Rare Diseases: Awaiting renewed focus

India needs to make significant investments in R&D, policy reforms, and measures to enable affordability and accessibility of medicines and healthcare to manage the burden posed by rare diseases
By Usha Sharma

The global rare disease drug market is expected to touch $242 billion by 2024 with a Compound annual growth rate (CAGR) of 12.3 per cent between 2019-2024. Globally, the definition of rare disease (RD) is at nascent stage although it is evolving constantly. It is assumed that there are approximately 8,000 different types of RDs, with more being discovered each day. Particularly in India, nearly 450 RDs have been enlisted. Due to its poor diagnosis mechanism, low prevalence and limited treatment options, often it is addressed as an ‘orphan’ disease.

Rare diseases in India
The Ministry of Health and Family Welfare, Government of India announced that so far only about 450 rare diseases have been recorded in India from tertiary care hospitals. The most common rare diseases include haemophilia, thalassemia, sickle-cell anaemia, primary immunodeficiency in children, auto-immune diseases, lysosomal storage disorders such as Pompe disease, Hirschsprung disease, Gaucher’s disease, cy

stic fibrosis, hemangiomas and certain forms of muscular dystrophies.

Dr Prashanth L K,Consultant Movement Disorders Specialist, Vikram Hospital informs, “ According to the definition, a rare movement disorder is one whose prevalence is less than 50 per 100,000 population. India constitutes 1/5th of this global scenario. Many of these disorders require dedicated healthcare services and some of them have dramatic medical care. Because of the rarity of these disorders, most of them are usually misdiagnosed and do not get proper interventions.”

Dr Sudheendra Rao,NR Scientific Advisor, Organisation for Rare Diseases India (ORDI) gives more update as he elaborates, “Due to lack of comprehensive national registry for RD or genetic disorders there is no exact data available in India. But, the clinical consensus is that apart from rare cancers, Duchenne Muscular Dystrophy, Limb Girdle Muscular Dystrophy, Spinal Muscular Atrophy, Primary Immunodeficiency disorders, Inborn errors of metabolism, Lysosomal Storage Disorders, Cystic Fibrosis

, Hirschsprung’s Disease, Haemangiomas and Genetically Determined Epilepsies certainly top the chart in the non-oncological orphan diseases. They have varied onset, high mortality depending on the underlying cause whereas, some such as muscular dystrophies are chronic in nature causing a loss in quality of life for one or two decades. It is essential to remember that each of the diseases mentioned above have multiple subtypes as well as genotypes.”

US FDA has designated orphan drug status to nearly 5198 drugs since 1983. There has been a six-fold increase in the orphan drug designations by US FDA in the last decade. This includes drugs developed for 363 different health conditions including some rare genetic diseases. However, the striking feature is that nearly 81 per cent of filing (4208) for orphan drug designation came from the US.

The rising number of rare disease profile indicates that it needs more research and development focus. Since India has a large population, it needs to give this subject considerable attention, especially in terms of research.

Significance of research 
India is 21st in the line of drugs developement of rare disease and between 2003-2019, it has filed 10 drugs for orphan drug designation covering 13 different conditions. The US has had the first-mover advantage with well laid regulatory processes, sufficiently funded R&D centres in both academia and industry and with the insurance industry bearing the cost of the treatments. All these factors have ensured that any investment in developing newer drugs remained lucrative. Therefore, what is apparent is that the focus for developing new drugs for rare diseases is very sharp in the US, however, the rest of the world is yet to catch up. Some of the countries for e.g., the UK, Switzerland, Canada, France, Israel, Sweden, Italy, South Korea and China are increasingly focusing on this growing need.

Rao comments, “Indians need to remember that even though we did not have the privilege of a stable and powerful economy like the US, within 60 years, we have captured 30 per cent (by volume) of the generic market of the US. Together these suggest that R&D funding and patents and licenses majorly guard the focus on developing newer drugs for rare disease portfolio. Purchase power parity and incomplete health insurance coverage are the other two factors dissuading novel formulation research in India.”

