India New Trial Rules - Sponsors Interested But 'FAQ' Could Help
Executive Summary
India’s new clinical trial regulations could revive sponsor interest in the country, but some norms around local Phase III trial waivers appear open to interpretation and could potentially weigh down momentum.
India’s New Drugs And Clinical Trials Rules 2019, which stipulate time-bound regulatory approvals and provide for conditional local trial waivers, appear to have improved the general outlook of large sponsors in the country, though nuances in the new norms offer “subjective interpretation”.
Large sponsors, CROs and sector experts believe that the new rules will buoy sentiment in the Indian clinical research sector, which has been through a rough time, singed by uncertainties and delays caused by evolving regulations, the cascading effect of certain instances of data integrity deviations and ongoing trial-related litigation. (Also see "Indian Clinical Research Sector: Hope And Despair Amid Shutdowns" - Scrip, 26 Aug, 2016.) Sponsors were particularly relieved when the recently notified new rules dropped a contentious clause pertaining to interim compensation that featured in an earlier draft version of the regulation. (Also see "Patient Safety First But India’s ‘Interim Compensation’ Trial Rule May Spook Sponsors" - Pink Sheet, 26 Apr, 2018.)
Novartis India told Scrip that the new trial rules appeared to be “balanced” and the Phase III waiver under certain conditions is a step in the right direction, helping drive patient access and shorten launch timelines for new innovative therapies.
“We believe that facilitating the conduct of ethical, quality clinical trials in India is in the larger interest of the Indian patient who will benefit from faster access to newer treatment modalities, particularly for life-threatening indications,” Novartis said.
The Swiss multinational, however, added that “notwithstanding the ecosystem as it existed so far”, the company had continued with its global development clinical trial programs in India, facilitating early access to its new product pipeline.
Subjective Interpretations
Prominent industry bodies too endorsed the new norms. The Organization of Pharmaceutical Producers of India (OPPI), which represents foreign firms in the country, said the new rules would streamline the new drug and clinical trials approval process and bring in transparency and ensure a stable regulatory environment in India.
“This will definitely boost medical research including conduct of clinical studies in India,” said Annaswamy Vaidheesh, OPPI president and managing director of
GlaxoSmithKline Pharmaceuticals Ltd. in India.
Sponsors also generally appeared enthused about the conditional Phase III local trial exemption provisions in the new rules, although some aspects around these norms seemed ambiguous.
OPPI noted that the provisions permitted a waiver of the requirement to conduct local clinical trials and facilitate an expeditious and accelerated review process for approval of a new drug.
“Though some of the provisions may be open to subjective interpretations, OPPI hopes that the rules would facilitate early access of said new treatments to patients,” Vaidheesh said, adding that OPPI member companies are committed to bringing in new treatments to address unmet medical needs in India.
Compliance And Practical Challenges
While local trial data waivers were earlier being permitted more on a case-by-case basis in India, the new rules now lay down specific conditions under which such data may not be required to be provided as part of an application to import a new drug for sale or distribution in the country. These include a trial waiver for new drugs approved and marketed in countries specified by the Central Licencing Authority and if “no major unexpected serious adverse events have been reported”.
The waiver is also applicable in cases where a new drug is approved for marketing in a specified nation [typically expected to include the US, Japan or Western Europe] even as trials for the drug, for which permission has been received by the Indian regulator, are ongoing in India as part of the global study. In such cases, there should be “no probability or evidence, on the basis of existing knowledge, of difference in Indian population of the enzymes or gene involved in the metabolism of the new drug or any factor affecting pharmacokinetics and pharmacodynamics, safety and efficacy of the new drug”, the new rules specified. Applicants are, however, required to provide an undertaking in writing to conduct Phase IV clinical trials to establish safety and effectiveness of such new drug as per the design approved by the regulator.
Dr Arun Bhatt, a clinical research and development consultant, maintained that the requirements seeking “no major serious unexpected events” could be difficult to comply with for newer biologics and immune-based drugs especially in serious conditions such as cancer and heart failure.
“Also, the condition on genetic/ethnic differences is difficult to comply with as there isn’t much literature supporting evidence of such pharmaco-genomic differences,” Bhatt, a former president of the Indian CRO, Clininvent Research, explained.
The industry veteran also referred to certain “practical challenges” that could emerge during the conduct of clinical trials given that the understanding of the new regulations was not uniform among sponsors, CROs, investigators and ethics committees. He cited the requirement of free medical management that is expected to be given [to trial subjects] till such time it is established that injury is not related to trial or “as long as required”, whichever is earlier.
“The use [of ] passive voice leads to confusion – whose decision will establish this? Investigator/ECs/CDSCO [Central Drugs Standard Control Organization] expert committee? Terms like life-threatening/serious disease/disease of special relevance/unmet need are broad terms open to diverse interpretations by the sponsors and regulators,” Bhatt said, suggesting that the regulator should perhaps consider issuing an “FAQ clarifying such ambiguities”.
Gradual Recovery Of Trials Sector
Nevertheless, the new rules have lifted overall sentiment in the Indian clinical research segment, though experts caution that regaining trust and confidence is a “slow and long-drawn out” process.
Suneela Thatte, head of R&D Solutions (India) at IQVIA, expects that there will be renewed interest in sponsors placing trials in India, though in the short term it will be a “slow and gradual increase” rather than a “significant” one.
“Those who have been sitting on the fence will be the early movers. There will be an ongoing need for the regulators to be transparent and provide updated data and statistics around approval timelines, compensation pay outs and so on,” Thatte stressed.
The new rules, the IQVIA executive said, are however a big step forward in reiterating the regulators’ commitment to building a strong and ethical regulatory framework in the country and in committing to a "strong clinical research agenda" for the country.
So, could India be heading back to the heady days of 2010, where trial approval numbers and sponsor interest soared? Thatte said it was too early to make any predictions and, reiterated that growth would likely be slow and gradual.
“What we are likely to see different this time round is more R&D that is home grown which will augur well for local R&D and the spirit of innovation in our country,” Thatte said.
Consultant Bhatt explained that the 2010 trial approval numbers included approximately 250 Indian company trials and 250 global trials and while the number of global Phase III clinical trials may reduce because of the waiver provisions [under the new rules], Phase IV studies may increase.
Industry is also hoping that a long running public interest litigation (PIL) concerning allegations of illegal trials being conducted in India amid seemingly lax regulatory procedures, checks and balances at the time, is resolved.
“It would be good if the PIL is also taken to a closure so that the efforts of all concerned can be more positively directed towards bringing new and safer medicines for patients who have been most impacted by the challenges of the recent past,” Thatte added.