My Perspective on the Rare Disease Landscape of India
The fight against Rare Diseases is an old one. Today, I invite to you understand how this fight is being fought in India and share my perspective on the same.
India is home to a significant number of patients afflicted by Rare Diseases [RD]. [1] This statement though falls short with the lack of complementary statistics; the statement cannot be said to be completely devoid of reality. With no clear definition of an RD in the nation of India, defining the ‘significant number’ remains at best either overestimated or underestimated, either way — a precarious situation. On the international stage, there is no uniform definition of rare diseases. Differences in the cut-off for a disease to be categorized as rare is a major hurdle in international collaboration as it limits and understates (or) overstates the required resources to combat the issue. According to the World Health Organization (WHO), a rare disease has an occurrence is 1 or less in 10,000 in the population, which in highly populated nations fails to be a reliable method of defining RDs.
A policy (here) is an accepted list of statements, commitments and course abopted by all parties in a discussion.
To understand how India can combat the threat posed by Rare Diseases [RD] we must accept the quasi-federalist nature of the Republic of India. Health is the subject of the state, and it is up to the interpretation of the individual needs of the state. This though, at first glance is counter-intuitive, it allows for states to tackle their problems uniquely without the shackles of a generalist blueprint provided by the Centre. [2]
Direct and indirect costs borne by the families and the government are significantly high. From enabling families to pay healthcare costs to providing subsidies to hospitals and patients to ensure that healthcare is disbursed at the right time and remains accessible strains the country’s socio-economic balance. In India, the Central Drugs Standard Control Organization (CDSCO) definition of RDs is considered the national standard benchmark. According to the new clinical trial guidelines, RD afflicts fewer than 500,000 patients in the country. [3] About 80% of RDs are genetic disorders and nearly 50% of the patients are children. [1]
The 21st century reminds us of the issues that India has with its healthcare systems. Now is the time to reduce the dependency of these systems on international production lines. Policies that are focused on encouraging domestic production of drugs against RDs and finding innovative cures for them must be at the forefront of our conscious effort to combat RDs. What we have to understand is that the landscape of rare diseases is continuously changing. Due to this dynamic nature, defining good and time-defined policies becomes extremely difficult and requires continuous real-time changes to compensate. So, what do we do about it? Perhaps by the end of this opinion piece, we can divine what could be done.
INTRODUCTION
The landscape of rare diseases is a mammoth challenge to tackle, even more so to define in the medical world. A cohort of unique medical conditions becomes a large concern because the definition of rare itself remains debated.
Most of these diseases are chronic and degenerative causing extreme disability, which progresses with age. As a result, patients suffering from RDs often require specialized supportive care. [1] So, it makes sense for rare diseases to be defined in the Republic of India for active policies and medical research to make sense of what the patient needs to improve their quality of life.
While enabling a better quality of life is of paramount importance, one must realize that a majority of RDs are incurable. Since they stem from genetic defects, medical regimes exist to dampen the effect of the symptoms. These drugs, hence must be administered throughout the lifetime of the patient and its procurement often leaves the patient and their family exposed to exorbitant financial burdens. As more light is being shed on the matter, we must strive to reduce the financial burden on one hand and on the other promote more robust and affordable science in the likes of genetic engineering.
Today the greatest concern that I believe plagues any comprehensive approach towards understanding and helping those affected by rare diseases is the information abyss we face when it comes to understanding the genetic predisposition in the Indian population. The lack of geneticists, inadequate and in some cases no insurance coverage, and an average period of seven years for diagnosis genuinely places a huge responsibility on the science, legislature, and the public to tackle it alone. [4] There are numerous articles out there on the internet, but the issue arises when we start converting the ideas, the plans, and the solutions to feasible and quantifiable results in the field.
We realize the problem. We have even started asking the right questions through the National Policy for Rare Disease 2017, and have looked towards international entities and their efforts in combatting RDs. Now, if one were to draw a spider’s web and connect the stakeholders of the RD landscape in India, we find ourselves looking at a plethora of entities all with a unique ability to contribute to better and change the landscape in the 21st century.
