Recently, OMS906, a drug of Omeros Corporation for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) received orphan drug designation from the U.S. Food and Drug Administration (FDA). Last month, Avrobio has received an orphan drug designation for its gene therapy, AVR-RD-05, from the US Food and Drug Administration (FDA) to treat mucopolysaccharidosis type II (MPSII) or Hunter syndrome. According to reports, 176 drugs have already received this designation this year so far. Instituted over 40 years ago, FDA’s orphan drug program has evolved a lot over the years. Let’s dive deep into what is this status and what has been its impact:
What is Orphan Drug status?
There are a certain number of diseases that affect a small number of people and are called rare diseases. There are around 8000 known rare diseases, however, only less than 5 percent have therapies available for treatment. According to a study in The Lancet journal, about 95 percent of rare diseases have no approved treatment and less than 1 in 10 patients receive disease-specific treatment. The drugs that are meant for the treatment of rare diseases are termed orphan medicines or drugs. In 1983, the US parliament passed the Orphan Drug Act to incentivise the development of orphan drugs. Since then, many companies have taken advantage of the orphan drug designation and its incentive programs for rare disease drug development.
According to experts, the Orphan Drug act came into existence to promote the development of drugs, biologics, devices, or medical foods that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions. Since this act came into existence, more than 4,500 orphan designation requests have been granted, and over 730 drugs and biologic products have been developed and approved for more than 250 rare diseases. According to reports, Although orphan drug designations have more than doubled in the last decade as compared to the previous one, only 16 percent of therapies with orphan tags have managed to gain FDA approval in some indications.
“Currently, in India, orphan disease is used synonymously with a rare disease and drugs to treat them are called “orphan drugs”. The Indian Ministry of Commerce and Industry’s Pharmaceutical Export Promotion Council hosts seminars, awareness campaigns, and other events to raise awareness of quality compliance, orphan drugs, and ethical Good Manufacturing Practices (GMP) compliance and introduces opportunities for orphan drugs at regular intervals. The Intellectual Property Rights (IPR) interacts with foreign Food and Drug Administrations (FDAs) to manage orphan drug export and other related strategies like GMP compliance,” Ruchi Sogarwal, Head, Public Affairs and Patient Advocacy for Takeda in India told Financial Express.com.
Moreover, as per the New Drugs & Clinical Trial Rules 2019, an Orphan Drug is defined as a drug intended to treat a condition that affects not more than five lakh persons in India.
What is the benefit of Orphan Drug status?
According to industry experts, one of the biggest challenges drugmakers face while dealing with orphan drugs and the cure of rare diseases is the small target population size and consequently lack of sponsors to recoup the cost of research, development, and approval for the orphan drug product. Meanwhile, the FDA has come up with various incentives to make the development of orphan drugs financially possible.
Several industry experts told Financial Express.com that after achieving the status of the orphan drugs the manufacturing companies can avail tax credits for qualified clinical trials, boosting research and development. Additionally, the companies get an exemption from user fees and earn the potential seven years of market exclusivity after the approval.
It is noteworthy that the designation of the Orphan Drug status is a very crucial point for all pharmaceutical companies involved in the development of orphan drugs.
As per the U.S FDA, Orphan Drug Designation Awardees are granted the following benefits:
- Tax credits of 50% off the clinical drug testing cost awarded upon approval
- Eligibility for market exclusivity for 7 years post approval
- Waiver of new drug application (NDA)/ biologics license application (BLA) application fee (approximately $2.2 million value).
‘Developing drugs for orphan diseases is complex process for Pharma firms’
Developing drugs for orphan diseases can be complex in comparison to bringing drugs for common conditions. According to Sogarwal, the fundamental challenges faced by pharmaceutical companies while developing orphan drugs are about lack of clear understanding of pathophysiology or natural history, a lack of standard comparator drugs, paucity of scientific evidence, and an absence of validated preclinical models.