To overcome the rare disease burden in India, besides pharma companies, research institutes are also engaging themselves.

Research projects initiatives in India 
Indian Council for Medical Research (ICMR) has been working on a national registry for a while now that is reported to include lysosomal storage disorders, neuromuscular disorders, skeletal dysplasia, haematological disorders, inborn errors of metabolism and primary immunodeficiency disorders.

Rao highlights that knowing the fact that around 70 per cent of rare disorders are due to genetic mutations. Therefore, if we talk about rare genetic disorders, then one of the rarest is genetically documented ribose-5-phosphate isomerase (RPIA) deficiency caused by mutations in RPIA gene. He further elaborates, “RPIA mutations lead to developmental delays, psychomotor regression by seven years, seizures and abnormalities in the nervous system including white matter changes in the brain. There have been only four reported cases worldwide. Apart from symptomatic, rehabilitative and supportive care, there is no specific treatment for this disorder even today. However, for research purposes, genetically modified mice having mutations in RPIA gene have been developed and archived.”

Recently, an official circular issued by the ICMR states that the research body among other things has proposed forming the task force to explore gene editing based therapeutic approaches to treat illnesses. ICMR has narrowed down on genetic diseases affecting the brain and muscles, eye disorders affecting the retina and cornea, heart diseases and blood disorders like thalassemia, sickle cell disease and haemophilia. It has also stressed on diseases like cancer, diabetes and lung diseases. The strategies proposed should have a possibility of translation into future human trials. While the western world has made considerable strides with regards to gene therapy over the past 30 years, ICMR stated that drugs like Luxuturna for Retinitis Pigmentosa, a condition which leads to breakdown of retinal cells in the eye, and leads to low vision, or Yescarta which is a cell therapy for cancer, are currently in clinical trial phase.

Besides ICMR, other research bodies like Council of Scientific and Industrial Research (CSIR) are also working aggressively tracking down the gene sequencing. Recently, CSIR announced the launched of an ambitious project, IndiGen, to sequence whole genomes of diverse ethnic Indian population to develop public health technology applications. It has mentioned that sequencing of 1,008 Indian genomes as part of the project. It aims to complete sequencing of at least 10,000 Indian genomes over the next three years. Many countries around the world have developed rules and guidelines to regulate gene therapy trials. Taking cognizance of situation, it was felt necessary to frame national guidelines and regulations to direct scientists and clinicians including industry regarding the procedures and requirements to be followed for performing gene therapy in India.

These is an indication of developing disease model systems, stem cell products to cheaper and reliable diagnostic methodologies. Rao emphasises, “The onus always falls on the orphan drug sponsor who has to sift through literature or available patient registries to justify the designation. Hence some of the well-kept disease-specific patient registries are with pharma companies and not with governments.”

Market trend
According to Evaluate Pharma- Worldwide Orphan Drug Report, the top 10 multinational pharma companies by 2020 would be Celgen, Novartis, BMS, Roche, Alexion Pharma, Pfizer, Vetex Pharma, Merck AbbVie and J&J. To beat the hit of the market competition, Indian origin companies like Sun Pharma, Biocon, ReGrow Bioscience, Piramal, Natco and Cadila Pharma have at least one designated orphan drug by US FDA. There are several other pharma companies from domestic as well as from the international market who are involved in different profile of rare disease. In addition, there are at least 14 different orphan drug related organisations in India developing therapeutic products or working towards diagnostics.

Rare diseases provide an opportunity to pharma companies for innovation because in contrast to lifestyle diseases, majority of them have discernible elements such as genetic mutations. This leads to an enormous room for novel targets, formulations, dosage all providing opportunities for intellectual property generation. “There are thousands of rare diseases and to tackle some of the rare diseases therapeutically, pharma companies had to resort to advanced therapies, including cell therapy, gene therapy, gene editing, RNA therapy etc., suggests Rao”. However, these newer therapy modalities provide unique advantages to pharma in terms of novelty, efficacy and achieving success and miracles in hard to tackle healthcare problems, thus positively affecting company finances.

