The FDA’s Cardiovascular and Renal Advisory committee voted 15-2 in favor of rivaroxaban. At least two Wall Street analysts have suggested, however, that the FDA may delay approval until it receives more data, pushing final approval into next year.

CardioBrief received detailed comments on the meeting from two panel members, Darren McGuire and Sanjay Kaul.

Here is Darren McGuire’s comments on the meeting:

The panel voted to recommend approval for rivaroxaban for prophylaxis of
venous thrombosis/embolism prophylxis for patients undegoing hip and
knee joint replacement surgery, based on data from a series of studies
individually and in aggregate showing incremental efficacy compared with
enoxaparin, at a noted increased bleeding risk.

The discussion mostly revolved around a) interpreting the individual
trial data versus the pooled trial analyses, the  latter with increased
power and precision to evaluate clinical outcomes, but with a number of
concerns and criticisms regarding the validity of the analysis methods;
b) elucidating the data regarding liver toxicity, with ultimate
consensus that no toxicity signal exists that should preclude approval,
and continued surveillance in ongoing trials will provide additional
information henceforth; and c) placing the increased bleeding risk into
context with the efficacy data.

Additional discussion focused on how to interpret the clinical
relevance of the primary efficacy assessment of all venous thrombosis,
driven almost exclusively by decreased asymptomatic thrombosis detected
by venography-a surrogate endpoint historically established by the FDA
for such indications. With the pooled analyses across studies revealing
estimates of treatment effect for symptomatic DVT/Embolism
quantitatively and qualitatively similar to the overall assessment based
largely on venography, the benefit/risk ratio was ultimately considered
favorable, yielding a vote for approval.

A secondary vote regarding whether the agency should approve a 5 mg dose
of rivaroxaban, ½ of that assessed in all the DVT prophylaxis studies,
based on potential utility in patients at high risk for excess drug
exposure, such as advanced kidney disease and those taking potently
interacting drugs, did not support this recommendation based primarily
on the absence of data with which to assess relative efficacy and
safety, acknowledging that the sponsor should consider studying such a
dose.

Here is Sanjay Kaul‘s commentary on the meeting:

I personally had issues with the choice of the endpoints, the pooling of data across the 4 trials, increased bleeding, a signal for hepatotoxicity which could not be excluded, and a signal for cardiotoxicity— reflecting possible “rebound” hypercoagulability after treatment cessation. Given these issues, in my opinion the benefit did not outweigh the risk.

Difficult assessment of benefit
Although the composite endpoint is recommended by the regulatory agencies to meet licensing requirements, this approach may mislead if the components are of widely differing importance to patients and the size of the effect differs markedly across components. That was the case in one of the trials (RECORD 1). The primary endpoint (composite of all DVTs, nonfatal pulmonary embolism and all-cause death) was driven by venography-determined DVTs, the most prevalent (85% of the composite) but not the most important endpoint. Nonfatal PE effect went in the wrong direction while death was neutral.

Venography is not routinely used to diagnose DVTs in clinical practice. Furthermore, most asymptomatic deep-vein thromboses diagnosed on venography do not progress to cause symptoms, and the proportion that does progress is expected to differ between populations (eg, higher rates of progression after hip than after knee surgery). By contrast, most confirmed episodes of bleeding that are reported in clinical trials are associated with symptoms and are clinically important. I do not believe that venography-determined venous thromboses are a valid surrogate for clinically-important DVTs. As such, they should not be used for regulatory approval.

In my opinion, RECORD 2 (where the comparator drug enoxaparin was given for a shorter period of time) and RECORD 3 (where a suboptimal and non-approved dose of enoxaparin was given) trials are a classic example of “stacking the deck” which is a ubiquitous tactic used in clinical trials. So, these trials should not have been pooled together with RECORD 1 and 4 trials.

Trials that use clinically important outcomes to assess both efficacy and safety would yield more definitive results that are easier to interpret and more relevant to clinical practice. However, reconciling trial feasibility with trial stringency can be a difficult challenge. I believe that trials should be done to inform and enhance clinical practice, not simply to gain regulatory approval for marketing.

Here is the Johnson & Johnson press release:

FDA Advisory Committee Finds Favorable Risk-Benefit Profile for Oral Anticoagulant Rivaroxaban for Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism after
Hip or Knee Replacement Surgery

Raritan, NJ (March 19, 2009)—Ortho-McNeil, announced today that the U.S. Food and Drug Administration’s (FDA’s) Cardiovascular and Renal Drugs Advisory Committee has determined that rivaroxaban, a novel, investigational, oral anticoagulant, has a favorable risk-benefit profile for the prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing hip replacement or knee replacement surgery.

