India issues new clinical trial rules to expedite new drug approvals

The Indian government has implemented new clinical trial regulations intended to expedite the registration of orphan-designated and innovative medicines in the country. While the measures constitute part of a wider policy drive to entice market entry of advanced new treatments, IHS Markit expects the affordability barrier to remain a major obstacle to patient access.

India's Central Drugs Standard Control Organization (CDSCO) last month implemented its New Drugs and Clinical Trials Rules, 2019. The changes encompass a new conditional approval pathway for orphan-designated medicines for rare diseases, and for new innovative medicines that have already been approved and licensed by regulators in the European Union, the United States, Australia, Canada or Japan. Qualifying products can now be launched in Indian without companies needing to conduct phase III clinical trials to test for efficacy and safety in the Indian population, provided the associated global studies included Indian patients. Companies will need to conduct post-marketing phase IV trials to evaluate long-term effects, but ultimately, the new rules should speed up the approval process and the availability of new medicines in India.

The new regulations define orphan drugs for the first time - as medicines to treat conditions that affect fewer than 500,000 people in India. Under the new rules, Indian regulators now have the authority to exempt orphan drugs from both phase III and IV clinical trials. Manufacturers or sponsors of orphan drugs can apply to India's CDSCO for an expedited review process, waiving the requirement for local clinical trials in recognition of significant unmet medical need.

Other measures aim to reduce timelines for granting approvals for clinical trials. For example, application processing has been reduced to a maximum of 90 days. In the case of an investigational new drug subject to discovery, research, and manufacture in India, the application will be processed within 30 days. Additionally, application fees for orphan drug trials in India will be waived. By streamlining the application process for clinical trials, these new provisions aim to encourage more indigenous research and development (R&D) for rare diseases affecting patients in India.

The need for reform in this domain could hardly be doubted; to date, few orphan drugs have been registered in India, with some patients resorting to importing these medicines directly. Similarly, only a small fraction of the innovative new oncology therapies that have been launched globally in recent years have reached the Indian market, despite an estimated 10 million cancer patients in the country. The new regulations, which also clarify the conditions for bioavailability and bioequivalence studies, have been welcomed by industry players and by the Indian Society for Clinical Research (ISCR). The ISCR states that the changes are "well balanced", will "further the conduct of ethical and quality clinical trials", and will speed up access to more effective treatments.

The new clinical trial rules were developed in collaboration with all stakeholders. By reducing costs, trimming approval timelines and cutting bureaucratic red tape, they create a more streamlined legal framework for biopharmaceutical market entry. By bringing greater clarity to clinical trial rules - and maintaining robust rules for safety reporting, patient protection and requirements for compensation payouts - the government hopes the new rules will also increase clinical research in India. The aim is to boost investment in domestic R&D of lower-cost innovative medicines that address the health needs and epidemiological profile of the Indian population. Currently, India hosts just 1.2% of the world's clinical trials, despite the country's high disease burden.

The new measures come as part of a wider policy drive to entice market entry by reducing regulatory disincentives that have long been linked by industry players to the lag in availability in India of the most effective new medicines. Implementation of the CDSCO's new clinical trial rules comes close on the heels of a new exemption for all new in-patent drugs from price controls for a period of five years. Under the same new policy, orphan drugs can also now circumvent all forms of price control, irrespective of their patent or new drug status, subject to application for an exemption.

However, despite the clear rationale behind these measures - to ease regulatory barriers and thereby encourage market entry - the apparent fillip to research-based pharmaceutical companies is deeply mired by the steep challenge of financing advanced and rare disease treatments in a country where out-of-pocket payments (OPP) still account for most expenditure on medicines. In short, the registration of advanced new treatments and orphan drugs is not synonymous with accessibility for all target patient populations, least not in a country where public health expenditure accounts for just 1% of gross domestic product (GDP) and GDP per capita stands at just USD2,024.68 (2018, IHS Forecasts).

Despite being the second most populous country in the world, India generates modest sales volumes for premium-priced medicines, irrespective of product value due to added clinical and economic benefit. This is due to the absence of a mandatory universal health insurance system and a comprehensive drug reimbursement mechanism. For now, access to new patented medicines - for the vast majority of the population - is either not possible, or it constitutes a catastrophic health expenditure. For orphan drugs, the affordability barrier is prohibitively high for all but an almost negligible fraction of the wealthiest patients in India. The launch last year of Indian Prime Minister Narendra Modi's flagship Ayushman Bharat - National Health Protection Mission (AB-NHPM) initiative, informally known as 'Modicare', has significantly improved prospects for affordable healthcare. However, there are several caveats that prevent it from being an immediate game changer with respect to access to medicines. For example, although the scheme targets approximately 500 million low-income and vulnerable beneficiaries, a per family annual ceiling on benefit cover of INR500,000 (USD7,210) is indicative of the scheme's constrained purchasing power.

By defining orphan drugs for first time, the new clinical trial rules do deliver a significant positive for the treatment of rare diseases in India. This should provide impetus for greater engagement in R&D initiatives that target rare diseases affecting Indian patients. However, the ongoing absence of any dedicated mechanism of public funding for the treatment of rare conditions blunts the benefit to patients in the immediate term. Furthermore, patient advocacy groups in India fear that the exemption of orphan drugs from price controls - without a pre-existing regulatory framework to formally govern and fund patient access programs - could in fact put these treatments even further out of reach for the majority of patients. The new clinical trial rules come after the government retracted its 2017 National Policy for Treatment of Rare Diseases (NPTRD), which had been drawn up to create a permanent funding mechanism for orphan drugs, due to implementation challenges and financial constraints. The health ministry has reportedly started to convene meetings with stakeholder groups as part of fresh efforts to formulate a comprehensive rare disease policy, but plans for funding access to orphan medicines still sit in limbo.

By reducing costs and time to market, the new clinical trial rules will help to entice earlier market entry of effective new drugs. They represent a step in the right direction and they signify recognition from the Indian authorities that availability of innovative medicines requires support for industry. However, it is unlikely that significant improvements in patient access will be achieved without higher public expenditure and more comprehensive reforms; in particular, further policy reforms are needed to establish more robust pharmaco-economic capabilities for evaluating a product's budgetary impact and economic benefits, in order to optimize rational use of resources. Additionally, the health system needs legal frameworks to formally govern risk-sharing agreements, patient access schemes and various alternative and flexible reimbursement models for higher cost medicines that deliver added value.