The meeting was jointly organized by Dr Rakesh Mishra (Tata Institute for Genetics & Society), Prof Alok Bhattacharya (World Without GNE Myopathy), Prof Y.K. Gupta (Y.K. Gupta Academy) and Prof Satyajit Mohapatra (All India Institute of Medical Sciences, Guwahati). The Organization for Rare Diseases India (ORDi) was also a sponsor of the meeting. The Indian Council of Medical Research and the Indian Society for Clinical Research were the knowledge partners. The meeting was held in hybrid mode, where speakers and panelists participated physically, while the majority of participants joined via a video conferencing platform. A few participants were also invited to attend the meeting in person.
 

DAY 1
 

In the inaugural session, the organizers summarized the motivation behind the meeting. They highlighted the problems faced by patients with rare diseases, mainly due to lack of accessible and affordable treatments in India. Therefore, the majority of rare disease patients either succumb to their disease, or lead a poor quality of life. The issues preventing the availability of drugs and treatments for patients in India were pointed out. Some of these issues are:
 

-For most diseases, there are no approved drugs as yet anywhere in the world. Even when therapies are available, the cost of treatment is generally very high and beyond the reach of most people in India.

-Drug development for rare diseases requires a multi-pronged approach that includes creating patient registries, constructing natural history models of disease progression involving local patients, developing technology platforms, and designing novel drug molecules free from intellectual property right protection.  The problem lies in our limited indigenous capability in the entire drug development landscape for rare disease drugs.

-Due to special problems associated with rare diseases, such as a small and dispersed patient population and variable genotype and phenotype, there is a need for a conducive regulatory environment with special provisions, that helps conduct clinical studies for drug approval.
 

It was noted that India requires a clear path and guidance, particularly for the drug approval process for rare genetic diseases.   Sensitization and collaboration among all stakeholders can help overcome stumbling blocks in conducting rare disease clinical trials, ultimately leading to the approval of much-needed indigenous drugs.
 

Dr Rajesh Gokhale, Secretary, Department of Biotechnology (DBT), and Chairman of the Biotechnology Industry Research Assistance Council (BIRAC), a company established by the DBT, delivered the inaugural lecture. He emphasized the need for India to develop its own business model to develop low-cost drugs, and to study our patient population for unique biomarkers and disease end points. Dr. Gokhale acknowledged the problems faced by researchers and clinicians to develop drugs for rare genetic disorders, and talked about various schemes that DBT and BIRAC have initiated. Some of these schemes, such as BIOE3 and UMMID, can have a disruptive influence on the discovery and manufacturing of genetic disorder drugs. DBT, along with the BIRAC fund, is translating projects on new drug discovery, including clinical trials and regulatory support. He ended his talk with backing for making special efforts in finding and developing drugs for rare genetic disorder.
 

Prof. YK Gupta (Chairman, AIIMS Jammu) then explained the fundamental issues involved in rare genetic disorder drug discovery, particularly post-discovery drug testing and development. He emphasized that rare diseases need out-of-the-box thinking as the procedures applicable for common diseases will not work for them. As an example, the acceptable ratio between anticipated benefits and anticipated risks of a drug for rare disease has to be considered differently. The definition of this ratio (which will be different from other diseases) will be highly helpful for design and implementation of all phases of clinical development. Regulators need to consider this when reviewing applications. Prof. Gupta emphasized that we need to re-examine many aspects, including the “standard of care” for each genetic disorder, that would be essential for trial design. Drugs for rare genetic disorders range from small molecules to proteins, nucleic acids, and cells. He suggested that we need to define what safety issues are likely to be faced for different diseases and drugs. Some of the other issues highlighted by him include the selection of the control group, patient selection (particularly the inclusion/exclusion criteria), clinical trial data monitoring, and criteria for taking a patient “off” the study. Prof. Gupta explained how an n of 1 study can help with testing drugs for rare genetic disorders and how to determine the sample size, that is n. He also mentioned a few other innovations in trial design that can be implemented such as adaptive/flexible trial design, using patient reported outcomes, and concept of “experimental medicine trials”. Finally, he mentioned that it is time for the country to implement a compassionate use policy due to unmet medical needs and the industry to come forward to create a “rare disease network support group”.
 

