The cohort of 7000 rare diseases is complex, heterogeneous and dynamic. Newer conditions are being identified and reported regularly in the medical literature on a day to day basis. For a long time, the medical fraternity, researchers, and policymakers were unaware of the wide spectrum of rare diseases and the emotional, social and financial burden they can create on the individual, the family, the society and the country as a whole. Until recently, there have been no exceptional research or public health policy addressing rare disease (RD) issues.
The diagnostic process for a rare disease begins with the definition of what constitutes a rare disease. According to the World Health Organization (WHO), a rare disease is defined as a chronic, debilitating condition affecting fewer than 1 in 1,000 people. However, different countries may have varying definitions based on their specific needs and considerations, including the characteristics of their population, healthcare system, and available resources. Many experts feel that besides the prevalence, other criteria such as –degree of morbidity-mortality, availability of treatment options, and whether the RD is heritable should be considered when framing any policy. Though these diseases are individually termed as “rare”, together they affect 5-7 per cent of the population in different countries, including India.
The next biggest challenge is early diagnosis. Establishing a diagnosis of an RD is a painstaking and time-consuming task. It is a diagnostic odyssey dependent on the clinician’s clinical expertise and the plethora of diagnostic tests that a patient has to undergo. Various factors play a role in either an underdiagnosis or a misdiagnosis of a RD. Firstly, during undergraduate or postgraduate days, RDs may only sometimes be seen or evaluated. Primary care physicians are unaware of these disorders and either misdiagnose them or ignore the clues toward a diagnosis. In a busy outdoor clinic, more time is needed to be spent with a patient and their family to come to a diagnosis. A RD often requires a detailed family history, thorough evaluation, and specific investigations to come to a conclusive diagnosis, unlike other illness seen in the routine OPD. The family is often seen “doctor shopping” to get a possible “early treatment”, leading to a delay in diagnosis and loss of financial resources. On an average, sometimes, there may be a delay of 7-8 years to get a conclusive genetic diagnosis and appropriate counseling, leading to more than one member being affected with the same disorder. Only then the suspicion of a genetic disease is entertained.
Once the disease falls under a “rare genetic disorder,” the challenge is getting an appropriate genetic test. Establishing precise diagnosis of RD highly depends on access to genetic testing. This is again an area where there needs to be more awareness of the availability of tests and prescribing the appropriate test. There is a high need for diagnostic centers providing quality-assured genetic test results. Moreover, the higher costs make it a prohibitive test for most of the affected population.
A delay in diagnosis or a wrong diagnosis increases the suffering of the patients exponentially.
Over the last decade, advances in sequencing technologies and their decreasing costs are making whole genome sequencing (WGS) and whole exome sequencing (WES) increasingly accessible. They have enabled the transition from using NGS in research applications and consumer genomics to routine clinical care. There has been an exponential decrease in the cost of advanced genetic tests with the increase in the number of tests being ordered. The one-time cost and the increased diagnostic yield based on which other decisions related to management, prevention, screening and personalized treatment can be offered, has proved its clinical utility in diagnosing an RD in time. An early diagnosis has a long-term effect on decreasing the lifetime cost of human suffering and financial burden for the family.
The biggest challenge is that almost 95 per cent of these rare genetic disorders are not curable. This makes doing the test and getting a confirmed diagnosis less cost-effective and not worthwhile to the family. Along with the guarantee of a confirmed diagnosis, they need the promise to be treated as well, and this is the biggest challenge in convincing them to get the appropriate test done. Even for the <5 per cent RD, the available treatment is of exorbitant cost and often has to be procured from western countries. Getting these drugs for a lifetime, either under charity or some schemes, is not feasible for all families because the long-term benefits may not be as promising for those with delayed treatment.
The low and middle-income countries probably also lag in two more areas. Firstly, need for easy access to genomic laboratory infrastructure. Secondly, coordinated efforts required to impart knowledge, skills, and attitudes to the healthcare workforce to successfully implement genomic medicine in clinical practice (Isaacson Barash, 2016). There is an urgent need i) to create awareness amongst the general public, patients & their families, and doctors, ii) training of doctors for early and accurate diagnosis, iii) to standardisation of diagnostic modalities iv) development of newer diagnostic and research tools and v) therapeutic support through government and orphan drug manufacturers to focus on treatment options for RDs.
Internationally, several countries have implemented domestic Acts and Laws on RDs. In India, the Ministry of Health and Family Welfare had formulated a National Policy for Treatment of Rare Diseases (NPTRD) in 2017. But its implementation faced certain challenges and unfortunately, it has been set aside, creating a lot of disappointment for the RD community. The major drawback was the cost-effectiveness of supporting such health interventions in many states of India with limited resources. A decision was taken to reframe the NPTRD, and MHFW constituted an Expert Committee in November 2018 to review the 2017 policy. The final NPTRD policy released in 2021 has tried to tackle a few issues faced in the previous approach, but the implementation and results are still to be seen.
The announcement by the Finance Minister, Nirmala Sitharaman, of the GOI’s plan to launch a mission to eliminate sickle cell anemia by 2047 can be considered an important population policy and a step towards the importance a RD should receive. She announced, “A mission to eliminate sickle cell anemia by 2047 will entail awareness creation, universal screening of seven crore people in the age group of 0-40 years in affected tribal areas.”
This is just one of the 7000 rare disorders, and a lot more needs to be done. But this step would probably lead to more inclusive research development and policy-making for other disorders that fall into the “rare diseases” category.
There are challenges for sure, but they can be addressed by creating awareness, creating a database to know the prevalence of each RD, making it mandatory to enter the birth of any child with an RD in the registry, and creating a public-private partnership to address the concerns of having training facilities, referral diagnostic laboratories, creating funds for procuring orphan drugs which are cost prohibitive, and most importantly to create an inclusive society for creating an environment for patient and families with RD to live without guilt or financial burden.