Restricted cross-border collaborations among governments, biotech companies and scientists severely curb the speed at which treatments for rare diseases could emerge. Clinical trials for rare disease treatments find it hard to recruit participants in the U.S.

Harsha Rajasimha, PhD, is founder and CEO of IndoUSrare

“There might only be a few patients in the United States for some rare diseases, and they are likely already enrolled in a trial. Researchers have to go outside the U.S. to find and recruit patients for new therapeutic programs,” says Harsha Rajasimha, PhD, founder and CEO of IndoUSrare, a non-profit on a mission to accelerate therapies for rare diseases by bridging efforts in India and the US. He is also the founder of Jeeva Informatics, a technology startup dedicated to developing inclusive software solutions for clinical trials.

Rajasimha’s foray into social entrepreneurship arose as a detour from his research career in genomics and data science that spanned roles at the NIH and the FDA, when he and his wife had a child born with Edward’s Syndrome in 2012.

“We were told that it was not a viable baby,” said Rajasimha. “That changed my perspective as a data researcher and exposed me to what families go through in this diagnostic odyssey.” Interacting with patients, their families, patient advocates and researchers in India and the U.S. led Rajasimha to establish IndoUSrare, a 501c3 nonprofit organization headquartered in Northern Virginia in 2019.

A recent report released by RARE-X, a global data sharing platform for rare diseases, estimates that there are 10,867 rare genetic diseases worldwide. These affect nearly 350 million people globally, including 30 million in the U.S. Less than ten percent of these disorders have any available treatments. When treatments do emerge for rare diseases, their costs put them beyond reach for most patients worldwide. For instance, the FDA recently approved the drug Hemgenix for hemophilia B that has been decades in the making, with the eye-watering cost of $3.5 million per dose.

“The clinical trial group for Hemgenix was only 54 subjects,” says Rajasimha. “If there had been a better mechanism for US researchers to engage in cross-border cooperation with researchers in India, perhaps they could have had a larger, more diverse trial sample.”

It might not be obvious, but the patient population recruited for orphan drug trials is in most instances a key factor in drug pricing. The larger the global distribution of the drug’s target population, and hence market, the less expensive the drug is likely to be, says Rajasimha. Moreover, for countries like India that offer grants to patients with rare diseases for treatment, drug manufacturers are partially reimbursed by the government, lowering drug prices further. Rajasimha emphasizes, engaging the Indian patient population during early R&D phases will accelerate timelines for patient recruitment and help reduce the cost of drug development.

The Indian subcontinent is home to nearly 25% of the world’s population, with an estimated 70 million patients with rare diseases. Yet fewer than 2% clinical trials include participants from the Indian subcontinent – most volunteers are based in the US and Europe. “This has created a longstanding divide,” says Rajasimha. “We must think about this problem on a global basis because for any given rare disease, patients are very small in number, and geographically distributed globally.”

Patti Engel, RN, BSH, is CEO and president at EngageHealth

Patti Engel, RN, BSN, CEO and president at EngageHealth, a rare diseases market research firm, says there are three major actions that could help rare disease patients: heightened awareness, accessible genetic tests and insurance coverage.

“Increased awareness of various rare diseases would help clinicians quickly recognize symptoms and pursue a diagnosis. Free or low-cost genetic tests would eliminate the need to rule out multiple conditions and get a quicker diagnosis,” said Engel. “This could allow patients to access medications or investigational products, and, hopefully, slow or halt disease progression. Insurance coverage would help patients access potentially life-saving therapies.”

EngageHealth is conducting a study in collaboration with IndoUSrare, in the U.S., India and China, to uncover motivators and deterrents for patients and families to participate in clinical research. Engel hopes this study will provide practical insights that drug developers could use to recruit patients with rare diseases in interventional trials that measure the safety or efficacy of potential therapeutic agents and non-interventional trials that help researchers understand rare diseases mechanisms and the experiences of patients and their families.

IndoUSrare, Engage Health, and Ginkgo Leaf Rare Disease Family Care Center are conducting a study to understand the cultural motivators and deterrents for rare disease patients and their caregivers in participating in clinical trials.

Mobilizing Indian healthcare policies

Unlike the U.S., India has lacked a unified organization advocating for rare diseases. So, in parallel to establishing IndoUSrare, Rajasimha co-founded the Organization for Rare Diseases India (ORDI) and advocated for a policy in India similar to the U.S. Orphan Drug Act, which provides financial incentives to attract companies to develop drugs for rare diseases.

“We have advocated in India over the last 10 years. This resulted in the national policy for rare diseases in India, which is very encouraging,” says Rajasimha. “This includes a nearly $60,000 USD grant from the government per patient toward their rare disease treatment. It’s not sufficient for certain rare diseases, where treatments can cost over $1 million. But it’s good enough for diseases like inborn errors of metabolism where nutritional supplements and other care options exist.”