Session I: Challenges, opportunities & designing early-phase clinical trials for rare diseases
 

Dr A. Vishala, Joint Drugs Controller at the Central Drugs Standard Control Organization (CDSCO), chaired the session.  She pointed out that the recent amendments to the Drugs and Cosmetics Act and the rules therein have many provisions that are likely to be beneficial for conducting trials for drugs treating rare genetic disorders. Specifically, she noted that Rule 101 permits the waiver of clinical trials under specific conditions. Schedule M, along with good manufacturing practice guidelines, are essential for starting trials for Investigational New Drugs (IND). Dr Vishala advised early discussions with regulatory authorities for help in designing different phases of clinical trials. In many instances, CDSCO and ICMR are creating a common platform for such discussions. She mentioned that CAR-T therapy was approved under the accelerated approval rule for orphan diseases with unmet needs.
 

Dr Monika Pahuja, Indian Council of Medical Research (ICMR) then outlined various schemes and funding opportunities for the development of drugs for rare diseases, initiated by ICMR. The ICMR has established a “National consortium for research and development on therapeutics for rare diseases in India,” in collaboration with other relevant departments and ministries, to consolidate research on rare diseases across various aspects of drug development. Although they have listed a few priority diseases, they are open to funding all high-quality RD drug-development projects. ICMR also supports the “ICMR National Registry of Rare and Other Inherited Disorders”, which is needed to develop policies for rare diseases. Dr Pahuja mentioned setting up “Medtech Mitra” and “Patent Mitra”, portals to help navigate complex pathways for setting up clinical studies and IPR issues. ICMR is in dialogue with patient leaders and industry partners, and is also looking at patient rehabilitation using assistive devices.
 

Prof. Satyajit Mohapatra (AIIMS, Guwahati) outlined the different approaches to clinical trials that can benefit the development of drugs for rare diseases. There are multiple stages in the drug approval process, including preclinical, Phase 1, 2a, 2b, 3, and post-marketing Phase 4. It is possible to combine phases 1/2a and 2b/3 for rare diseases, shortening the time taken to obtain approval. There are various design approaches for clinical trials, including group sequential design and multi-arm, multi-stage design (MAMS). Group sequential designs are a type of adaptive clinical trial design that allows for interim analyses. The trial can be terminated early or continued based on the efficacy and toxicity parameters from the data. Unlike traditional fixed-sample designs, where researchers collect data until the study is completed, group sequential designs incorporate interim analyses at pre-specified time points. MAMS is also a form of adaptive clinical trial design that allows testing multiple drug-like molecules simultaneously, allowing the addition or removal of a new molecule at any time without increasing the patient number. Prof. Mohapatra also highlighted the usefulness of the basket or umbrella design approach in rare disease drug development, as well as the use of real-world data as controls or as an alternative to a placebo arm. His talk showed the importance of carefully selecting the trial design for a rare disease so as to maximize the information gained from the small number of available patients.
 

Dr MP Venkatesh (JSS Medical School) focused on trial parameters that could help determine the efficacy of treatment and reach endpoints. He highlighted the importance of natural history study-based disease progression models in determining endpoints. Data acquisition can be enhanced by communicating clearly with patients through patient representatives. In many situations, direct disease-related biomarkers or surrogate biomarkers can be very useful in trial design. However, the certification or registration of these biomarkers is vital for their inclusion in trial design. He also mentioned that AI has considerable application in regular and decentralized trial design.
 

Session II: Navigating ethical frontiers: Addressing challenges and ensuring equity in rare disease clinical trials
 

The session was chaired by Dr Kavita Singh, Director, Drugs for Neglected Diseases India (DNDi). Ethical issues are the cornerstone of all human clinical studies. However, for rare disease studies, there is an added complexity due to the small number of patients affected by any disease and the devastating nature of these diseases. There are very few drugs available, and the number of clinical trials is limited. Dr Singh pointed out the special problems associated with ensuring equity in clinical trials for rare diseases.
 