While making a comparison of global scenario with Indian context, particularly in research and development of rare disease, it indicates that pharma companies in the US, Europe and Japan have been investing more on the rare disease portfolio. Analysing the possible reason for the thrust there could be the support from government/regulatory agencies!
To name a few, a move of US FDA granting a research grant for rare disease research is an example!

Research grants for rare disease
Recently, the US Food and Drug Administration (US FDA) has awarded 12 new clinical trial research grants totalling more than $15 million over the next four years to enhance the development of medical products for patients with rare diseases. The FDA awarded the grants through the Orphan Products Clinical Trials Grants Programme, funded by Congress to encourage clinical development of drugs, biologics, medical devices and medical foods for the treatment of rare diseases. The grants are intended to substantially contribute to marketing approval of products to treat rare diseases or provide essential data needed for development of such products. The grants awarded are focused on supporting product development to meet the needs of patients impacted by a variety of rare diseases, mainly those affecting children and cancers.

“For more than 35 years, the FDA has been providing much-needed financial support for clinical trials of potentially life-changing treatments for patients with rare diseases. To date, the Orphan Products Clinical Trials Grants Program’s grants have supported research that led to the marketing approval of more than 60 treatments for rare diseases,” informs Amy Abernethy, FDA Principal Deputy Commissioner.

Besides this, there is also a provision for developing orphan drug (OD) which has been financially incentivised through US law via the Orphan Drug Act (ODA) on 4 January, 1983. The enactment of ODA in the US and EU emerged as ground breaking and provided the necessary support to guide research focused on RDs worldwide. The orphan designated drugs (ORD) are granted important incentives which include market exclusivity and fee reduction. Prior to the 1983 Act, only 38 ODs were approved. The success of the original ODA in the US led to its being adopted in other key markets, most notably in Japan in 1993 and in the European Union in 2000. Currently, Singapore, South Korea, Canada, and New Zealand also have their own country specific ODA. India launched Organization for Rare Diseases India (ORDI) on 18 Feb 2014.

Clinical Trial Advantage
Increasing traction of private capital towards rare diseases and unmet medical needs has also been influencing the focus spectrum of pharma companies. Coupled to R&D ecosystem and regulatory help, pharma companies from US, Europe and Japan have been investing on rare disease portfolio. Naturally, compared to non-orphan drugs, orphan drugs incur substantially less cost in clinical trials.

The advantage of conducing clinical trials on rare disease drugs or orphan drugs, against conditional disease profile are varied as it requires fewer patient against other chronic disease profile, expediting the regulatory approval process of US FDA as well as assisting in providing grants to conduct the clinical trials. Does the situation remain similar in India as well?

The Ministry of Chemicals and Fertilizers (Department of Pharmaceuticals) has notified an order amending the Drugs (Prices Control) Order 2013. Effective January 3, 2019, Drugs for treating orphan diseases as determined by the Ministry of Health and Family Welfare will be exempted from price control. The five-year window starts from the date when the manufacturer starts commercial marketing in India.

The orphan drug exemption is expected to encourage domestic companies to develop drugs for orphan diseases and to foreign pharma companies to market their drugs in India. There are about 8,000 rare diseases across the globe, of which 450 have been reported in India and India itself has about 70 million patients of rare diseases. This indicates that there is a dire need for research and development in this arena. Are there any policy or guideline in place for the development of research molecule?

Indian regulatory scenario
In 2016, Stempeutics Research, in a joint venture with Cipla Group granted limited approval for manufacturing and marketing of stem cell based biological product Stempeucel for the treatment of Buerger’s Disease (a rare and severe disease affecting the blood vessels of the legs), by the Drugs Controller General of India (DCGI). If such programmes and initiatives are in place, then why the Indian pharma companies are hesitant in conducting the researches?