“There are challenges related to patient pool being small and this often results in adequate patient participation and impact evaluation of the clinical trial outcomes in rare disease patients as they often exhibit huge diversity in clinical presentation and histories including age, disease progression, and disease severity influence reported outcomes. The high cost of drug development is also a significant blockade,” she said.
Meanwhile, Dr Bruno Jolain, Chief Medical Director, Roche India told Financial Express.com explained that due to the basic obstacle in research and development for these diseases there are few participants.
“Only a small number of pharmaceutical companies are actually spending money on developing new medications for uncommon diseases. To be able to finance new endeavours in the future, pharma makers must amortise their operational costs, research investments, and reasonable earnings,” Dr. Jolain informed.
As with all drug development, orphan drug development is an expensive process. Industries exhibit minimal excitement for the development of treatments for rare diseases because there is less return on investment, industry insiders told Financial Express.com. Generally, government funding is required for orphan medication research, Jolain added.
What is the eligibility for Orphan Drug Status?
Sogarwal explained that the eligibility for Orphan Drug is given on the basis of a comprehensive and critical evaluation of the proposed medicines.
“To be eligible for the allotment of the status the proposed drug candidate should be a previously unregistered medicine, or it can either be an already registered medicine with a new orphan indication or a new dosage form medicine. Also, the proposed candidate should fulfill all relevant criteria including the significant benefit criterion,” she added.
A drug must fulfill certain requirements to qualify as an orphan drug, including:
- Rarity: A drug that has never received FDA approval or for a new orphan indication for an already marketed drug.
- Seriousness: It is used for treatment, prevention, or diagnosis of a life-threatening or seriously debilitating condition
- Safety: It should be safe to use.
- Comparison with alternative method: If an alternative method exists, then the benefit the new drug will bring should be established.
What happens when the Orphan Drug status is allotted?
Dr Jolain that drugs for rare diseases go through the same rigorous scientific review process as any other drug for approval or licensing.
“FDA can award Rare Pediatric Diseases Priority Review Vouchers. The Companies get support from the FDA office of Orphan Products for grants related to Clinical. Trials and Natural History Studies. The FDA medical Centers conduct specialized training for FDA staff. They hold and participate in patient focused meetings and listening sessions,” he explained.
He also said that in the EU Sponsors who obtain orphan designation benefit from protocol assistance, a type of scientific advice specific for designated orphan medicines, and market exclusivity once the medicine is on the market. Fee reductions are also available depending on the status of the sponsor and the type of service, Jolain said.
How has the development of orphan drugs changed over the years?
According to Sogarwal, the unavailability of viable options, rare or orphan diseases created an opportunity for pharma companies to transform their business model from just developing essential medicines to also developing orphan drugs. However, due to the absence of an orphan drug policy, the production of medicines and therapeutics remained limited to the varying regional definitions of rare/orphan diseases leading to the unavailability of effective and viable treatment.
“Over the years, several countries have brought in regulations that have streamlined the identification of rare diseases and development process of orphan drug and biologic products but there is still a need to encourage research and development initiatives independently and through partnerships for the development of orphan drugs,” she said.
Guidelines for orphan pharmaceuticals have already been created by nations like the United States of America, Europe, Japan, and Australia. “hese regulations provide orphan medicine producers with extraordinary incentives, which boosts the manufacture of orphan pharmaceuticals. The situation with uncommon diseases needs quick attention from the Indian government. The orphan drug policy must be appropriately implemented,” Dr. Jolain told Financial Express.com.
Orphan Drugs and India
Sogarwal pointed out that in India, the development of the National Policy for Rare Diseases 2021 has been a revolutionary step to encourage the identification, diagnosis and treatment of certain orphan/rare diseases.
“But there is a need for encouragement and initiative from the Government and other stakeholders including pharma companies, academia or research organizations to support the development of orphan drugs in the country,” Sogarwal told Financial Express.com.
