Bayer Rivaroxaban tablets win CDSCO Committee nod for waiver of local clinical trial; directed to carry Phase IV trial

New Delhi: The apex drug regulatory body, Central Drugs Standard Control Organisation's (CDSCO) Technical Committee has recommended for grant of permission to market giant Bayer to import and market the drug Rivaroxaban 2.5mg tablet with local clinical trial waiver. However, the firm has been directed to conduct a Phase IV clinical trial and submit the protocol for the Phase IV trial within three months of approval of the additional indication for review.

Rivaroxaban 2.5mg tablet, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with coronary artery disease (CAD) or symptomatic peripheral artery disease (PAD) at high risk of ischaemic events.

The recommendation came following the deliberation of the proposal presented by Bayer to seek Import and Marketing permission for the additional indication of Rivaroxaban tablets 2.5mg with a request for waiver of a local clinical trial by CDSCO Committee. The firm in its proposal mentioned the international approval status wherein new indication of the said drug is already approved by EMA in August 2010.

CDSCO approval status states;

• Rivaroxaban Tablet 10mg indicated for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery on 03.02.2010.


• Rivaroxaban tablet 15/20mg (Additional strength/indication) on 02.09.2014, indicated as:-

a) Treatment of deep vein thrombosis and for prevention of recurrent DVT and pulmonary embolism.

b) For the prevention of stroke and systemic embolism in a patient with non- valvular arterial fibrillation.

• Rivaroxaban tablet 2.5mg (add. strength), Rivaroxaban 2.5mg tablet, co-administered with Acetylsalicylic acid (ASA) alone or with ASA plus Clopidogrel or Ticlopidine, is indicated for the prevention of atherothrombotic events in adult patients after an acute coronary syndrome (ACS) with elevated Cardiac biomarkers" on 13/07/201 o. (To M/s Bayer Pharmaceuticals Pvt Ltd.):-

The proposal was taken up by the Subject Expert Committee (SEC) wherein SEC recommendation reads;

Recommendations of SEC (Cardiology) meeting held on 27.11.2018:- The committee after detailed deliberation recommended that the firm should conduct Phase III clinical trial in the Indian population as there is no clinical data in the proposed indication on patients from South East Asia. Accordingly, a clinical trial protocol should be submitted for review by the committee."

Recommendations of SEC (Cardiology} meeting held on 04.01.2019:- In light of recommendation of the previous SEC meeting held on 27.11.2018, the firm presented their justification for waiver of local Clinical trial for approval of the additional indication Committee however noted that no new justification & rationality was presented by the firm in support of their proposal.

After detailed deliberation, the (CDSCO)committee reiterated its earlier recommendation that phase III clinical trial should be conducted in Indian patients. Accordingly, the protocol should be submitted for review by the committee".

Subsequently, the firm had requested for deliberation in the Technical committee meeting, based on the already available efficacy and safety data of Rivaroxaban 2.5mg tablet for CAD/PAD indication quoting various global clinical trials conducted.

The firm has given the following rationality/justification for Clinical Trial Waiver for Rivaroxaban 2.5 mg tablets as follows:

• Disease in the coronary arteries (as CAD), peripheral arteries (as PAD), or cerebrovascular arteries (cerebrovascular disease) may be present but remain unrecognized Until an affected arterial hell develops the first signs or symptoms, representing the clinical - presentation of the disease.


• "The life expectancy of patients with cardiovascular diseases is decreased by " 7.7 years and by 9.2 years for patients with prior MI, as compared to healthy people.


• The Registrar General of India reported that CHD led to 17% of total deaths and 26% of adult deaths in 2001-2003, which increased to 23% of total and 32% of adult deaths in 2010-2013


• The patients with CAD/PAD are at high risk for developing acute thrombosis in form of stroke, MI or CV death despite current optimal medical therapy including anti-hypertensive, lipid-lowering and antiplatelet drugs.


• CAD is one of the most important causes of mortality and morbidity in India. The prevalence of CAD ranged from 2.5% to 12.6% was observed in urban parts of India between 1990 and 2012. Therefore to counter the burgeoning epidemic of CAD in India, we urgently need effective and improved treatments for the prevention of CAD complications.


• Although ASA is the cornerstone in the long term treatment of CAD/PAD, a high residual risk for atherothrombotic events exists in patients with CAD/PAD despite intensive antiplatelet therapy.


• Thrombogenesis is a complex process that includes adhesion, activation, and aggregation of platelets and thrombus propagation. Therefore the role of antiplatelet and anticoagulant therapy is reasonable.


• Rivaroxaban has the potential to address this unmet need and could significantly reduce the CV events of death, MI and stroke when used in conjunction with the current standard of care.


• In the study population of COMPASS(n = 27395), which included subjects with objectively established CAD or PAD who had no requirement for dual antiplatelet therapy and no requirement for full anticoagulation, the primary efficacy objective for superiority was met for rivaroxaban 2.5 mg bid/ASA 100 mg od compared with ASA 100 mg od alone for the prevention of the composite primary outcome of MI, stroke, and CV death(HR 0.76; 95% CI 0.66-0.86; p-value <0.00004).


• The positive treatment effect was also seen in consistent and clinically meaningful relative risk reductions in all components of the composite: 14% for MI (HR 0.86; 95% CI 0.70-1.05), 42% for stroke (HR 0.58; 95% CI 0.44-0.76) and 22% for CV death (HR 0.78; 95% CI 0.64-0.96)


• In addition, two important secondary endpoints were also reduced. All-cause mortality showed a relative risk reduction of 18% and acute limb ischemia showed a relative risk reduction of 45%.


• The benefit was observed early with a constant treatment effect over the entire treatment period.


• Significant 1.7-fold increase of the primary safety outcome (modified ISTH major bleeding events) was observed in patients treated with rivaroxaban 2.5 mg bid in combination with ASA 100 mg od compared to patients who received ASA 100 mg od.


• The incidence rates for fatal bleeding events, non-fatal symptomatic bleeding into a critical organ as well as intracranial bleeding events showed no statistically significant difference.


• Rivaroxaban 2.5 mg has been studied in Indian patients (n = 1469) with recent acute coronary syndromes to reduce the risk of a composite endpoint of death from cardiovascular causes, myocardial infarction, or stroke (ATLAS ACS 2-TlMl 51, phase III trial) enrolled and randomized at 53 study sites. The results of the subgroup analyses for the India cohort were generally consistent with the results of the overall primary efficacy and safety endpoint analysis, on the basis of the same Rivaroxaban 2.5mg was approved by the Indian health authority for use after ACS.


• In COMPASS trial, the pre-specified composite outcome for net clinical benefit (cardiovascular death, myocardial infarction, stroke, fatal or symptomatic critical- organ bleeding events) was reduced with rivaroxaban 2.5 mg bid in combination with ASA 100 mg OD.

The firm presented its proposal before the Technical Committee (CDSCO), that after detailed deliberation, recommended for grant of permission to import and market the drug Rivaroxaban 2.5mg tablet for additional indication - co-administered with acetylsalicylic acid (ASA), for the prevention of atherothrombotic events in adult patients with coronary artery disease (CAD) or symptomatic peripheral artery disease (PAD) at high risk of ischaemic events, with local clinical trial waiver subject to the condition that the firm should conduct a Phase IV clinical trial. Accordingly, the firm should submit the protocol for the Phase IV trial within three months of approval of the additional indication for review.