CONCERNS WITH MAPPING RARE DISEASES IN INDIA
A dynamic list of advancements in medical research inadvertently leads to new definitions of what is considered treatable and which diseases are considered otherwise. New treatment modalities and growing or waning public awareness affect the efficacy of systems that exist in dispensing the required aid. [5]
It is evident from a study conducted on GNE myopathy, an autosomal recessive muscle disease. About 150 cases of this disease have been reported in India so far. On the contrary, based on the frequency of pathogenic founder mutation (V727M), about 40,000 cases of GNE myopathy could be estimated [6]. Therefore, it is a logical assumption that more diseases have been under-reported adding to the already mammoth task of mapping the Indian diaspora.
Another group of researchers talk about another scary finding. [7] The concept of carriers makes tackling genetic conditions all the more akin to finding a needle in a haystack. Singh et al. provide a much-needed insight into the sheer complexity of RDs. In their sample study of two hundred participants, fifty-two (26%) were found to be carriers of one or more disorders. This high carrier frequency for genetic deafness, cystic fibrosis, and Pompe disease contrasts the generally held view about their prevalence in the Indian populace. Therefore, the learning here is quite simple yet extremely difficult to materialize — Testing modalities and protocols in India must be different from that of the West. Testing should comprise the study of all the coding exons with their boundaries in the genes through NGS [Next Generation Sequencing]. Through the study of entire coding regions in the gene can we detect carriers with the required efficiency which in turn shall reduce the burden of genetic disorders in India and other developing countries. [8]
UNDERSTANDING THE NPRD 2021
Defining a rare disease in India requires a thorough understanding/assessment of the prevalence of said RD in the community. The nature of such an undertaking requires sufficient financial support to employ genetic screening tests and inclusive clinical trials.
Treatment options are either unavailable, inaccessible (expensive), or difficult to disburse. A classic example would be the cost of voretigene neparvovec, sold under the brand name Luxturna, a gene therapy medication for the treatment of Leber congenital amaurosis (LCA) developed by Spark Therapeutics. The cost of the one‑time therapy is USD 850,000, which is over INR 5 crores, which puts it out of reach of most patients. [5]
As it stands, most of the funding for the treatment of RDs has been disbursed through different legal proceedings. Funding allocated remains a small fraction of the total money which is required on the ground, which is felt all the more by medical professionals with the lack of funds for research and development and local production of drugs.
The policy stresses promoting public awareness and information dissemination apparatus on RDs, patients, and patient groups and improving connectivity between experts and clinics. These entities are all vital parts of the policy formulation process. Various countries have actively popularized online awareness platforms, and with Digi Yatra, Arogya Setu, and MyGov apps paving the way for a connected Indian society we might just be on the right track in combatting RDs.
In India, public forums and workshops have also been conducted to reinforce the need for a more inclusive policy formulating an ecosystem for the treatment of RDs. There is an undeniable need for a structured regulatory framework in place to encourage debate and action to tackle concerns with the public health systems and economic growth and development.
Lack of actionable epidemiological data. India as a nation has its fair share of inherent problems. This makes the mammoth task of compiling good data all the more difficult. Understanding the economic burden, morbidity, and mortality of these diseases becomes very cumbersome and impossible. Here, the NPRD introduces a much-needed distinction between the nature of RDs and how they should be documented.
A) GROUP 1 diseases respond to one-time curative intervention.
B) GROUP 2 diseases require lifelong treatment, with lower cost of treatment, and clear quality of life improvements.
C) GROUP 3 diseases have definitive treatments but require to be disbursed to optimal patients. Very high costs and life-long therapy are also required.
WHAT SHOULD INDIA BE DOING?
India is a socialist nation. Hence the onus falls on the Government to provide health care to all its citizens equally and respectfully.
A) Maintain region-specific registries
B) Spend on advertising and building public awareness of Rare Diseases
C) Introduce supporting RD research or patients as part of CSR
D) Identify and maintain Centres of Excellence across the nation
The Indian Council of Medical Research (ICMR) announced the launch of a national registry in 2017, with the National Initiative for Rare Diseases. It aimed to cover a set of rare and ultra-rare disorders prevailing in the country, however, the process is yet to begin.
I discuss more about what India can do later in this article.