Anil Khanna, Partner, Wisdomsmith Advisors, informs. “Effective research in ODs is not widespread in India. Currently, drug developers in India receives no formal incentives from the government and hence they are more focused on developing affordable drugs for more common diseases. Only few Indian companies like Cipla, Natco Pharma and Troikaa pharmaceuticals are doing research in ODs.”

Dr Ketan R Patel, Chairman and Managing Director, Troikaa Pharmaceuticals too agrees to his industry colleagues views and comments, “As of now, there is no definite list of rare diseases and hence there is no policy in place to help quick approval of medicines for such diseases. A fast track approval would bring down costs and make the treatments of such diseases available. A low or negative return on investment is not a deterrent if a proactive policy in place when it’s a question of alleviating the suffering of such patients.”

Rao points out that no special financial incentives are available for orphan drug developers looking to develop a treatment in India. He suggests, “There is a growing demand that the government of India should focus heavily on local R&D for orphan drugs. The outcomes and the effectiveness of government intervention in R&D can be measured by the number of patents filed. Incentives such as tax credit on R&D costs or access to national research infrastructure or facilities to aid industrial R&D, phase I and II clinical trial grants or tax credits, market exclusivity and subsidies on orphan drugs market value will certainly help local development of orphan drugs. Since a huge chunk of orphan drugs getting developed now are biologics, incentivising, supporting and strengthening the industry infrastructure to support biologics manufacturing is the need of the hour. This will also align with growing focus on reaping benefits from the $240 billion biosimilar market, in which a large number of patents are set to expire. In addition, the government needs to come up with a policy on drug repurposing R&D, incentivising it with funds for national and international industry-academia collaborations. There is also a need for a clear directive as to how to proceed if a repurposed drug is found to be beneficial as an orphan drug, but the original manufacturer refuses to enter a required regulatory process in India.”

Pointing out the regulatory challenges, Khanna says, “Though there are not much-documented differences in approval criteria for ODs and non-orphan drugs, sponsors have to prove substantial evidence of the effectiveness of the drug using adequate and well-controlled investigations. Nevertheless, FDA has publicly expressed sensitivity for applying flexibility in its approval standards to new therapies for RDs. Although ODs may qualify for fast-track regulatory review and smaller safety data set requirements, regulatory approval may also come with a laborious risk evaluation and mitigation strategies requirements. The regulatory complexity in determining what evidence is sufficient to support FDA approval of ODs is due, in part, to the lack of clinical trial precedents and limited scientific understanding of RD processes.”

He further elaborates that ODs have a significant competitive advantage being first in the market. The additional market exclusivity provides long term benefits to the sponsor/ manufacturer. The time from phase II to market is often shorter for ODs due to shorter and smaller clinical trials and FDA fast track designation. Timelines for FDA approval for OD is 10 months v/s 13 months for non-orphan drugs. And, expected return on investment of phase III/ filed ODs is 1.89 times greater than the non-orphan drug.”

Khanna informs the steps taken by the Indian regulators and says “Drug Control General India (DCGI) has given waive off in conducting clinical trial for approval of ODs and drugs indicated for conditions/diseases for which there is no therapy. This condition is applicable only if the OD is already approved in the US and Europe. If the drug is a new molecular entity (NME), it has to undergo clinical trials.”

Highlighting the advantage of conducting clinical trials for rare diseases, Khanna emphasises, “Developmental drivers such as government incentives, shorter development timelines and high rates of regulatory approval are making OD development as economically viable as non-orphan drug development, even though there is a small patient pool.”

Majority of rare disease cases are diagnosed at a chronic stage which, requires long term treatment procedures and it turns out to be a huge financial and psychological burden not only for patients but also for their family members. Do they get financial assistance?

Patient assistance programme
In India, a National Policy for the treatment of rare diseases (NPTRD) was formulated in 2017 by Ministry of Health and Family Welfare, Government of India, which earmarked as a corpus of Rs 100 crores for the scheme. Additionally, another corpus was to be maintained by the state governments under the ratio of 60:40. However, it was withdrawn suddenly, by the government, without assigning any reason.

