Keytruda’s Catch-22 Situation In India Amid Compliance Questions
Executive Summary
Merck & Co’s immuno-oncology therapy Keytruda appears be facing a rather paradoxical situation in India, after an expert panel noted that the US multinational had failed to comply with Phase IV study requirements pertaining to the product in the country.
Merck & Co. Inc. has been asked to comply with an existing Phase IV study requirement in India for Keytruda (pembrolizumab), with its modified protocol for the anti-PD-1 therapy seemingly not finding favor with an expert panel that considers such proposals, at least for now.
A subject expert committee (SEC), which advises the Indian regulator on trial-related approvals and marketing clearances, recently observed that MSD, as Merck & Co is known outside of the US and Canada, had not fulfilled the requirement of a “structured Phase IV” for the approved indication of the drug - melanoma - in India.
The SEC (oncology and hematology) had in August 2017 recommended that MSD should conduct a Phase IV trial for Keytruda in at least 100 subjects “as availability of patients is not a problem in India”. MSD had, at the time, apparently proposed that 15 subjects be part of the study, which the SEC said was too few.
Now as a result of the “non-compliance” by MSD, the SEC has declined to consider “at this stage” its request seeking clearance for the additional indication of non-small cell lung cancer (NSCLC). The PD-1 inhibitor was granted permission for import and marketing in India in 2016 with a waiver of local clinical trials but subject to the condition of conducting a Phase IV study in Indian patients.
India currently provides for a waiver of clinical trials in the Indian population for new drugs, which have already been approved outside India, only in cases of "national emergency, extreme urgency, epidemics and for orphan drugs for rare diseases and drugs indicated for conditions/diseases for which there is no therapy."
Modified Phase IV Protocol
Merck now appears to have a tough row to hoe given that it had presented a “modified Phase IV protocol” for conducting the study for “100 combined subjects of melanoma and NSCLC” before the SEC, but the committee does not appear to have budged, at least for now.
At its meeting last month, the SEC (oncology and hematology) noted that NSCLC is not yet an approved use in India for Keytruda. It also specified that Keytruda was granted approval in 2016 with the condition to conduct a Phase IV trial in 100 subjects and that the firm had not adhered to that.
“The committee recommended that firm should conduct a Phase IV clinical trial in 100 patients of melanoma as was the decision in the earlier SEC meeting held on Aug. 8 2017,” details of the SEC meeting on March 21, 2018 indicated.
MSD did not respond to specific queries around Keytruda’s trial-related apparent non-compliance status in India, including whether it was largely on account of the limited patient pool due to the lower incidence of melanoma in India compared with the West. MSD also did not specify whether it intends to appeal against the SEC decision.
The US firm only stated that it had launched Keytruda in India for the treatment of unresectable or metastatic melanoma in compliance with all regulatory requirements.
“We look forward to making Keytruda available to other patients in India upon approval from regulatory authorities for additional indications. To re-iterate, we comply with all local legal and regulatory requirements, as always.” Keytruda had been launched at an “India-specific” price last year. (Also see "Will Keytruda Price Differential Really Count In India?" - Scrip, 13 Sep, 2017.)
Fuzzy System?
While there have been a few instances of seeming post-facto requests from companies for tweaks in surveillance plans and post-marketing study protocols in India, some industry experts say that the Keytruda case highlights the “fuzzy” trial approvals system in India, despite efforts to streamline processes. (Also see "Boehringer Navigates ‘Impractical’ Nintedanib Surveillance Plan In India" - Pink Sheet, 19 Sep, 2017.)
The former head of an Indian CRO told the Pink Sheet that Phase IV study requirements are not well defined in India and industry, at times, is subject to less objective requirements.
“In such niche indications, how does the SEC determine the number of subjects for a study?” the official asked, also referring to concerns around the overall processes followed by the SECs in considering proposals – a seemingly continuing pain point for industry and trial applicants.
He also referred to the extensive studies and regulatory approvals pertaining to Keytruda internationally – Indian regulatory requirements should factor in these aspects, he believes. Keytruda is approved by the US FDA for various indications including the treatment of certain patients with metastatic melanoma, metastatic non-small cell lung cancer, recurrent or metastatic head and neck cancer, refractory classical Hodgkin lymphoma, and urothelial carcinoma. Last month the FDA granted priority review to Merck’s Supplemental Biologics License Application for Keytruda for the treatment of advanced cervical cancer.
Other experts, however, cautioned that in general, it is not unusual for pharma to try and use gaps in the system to its advantage. Some experts have, in the past, suggested that the Indian regulatory apparatus should perhaps have “strict guidance” on all protocol review and similar requests, to ensure that only genuine ones are revisited. (Also see "Indian Panel Nudges Eisai Towards Phase IV Compliance For Halaven" - Pink Sheet, 26 Oct, 2017.)