Shagun Sharma, Vipul Kumar Gupta, and Helene Sou of Takeda, writing in the December 2024 edition of DIA’s Global Forum magazine, look at how updates to India’s regulatory framework for pharmaceuticals are impacting the industry.
Important changes include implementation of the Indian Good Clinical Practices (GCP) guideline in 2001 and an amendment to Schedule Y in 2005. This 2005 amendment introduced the formal definition of a clinical trial and allowed trials in India to be conducted in step with the same trial phase of drug development as elsewhere in the world, resulting in greater inclusion of India sites in global clinical trials.
In 2019, India witnessed another regulatory leap forward with a new framework for clinical trials that added clarity to provisions for compensation to trial participants in case of injuries/death, details on the medical management of clinical trial-associated injuries/hospitalization, and specifics on clinical trial waivers under specific conditions. This article overviews recent key regulatory changes that have particular significance to the pharmaceutical industry and a general, global industry impact assessment.
Clinical Trials and New Drug Approvals
New Drugs and Clinical Trials (NDCT) Rules, 2019
The NDCT Rules introduced key changes to India’s clinical research, replacing Part XA and Schedule Y of the 1945 Drugs and Cosmetics Rules in March 2019. These new rules simplified and outlined the legal and Good Clinical Practices (GCP) requirements for conducting clinical trials in India and aimed to protect participants, enhance data quality, and promote collaboration in the pharmaceutical industry. NDCT Rules cover new drugs, investigational drugs, clinical trials, bioequivalence and bioavailability studies, as well as Ethics Committees, to ensure high standards of conduct.
Key updates include:
- Orphan Drugs: Orphan drugs are now defined as “drugs intended to treat a condition which affects not more than 5 lakh persons in India” (500,000 people in India).
- CTA Reduced Timelines/Deemed Approval: Approval timelines are now 30 working days for domestic trials and 90 working days for global trials. In the absence of communication from regulators at the end of these respective periods, permission to conduct the clinical trial shall be deemed granted.
- Compensation for Injuries and Death: Schedule VII specifies a formula for compensating trial-related injuries or deaths. Decisions are now made by the Drug Controller General of India (DCGI) based on an expert committee’s advice.
- Waivers for Local Clinical Trials in India: Waivers may apply if the drug is already approved in specific countries, addresses unmet medical needs, is for a rare disease, is not presumed to have different effects across India’s various ethnicities, and the sponsor commits to a phase 4 study in India.
- Post-Trial Access: Sponsors are expected to provide continued access to beneficial drugs at no cost post-trial if no alternative therapy is available and other conditions are met, such as the investigator recommends continued access, the Ethics Committee approves, and the trial patient consents and signs a disclaimer waiving sponsor liability for such post-trial use of the investigational drug.
- Post-Marketing Studies: Phase 4 trials, including drug-drug interaction, dose response, or safety studies, must adhere to approved indications and conditions.
- Accelerated Approval: This process applies to certain drugs treating severe, rare, or prevalent diseases where existing treatments are inadequate.
- Pre-Submission Meeting: Upon receiving a meeting request from the applicant, the Central Licensing Authority (CLA) will provide clarifications or request additional information within 30 days.
Amendments to the New Drugs and Clinical Trial Rules: Following the 2019 issuance of these NDCT Rules, several important subsequent amendments further aligned local standards with international guidelines and practices and streamline regulatory processes:
- Replacing Animals in Research (9 March 2023): This amendment encourages the exploration of alternative methods to animals for nonclinical testing of new drugs. This includes advanced technologies such as 3-D organoids, bioprinter organs-on-a-chip, and sophisticated computational methods.
- Specification of Reference Agencies (7 August 2024): Local clinical trial waivers may be granted for drugs approved in the US, UK, Japan, Australia, Canada, or in the EU (by EMA) under the conditions defined in Rule 101 of the 2019 NDCT Rules, and for specific categories of drugs, such as orphan drugs, gene and cell therapy products, new drugs used in a pandemic, special defense (most likely for matters of national security), or which provide significant benefit—which is not explicitly defined—over existing standard of care.
- Deemed Approval Timelines (14 October 2022): Specific timelines were introduced for various rules:
– Registration to Ethics Committee: Within 45 working days
– Permission to conduct clinical trials: Within 90 working days
– Permission to conduct bioavailability (BA) or bioequivalence (BE) studies: Within 90 working days
– Permission to manufacture new drugs or investigational new drugs for clinical trials or BA or BE studies, or for examinations, tests, and analyses: Within 90 working days. - Compassionate Use of New Drugs (18 January 2022): Provisions were defined for the compassionate use of any unapproved drug undergoing phase 3 trials, either in India or globally, by importing or manufacturing it in the country.
Overall Impact: Introduction of NDCT rules and the associated amendments brought a positive impact on the clinical research and drug research and development (R&D) ecosystem in India by providing greater transparency and predictability of timelines. These amendments are an encouraging step towards expedited approvals and broader access to innovative medicines for patients with life-threatening diseases, unmet medical needs, and rare diseases.
Central Drugs Standard Control Organisation (CDSCO) Guidance for Industry (Biologicals) version 1.2
In May 2024, CDSCO published a revised guidance for the submission of clinical trial applications for biological products that was developed in conformity with the 2019 NDCT Rules and GCP Guidelines of India. This document comprises information on Submission of Clinical Trial Application for Evaluating Safety and Efficacy (biologicals); Requirements for Permission of New Drug Approvals (biologicals); and Preparation of the Quality Information for Drug Submission for New Drug Approval: Biotechnological/Biological Products.
Of note, the clinical trial application submission guidance clarifies the responsibilities of sponsors, such as the requirement to establish a rigorous Quality Assurance system, submission of status or termination reports, and Chemistry, Manufacturing, and Controls (CMC) requirements for Clinical Trial Applications (CTAs). Overall, while the terminology may be specific to India, the content is aligned with international standards, particularly the requirements set forth by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).
Overall Impact: The revised CDSCO guidance which now aligns with international standards positively impacts global pharmaceutical companies working in India. Previously, differing regulatory requirements could delay trial initiation and drug approvals in India, in addition to complicating global drug development. With the new guidance, global companies can streamline their processes, reducing redundancies by using a common protocol that satisfies both Indian and international standards. A new vaccine or biologic can be tested in clinical trials simultaneously at Indian sites and other locations, leveraging India’s diverse patient population for more comprehensive data. Such alignment can also facilitate faster entry into the Indian market, potentially leading to faster access for patients.
For novel candidate vaccines discovered or developed in India, clinical trials must be carried out in India beginning from phase 1, and submitting this local study data is required. For novel candidate vaccines discovered or developed in countries outside India, the corresponding phase 1 data generated outside of India should be submitted along with the application. After submission, CLA may require the sponsor to either repeat phase 1 trials or allow the sponsor to conduct phase 2 and subsequently phase 3 trials concurrently with other global trials for that vaccine. For vaccines already approved in other countries which have well-established safety, immunogenicity, and efficacy, the applicant should demonstrate that the proposed vaccine is noninferior to a vaccine already approved in India. If no vaccine is yet approved in India, the agency may ask to conduct an entire clinical trial or an immuno-bridging study in India. In accordance with Rule 75, the Indian health authority has discretion to grant a phase 3 clinical trial waiver in case of unmet medical need, and rare disease.
Overall Impact: The vaccine approval policy is a comprehensive document outlining the requirements for approval of vaccines with the goal of expediting approval of novel vaccines to bring them to patients faster. It is expected that the new approval policy will energize pharmaceutical industry-sponsored research, development, and commercialization of vaccines in India.
