Rare Diseases and Orphan Drugs: Challenges and Innovations in Developing Treatments for Rare Diseases, including the Importance of Orphan Drug Designation

This article explores the challenges and advancements in rare disease treatment in India, highlighting the need for awareness and policy support.

Suhani Bhatnagar, the 19-year-old actress known for her role in 'Dangal', breathed her last this year, after a long battle with dermatomytosis¹, a rare ailment. Following her death, media and internet was flooded with information on Dermatomytosis! Everyone was suddenly worried, whether they too were vulnerable! Since then, we came across extensive discussions on such diseases, and we wondered, what is rare? is it the knowledge, the incidence, or the therapy that is rare? Indeed, Suhani’s case was very unfortunate, medical science couldn’t save the precious life. But this miserable untimely loss of life did precipitate a significant question in the mind –do we value life, even when it slips away due to a rare illness?

In India, the understanding is rare, the correct diagnosis is rare, and appropriate treatment is rare. The paradox is, though the “diseases are rare, rare disease patients are many”.

Close to 90 million Indians suffer from rare diseases. (As per IORD, a disease is rare if it affects 1 in 5000 people or less)

We believe that India is shadowing the western trend, transitioning from communicable diseases to lifestyle disorders. But we are not so far behind in rare diseases too! Together we hold one-third of the global burden of rare diseases, and the actual numbers may be even higher. Out of 7.5k rare diseases present worldwide, only 450 have been documented in Indian hospitals so far.²

According to the Rare Diseases in Pediatrics – A Handbook edited by Dr. Ashok Gupta, Rare disease in itself is the cause of physical suffering, but several difficulties arise directly from the rarity of the disease too.

An accurate diagnosis is difficult to be reached without eliminating several of common conditions with overlapping symptoms
Inaccurate diagnosis & treatment pose greater risks
Patients / Cohabitees do not know where to obtain help, accurate scientific knowledge resources are limited
There is a huge time gap until the patients are referred to the right qualified person
Delay in getting the right diagnosis also delays access to the right treatment

80% of rare diseases have a genetic aetiology. The sufferer is often a child who ends up with a disrupted childhood, not being able to live a life like others their age. Multiple doctor visits, changing postulations and recommendations, yet the condition of the child does not improve. It becomes a relentless trauma with inevitable worsening of the child’s condition!

Challenges in developing treatment for rare/orphan diseases.

Orphan diseases, as the term accurately reflects that no one has taken responsibility for them.

The unfortunate few, who suffer, face the following different kinds of challenges:

Accurate diagnosis & treatment

The biggest challenge of all, is the paucity of tools to correctly diagnose the disease. Differential diagnosis doesn’t reach for that rare possibility. The symptoms are often misunderstood for other common conditions. According to IORD, 72% of rare disease patients face a substantial time gap before they are diagnosed correctly. Due to this delay, the disease has already progressed further. A systematic neonatal screening program would help in early intervention for such conditions.

Available drugs are exorbitantly priced

A decade ago, 7 year old Mohammed Ahmed, suffering from Gaucher's disease, pleaded before the Delhi High Court that he wanted to be "alive", to live his dream to serve the Indian army. He regularly needed Enzyme Replacement Therapy (ERT), which costed 4.8L per month. It was far off a dream for Ahmed’s family to afford the treatment. The court ruled in his favour that the government of Delhi would provide him with ERT at AIIMS free of charge as and when he required it. This case was significant, since it contributed to draw critical attention to the plight of such devastating illnesses.

This year, the court came to the rescue of over 100 people, sufferers of rare diseases across the country by asking the centre to set up a corpus of Rs 974 crores for the treatment and support of those suffering from rare diseases, corroborating "right to health is part of right to life" ⁴

Inadequate public voice on the ‘exorbitant treatment cost’ and ‘lack of research’

There are not many who speak for these patients. For the few who have an option of treatment, the cost is abysmally high. For Pharma companies, rare diseases are practically infeasible return on investment to spend in research to develop treatment options. Those who invest are compelled to recover the extraordinary research cost at price to the patient.

In situations like this, public voice is typically more successful in attracting government support for a positive resolution than for short-term assistance. The evidence is here. World’s most expensive medicine, Zolgensma (Novartis), is used in the treatment of spinal muscular atrophy (SMA), costing 2.1 million US dollars (Rs 15.24 crore). SMA is a genetic disorder in which one defective gene causes muscle weakness and degenerates its normal functions. One in every 10,000 babies has this rare disorder, and most do not survive for more than a few years. Mumbai-based Priyanka & Mihir Kamat gathered Rs 14.92 Cr. through crowdfunding for their six-month-old daughter Teera, suffering from Type I SMA, who requires a ventilator at home and a feeding tube. In this case, PM Narendra Modi waived off Rs 6.5 crore for GST and import duty to import the medicine from the US. ⁵

Limited progress on treatment / technological development

As explained above, least attention to develop treatment by the commercial organisation due to small number of patients
There is no reimbursement / insurance does not cover any drug for a rare disease (entirely Out of Pocket) Patients have to rely on their own financial resources for treatment.
It is difficult to recruit substantial number of people for the clinical trials because of the rarity
There are scientific knowledge gaps regarding the pathophysiology of many rare diseases. Even among clinicians and scientists there is a lack of understanding.⁶ Despite global advancements in genomics and personalized medicine, India is still not on the forefront. Rare diseases require specialized research, which is resource-intensive and difficult to scale in low- and middle-income countries (LMICs)..