Dr Rolli Mathur (ICMR) was one of the architects of the ICMR “National Ethical Guidelines for Biomedical & Health Research Involving Human Participants”, the guiding document for all human research, including clinical research. It mandates the establishment of an Institutional Ethics Committee (IEC), whose approval is required before any clinical studies on humans can be conducted. For clinical trials, IEC approval is necessary to obtain CDSCO permission. Dr Mathur explained the ethical principles by describing two studies, namely the newborn screening program and the lysosomal storage disorder task force studies, which the ICMR initiated. She emphasized that ethical issues should be addressed from the outset and should be integrated into the entire study system. The investigators should imbibe the philosophy and principles.
 

Dr Niveditha Devasenapathy (George Institute) highlighted the importance of registries as a source of historical or real-world data in designing clinical trials for rare genetic disorders. Medical records can also be used to populate registries. She emphasized the importance of data quality, its management and statistical analysis. Data collection should adhere to ethical principles, such as privacy, and databases should include as many features or biomarkers as possible. A high-quality registry/database of patients can attract foreign drug developers to set up clinical trials in India. One of the significant problems in such registries is a lack of data from remote areas and different ethnicities. She suggested making special efforts to maximise diversity by providing funding support.
 

Dr Mahua Chakraborty (Department of Science and Technology Centre for Policy Research) highlighted the importance of equity in selecting patients for a trial. She advised a clear definition of who is in and who is out of the trial. Rare disease registries should be more inclusive and adhere to internationally recognized data standards. We should also be open to data sharing both nationally and globally, after providing appropriate safeguards. Dr Chakraborty recommended that we need new ethics guidelines in light of recent developments in AI and data science. She suggested integrating rare diseases into the National Health Mission to improve the delivery of healthcare to patients with these conditions. She also stressed boosting the new born screening program to detect rare diseases at birth for early intervention. 
 

Session 111: Sharing early experiences in clinical trials
 

The session was chaired by Prof Sheffali Gulati (AIIMS, New Delhi). The panellists were Dr Arkasubhra Ghosh (GROW Labs), Dr Debojyoti Chakraborty (CSIR-Institute of Genomics and Integrative Biology), Dr Kavita Singh (DNDi) and Dr Nitya Wadhwa, Translational Health Science and Technology Institute (THSTI). Several clinical trials on rare disease drugs are being conducted in India. However, most of these drugs were developed outside India, and the trials are being conducted in multiple sites across the world, including India. Currently, there is a lack of experience in transitioning a molecule from the lab to final approval and marketing. Since some of the panel members are involved in advancing lab developments, a fruitful discussion ensued on the hurdles faced by rare disease drug developers in conducting clinical trials. Dr Ghosh emphasized the importance of performing all experiments under GLP (Good Laboratory Practice) and GMP (Good Manufacturing Practice) certification, starting from preclinical studies. He also mentioned the problem of finding suitably trained personnel for all work related to drug development and suggested instituting training programs to address this issue. He described their experience in setting up a GMP-compliant AAV vector production facility and their expectation of receiving approval to start a Phase 1 clinical trial. He also mentioned that they have obtained the IPR for the AAV vector they are using for gene delivery.
 

Since the majority of drug development occurs in academic institutions, investigators must consult or partner with experts to advance the development process. Dr Singh suggested that educational institutions should partner with industry or CROs for clinical development. Several clinical research support organizations have also been established within government institutions. Dr Wadhwa heads one such organization, "Clinical Development Service Agency", that helps scientists in all aspects of clinical development.
 

Dr Chakraborty described their experience in developing a gene-editing platform for rare genetic disorders. They plan to use it for treating sickle cell disease. Since most of this technology is protected by patents, Dr Chakraborty's group first developed a novel Cas enzyme for which they got a US patent. It allowed them to work freely and collaborate with others due to the IPR rights. They got extensive help from different Government agencies (ICMR, DBT, CDSCO) under the guidance of NITI Aayog. Due to a lack of experience in India, Dr Chakraborty received assistance in designing the protocols from a US expert, thanks to the help of NITI Aayog.
 

