How New Regulations Are Changing Product Approvals in India

he regulation of new drug development and approval in India has evolved significantly in recent years and has enabled the entry of important new medicines onto the market for the benefit of millions of Indian patients. The change has been gradual but steady; key success factors have included the establishment of Subject Expert Committees (SECs) empowered to evaluate complex clinical data in depth and detail and advise the Regulatory Authority.

The gold standard for studying the safety and efficacy of new medicines in development is the randomized controlled trial (RCT). RCTs are designed to answer specific disease outcome and other patient-related questions, and are usually required by regulatory bodies across the world as the basis for their approval of new medicines. Clinical research studies on human participants are designed to answer specific questions about new medicines through key considerations such as study population and design, choice of comparator(s), adequate number of subjects, efficacy end-points and statistical analysis, safety data, patient-reported outcomes, and relevance to specific countries or regions for future clinical use. These trials are conducted after the required regulatory authorities and ethics committees review and approve their study protocols, which document these considerations; this often includes providing feedback on that investigational product’s clinical development plan.

Depending on the disease condition, regulatory authorities across the world base their authorization/approval of new medicines on evidence generated from several RCTs which, ideally, result in hundreds to thousands of patients demonstrating a favorable benefit-to-risk profile when treated with the investigational medicine. Specific areas that regulatory decision-making bodies consider in this decision include clinical benefit (survival advantage in serious conditions, or at least clear reduction in disease morbidity); and safety, including and especially cardiovascular risks and any adverse impact on renal function.

Changes to New Drug Product Approvals in India

In India, the process for review and approval of new medicines in India has significantly changed over the past decade.

From 2001-2011, the Central Drugs Standard Control Organization (CDSCO) regulatory authority typically approved or declined new drug product applications based on the data and results from clinical trials sponsored by the applying biopharmaceutical company across different countries in the disease condition(s) intended for its clinical use. The CDSCO would review the application and supporting data according to its own internal knowledge and expertise, but also reference feedback from experts in the therapeutic area and clinical use for which the product was intended as part of making its decision. These clinical trials may or may not have included patients from India, with applicants providing supplemental justification for the relevance of the product to Indian patients. This has now changed.

SECs Part of New Regulations Established in 2012

India established new regulations for the approval of new drugs and supporting clinical trials in India in 2012. Regulatory review of new product applications and accompanying clinical trial data and results are now conducted by a dedicated expert committee consisting of medical specialists plus other invited experts. There are currently more than twenty Subject Expert Committees (SECs).

The new regulatory process features presentation and defense, in a face to face meeting, by the sponsor’s technical team regarding its product’s background and clinical trial results (including results from Indian patients whenever available). Important scientific considerations in this review include the product’s benefit-to-risk assessment, unmet medical need in the disease condition(s), and its relevance to the Indian population. New or investigational products could also be reviewed and approved for use in an expedited manner in case of emergency or other urgent situation. New Draft Rules for Clinical Trials and New Drugs, released in 2018 and anticipated for final release in 2019, include faster review pathways for orphan products; experts anticipate a similar approach on diseases with significant unmet medical need in India.

Two specific examples which have led to additional treatment options or to better patient outcomes in areas of unmet medical need for oncology and diabetes are highlighted below.

Better Patient Outcomes in Oncology

Epidermal growth factor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib show good clinical efficacy and are generally well-tolerated in patients with advanced non-small cell lung cancer (NSCLC) with EGFR mutations. Both these medicines were initially approved fifteen years ago in the EU, Japan, and US, as monotherapy in patients with advanced NSCLC who had failed first- or second-line chemotherapy. These agents were used in a broad population and often resulted in modest clinical benefit for patients.

However, clinical data emerging from multi-country, multi-centric trials throughout different parts of the world suggested that patients with certain clinical characteristics–importantly, patients with EGFR mutations–could specifically benefit more than others. In India, regulatory authorities approved the use of these products in specific populations, based on the recommendation of the SEC reviewing the submitted clinical trial data, via label updates. These updates enabled use of these medicines in specific NSCLC patients in India who were more likely to derive greater clinical benefit from them.

Better Patient Outcomes in Oncology

Over the past two decades, type 2 diabetes has increased dramatically in India and many other countries, increasing the healthcare burden on millions of people. In type 2 diabetes, tight glycaemic control can reduce diabetes-related morbidity and mortality. This control can be achieved by both lifestyle changes (diet and physical activity) along with use of various anti-diabetic medicines, including insulin.

Over the past decade, various classes of anti-diabetic medicines–Dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin, vildagliptin, saxagliptin, alogliptin and others); GLP-1 (Glucagon-like peptide) analogs (liraglutide, dulaglutide, exenatide); and SGLT2i inhibitors (canagliflozin, empagliflozin and dapagliflozin)–have been approved and are now available for use in India. All of these anti-diabetic medicines were approved in India between 2013 and 2017, based on rigorous review by SECs and other experts of clinical trial data and results from across the world, including an adequate number of patients in India. These included safety data from randomized controlled clinical trials, including long-term studies. A number of basal, long-acting, and combination insulins have been approved by the regulatory authority for clinical use in India, again on the basis of positive data, including Indian patients, and the relevance of these insulins to diabetes patients in India.

Technology Promises More Change to Come

In India as elsewhere, clinical trials are conducted to generate safety and efficacy data from potential new medicines in specific disease conditions. In India as elsewhere, regulatory authorities actively engage with sponsoring biopharmaceutical companies and other stakeholders to ensure that clinical trials incorporate advances in science and medicine to generate increasingly more reliable and relevant data for the condition(s) being studied. The regulatory system for review and approval of new medicines has changed significantly in India over the past decade; it is more scientifically robust, for example, in expert analysis of clinical data generated in and of relevance to the Indian population. Greater use of technology in the conduct of clinical trials as well as analyses of their results will continue to drive changes in all these systems.

References available upon request.