The advisory committee agreed by a 15-2 vote that the available clinical data demonstrate a favorable risk-benefit profile.

“The robust data from our clinical trials support the effectiveness of rivaroxaban in the prevention of dangerous blood clots following hip or knee replacement surgery,” said Peter DiBattiste, M.D., Vice President, Johnson & Johnson Pharmaceutical Research and Development, L.L.C. “We are very pleased that the advisory committee voted in support of the risk-benefit profile of rivaroxaban shown in our studies. We appreciate the thoroughness of the advisory committee’s review and we will continue to work with the FDA as they finalize their review.”

Data presented at today’s advisory committee meeting included comprehensive results from the global RECORD (REgulation of Coagulation in major Orthopedic surgery reducing the Risk of DVT and PE) clinical trial program, including four pivotal Phase III studies that involved more than 12,500 patients. These studies compared oral rivaroxaban with injected enoxaparin for the prevention of DVT and PE in patients undergoing either total hip (RECORD1, 2) or knee (RECORD3, 4) replacement surgery. In a pre-specified pooled analysis of these trials, which included head-to-head comparisons with enoxaparin (RECORD1, 3 and 4) as well as a comparison of extended-duration (5 weeks) rivaroxaban with short-duration (2 weeks) enoxaparin (RECORD2), there was a statistically significant lower incidence in the primary efficacy endpoint (4.3% of rivaroxaban-treated patients and 9.4% of enoxaparin-treated patients, p<0.001) of total venous thromboembolism (a composite of proximal or distal DVT, non-fatal PE or death, any cause). Overall, rates of major bleeding, the primary safety endpoint, were less than 1% in the total treatment duration pool (0.4% of rivaroxaban-treated patients and 0.2% of enoxaparin-treated patients, p=0.0076).
J&JPRD submitted the NDA for rivaroxaban on July 28, 2008. If approved by the FDA, Ortho-McNeil will commercialize rivaroxaban in the U.S. The U.S. Bayer HealthCare sales force will support the Ortho-McNeil sales force by detailing rivaroxaban in designated hospital accounts.

Unmet Needs in Venous Thromboembolism (VTE)
VTE includes DVT and PE. DVT is a blood clot in a deep vein (usually in the leg). These clots can break apart and travel through the bloodstream, blocking blood flow to vital organs. In the case of a PE, a blood clot traveled to and lodged in the lungs. PE can be a serious, life-threatening condition. Both DVT and PE are often preventable conditions.

Patients undergoing major orthopedic surgery may be at high risk for VTE because during hip or knee replacement procedures, the large veins of the leg that carry blood back to the heart can be damaged, significantly increasing the risk of VTE. In fact, venous blood clots occur in 40-60% of patients undergoing major orthopedic surgery who do not receive preventive care. Each year, approximately 800,000 Americans elect to have hip and knee replacement surgeries, and VTE is the most common cause of re-hospitalization for this patient group.

About Rivaroxaban
The extensive program of clinical trials supporting possible approval of rivaroxaban by healthcare regulatory authorities makes rivaroxaban the most studied oral, direct Factor Xa inhibitor in the world today. More than 60,000 patients are expected to enroll in the rivaroxaban clinical development program, which will evaluate the product in the prevention and treatment of a broad range of disorders in which blood clotting plays a major role. Rivaroxaban is being jointly developed by J&JPRD and Bayer HealthCare AG.

Ortho-McNeil
Ortho-McNeil, a Division of Ortho-McNeil-Janssen Pharmaceuticals Inc. (OMJPI), a Johnson & Johnson company, is committed to providing innovative, high-quality prescription medicines and resources for healthcare providers and their patients in hospitals and other care facilities.

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(This press release contains “forward-looking statements” as defined in the Private Securities Litigation Reform Act of 1995. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from OMJPI and/or Johnson & Johnson’s expectations and projections. Risks and uncertainties include general industry conditions and competition; economic conditions, such as interest rate and currency exchange rate fluctuations; technological advances and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; domestic and foreign health care reforms and governmental laws and regulations; and trends toward health care cost containment. A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99 of Johnson & Johnson’s Annual Report on Form 10-K for the fiscal year ended December 28, 2008. Copies of this Form 10-K, as well as subsequent filings, are available online at http://www.sec.gov, http://www.jnj.com or on request from Johnson & Johnson. Neither OMJPI nor Johnson & Johnson undertake to update any forward-looking statements as a result of new information or future events or developments.)