SCIENCE & MANUFACTURING
The more I think about helping build a better society I find that good decision is based on good science. Research and Development [R&D] have not been given the due attention that it must be given today to genetic diseases. Traditionally it’s fair to say that the GOI focused on eradicating more common and debilitating diseases like smallpox and malaria. Now, as we gradually start asking questions about the prevalence of genetic conditions in the population, the science and the required technology to reach the masses are yet to be organized and deployed. From large-scale genetic screening to well-maintained registries.
Lack of research has hindered the development of evidence-based clinical guidelines to inform best practices [9]. Promotion of local research on RDs has to be enabled through initiatives such as tax credits to academic institutions, collaborative research projects with the domestic clinical research infrastructures, financial subsidies and grants to groups pursuing RD research, and encouraging non-clinical research to better understand the situation surrounding research and interest in RDs.
Strong and reproducible science stands to encourage the local production of drugs. Through this feedback loop made up of science and manufacturing, India stands to improve its R&D activities with clear incentives to become self-reliant. Science and Manufacturing go hand in hand. Enabling opportunities and incentives for pharmaceutical companies and research institutions to commit to RD research with an assurance for manufacturing the drug domestically allows for domestic opportunities for Indian entities, thereby ensuring reduced costs and improvement in quality.
On the topic of science, to date, a few RD conditions have seen considerable progress. Rare disease research is incredibly nascent and largely unexplored. This reality affects scientific communication which in turn erodes the trust of the larger public and legislature in flooring new policies.
Some focus areas to support better science and manufacturing domestically could very well be — Preventive Medicine, Rehabilitation/Patient Care, Research Budget, Open Science, and Genetic Screening and counseling
LEGISLATURE
The Government of India took a bold step in the right direction to address the topic of rare diseases through the National Policy for Treatment of Rare Diseases (NPTRD) in July 2017. Formulated by the Ministry of Health and Family Welfare, GOI its implementation was difficult due to the unaddressed gaps that exist in our national understanding of the rare disease landscape. The gaps include the issue of cost-effectiveness, defining the role of states, understanding regional differences in medical facilities, and more. [5]
In a recent court case, the Delhi High Court ordered All India Medical Sciences to treat a young patient with Gaucher’s disease (PTI, 2020). Similarly, in April 2021, the Karnataka High Court ordered the state government to release ₹59.5 million for the next 4 months for the treatment of 45 existing patients from its unutilized corpus fund (The Hindu, 2021). In January 2020, The Madras High Court called upon the State Government of Tamil Nadu to allocate ₹50 million per annum and directed the central health ministry to allocate ₹44 million as an annual budget for the treatment of 11 patients (Imranullah, 2020).
In a landmark case, titled Mohd. Ahmed (Minor) vs. Union of India & Ors. [reference] The petitioner, a minor child suffering from Gaucher’s disease and who was the only surviving child of his parents, having lost three siblings to the disease, approached the Delhi High Court seeking free and lifelong treatment. He submitted that health should be guaranteed under Article 21 of the Constitution as a Fundamental Right. The cost of the enzyme replacement therapy was about Rs. 600,000 per month, which was unaffordable for the family. The State argued that there were no “unlimited resources” at its disposal and provision of facilities cannot be “unlimited.” The Court ruled that “health is not a luxury and should not be the sole possession of a privileged few” and termed it a violation of Article 21 and directed the Government to provide the child the required therapy at the All-India Institute of Medical Sciences for as long as he required it. [5]
INVOLVING THE PUBLIC AND STAKEHOLDERS
Numerous of these limitations were addressed and can be addressed through public opinion. From stakeholders, organizations, and states, whose participation culminated in the more refined and recent National Policy for Rare Disease 2021. [10]
The NPRD of 2017 failed to involve representatives of the academic and patient community in drafting solutions for a widespread problem. Today in a world that understands the benefits of collaboration it behoves public policymakers to take into account the numerous patient groups while designing policies. Diversity and inclusivity of such lobbyists in policy formulation, research, communications, and resource sharing for better treatment can go a long way in improving the quality of life of the patients and instilling trust in the nation’s institution. [11]
The Indian Organization for RDs and ORDI are some of the well-known patient organizations in India. [12] These organizations stand at a strategic point in communicating science and avenues through which patients and their families can avail themselves of much-needed help. Their support in drafting and formulating a comprehensive national policy, though welcome would only provide one-half of the picture if we fail to include stakeholders for a more fair and balanced approach.
