ince 2001, the regulatory environment for clinical research and drug development in India has undergone a substantial transformation. Key regulatory changes have significantly impacted the pharmaceutical industry and led to ongoing and upcoming regulatory developments in India. These industries will need to adapt to this new environment to remain competitive on the local and international markets.

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.

Vaccine Approval Policy

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.

Post-Approval Changes and Monitoring

Post-Approval Changes (PAC) in Biological Products’ Quality, Safety, and Efficacy Documents

This guidance document introduces a classification system for PACs, dividing them into four distinct levels; each level corresponds to the magnitude and potential impact of that change on product quality, safety, and efficacy.

Further considerations are provided within each level of change:

• Administrative Product Labeling Information Changes: These changes do not impact the safe and effective use of the biological product.
• Post-Approval Change Management Protocol (PACMP): Provides a structured plan for quality changes, ensuring no negative impact on product quality, safety, or efficacy.
• Expedited Review/Reliance Pathway: Available for biological products treating serious or life-threatening illnesses, public health emergencies, shortages, and orphan products.
• Similar Biotherapeutic Products (SBP): Lifecycle management is independent from the reference product, but major changes in clinical use may be reviewed by CDSCO on a case-by-case basis.

Overall Impact: This new PAC guidance provides detailed dossier requirements and more predictability in the approval timelines for biologics. Furthermore, the explicit inclusion of Expedited Review/Reliance Pathways for products of greatest need, such as those treating serious or life-threatening illnesses or that address public health emergencies or shortages, are anticipated to facilitate faster access to patients in these situations.

Not of Standard Quality (NSQ) products

NSQ means a product that fails to meet or is out of any defined specification or quality parameter.

The CDSCO has issued new guidelines to enhance the surveillance of the quality and efficacy of drugs and cosmetics in the market through a standardized drug sampling methodology. These guidelines aim to mitigate the risk of products failing quality specifications by utilizing available data to identify risks and effectively select samples and locations. This approach covers a wide range of drugs, cosmetics, and medical devices distributed from manufacturing facilities, wholesale and retail outlets, and government distribution channels in urban, suburban, and rural areas.

Overall Impact: Introduction of Not of Standard Quality (NSQ) product guidelines will enhance quality control and compliance across the Indian market. The new guidelines help ensure that products meet stringent quality standards through enhanced surveillance and standardized sampling methodologies. This is crucial for products like over-the-counter medications and cosmetics, which need consistent quality to maintain consumer trust. By reducing the incidence of substandard products, companies can avoid costly recalls, protect their reputations, and secure consumer confidence in their brands.

Ongoing Regulatory Developments

Draft National Pharmaceutical Policy (2023)

The National Pharmaceutical Policy (2023) is still being drafted and will provide a comprehensive framework to address challenges faced by Indian pharmaceutical companies and definitive policy interventions to enhance the collective pharmaceutical ecosystem. Overall, the policy aims to encourage a paradigm shift by promoting R&D in India and moving away from the conventional approach of manufacturing generics and “incremental innovation” to embracing “disruptive innovation” with the introduction of novel drugs, devices, and technologies, and establishing “Innovation-Hubs” in India. There is currently no official timeline for issuance of the final policy.

Overall Impact: The Draft National Pharmaceutical Policy (2023) offers transformative potential for global companies that are heavily invested in R&D. The policy’s focus on creating Innovation-Hubs provides a fertile ground for global companies to collaborate with Indian start ups and research institutions. For instance, global companies could partner with an Indian biotech firm to develop novel drug delivery systems, leveraging local talent and resources. This collaboration not only fosters innovation but also allows global companies to tap into the growing Indian market with new, locally developed technologies. Moreover, the policy encourages both incremental and disruptive innovation supporting global companies’ strategic goals to remain at the forefront of global pharmaceutical advancements.

Revised Draft Guideline: Pharmacovigilance Requirements for Human Vaccines, version 2.0

Among broader developments in pharmacovigilance requirements over the past decade, CDSCO published a revised draft guidance on pharmacovigilance requirements for human vaccines to enhance vaccine safety and efficacy through robust pharmacovigilance practices in May 2024. The draft guidance aims to assist stakeholders, including Marketing Authorization Holders, in vaccine safety monitoring, audits and inspection, risk management plan implementation, and the periodic submission of Risk-Benefit Evaluation Reports to the Licensing Authority. It also details roles and responsibilities of authorities such as CDSCO, the pharmacovigilance program of India, and the Immunization Division. Overall, the document emphasizes the need for effective pharmacovigilance systems to ensure patient safety across the vaccine product lifecycle.

Draft Guidelines on Good Distribution Practices (GDP) for pharmaceutical products, version 00

In May 2024, CDSCO issued draft guidance on Good Distribution Practices (GDP) for pharmaceutical products. This guidance is framed in line with the WHO Technical Report Series (TRS) on Good Storage and Distribution Practices for pharmaceutical products to prevent the risk of introduction of spurious, adulterated, misbranded, and “Not of Standard Quality (NSQ)” products into the market. The guideline explains the procedures to follow in transportation, shipping, labeling, dispatching, and receiving pharmaceutical products and documentation related to distribution. It also details the methods to file complaints, for recalls and returns, and the handling of spurious, misbranded, adulterated, and NSQ pharmaceutical products. Self-inspections in the quality system by a designated, competent person, and maintaining records of such self-inspection results along with all observations made during the inspection, and (if required) proposals for corrective measures, are advised.

Overall Impact: The draft Guidelines on Good Distribution Practices is an important cornerstone for the transformation of the Indian pharmaceutical product R&D ecosystem. To date, guidelines on the process for recalls and returns had been missing; the new guidelines are critically positioned to mitigate the risks of spurious, adulterated, misbranded, and NSQ products in the country. Global companies usually have complex supply chains for distributing vaccines and pharmaceuticals, and implementing standard GDP guidelines provides a robust framework aligned with WHO standards and supports a global company’s commitment to delivering high-quality products and their reputation as reliable pharmaceutical provider.

Conclusions

Since the implementation of the New Drugs and Clinical Trial Rules in 2019, India’s regulatory landscape has been evolving to align more closely with global standards while also ensuring that drugs remain affordable and accessible for its large population. The pharmaceutical industry has particularly benefited from increased clarity and predictability of processes and timelines, including expedited pathways. In recent years, the number of national and international clinical trials in India has significantly increased, with trial approvals rising in the double digits. As India’s regulatory system is strengthened through new regulations, guidelines, and rules, the country is emerging as a valuable partner in global clinical trials. These advancements aim to generate high-quality clinical research data, create a supportive regulatory environment for drug and vaccine manufacturers, and provide a robust ethics framework for the protection of patients, leading to greater and more equitable access to novel medicines and vaccines for patients in India and around the world.

REFERENCES

1. Regulatory requirements for clinical trials in India: What academicians need to know – PMC (nih.gov)
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4. New Drugs and Clinical Trials (NDCT) Rules, 2019
5. Amendment to the New Drugs and Clinical Trial Rules (2023)
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