CDSCO Panel Flags Gaps in Serum Institute's rBCG Vaccine Data, Calls for Stronger Trial
New Delhi: Serum Institute of India's proposal for its Recombinant BCG (rBCG) Vaccine for Tuberculosis has hit a regulatory hurdle, as the Special Subject Expert Committee (SEC) under the Central Drugs Standard Control Organisation (CDSCO) noted that the clinical evidence submitted for the Recombinant BCG (rBCG) Vaccine for Tuberculosis (Freeze Dried), primarily derived from post-hoc analyses, was neither adequate nor conclusive to support a decision on the new drug application.
Consequently, the committee recommended that Serum Institute conduct an adequately powered study before the proposal can be considered further.
The firm presented excerpts from two clinical study reports:
Study 1: A multicenter Phase II/III double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of VPM1002 in preventing tuberculosis (TB) recurrence in pulmonary TB patients after successful TB treatment in India [Protocol No. VPM1002-IN-3.01TBR, Version 2.0, dated 10.12.2016].
Study 2: A Phase III, randomized, double-blind, three-arm placebo-controlled trial to evaluate the efficacy and safety of two vaccines—VPM1002 (rBCG of Serum Institute) and Immuvac (Mw) of Cadila - in preventing TB in healthy household contacts of newly diagnosed sputum-positive pulmonary TB patients [Protocol No. ICMR/ITRC/VAC/001/2018].
The application sought permission for the following indications:
Active immunization for prevention of extra-pulmonary tuberculosis in individuals aged 6 years and above, and
Active immunization for prevention of pulmonary tuberculosis in individuals aged 6 to 18 years.
During evaluation, the committee recorded the following observations exactly as presented:
The firm submitted the new drug permission application for the above indications along with the study reports.
In Study 1, the difference of efficacy endpoints between the study vaccine and the placebo group for all TB recurrence cases (bacteriologically confirmed + clinically diagnosed) and bacteriologically confirmed TB recurrence cases (symptomatic + asymptomatic) were not statistically significant—13.5% and 7.8%, respectively—as per the presented post-hoc analysis data.
Similar non-significant results were noted in the post-hoc age subgroup analysis.
The primary objective of Study 1 was to evaluate the efficacy of VPM1002 in preventing TB recurrence, and the study concluded that the vaccine failed to meet the primary endpoint of reduction in bacteriologically confirmed TB recurrence.
The objective and endpoint of Study 1 were not related to the claimed indications, and no inference was drawn by the firm to support the indications sought.
In Study 2, the firm relied on subgroup analysis of primary and secondary endpoints of the Phase III clinical trial conducted by ICMR for the claimed indications.
The primary objective of Study 2 was to evaluate reduction and incidence of TB over a 3-year period among Indian healthy household contacts vaccinated with VPM1002 compared to placebo, with the primary endpoint being the percentage of confirmed TB cases (PTB and EPTB) as per NTEP guidelines from two months after the first dose until 38 months of follow-up.
Vaccine efficacy against microbiologically confirmed EPTB (PP population) was concluded as 50.4% (VPM1002 – 12 and placebo – 24) based on primary endpoints of the ICMR study. However, the overall vaccine efficacy against all microbiologically confirmed TB (PTB and EPTB) was 16.9% (VPM1002 – 73 and placebo – 88), which was statistically non-significant.
The statistically non-significant result was interpreted and concluded as statistically significant by calculating two-arm data instead of three-arm data of the ICMR study.
The primary objective of the study was not met, and the firm did not draw any inference from the same.
In the ICMR study, differences in secondary endpoints between the vaccine and placebo groups for microbiologically confirmed, clinical/microbiologically diagnosed, and clinical/microbiologically confirmed cases in the intended age groups for both PTB and EPTB appeared statistically significant only in post-hoc analysis using Haldane modification, while overall results remained statistically non-significant without post-hoc analysis.
Based on the above findings, the SEC concluded that the data presented—largely dependent on post-hoc analysis—were not adequate or conclusive to support the new drug application. The committee recommended that the firm should plan an adequately powered study based on the secondary endpoint outcomes of the ICMR trial to enable a conclusive decision.
The minutes also noted conflict of interest declared by the following experts:
Prof. (Dr.) Urvashi B. Singh, Dy. DG (TB), CTB Division, MoHFW, New Delhi;
Dr. Srinath Satyanarayana, Director, ICMR-NIRT;
Prof. R. M. Pandey, Ex-HOD Biostatistics, AIIMS, New Delhi; and
Dr. Sonali Sarkar, Professor, Preventive and Social Medicine, JIPMER.
