serve that population (Fig. 1). For example, in Egypt, as most people with GD present with massive visceral and hematologic disease in childhood, the medical advisory board had a preponderance of pediatricians and pediatric hematologists.

To evaluate the program and solicit opinions on future enhancements, 320 physicians with experience of treating LSDs were invited to take part in an online survey. Overall, 114 respondents from 42 countries completed the survey, of which 63% of physicians had individuals currently enrolled in the program. Respondents represented a broad range of specialties, including geneticists (27%), pediatricians (21%), and neurologists (13%; Fig. 4A).

Over 92% of physicians became aware of the Humanitarian Program through local or regional medical Sanofi Genzyme contacts (Fig. 4B). Two-thirds of physicians had up to five individuals that had participated in the program, with some physicians having over 20. A third (34%) of physicians reported that it took < 6 months following confirmed diagnosis for individuals to start receiving treatment, with half (54%) of all physicians reporting receiving treatments within 1 year; treatment disruptions due to COVID-19 (a lack of safe areas for infusion, country lockdowns, and travel restrictions) were noted by 35% of physicians.

Most physicians (94%) reported that individuals under their care received the scheduled treatment regularly. The remaining 6% reported challenges to treatment access, including: government regulations, challenges with storage logistics, individuals unable to comply with all the monitoring guidelines, limited financial resources for logistics of getting infusion treatment/challenging environment, delays in receiving medication, and challenges in contacting individuals.

Most physicians (92%) reported that they did not experience any problems when completing the required application forms or providing medical updates every 6 months, however, some suggestions for improvements to the program included digitizing the enrollment process, reducing the ongoing paperwork, and improving disease awareness and support.

Country-specific examples of the successful implementation to build healthcare infrastructure serving LSDs in underserved populations illustrate how, the entire clinical spectrum of GD, for example, has been redefined to serve the individual’s unique needs. Figure 5 depicts examples of individuals with LSDs who have benefited from the program. Cases 1, 2, and 4–6 show the common phenotypes of severe hepatosplenomegaly and failure to thrive pre-ERT due to GD, and resolution post-ERT. Case 3 shows infantile onset of PD with reversal of cardiomyopathy post-ERT. Of note, in some cases the benefit has extended further to the individuals’ siblings, enabling their early diagnoses and treatment.

The numbers of individuals with GD needing medical care became immediately evident upon inception of the program in 1999, when the number of individuals grew from 12 to 37. Project HOPE was a key partner, raising awareness of GD and assessing the gaps in treatment access. It was considered the most effective partner to manage the Gaucher Initiative, having operated in Egypt since 1975, and collaborating with the Ministry of Health and University Hospitals across the country for other healthcare initiatives. This collaboration with Project HOPE was critical in implementing many aspects of the program, including annual training for Egyptian doctors via international and national experts, and patient and family awareness activities. This initiative robustly models the key pillars of building healthcare systems, starting with affected individuals and their families, mentorship, and development of thought leaders within medical committees to achieve high-level expertise on how best to evaluate candidacy for treatment, assessing outcomes, and contributing gained knowledge to benefit the global community. To date, the program has supported > 250 individuals in Egypt with GD treated at centers of excellence established across the county, obviating the need to travel long distances for diagnosis, evaluation, and treatment.

Initiated 20 years ago, the program in India has supported > 200 individuals across four LSDs. The program has resulted in improved awareness, diagnosis, and management of individuals with LSDs through the development of several centers of excellence and diagnostic capabilities, along with the implementation of medical-education initiatives for individuals with GD, FD, and PD [12‐15]. Local physicians who had experience in inborn errors of metabolism expedited the rapid configuration and operation of the India Medical Advisory Board, which comprises of these experts and a group of international practitioners, chosen for their specialist knowledge of LSDs, culturally sensitive ethical considerations, and understanding of the local healthcare system. Medical educational activities and workshops played an important role in upskilling physicians caring for individuals with LSDs. There is now a cadre of expert physicians in India who are contributing new knowledge to the field.

The China CAP has grown to support > 180 individuals with GD since its initiation in 1999. Since 2009, centers have spread across China, providing accurate diagnostic support and treatment for LSDs, and obviating the need to travel long distances. A growing number of provinces contribute toward costs through government medical insurance. The program’s flexibility allows for partial humanitarian support for > 50 individuals. The expert medical committee in China has developed treatment guidelines and provided country-wide clinical expertise.

Since the late 1990s individuals severely affected with GD unable to receive treatment in Central and Eastern Europe have been treated via the Humanitarian Program. Individual European countries such as Albania, Belarus, Bosnia, North Macedonia and Serbia, rapidly adopted management of individuals with LSDs, propelled by powerful advocacy groups, which has transformed care. Early access to treatment in these countries has advanced physicians’ knowledge, shortening diagnostic journeys, and improving treatment outcomes.

The impact on the lives of individuals with LSDs has been transformative. Thus far, the Humanitarian Program has provided treatment to > 3300 individuals across more than 100 countries, some for over 20 years, with the average treatment duration ranging from 3 years (for MPS type II) to 9.8 years (for GD; Fig. 6). There are currently > 1000 individuals active in the program as of May 2021, with 156 individuals initiating treatment in 2020 alone. The program has also successfully allowed individuals to become disease advocates helping to increase awareness. Examples of the cascade effect of the program are demonstrated by the formations of the Organization for Rare Diseases India (ORDI), by a father of an individual with PD treated in the program in India, and the Philippine Society for Orphan Disorders (PSOD), by another individual with PD and his family in the Philippines (Fig. 7).

Experienced members of advisory boards have also played a pivotal role, with overseas experts mentoring local physicians in all aspects of LSDs. This mentorship has been central to the program, with local physicians emerging as experts contributing new knowledge to benefit the rest of the world [14, 15]; local physician communities have become highly knowledgeable in rare diseases, shortening diagnostic odysseys, and allowing for maximum clinical impact of ERT.

Operating a program of this magnitude and global reach is challenging. The lessons learned and the measures implemented to overcome obstacles at the local and global level are key to ensuring the resilience of the program.

A hallmark of the program is providing access to treatment for affected individuals who meet the medical criteria, regardless of geography. This includes sanctioned markets such as Cuba, Iran, and Sudan, where treatment access has been provided through the program for 20 years. Other examples include supporting individuals with rare diseases in Palestine, and those displaced due to war or conflict in their countries of origin, for eg, Syrian and Iraqi refugees living in Turkey. In some of these geographies, the program enlists the help of NGO partners to ensure long-term therapy and overcome barriers to treatment access. The ethical underpinnings of the program were tested during a global supply shortage of agalsidase beta in 2009 and imiglucerase in 2010 that required dose-conservation guidelines to be implemented. However, doses were rationed equitably among the most critically affected individuals and Humanitarian Program recipients to ensure that the reduced product supply was distributed based solely on medical need [16]. One of the current challenges faced by the program is the COVID-19 pandemic, which has resulted in altered relationships between international and local humanitarian organizations, deepening inequalities in access to service and the need to find creative solutions for providing access to treatment for individuals with rare disease. Nonetheless, the resiliency of the program is evident in continued treatment of affected people without interruption. Other challenges, with potential solutions, are outlined in Table 3 .