INTERNATIONAL EFFORTS
In my personal experience, the ability to observe and adapt one’s strategy is vital in tackling new and expansive problems. Extrapolating this learning to the international scale, several countries have implemented domestic acts and initiatives to combat RDs. Taiwan has implemented the RD Control and Orphan Drugs Act since 2000 under the umbrella of a special counseling window. This has allowed for a centralized approach towards drug distribution, food supply, nutrients, etc. Similarly, the RDs Act (2016) of the Philippines focuses on diagnosis, clinical and genetic counseling, drug research development, data registry, and newborn screening. The USA’s RD Act (2002) is a public law that allows the establishment of an Office of RDs at its National Institute of Health. Brazil in 2018 approved its RD policy which allows for access to treatment of such diseases as a part of its National Unified Health System.
Exploring how such economies reduce the financial burden on the families/households in countries like Taiwan, Orphan Drug Distribution and Special Nutritional Supplement Supply Centres facilitate the distribution of drugs and reimbursements of up to 70–100% of costs incurred by RD patients on treatments, depending upon the income levels of households. By establishing and maintaining genetic counseling centers besides neonatal programs the country can ensure proper diagnosis and care. Similarly, Japan’s National Health Insurance negotiates prices with the local pharmaceutical companies, offering reimbursement facilities for manufacturing through insurance and loans.
Corporate Social Responsibility of industries could aid in raising funds and enabling research into RDs. France’s Genethon is an example of one such initiative. Genethon was set up for the design and development of gene therapy treatments, mainly funded through charity funds raised at events of the Muscular Dystrophy Association.
Patient advocacy groups are a huge asset that must be given due respect and attention. In the USA, parent project muscular dystrophy has demonstrated that the best interests of patients could be ensured through organized efforts of their families that allowed for societal and economic foresight by the families in supporting their loved ones. In South Korea, the RD Information Database and Korean Organization provides information on RD patients, researchers, pharmaceutical companies, etc. is a testament to digital infrastructure to support medical efforts against RDs. Similarly, Taiwan’s Foundation for Rare Disorders provides general information and support to RD patients concerning medication, education, employment, and long-term care. Malaysia’s RD Society and other patient groups host awareness campaigns through social media and other offline channels.
Local research is vital. Government-funded RD-driven research initiatives such as in Japan, conduct programs to promote local research on RDs under the Specified Disease Treatment Research Programme, supported by its Ministry of Health, Labour, and Welfare. The country also offers tax credits to institutions, to the tune of almost 15% of research costs. South Korea’s Research Centre for RDs was established with the help of its Ministry of Family Affairs, Health, and Welfare to oversee RD-centric collaborative research projects and clinical research networks.
FOCUSED PERSPECTIVES
Health-care professionals
Can we sufficiently say that there are long-term solutions for rare diseases? Are there sustainable approaches to tackling the financial burden borne by the patient and their family? How are we strengthening primary prevention through genetic screening of high-risk couples before conception? Are we creating secondary prevention strategies? We have to find ways to make universal prenatal screening affordable. Healthcare professionals must put forward compelling evidence and design experiments that can communicate the need for a unified approach toward tackling the prevalence of rare diseases in the nation.
Rare Disease Watchdogs and Organizations
India as the third largest economy must find ways to focus and introduce ordnances towards the financial barriers posed by rare disease infrastructure. This means finding prudent solutions through local talent and labor. Organizations such as the ORDI, DBT, and other well-known research institutes must start considering RD as an avenue of research. Scientific communication from these organizations is vital in ensuring that more of the new talent is attracted toward solving rare diseases in the nation.
Our immediate goal must be to reduce the time taken to diagnose, provide adequate treatment facilities, and encourage the domestic production of drugs. The road is long and hard, but the travel is inevitable. The diseases may be rare, but compassion and care combined with a more robust approach through science and technology must be commonplace. [5]
Economic and Social Burden of RD
Socio-economic burden is the aftermath of numerous economic and social factors interacting in distinct ways, which result in direct and indirect costs borne by the families of the patients. Excessive financial burden plagues the journey of any family in supporting their loved one through the treatment prescribed by medical professionals. Though this is a concern that cannot be solved simply through better treatment plans, one must understand the exorbitant costs of diagnosis, therapy, hospitalization, and life-long drugs that must be available at every instant to ensure a meaningful quality of life for the patient. This reality must be explained to the larger populace to inculcate a sense of empathy and social support towards the families.