The Indian grant for patients with rare diseases could be a game-changer for global rare disease R&D on many levels. “This makes India a potential market in global orphan drug launch strategies for biopharmaceutical sponsors in the U.S. and Europe who have predominantly taken the U.S. FDA, EMA, Japan approvals approach,” says Rajasimha. “It’s a long time before these products are commercially launched for patients in the rest of the world.”

The government grant for a lifetime of rare disease treatment in India, also makes setting up treatment sites for clinical trials in India a viable option, based on the economics of drug pricing and target patient population. “It’s an exciting time for all rare disease patients, but also for the biotechnology industry to accelerate their drug development programs and reconsider their global launch strategies, making India an important part of their launch strategy,” says Rajasimha.

Reaching, recruiting and retaining Indian patients in U.S. clinical trials

Essential prerequisites in driving clinical development programs for rare disease treatments include the development of inclusive patient registries and natural history studies. Sponsoring companies generally obtain this data from public databases developed by the NIH and patient advocacy foundations. While there is increasing awareness for the need for a global outlook in developing such registries, nearly 90% patient registries are still U.S. and Europe-centric and primarily Caucasian.

“If a patient does not exist in these registries, they just don’t exist when it’s time to analyze data and design strategies for clinical trials or commercial launches. Until the NIH’s All of Us precision medicine research initiative, programs suffered from severe lack of diversity,” says Rajasimha. “We are encouraging the Indian diaspora to contribute and participate in patient registries and natural history studies.”

Most parents of rare disease patients in India avoid programs that do not offer treatments. This often leads to disappointments. “When a clinical trial comes up, patients who have been participating in natural history studies get preference because they have baseline data against which the new treatment can be assessed for safety and efficacy,” says Rajasimha.

IndoUSrare conducts awareness programs across India to inform patient groups of such facts. Rajasimha points out that U.S.-based patient advocacy groups are more focused on developing registries and conducting natural history studies, which in time leads to the development of new therapies through collaborations with biotech companies.

In addition to the clinical trial processes, IndoUSrare educates patient groups on the risks and benefits of clinical trials, highlighting reasons as to why they should consider participation. “Clinical trials are likely to be better than standard-of-care, because the FDA would not approve a new drug to be tested on humans unless the benefit over the standard-of-care far outweighed the risk,” says Rajasimha.

Culturally aware clinical trial software

One of the barriers in reaching, recruiting, and retaining patients with rare diseases worldwide for clinical trials based in the U.S. and Europe is language. Online information on clinical trials is almost exclusively provided in English. “We need information on clinical trials and healthcare related to rare diseases, made available in local Indian languages to generate awareness among rural and urban populations across India, and among medical doctors, geneticists, and professionals,” says Rajasimha.

However, the barrier is more than linguistic, it’s cultural. Although direct translations of information available in English get across basic messages, software platforms must be culturally aligned to recruit and retain patients over the duration of clinical trials. Most clinical trial management software has been built with the Western, English-speaking population in mind.

“With growing adoption of decentralized virtual telemedicine approaches, there is need for multilingual and multicultural software platforms. That’s where Jeeva Informatics is headed,” says Rajasimha. “We need clinical trial software to be culturally aware and truly inclusive. We can bring in diversity, but if the platform doesn’t communicate in the patients’ language, in the style that each underrepresented minority population expects, patients are unlikely to stay and complete the trial.”

In addition to a lack of inclusivity, rare disease clinical trials generally lack efficiency from a time, cost and quality point of view. This unmet need led Rajasimha to establish Jeevatrials, an inclusive decentralized clinical trial (DCT) platform, which is being used for several rare disease patient registries, natural history studies, and cell and gene therapy trials in the U.S. and India.

“We want to increase the representation of Asian and Indian diaspora in clinical trials through this inclusive software, not just from a language point of view, but by being culturally aware,” says Rajasimha. “For example, various Indian communities observe different religious and social holidays, requiring culturally aware calendar scheduling. Other barriers include technology savviness. We make sure the software has the right features to engage and retain all patients in these clinical studies. We don’t want technology to be a barrier, but an enabler.”

Data sharing and privacy

Cross-border collaborations require safe and seamless data-sharing systems.

Data sharing across borders is not a technical problem, but a governance problem, which remains unsolved. Research data, including de-identified and aggregate data, remains largely inaccessible, even for non-profit organizations such as IndoUSrare.

“While India, China and other countries have massive whole-genome sequencers now and are sequencing either gene panels, exomes, or whole genomes, those datasets are available within those regions, but not necessarily shared globally,” says Rajasimha. “This is a major barrier that has to be overcome if we have to truly achieve cross-border collaborations and approach this as a global problem.”

Barriers in data sharing primarily stem from data protection and privacy concerns. The Indian Council for Medical Research (ICMR), that had set up a rudimentary rare disease national patient registry was recently hacked by ransomware and the attackers’ IP addresses were traced to neighboring countries. The registry remains inaccessible.

The Indian government’s efforts on health data regulations, akin to the US HIPAA (Health Information Portability and Accountability Act) or the EU GDPR (Global Data Production Regulation Act), are still a work in progress. However, India’s success in implementing financial data protection for digital payments makes Rajasimha optimistic about similar efforts in protecting health related data.

