India’s Trial Approval Timelines Report Card – Some Red Lines?

India’s streamlined clinical trial approvals process appears to have made some gains, but top industry experts tell Pink Sheet how the non-standardized approach of Subject Expert Committees is a “major handicap” for applicants.

India’s attempt to move towards a time-bound approach for the approval of clinical trial applications appears to have made some progress, but gaps and challenges on the ground, including those around the functioning of Subject Expert Committees (SECs), continue to set back these efforts, according to some senior industry experts

SECs advise the Indian regulator on trial-related permissions as part of a layered approval process. India currently follows a three-tier review process for clinical trials, under which applications are initially evaluated by specialized SECs; these are then vetted by a technical committee and finally cleared by an "apex committee”.

India’s Central Drugs Standard Control Organization (CDSCO) recently made public the findings of its “review of the progress achieved vis-a-vis pendency in approval of applications” relating to new chemical entities (NCEs), global clinical trials and new drugs for the last three years, against the backdrop of timelines devised for the “disposal of different work schedules”.

The CDSCO notice, dated Dec. 26, 2016, lists 78 pending cases of 2015-16 for grant of clinical trial NOCs [no objection certificates] and trial waivers across various types of applications including those for global clinical trials, 15 (for 2014-15) and three (2013-14).

A footnote in the CDSCO notice says that the “delay” pertaining to the applications is because of various reasons like “non-submission of reply by the applicant”; the replies received are under review by the concerned division of CDSCO, it adds.

The Drugs Technical Advisory Board (DTAB), the highest technical body under India's Drugs and Cosmetics Act, had at its meeting on Jan. 3, 2017 recommended the rechristening of the CDSCO as the Indian Drugs Administration to make the name “simple and befitting to its activities”.

Not Well-Orchestrated?

A senior functionary of the Indian Society for Clinical Research (ISCR) said that while there has been a “definite and perceivable” attempt by the regulator towards being more focused in terms of granting approvals in a time bound manner, it hasn’t translated to gains on the ground to the extent expected.

“There is a small disconnect. They [regulatory officials] are aligned, committed in terms of facilitating the review and approval process but there are gaps and challenges,” the official from the ISCR told Pink Sheet. The ISCR’s members include several large multinational firms and clinical research organizations.

The official referred to inadequate resources and infrastructure at the regulator’s end, avoidable back and forth of queries in different time frames and SECs that function without standard operating procedures, among other challenges.

“It’s not a very well-orchestrated, rationally and scientifically driven approach overall,” the official maintained, but acknowledged that at times it may well be the case of the response of applicants not being completely up to the mark.

An industry veteran in the clinical trials segment told Pink Sheet that while there is improvement in trial approval timelines compared to 2013-14, the process remains “uncertain and unpredictable”.

“Sometimes the approval letter contains new conditions which were not discussed during the SEC meeting,” he noted.

Fixing such gaps may be critical in the backdrop of the slowdown in new industry-sponsored trials starting in India over the recent past. Last year, Informa’s Trialtrove noted how the “rosy view” of India as a location for relatively low-cost clinical trials with a readily available, treatment-naïve patient population became shaded over the past five years by an untenable time to approval.

India's clinical research sector has, in general, been dented amid uncertainties and delays caused by evolving regulations and ongoing trial-related litigation among other factors. Compliance issues pertaining to a few local CROs have only compounded problems for the rest of the industry.

The Organization of Pharmaceutical Producers of India (OPPI), which represents leading foreign firms in the country, said that it welcomes recent measures taken by the government to streamline the drug regulatory mechanism, but did not comment on specific queries pertaining to the trial approval timelines.

“New initiatives, such as online submissions, increased number of SEC members, [the] decision to revisit drugs regulations undoubtedly are steps taken towards facilitating ease of doing business in India. OPPI looks forward to a constructive engagement with the government in its endeavor to establish a transparent, process-driven and standardized regulatory structure,” Kanchana TK, director general of the OPPI, told Pink Sheet.

Major Bottleneck

The functioning of the SECs appears to be a significant pain point for trial applicants. Industry experts claimed that getting a protocol cleared by the SEC was still a “major handicap”.

“The SEC experts do not really know the regulatory pieces very well, there is generally no structure to conduct these meetings. Invariably one or two very vocal experts carry the discussion the way they want. Science is not driven by consensus, you can always have diverging opinions,” an expert said, referring in particular to the close vote pertaining to the label expansion for Jardiance (empagliflozin) in the US.

The US FDA, on Dec. 2, 2016, approved the first cardiovascular label expansion for the Boehringer Ingelheim GMBH /Eli Lilly & Co. antidiabetic. FDA clearance for the label expansion was based on results from Jardiance's EMPA-REG cardiovascular outcomes trial (CVOT) and a 12-11 vote in favor of the label addition by the Endocrinologic and Metabolic Drugs Advisory Committee previously. (Also see "Jardiance's Label Expansion Will Change Diabetes Management" - Scrip, 5 Dec, 2016.)

Industry experts also referred to the inadequate level of preparation by the SEC members in India that often ends up in suggestions which may be tough to implement and then require multiple rounds of discussions.

Among a string of suggestions, the industry veteran in the clinical trials segment quoted previously recommended “regularizing” SEC meetings by using digital approaches - such as web/Skype meetings - and the training of SECs to focus on the main issues in clinical trials. Currently, SEC members spend “too much time” on non-regulatory aspects, the veteran claimed.

Earlier, a task force constituted by the Drugs Controller General of India under Dr. Neelima Kshirsagar, ex-dean of Mumbai's KEM Hospital, set up to review the functioning of SECs, is said to have suggested detailed standard operating procedures and proposed an agenda for workshops, though things have believed to have moved rather slowly thereafter. The indications, though, are that things may pick up pace soon. (Also see "Five Key Indian Trial Regulation Play-Outs For 2016" - Scrip, 14 Jan, 2016.)

Approval Timelines

Industry experts also suggest that the current approval timeline of 180 days for global clinical trials - where India is a participant in a global study - is a bit too long.

“Global clinical trials are to be conducted along with other major markets in the world and the six-month window is not good enough. Ideally a three- to four-month time frame is what we must work towards,” the ISCR official suggested.

Again, in areas such as import registration of drugs and medical devices, the 270-day timeline specified for approvals appears too long, though the official noted that in most cases the regulator is able to consider and dispose these of ahead of the stipulated timeframe.

The industry veteran in the trials segment, however, referred to the fast approval timelines in markets like the US. He explained that global clinical trial approval proposals are typically based on approvals in the US/Europe and the sponsor provides assessment of risk versus benefit.

“So one wonders what special review is done by the CDSCO and three committees and why can’t this be done faster? Clinical trial approvals in 90 days and protocol amendment approval in 30 days would be desirable,” he underscored.

The ISCR official said that while equating the US and Indian scenario may not be rational, the CDSCO should avoid “building stereotypes”.

He explains that if for example there is a global study approved with a certain drug and the applicant expects to mimic the same clinical development protocol in the next study where “everything remains the same”, except for maybe the comparator, then there’s probably no need for a full-fledged SEC and technical committee review, though that kind of discretion does not appear to be currently available with the regulator.

“Such steps can help where you are not circumventing rules but are approaching things innovatively within the overall framework,” the official added.