Innovations so far ...

1. Genomic medicine has seen big advancements in India. The IndiGen Initiative, led by the Council of Scientific and Industrial Research (CSIR), sequenced the genomes of more than 1,000 Indians. ⁷ This sparks a new hope, as this advancement can help better identify genetic markers for rare diseases, leading to early diagnosis & targeted therapy development in the near future.

2. #EveryLifeIsPrecious: Sanofi’s India Charitable Access Program (INCAP) – part of Sanofi Genzyme’s global humanitarian program – provides free treatment to patients (around 120) in India afflicted with Rare Diseases like Gaucher, Pompe, Fabry and MPS Type I (aka Lysosomal Storage Disorders)’ ⁸

3. ICMR initiated National Registry for Rare and other Inherited disorders (NRROID) in collaboration with AIIMS, New Delhi to collect useful data on demography, phenotype, natural history, evolution and outcomes of specific diseases with/ without treatment. ⁹

4. Indian manufacturers have developed medicines for Tyrosinemia Type 1, Gaucher's Disease, Wilson's Disease, and Dravet-Lennox Gastaut Syndrome, reducing treatment costs significantly. For instance, domestically manufactured Nitisinone capsules for Tyrosinemia Type 1 are available at Rs 2.5 lakh, compared to the annual cost of imported Nitisinone capsules (2.2 Cr.) ¹⁰

5. The National Policy For Rare Diseases, 2021, provides financial support of up to ₹50 lakh per patient for 63 rare diseases during treatment at centres of excellence, benefiting approximately 1,118 patients since its launch in 2021. ¹¹

6. The following initiatives shall be taken for patients of Rare Diseases: Financial support upto Rs. 20 lakh under the Umbrella Scheme of Rashtriya Arogaya Nidhi shall be provided by the Central Government for treatment, of those rare diseases that require a one-time treatment (diseases listed under Group 1) ¹²

7. The NPRD, 2021 has provisions for promotion of research and development for diagnosis and treatment of rare diseases; promotion of local development and manufacture of drugs and creation of conducive environment for indigenous manufacturing of drugs for rare diseases at affordable prices. ¹³

Recently Union Health Minister of India announced...

“As part of India's drive towards becoming a global leader in affordable healthcare, DHR is set to launch a programme developing 12 indigenous drugs for 8 rare diseases. This initiative will aim to drastically reduce the cost of treatment for conditions like muscular dystrophy and Gaucher's disease, making life saving therapies accessible and affordable for the masses,” ¹⁴

Importance of orphan drug designation

The Indian Organisation for Rare Diseases (IORD) is the esteemed body for information on rare disease / orphan drugs. It aims to accurately represent rare diseases, working in close association with the GOI to drive better outcomes for sufferers. Prof Ramaiah Muthyala, IORD CEO & President elucidated critical aspects on this topic (A summary of his key opinion is given below) ^{15 16 17}

Though we manufacture most of the key APIs for over 400 FDA-approved orphan drugs, patients in India face exorbitant costs to access these medications. Orphan drugs are not profitable without gov. assistance. Therefore, Indian manufacturers export the APIs to foreign companies, which then sell the finished drugs back to India at high prices.

High import costs and manufacturing challenges are significant. Exported as powder, when APIs are shipped back to India as a tablet, they need an import license, which requires paying 10% of the drug's cost along with the package cost. Additionally, some drugs are unstable above room temperature, so they must be sent in a cold box or chain, further increasing the cost.

There is high focus on common bulk drugs production. As orphan drugs volume is much smaller & manufacturing involves multistep processes, specialized equipment and newer technologies, capital investment is high.

The US Orphan Drug Act 1983 offers incentives like market exclusivity, tax breaks, and clinical trial grants, but they only apply to new drug discovery. As primarily generic drug manufacturers Indian companies should have incentives specific to them.

In 2017, Ministry of Health and Family Welfare drafted the National Health Policy for Rare Disease Treatments. Since then, significant activities have taken place at the government level:

The Indian Drugs and Cosmetics Act 1945 was amended to include “rare diseases” and “orphan drugs.”;
Production-Linked-Incentives included orphan drugs; rare diseases are eligible for Corporate Social Responsibility funding;
Clinical trial rules have been modified;
Preventive strategies have been initiated selectively for some blood disorders;
Alternate therapies – AYUSH system of medicine – are encouraged,
Orphan drugs are exempted from import duty;
Rare diseases are included in the newly drafted medical device policy, and were included in the national health schemes.

Yet, despite incentives & developments, pharma is not able to make reasonable attempts to reach the expectation of “Make in India” regarding orphan drugs. Most rare disease patients, drug manufacturers, and other concerned stakeholders are unaware of these incentives and accomplishments.

In the country, there are very few experts on rare diseases. It is an ‘identity crisis’ that lacks recognition for rare diseases and not a lack of information. The information is buried under the plethora of information on common diseases. A dedicated office for rare diseases and orphan drugs will play a pivotal role in the Indian pharma industry and national economy, lowering the rare disease burden in the country.

IORD: Indian Organization for Rare Diseases

ICMR: Indian Council of Medical Research

DCGI: Drugs Controller General of India

NPRD: National Policy for Rare Diseases

DHR: Department of Health Research