At the end of this session, it became clear that if investigators come up with promising investigational drug molecules, the different Government agencies, and industry will come forward to assist in moving the drug towards further testing and approval.
 

Interaction and discussion with patient advocacy groups
 

The session was chaired by Prof Sudha Bhattacharya (Patient advocate, World Without GNE Myopathy) and Mr Prasanna Kumar Shirol (Patient advocate, ORDI). The panellists were Ambrish Kapadia (Patient advocate, Parent Project Muscular Dystrophy-India), Samir Sethi (Patient advocate, Indian Rett Syndrome Foundation), Dr. Gayatri Saberwal (Consultant, TIGS), Dr. Aravindan Veerapandiyan (Professor of Paediatrics, University of Arkansas College of Medicine, USA).

Patients are at the centre of the whole enterprise of drug discovery and testing; yet they have been largely left out of the discourse so far. It is important that their voices should be heard, and patient representatives should be included from the start. The panellists raised several critical concerns of the patient community. A major concern is that rare disease drugs are being developed and tested abroad, are priced extremely high, and most of our patients have no access to them. Mr. Ambrish suggested strongly that India needs to push for indigenous efforts to develop rare disease drugs. We need to have more faith and trust in our own capabilities rather than relying on products developed and certified abroad. Mr. Samir highlighted the communication gap that exists between the average patient and the consulting physician. Most patients and caregivers have little understanding of the disease and what outcome to expect from a new drug, since they get swamped with technical jargon. They also do not have access to timely information about new research and clinical trials. Dr. Gayatri talked about the need to develop tools for responsible access of patient data to extract the maximum information without compromising on privacy and anonymity. She illustrated her point through the OPENSafely initiative for safe data access by Dr. Golacre’s team in UK. This platform ensures individual privacy while maintaining data transparency. She also spoke about her own empirical data on paucity of foreign companies conducting clinical trials of their drugs in India. Dr. Aravindan also talked about this issue as he has been involved in many DMD drug trials in USA. He highlighted various factors that could deter foreign companies from conducting trials in India. Some of these include different standard of care protocols in India, lengthy approval process even for repurposed drugs, incomplete patient data records, and lack of data sharing. Comparing the involvement of patient advocates in USA in every stage of drug development and testing, he emphasized the need to empower patient advocates in India to get involved right from the beginning. The panel discussed about the gap between promises in the NPRD and the ground reality faced by patients. It remains a challenge for patients to receive uninterrupted supply of life-saving drugs.

There is need to work closely with policy makers to address these issues and suitably amend the policy. It is equally important for patient representatives to work closely with clinicians involved with a clinical trial to answer the queries of their patient group, including the inclusion/ exclusion criteria, the need for placebo, the risk/ benefit ratio of a drug, which will help to build the trust and compliance of patients.

Open Session with Industry
 

This session was chaired by Dr Surendra Das (PFC Pharma India). The panel members were Dr Dinesh Kundu (East Ocyon Bio), Dr Shubhadeep Sinha (Hetero Drugs), and Dr Sandesh Sawant (Cipla Ltd.). It was mentioned that most initial drug identification and development occur in small companies and startups. Big companies then buy out the product or the company for further development.

Therefore, India should encourage the startup ecosystem in drug discovery. Some of the points raised were:

- Importance of taking home-grown molecules for further development and reducing the cost of clinical development
 

- Reduction of the cost of clinical development for startups to encourage their entry

Collaboration of industry with academic groups
 

- The problem of patient retention in clinical trials and the role of patient groups in helping patient retention
 

- It is challenging for a company to complete clinical development; therefore, a consortium approach is necessary to reduce costs and share expertise.
 

- Consultation with CDSCO at every stage, including pre-IND discussions
 

- It was also pointed out that the time taken to approve minutes of the CDSCO (due to the need for a physical signature) is very long, and valuable time is lost. A timeline for approval should be established if one is not already in place. We also need well-trained pharmacologists as part of the clinical trial team. Currently, these are managed by only clinicians.
 