The withdrawal of the amount became huge hue and cry. Not only the Indian pharma industry, but many multinational pharma companies also felt offended. To take a remedial step on the earlier decision of withdrawal of fund, last year (2019) in November end, the Modi government made an announcement of providing a one-time payment of Rs 15 lakh to economically backward patients suffering from rare diseases, which will affect an estimated 70 million people in India. An expert committee is currently devising a new policy and the expert committee [working on the proposal] is likely to finalise its draft report soon. Thereafter, consultations with state governments and other stakeholders will be held.

Rao informs, “A rare disease patient below the poverty line is eligible for one-time assistance of up to 25 lakhs under Rashtriya Arogya Nidhi (RAN). This type of monetary support is really helpful for surgeries or organ or bone marrow transplant procedures. Whether this can also be used for cell and gene therapy products needs to be clarified.”
GoI has also launched UMMID (Unique Methods of Management and Treatment of Inherited Disorders) initiative and inaugurated NIDAN (National Inherited Diseases Administration) Kendras with the help of Department of Biotechnology, GoI. This initiative should enable a rough prevalence estimation through the genetic screening of 10000 pregnant women and 5000 new-borns. However, practical issues of sampling bias, handling error, testing methodologies etc will determine the integrity of the generated data.

According to the IRDAI guidelines, internal congenital disorders and genetic diseases, or diseases to which a definite cause is not known, cannot be exclusions in a health insurance policy. Hence, covering the pre-existing conditions themselves is the biggest help as of now because denial will have huge repercussions on the care provided to rare disease patients. Pre-approval access to investigational drugs developed outside India could be one way to assist therapy ultra-rare genetic disorder patients in India, though this might require a waiver of compensation in clinical trials.

Some of the governments (Punjab, Haryana, Karnataka, Kerala) are also engaging in subsidising or reimbursing some rare disease medicines such as IVIG for primary immunodeficiency disorders, Enzyme Replacement Therapy for lysosomal storage disorders. However, funding crunches, administration changes have often plagued a continuous supply of these lifesaving medicines. Having a stable reimbursement scheme, expanding coverage of reimbursement scheme to other rare disease medicines and uninterrupted reimbursement of life-saving rare disease medicines will certainly help. Supportive therapies related to few rare diseases (e.g., Hirschsprung’s disease) are covered under package schemes of PM-JAY and state schemes such as Arogya-Karnataka.

Expressing the concern on some of the work carried at the government level and its impact on patients, Khanna explains, “Government has announced the formation of a committee. Among the four terms of reference of the committee, one is to define ‘rare diseases’ for India! This is absolutely criminal, as one expert pointed out. People are dying due to lack of medicines and you say you are looking for definitions.”

The key problem is the availability of drugs, which the government policy itself underscored. “Wherever the drugs are available, they are prohibitively expensive, placing immense strain on resources of families, health systems and donor agencies alike. It is estimated that for a child weighing 10 kg, the annual cost of treatment for some rare diseases may vary from Rs 18 Lakh to 70 lakh,” states the NPTRD document.

Khanna says, “Since the healthcare system in India is mostly self-funded, price becomes a significant challenge, and so does the patients’ need for financial assistance. For this purpose, they usually look for support from patient foundations, other non-governmental organisations and charitable access programs offered by certain pharma companies to cover these costs. Recently, the Bangalore based Vikram Hospital opened the state-of-the-art ‘Center of Excellence’ for Huntington Disease. In the coming time, the hospital is also planning to open up new exclusive clinics for various other rare disorders and aiming to fill the void of care in the health sectors.

Conclusion
Presently, there is a lack of diagnosis methods and facilities for rare diseases and the treatment for such them is quite expensive. To overcome these challenges, a lot of effort needs to be made by the government bodies as well the pharma companies. People also need to take measures like self-examination and healthy lifestyle adoptions. Even insurance players need to understand the severity of the disease and their financial burden on the patient, and they should consider incorporating rare disease profile in the insurance coverage as well.

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