Jolain highlighted that the definition of Orphan Drugs in India was for the first time specified in NDCT Rules 2019 and “National Policy for Rare Diseases 2021” was notified on 30th March 2021. He also said that even after so many years no regulations for the production or promotion of orphan drugs in India.
Currently, there is an absence of a designated law for the validity of orphan drug status.
“However, a need to institute the Orphan Drug Act in India has been advocated by multiple stakeholders including pharmacologists and patient organizations. This is a space for pharma companies to support and collaborate with the Government to strengthen the healthcare system and address the needs of patients with orphan and rare diseases,” She added.
Meanwhile, globally, very few pharmaceutical companies manufacture drugs for rare diseases, and the only domestic manufacturer in India is Food for Special Medical Purposes (FSMP) for small molecule inborn errors of metabolism.
Most therapies are expensive, so the government hasn’t been able to provide them free of charge, Jolain said.
“Considering the complexity of various diseases and the difficulty in diagnosing them, systematic epidemiological studies to determine the number of people suffering from rare diseases in India is obviously necessary,” he added.
He also said that the orphan drug policy must be appropriately implemented. “This would help India’s indigenous pharmaceutical and biopharmaceutical companies grow quickly and become a force to be reckoned with in this vast global arena. The population of India with rare diseases may benefit from such laws,” he said.
Can India indigenously produce orphan drugs?
The production of orphan drugs often requires a robust research and development set-up, conduction and evaluation of clinical trials and approvals from inbound and international authorities.
Takeda’s Sograwal said that in India, the development of orphan drugs can be encouraged by supporting collaborations along with the inclusion of separate regulations for orphan drugs in the country.
“Recently, the Government of India has formed the National Consortium for Research, Development and Therapeutics for Rare Diseases to promote R&D of indigenous treatment for rare diseases, manufacturing of drugs, and inclusion of people in clinical trials. Partnering institutes, nodal centres, individual researchers, the rare diseases research groups and patient organizations within the consortium are working together to study rare diseases across the nation towards better diagnosis and therapy,” she said.
Meanwhile, Roche’s Jolain informed that the government is working on a plan to manufacture the medications locally or import generic versions of those that are currently off-patent while also developing process chemistry for those that are currently patented in order to make them more affordable once the patent expires.
“India is home to 8 crore people suffering from rare genetic diseases, but there are currently no domestic manufacturers developing medications for these patients. Therefore, there is a significant unmet need for locally produced therapeutic medicines for rare disorders,” he told Financial Express.com.
What are the steps that need to be taken to improve diagnosis and patient care in rare diseases?
Dr. Jolain revealed that India is still in the development stage, so there are setbacks in terms of regulation and advancement in the research of orphan diseases.
“The assessment of the scope and impact of orphan diseases, as well as a widespread awareness campaign about orphan diseases, are urgently needed in the current situation. Orphan drug development requires strong policies and initiatives from both public and private institutions,” he said.
Catering to patients with rare diseases can be challenging in terms of identification, diagnosis, and critical care due to multiple factors like- heterogeneity and geographical dispersion of patients, lack of awareness among individuals and medical professionals and absence of favorable policies and appropriate healthcare infrastructure, experts opine.
Dr. Jolain emphasised that due to the absence of regulatory standards on rare diseases, millions of Indians continue to suffer from debilitating orphan diseases every day.
According to Dr. Bruno Jolain, the most notable effect of the lack of any workable regulatory framework or standards is the accessibility and affordability of the majority of orphan medications approved by the USFDA.
“The lack of any regulations targeted at fostering R&D in orphan pharmaceuticals, along with the attitude of the relevant authorities, frequently discourages the industry from demonstrating any interest. It is past time for the Indian authorities to wake up and take urgent action to address the issue in our country given the factors that have compelled a paradigm change in the pharmaceutical business toward orphan drugs as well as the potential profitability of this under-utilised domain,” he said.