- One of the ideas presented was the role of philanthropy in the development of drugs for rare diseases. The consortium for rare disease drug development should have a philanthropist or a philanthropic organization as a member.
 

DAY 2
 

Session I: Innovation in clinical trial design in rare diseases: Exploring the role of AI-ML in data analysis, RWE research and decentralized trials
 

The session was chaired by Prof Alok Bhattacharya (WWGM, Ashoka University). The panel members were Prof. Anurag Agarwal (Ashoka University), Dr Krithika Rangarajan (AIIMS, New Delhi), Dr Shoibal Mukherjee (Medanta Hospital), and Dr Vaibhav Salvi (Sanofi).  
 

Prof. Agarwal, in his presentation, highlighted some recent developments in artificial intelligence (AI) applications that can benefit the development of drugs for rare diseases. He emphasized the importance of adopting conversational diagnostic AI, which aims to enhance medical diagnosis through AI-driven dialogue, demonstrating superior diagnostic accuracy compared to that of human clinicians. This can help in improving the diagnosis of rare genetic disorders. He also mentioned recent work on phenotype-driven diagnosis for rare genetic disorders, such as the SHEPHERD system. Phenotype-driven diagnosis using AI involves analysis of patient phenotypes (observable characteristics) and their relationship to genetic information. Since AI algorithms can process large datasets of phenotypic and genetic information, it enables the rapid identification of potential disease-causing genes and enhances diagnostic accuracy. Some of the new foundational AI models, such as EVO, can design DNA or RNA molecules that can be utilised for therapeutic purposes. He pointed out the emergence of many models that can be used to find new drugs or repurposed drugs.
 

Dr Mukherjee pointed out the importance of the digitally analyzable data for use in AI-based clinical studies. Medanta is in the process of digitising all its data from six hospitals. AI can help analyse all this data much more easily compared to traditional methods. He also mentioned that for many diseases, clinical protocols can be generated using LLM. Dr Salvi described the use of AI in clinical development at Sanofi based on their worldwide operation. He also mentioned how AI can be used at different stages, starting from patient selection. Clinical studies for approximately 70% of the molecules have utilised AI at various stages in their organisation. Patients who are likely to respond can be identified using AI. Sanofi has conducted two completely decentralised trials utilising AI. Dr Rangarajan pointed out the need for policy support to facilitate the easy conduct of clinical research for rare diseases. In many hospitals, there is no ethics committee, and the establishment of such committees requires following a strict set of guidelines that need modification. She suggested that rare diseases should be notifiable (like COVID-19 or HIV/AIDS) so that proper epidemiological data can be collected. Often, a lack of data becomes a hurdle in drawing a conclusion or completing a clinical study to its logical conclusion. The concept of digital trials can be applied, and a completely decentralised trial can be done using digital tools. One can also consider using AI-based synthetic data to overcome data scarcity.

Some of the novel suggestions presented include combining multiple endpoints or markers and developing a composite index, as well as the use of surrogate markers. The design can have different goals, both short-term and long-term. Most of the above points can be combined into one design. Data from patient registries, and informal data with patient groups could be structured using AI, and used to construct natural history of a rare disease.
 

Session II: Role of disease progression models, early indicators and biomarkers for success of clinical trial design
 