“A push is being made from the Prime Minister’s office for health data. That revolution is probably coming very soon, but we are not there yet,” says Rajasimha. “Patient advocacy groups in collaboration with medical researchers would be ideally suited to create, manage and steward such patient registries as they have a sense of urgency to drive these drug development programs. They can potentially collaborate with multiple biopharmaceutical companies to share data and drive drug development programs.”

Major programs

IndoUSrare is focusing on five programs at present. The first is a patient concierge service where the team compiles publicly available information from the NIH, FDA and other databases globally, for patients who contact the organization for assistance. “We encourage patients to go back to their respective medical doctors and seek medical advice based on that information,” says Rajasimha. “It’s a free service provided to any patient, anywhere in the world.”

IndoUSrare’s second program, the patient foundation alliance, helps identify, contact, and engage patients with rare diseases in India and include them in patient registries and other organizational efforts in the U.S. The program, which includes 33 advocacy organizations covering over 500 rare diseases and 25,000 patients, continues to expand.

The third program is the corporate alliance. “Ultimately, the goal of patient groups is to get a treatment option for a disease where no FDA-approved treatment exists, which is true for 93% of rare diseases,” says Rajasimha. In such cases, patient groups must collaborate with industry and induce them to develop new therapies. “Our corporate alliance program engages small, medium and large companies in partnership. We have five industry members, and aim to expand to more than 20 next year.”

IndoUSrare’s fourth program is to create a network of medical geneticists across India that comprises their research core. At present, the research core comprises about 80 medical geneticists trained by doctors who run the 10 centers of excellence for rare diseases recognized by the Indian government. “We access this network when a new member organization joins us,” says Rajasimha. “We ask them how many patients they have seen with this particular mutation or disease in their clinic, and we usually hear back from a handful of these doctors each time. We then connect the doctors and the patient groups.” For diseases that have no patient organizations in India, IndoUSrare provides resources in collaboration with organizations like Global Genes to help set up a new organization in India that then drives the program forward.

And finally, IndoUSrare advocates for rare disease issues with patient alliance members, and the EveryLife foundation by communicating with senators and congressmen in the U.S. at the bicameral and bilateral rare disease congressional caucus and the India caucus. Similarly, in India, IndoUSrare’s member organizations provide public comments on draft policies issued by the Ministry of Health and Family Welfare, DST [Department of Science and Technology], and DBT [Department of Biotechnology].

“We want to make rare disease, biotechnology and orphan drug development a core part of Indo-US relationships. It’s a win-win relationship. It’s not all charity or humanitarian but a necessity for a thriving cell and gene therapy industry to be able to recruit patients, which is the biggest bottleneck in therapy development,” says Rajasimha.

FDA draft policies box Asians and Pacific Islanders together. Lumping nearly half the world’s population into one box not only limits the diversity achievable in clinical trials, it poses a barrier in engaging the Indian diaspora. No statistics are available on the number of individuals of Indian origin participating in US clinical trials because all Indians are grouped under the same Asian and Pacific Islander radio button.

“We are encouraging the FDA to break that down because each subpopulation is unique. Indians and more broadly Asians continue to be underrepresented in US healthcare. It’s important we understand each subpopulation under the Asian and Pacific Islander umbrella,” says Rajasimha. “About 3.2% of clinical trial participants in the US are Asian American or Pacific Islander whereas the overall population is more like 6.8% of the US population. That’s about 50% less than their proportion in the US population. Globally, the underrepresentation is even more severe.”


The patient population recruited for orphan drug trials is in most instances a key factor in drug pricing [Credit: Sergey Baybara/Fotolia]
Funding rare disease clinical trials beyond the U.S., often comes with limiting conditions. Some U.S. funders require patients to travel to the U.S. to be enrolled in clinical trials, which can pose logistic problems. Rajasimha believes getting patients from anywhere in the world to qualified clinical trial sites in the US or Europe, is feasible for one-and-done treatments, such as cell and gene therapies, if remote long-term follow-ups are made possible for safety studies.

“For drug repurposing, small molecule-based or biologics-based studies there are very well qualified sites in India and countries in Africa where patients can be treated,” says Rajasimha. However, in these cases it is vital that sponsors make the drug commercially available in countries where patients are located after the clinical trial concludes, so that patients retain access to these treatments.

“U.S. companies don’t want to commercially launch the drug in India. Instead, they want to make drugs available to patients in India through a compassionate use program or an expanded access program where the sponsor hires a third-party nonprofit CRO that manages the logistics so that the supply chain is protected,” says Rajasimha. “This is an unsustainable model.”

Discussions among multiple stakeholders are needed for global collaborations that could make treatments for rare diseases available in India and other countries on a commercial basis.

Financial support for IndoUSrare’s charitable programs primarily relies on corporate partners and industry collaborations through their corporate alliance membership program. The nonprofit charges a nominal $50 membership fee for the patient alliance program from foundation members. IndoUSrare is currently seeking collaborations with orphan drug companies and philanthropic organizations to fund its diverse programs.

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