On the other hand, lack of access to timely and corrective treatments for patients besides regular hospital visits could lead to further inabilities in completing one’s education, finding employment, and accessing physical space in society. Moreover, problems in social acceptance might lead to despondency, physical and psychological stress, emotional distress, and disillusionment among the patients. [4]
WHAT SHOULD WE [INDIA] BE DOING? AND PERHAPS HOW
Indian healthcare policies and industry are yet to be fully equipped to tackle RDs, but I have to point out that GoI [Government of India] has come a long way in combating RDs. So, it pays dividends to adopt a more proactive stance, a collaborative approach towards bringing government, academic, healthcare services and providers, healthcare industry and allied industries, patients, and patient advocacy groups on the same table and encouraging dialogue. GoI and its policymakers must find the right incentives for the stakeholders in the landscape of RDs for it is the only method that invites active participation. I do not say this to berate entities/stakeholders who could do more to combat RDs but are not, I say this because of the nature in which we are all connected — a series of dependencies held together. We must understand this and our policies must cater to the mission of healthcare for all and at the same time provide the right incentives to stakeholders.
The International Rare Diseases Research Consortium has come a long way in providing valuable insights into combatting RDs. Here are the links and literature that stand to be great reads into understanding the international bulwark against RDs, ideas in making combatting RDs a lucrative opportunity for businesses, and new approaches in leveraging science in hopes of finding a more permanent solution. [9]
Let’s start by defining what our long-term and short-term objectives are. Perhaps finding actual cures to these RDs. A cure-for-all approach, though desirable might just fail to take into the myriad ways in which RDs take form in a population. A population as diverse as India’s with different cuisines, climates, and environments compounds this problem. Or perhaps, we could start by creating and supporting active registries to keep track of the affected populace?
Not relegating the cure-for approach just yet, I believe that it should remain the core philosophy behind future policies and legislature. Our recipes for the cure and timely diagnostic of patients, clinical management, supportive therapies, caregiving, and suitable healthcare insurance support. Moreover, our efforts must ensure and encourage the following:
a. Promote and enable advanced research and open science in the allied fields of rare diseases through academic-industry partnerships. Smart India Hackathon is an interesting avenue that could be used to invite startups and medical professionals to tackle this nuanced problem;
b. Deploy resources to build and develop skills of our workforce engaged in research and clinical vocations to bolster Centres of Excellence established across the nation;
c. Enable innovation through economic incentives to facilitate domestic production of drugs in the country;
d. Public awareness must be made a top priority to enable a more inclusive quality of life for families and individuals afflicted by rare diseases. This could be achieved through targeted education reforms for secondary grades and below, digital learning platforms, and marketing concessions for RD help groups;
e. Engage patients and patient groups in the decision matrix, such as policy formulation and economic decisions;
f. Encourage the populace to volunteer for genetic screening through subsidies in the hopes of inspiring better and informed family planning;
g. Encourage and support academic institutions to spearhead think tanks to debate and find solutions aimed at supporting the Indian population and its unique situation. For instance, GenomeIndia by the Indian Institute of Science, Bengaluru, and the Whole Genome Sequencing of the Council of Scientific Industrial Research under the IndiGen initiative;
h. Understand and elaborate on the difference between Persons with physical and/or medical disability. By doing so we must enable and encourage the inclusion of persons with RDs in the Rights of Persons with Disabilities Act of 2016;
i. Create and push similar applications such as Digi Yatra, Arogya Setu, and many more in the spirit of creating a national nodal point of information and updates for Rare Diseases
j. Explore and leverage the role of public-private partnerships (PPP) and initiatives to increase and bolster outreach and last-mile medical support;
k. Explore the possibility of genetic screening as an element of being assigned a passport by the GoI to enable a better understanding of the genetic distribution of the population;