The session was chaired by Dr Ruchi Singh (ICMR). Most of the rare diseases do not have an animal model that mimics the human disease. Therefore, complex in vitro models (CIVMs) can be beneficial for generating preclinical data for drugs treating rare genetic disorders. Dr Singh informed that the FDA USA has created an innovative portal, "ISTAND," which refers to Innovative Science and Technology Approaches for New Drugs (ISTAND), as a pilot program. This program aims to encourage the development and qualification of innovative drug development tools (DDTs) that fall outside the scope of existing qualification programs. Dr Surat Parvatam (Humane World for Animals) described cellular organoids as a replacement for animals. She explained the methodology and the process by which these can be created in the laboratory. The cells needed for making the organoids can come from patients. The problem is to generate organoids that have a multicellular structure similar to that of human tissues. It is not yet clear whether these organoids display a human disease phenotype, even for a short time. Both Dr T. Vasanth (TIGS) and Dr S. Ramalingam elaborated on the concept of cellular models that can be created using patient blood or fibroblast cells. There are two significant steps: the conversion of patient cells into induced pluripotent stem cells (iPSCs) and then the transformation of these stem cells into specialised cells, such as muscle cells. They demonstrated, using examples from their laboratory, that the protocol enables the generation of patient-derived tissue cells without requiring a patient biopsy. These cells can be stored frozen and revived at any time. Many tissue cells derived from iPSCs exhibit some of the features of diseased tissues and can be used for preclinical development. The CDSCO has recently allowed the use of data generated from cellular models for submission. These CIVMs need to be certified as an appropriate model for a specific disease.
 

Session III: Transforming rare disease therapeutics: Harnessing genomics and IPR
 

The session was chaired by Dr Rakesh Mishra (TIGS). Dr Manisha Sridhar (WHO) began her presentation with the landmark agreement reached at the World Health Assembly at WHO and the acceptance of document WHA 73.11 2025 by a large number of Governments. The document affirms that rare diseases are a global health priority for equity and inclusion, as patients with rare diseases are currently underrepresented in health agendas. IPR issues are playing a significant role in preventing patients from accessing medicines that are available behind IP protection regimes. She also suggested utilising some of the provisions available under the WTO TRIPS agreement that can help circumvent IPR restrictions. She indicated that the emergency approval process can also be extended to the approval system for rare disease drugs. The emergency drug approval process helped India develop COVID vaccines at a record time. Finally, she also emphasised that engaging with regulators early can be beneficial in reducing the time taken for clinical development.
 

Dr Bharat K Servapalli (Karkinos) described the usefulness of genomics in planning precision medicine. Most of the databases are populated with data from Western countries (mostly Caucasians). Therefore, their usefulness is limited for any applications targeted at our population. The availability of GenomeIndia data on 10,000 Indians will help initiate India-specific studies and applications. He mentioned the usefulness of the MORPHEUS system to find potential drug-like molecules.
 

Conference Summary and Way Forward
 

Prof. Y.K. Gupta coordinated it. The following action points were suggested, and it was decided to move forward with them.
 

-To have a seamless interaction among different stakeholders, it is essential to set up a special cell in CDSCO. The DCGI should establish a separate cell, under the leadership of a senior official, specifically to handle and promote the approval of drugs for rare diseases.
 

-The Ministry of Health and Family Welfare (MOHFW) should make rare genetic disorders notifiable diseases similar to COVID, HIV, etc. If a portal is used for this purpose, it will not be difficult to track the incidence of diseases in this country.
 

-The rare disease policy should promote equity and inclusion in all phases, starting from the registry to support for treatment. Many diseases are not included, and efforts should be made to develop treatments for those diseases for which no current treatment is available.
 

-Many patient groups have informal registries of different diseases. There should be an inventory of the data available with them, and the patient groups should be trained to collect, process, and handle data according to basic data standards.
 

-Clinical trial databases should be made Up-To-Date, and the data deposited should be as authentic as possible.  It is essential to popularise this database among the stakeholders.
 

-Patients should be given a basic understanding of Natural history studies and clinical trials, and how they are essential for finding drugs. It will help more informed participation of patients in clinical studies.

-Clinicians and scientists should also be trained in conducting clinical studies towards drug development and the use of AI.
 

Some of these exercises can be conducted using webinar platforms under the auspices of the National Academy of Medical Sciences.
 

It was also pointed out that the peer group conducting clinical studies on rare diseases is very small, and the creation of a networked system connecting all the researchers can be beneficial. DBT-BIRAC can help in creating such a portal. It is also crucial that the industry join this effort.
 

There was a suggestion to institute an ID for all patients with rare diseases. It is being done for a few blood disorders.