l. Enable easier access to genetic libraries and data-sharing protocols to support ideation and inter-institutional communication to develop superior models of disease, vectors, and compounds;
m. Support domestic manufactured medical supplies and opportunities by earmarking a specific number of days where marketing avenues air these products exclusively;
CONCLUSION
Rare Diseases is a term given to diseases and afflictions that are rare relative to the immediate local population in terms of the population size and frequency of the disease resurfacing in the future. Understanding RDs to this day remains complex, sophisticated, and constantly evolving and requires scientific knowledge and infrastructure to use daily. These diseases affect patients, caregivers, physicians, and society in different proportions. The economic burden on the nation is dependent on its population size and demographics which define and dictate the extent of medical infrastructure that is available and monetary support deployed to make meaningful additions. This fact has handicapped developing nations and continues to affect developed ones as well. Unfortunately, due to the very fact such diseases are rare general logic fails to produce compelling arguments for Governments to commit substantial resources to combatting RDs. Hence, it is up to policymakers to realize and tap into different natures of incentives for the different stakeholders to feel the need to commit resources, time, and manpower to be able to take part in these returns on investments. GoI must pursue national policies and programs to encourage knowledge-sharing, R&D, interdisciplinary studies, drug discoveries and innovative therapies, startups and innovation, and academic and industry partnerships among other steps. Therefore, with specific incentives and the provision of suitable export opportunities, GoI can also pave the way for pharmaceutical companies to invest in R&D to manufacture these drugs at a much lower cost, without compromising on quality. There is a desperate need for more dialogue and deliberation to chart a national path to combatting RDs. A path built on pillars of science, economy, policy, and society. In the end, when these pillars are given due importance through collaboration and observations a nation as populous and developing, with a young population can find reasons to combat RDs and emerge stronger than before.
References
[1] A. Taneja, L. S. Shashidhara, and A. Bhattacharya, “Rare diseases in India: time for cure-driven policy initiatives and action,” 2020.
[2] M. C. Choudhury and P. Chaube, “Integrating rare disease management in public health programs in India: exploring the potential of National Health Mission,” Orphanet J Rare Dis, vol. 17, no. 1, Dec. 2022, doi: 10.1186/s13023–022–02194-z.
[3] “MOHFW, New drugs and clinical trial rules. Ministry of Health and Family Welfare, Government of India (GoI), 2019, pp. 149–264;”
[4] “Sukumaran, A., Am I going to live? Genetic diseases leave 70 mil- lion Indians at God’s mercy. Outlook Magazine, June 2019, 1–6.” [Online]. Available: https://www.outlookindia.com/magazine/story/
[5] A. Vinekar and C. Jayadev, “Balancing patient need with public policy in rare diseases — A legal perspective,” Indian Journal of Ophthalmology, vol. 70, no. 7. Wolters Kluwer Medknow Publications, p. 2584, Jul. 01, 2022. doi: 10.4103/ijo.IJO_905_22.
[6] “Bhattacharya, S., Kotach, V. M., Majumder, P. P. and Bhatta- charya, A., Rare diseases in India: current knowledge and new possibilities. Proc. Indian Natl. Sci. Acad., 2016, 82(4), 1183– 1187.”.
[7] K. Singh et al., “NGS-based expanded carrier screening for genetic disorders in North Indian population reveals unexpected results — a pilot study,” BMC Med Genet, vol. 21, no. 1, Dec. 2020, doi: 10.1186/s12881–020–01153–4.
[8] K. Singh et al., “NGS-based expanded carrier screening for genetic disorders in North Indian population reveals unexpected results — a pilot study,” BMC Med Genet, vol. 21, no. 1, Dec. 2020, doi: 10.1186/s12881–020–01153–4.
[9] C. P. Austin et al., “Future of Rare Diseases Research 2017–2027: An IRDiRC Perspective,” Clinical and Translational Science, vol. 11, no. 1. Blackwell Publishing Ltd, pp. 21–27, Jan. 01, 2018. doi: 10.1111/cts.12500.
[10] “Ministry of Health & Family Welfare. National Policy for Rare Diseases 2021. Government of India; 2021.”.
[11] T. I. Joseph Mattingly, “Patient-Centered Drug Approval: The Role of Patient Advocacy in the Drug Approval Process,” 2017. [Online]. Available: www.jmcp.org
[12] M. C. Choudhury and G. Saberwal, “The role of patient organizations in the rare disease ecosystem in India: An interview based study,” Orphanet J Rare Dis, vol. 14, no. 1, May 2019, doi: 10.1186/s13023–019–1093–6.
